Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 19.2) (300 mg), DCM (5 mL) and TFA (1 mL) is stirred for 4 h at rt, quenched by addition of a saturated solution of NaHCO3 (50 mL), and extracted with DCM (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 181 mg of the title compound as a yellow solid: ESI-MS: 271.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O1CCOCC1>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(F)cc1)cn2C
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.17 g, 0.9 mmol), prepared using procedures as described in Example 1, Ag2O (0.22 g, 0.95 mmol), 4-fluoro-benzyl bromide (0.18 g, 0.95 mmol) and dioxane (4 mL) were heated to reflux for 16 hr, then more 4-fluoro-benzyl bromide (90 mg, 0.5 mmol) was added and the solution was heated at reflux an additional 4 hr. After cooling to room temperature, the reaction mixture was diluted with ether (60 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:3) to provide 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (58 mg, 22% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].S(C1C=CC(C)=CC=1)(O[CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O>>[F:16][C:15]([F:18])([F:17])[CH2:14][NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1N
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Product: Cc1ccc(O)cc1NCC(F)(F)F
Reaction time: 5 h

Procedure:
3-Amino-4-methylphenol (9.84 g; 0.08 mole) and trifluoroethyl tosylate (20.32 g; 0.08 mole) were mixed in a 500 ml round-bottomed flask and the flask purged with nitrogen. A short air condenser was added, the nitrogen stream was slowed and located towards the top of the condenser, and the flask was immersed in an oil bath at 200° C. A temperature in the range of 150°-250° C. is acceptable. After the molten reagents had been swirled to complete mixing, the heating was continued for five hours. The flask was allowed to cool and before the mixture had solidified, it was dispersed and dissolved in 200 ml of chloroform. Over four days a light brown precipitate of the tosylate salt of 3-amino-4-methylphenol appeared which was filtered off and recovered. The chloroform was extracted with 10% aqueous sodium hydroxide and the dark brown aqueous phase was extracted with chloroform 50 ml. Ice and concentrated hydrochloric acid (21 ml) were added to the aqueous phase and the brown oil was extracted into chloroform 100 ml plus 50 ml. The chloroform solution was washed with 1N hydrochloric and the chloroform layer was separated, dried with sodium sulfate, filtered and evaporated to give a brown gum that crystallized over a day 8.0 g (49%). Recrystallization from petroleum ether 60/80 gave white, fluffy needles mp. 64°-65°. NMR (deuterodimethylsulfoxide): δ8.86 (s, 1H, OH); 6.8-5.9 (m, 3H, ring protons) resolved as AB quartet at 6.74 (C-5 CH) and 6.01 (C-6 CH), J=8.0 Hz together with 6.13 (d, 1H, J=1.0 Hz, C-2 CH) which in turn coupled with the high-field half of the AB quartet; 5.33 (t, 1H, J=6.8 Hz, N-H); 4.0-3.7 (m, 2H, CH2) resolved as two quadruplets, JCF3, CH2 =9.6 Hz, JCH2, NH=6.8 Hz; 1.99 (s, 3H, CH3). Anal. calc. for C9H10F3NO: C, 52.68; H, 4.91; N, 6.83. Found: C, 52.58; H, 4.99; N, 6.80.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2cccc(C(F)(F)F)c2)CO3)N1
Temperature: 85 °C
Yield: 19.6 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.01 g, 2.70 mmole) and 3-trifluoromethylbenzylamine (1.75 ml, 12.0 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.20 g, 20%) thus obtained was crystallized from isopropanol with the addition of one equivalent of fumaric acid to give 0.17 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, one-half hydrate, m.p. 158-160° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[N:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([NH:24][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 316.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C1COCC1.C(O)(=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Yield: 40.4 %

Procedure:
A solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (307.5 mg, 1.107 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (248 mg, 1.107 mmol) in THF (3 mL) and acetic acid (3.00 mL) was heated at 80° C. overnight. The solvent was removed in vacuum and the residue was triturated with methanol, cooled in the freezer and filtered. The precipitate was thoroughly washed with methanol and dried to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (207.9 mg, 0.447 mmol, 40.4% yield) as off-white solid. LC-MS (M+H)+=465.0. 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (1H, s), 8.15 (1H, d, J=1.8 Hz), 7.73 (1H, d, J=1.5 Hz), 7.41 (1H, d, J=1.5 Hz), 7.18-7.26 (2H, m), 7.07-7.18 (2H, m), 6.88-7.00 (1H, m), 4.12-4.20 (1H, m), 4.04-4.12 (1H, br s), 3.60 (3H, s), 3.17 (1H, s), 2.96 (3H, d, J=4.6 Hz), 2.71-2.81 (1H, m), 2.52-2.66 (2H, m), 1.83-1.96 (1H, m).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:6]1[CH:7]=[CH:8][C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:4])[CH:5]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Nc1cc(Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(Cl)cc2N)OC1(C)C
Temperature: 100 °C
Reaction time: 10.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-5-chloroaniline (20.0 g, 96.9 mmol) in 1,4-dioxane (200 ml) were added triethylamine (54.0 ml, 487 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.96 g, 4.84 mmol), and under a nitrogen stream, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.3 ml, 290 mmol) was added dropwise. The mixture was stirred at 100° C. for 10.5 hr. The mixture was allowed to cool to room temperature and filtered through celite. To the filtrate was added dropwise methanol (25 ml) at 0° C. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (16.5 g, yield. 65%).
Reaction SMILES: C[O:2][P:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19](Cl)=[O:20]>CCOCC>[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19]([P:3](=[O:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:20]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
648 parts of methoxydiphenylphosphine are added slowly to 547.5 parts of 2,4,6-trimethylbenzoyl chloride at 50°-95° C. in a stirred apparatus equipped with a reflux condenser and dropping funnel. The mixture is then stirred for 4-5 hours at 50° C., the contents of the flask are dissolved in ether at 30° C., and petroleum ether is added until the mixture starts to turn cloudy. On cooling, 910 parts (87% of theory) of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide crystallize. Pale yellow crystals, melting point 89°-92° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccccn2)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 96.4 %

Procedure:
Pyridin-2-yl-1H-pyrazol-4-carboxylic acid ethyl ester (0.81 g, 3.73 mmol) was dissolved in a THF/ethanol (50 ml/10 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (11.2 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature and subsequently stirred at that temperature for 7 h. The reaction mixture was extracted with dichloromethane (4×100 ml) and the combined organic phases were dried and evaporated to yield the product as white solid (0.68 g, 96%) which was used without any further purification.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.[CH2:40]=[C:41]1[O:45][C:43](=[O:44])[CH2:42]1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:8]([N:7]([CH2:6][C:5]2[CH:31]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=2)[C:43](=[O:44])[CH2:42][C:41](=[O:45])[CH3:40])[C:9]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][C:10]1=2)=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of (S)-5-(3,5-bis-trifluoromethyl-benzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (Example 3, Step 14) (1.0 g, 1.75 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in dry tetrahydrofuran (10 mL) at 0° C. under a nitrogen atmosphere, add diketene (0.147 mL, 1.93 mmol). After stirring 1.5 h at 0° C., remove the solvent under reduced pressure. Purify the by flash chromatography, eluting with hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound as an off-white solid (1.12 g, 97%). TLC Rf 0.40 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.10-2.10 (m, 13H), 2.29 (s, 3H), 2.52 (s, 3H), 3.41-3.53 (m, 1H), 4.14-4.54 (m, 4H), 4.89-5.12 (m, 1H), 5.57-5.69 (m, 1H), 6.89 (s, 1H), 7.24-7.92 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=459.09.
