Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C@@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][C@@H:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:15]([F:18])([F:17])[F:16])[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.850 g, 4.24 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.70 g (99% yield) of tert-butyl (2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:33]3[CH:32]=[N:31][C:30]([NH2:44])=[C:29]([C:21]4[S:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:34]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)s2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.079 g, 0.229 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.105 g, 0.298 mmol), potassium carbonate (0.101 g, 0.732 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol) in previously degassed DME/H2O (4:1) (4.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on prep-TLC eluting with 3% 7M NH3 in MeOH/DCM yielding 4-[5-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=495.06 [MH+]. To a solution of this compound in DCM (1.0 mL) was added 1M HCl in ether (2.0 mL, 2.0 mmol), and the mixture was stirred at room temperature overnight. The solid that formed was filtered off and purified on the MDP. To a solution of the material thus obtained in DCM (1.0 mL) was added 1M HCl in ether (1.0 mL, 1.0 mmol). The precipitate was filtered off and dried in vacuo, yielding the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.95-3.00 (m, 4H), 3.46-3.53 (m, 4H), 7.40 (s, 1H), 7.42-7.48 (m, 1H), 7.53 (dd, J=15.3, 1.1 Hz, 1H), 7.98-8.05 (m, 2H), 8.07 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H). MS (ES+): m/z=395.06 (55) [MH+]. HPLC: tR=2.11 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:28])[CH2:26][CH3:27]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: CCC(=O)Cl
Solvent: CN(C)c1ccccc1
Product: CCC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Yield: 62 %

Procedure:
2.17 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were treated with a mixture of 12.1 g (0.10 M) of N,N-dimethylaniline and 4.62 g (0.05 M) of propionyl chloride as indicated in Example 3 to give 1.7 g (63%) of the desired ester, b.p. 100°-110°/0.5 Torr.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[CH3:18][S:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: CS(=O)Cl
Reactant: C1CCC2NCCCC2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of decahydroquinoline (1.07 g, 7.68 mmol) in anhydrous dichloromethane (10 mL) was cooled to −15° C. The reaction mixture was treated with triethylamine (1.07 mL, 7.68 mmol) and methanesulfinyl chloride (800 mg, 8.11 mmol). After 1 hour, the reaction mixture was placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temperature and treated with 5% aq. NaHCO3 (10 mL) and additional dichloromethane (10 mL) and was separated. The organic layer was washed with 3% aq. HCl (1×20 mL), 5% aq. NaHCO3 (2×20 mL), water (1×20 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as a yellow oil (1.2 g, 77%): 1H NMR (CDCl3, 600 MHz, δ) 3.41-2.70 (m, 4H), 2.52 (s, 1.3H, C1′-H), 2.51 (s, 0.4H, C1′-H), 2.49 (s, 1.3H, C1′-H), 1.75-1.26 (m, 12H); 13C NMR (CDCl3, 125 MHz, δ) 54.2, 49.2, 48.3, 47.8, 43.2, 42.6, 42.3, 41.6, 41.5, 41.4, 41.6, 41.5, 41.4, 39.0, 38.9, 38.84, 38.77, 35.6, 35.4, 34.0, 33.9, 33.1, 32.6, 32.5, 30.1, 30.0, 26.0, 25.7, 25.6; ESIMS m/z 224.2 (4, MNa+), 204.1 (5, 32S), 203.0 (13, 13C), 202.0 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:26][CH2:25][CH2:24][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=2)[NH:20][CH:19]=1
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Reactant: NCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 16 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.0 g, 10.0 mmole) in DMF (100 ml) was slowly added to the mixture of 5-fluoro-3-(3-bromopropyl)indole (2.6 g, 10.0 mmole) and diisopropylethylamine (8.7 ml, 50 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (0.5 g, 1.6 mmole, 15