Reaction SMILES: [OH:1][N:2]([CH3:13])[C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:24]([O:23][C:21]([C:14]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:1][N:2]([CH3:13])[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])=[N:12]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccccc1C(=N)N(C)O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2OC)N(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a stirred solution of N-hydroxy-2-methoxy-N-methyl-benzamidine (3.3 g) in ethanol (100%) was added diethyl acetylenedicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred for 2 h at room temperature. The reaction mixture was then concentrated and purified on silica gel column using (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a yellow oil (4.93 g, 70% yield). 1HNMR (500 MHz, CDCl3) δ: 7.56 (1H, dd, 7.6, 1.5 Hz), 7.44 (1H, td, J=7.6, 1.6 Hz), 6.99 (1H, t, 7.5 Hz), 6.95 (1H, d, J=8.2 Hz), 4.36–4.10 (4H, m), 3.85 (3H, s), 3.43 (1H, d, J=16.48 Hz), 3.05 (3H, s), 3.04 (1H, d, J=16.48 Hz), 1.32 (3H, t, J=7.02 Hz), 1.25 (3H, t, J=7.02 Hz). HRMS (ESI) calcd for C17H23N2O6 (M+H): 351.1556; found: 351.1553.
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:45])[CH3:44])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-alanine benzyl ester hydrochloride (216 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (210 mg, 48%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=[C:6]2[C:5]21[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2.[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:19]2[CH2:20][CH2:21][C:5]3([N:4]([CH3:3])[CH2:9][CH2:8][N:7]4[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=[C:6]34)[CH2:17][CH2:18]2)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23]
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride (69 mg, 0.20 mmol), 4-isopropoxy-3-methoxybenzoic acid (42 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), Et3N (112 μL, 0.80 mmol) and DMF (2 mL) was allowed to stir at room temperature for 3 h. The mixture was filtered and purified by reverse-phase preparatory HPLC (10-99% ACN/water). The desired fractions were concentrated to give (4-isopropoxy-3-methoxyphenyl)(2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1-yl)methanone as an amorphous white solid. ESI-MS m/z calc. 465.2, found 466.3 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.2, 1.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 5.94 (d, J=3.5 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.40 (s, 1H), 3.34 (t, J=5.4 Hz, 3H), 2.39 (s, 3H), 2.11 (s, 2H), 1.82 (s, 2H), 1.38 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:12][CH2:11]1)=[O:28]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
The compound (100 mg, 0.215 mmol) obtained in Example 4g was dissolved in ethanol (6 mL), tert-butyl 3-aminobenzoate (54 mg, 0.279 mmol) and sodium triacetoxyborohydride (59 mg, 0.279 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (80.0 mg; yield, 58%) as a colorless oily substance.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1.C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[C:8]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: CC(C)(C)N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
tert-Butylamine (5.28 g, 72 mmol) was added to 5-bromo-2,4-dichloropyrimidine (15 g, 66 mmol) and triethylamine (19.9 g, 197 mmol) in acetonitrile (450 mL) at room temperature and the mixture was stirred at room temperature for 16 hours. Then the mixture was evaporated in vacuo and the crude residue was partitioned between EtOAc (450 mL) and water (400 mL). The organic layer was separated, washed with brine (400 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 52% yield, 8.8 g.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.[BH4-].[Na+].CO>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH2:25][OH:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(-c2ncccc2CO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (180 g, 377 mmol) in anhydrous dichloromethane (1.5 L) at 0° C. is sequentially added sodium borohydride (7.2 g, 188.5 mmol) and anhydrous methanol (0.5 L) and the contents are allowed to reach room temperature while stirring 30 min. LC/MS analysis of the reaction mixture reveals completion. Volatiles are removed under reduced pressure and the residue obtained is partitioned between dichloromethane (2 L) and water (300 mL). The layers are separated and the organic layer is sequentially washed with 1 N aqueous solution of sodium hydroxide (300 mL), water (3×300 mL), brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 50-55% ethyl acetate in hexane containing 1% triethylamine to afford [2-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol as a solid (167 g, 92% yield). MS (m/z): 481 (M+1).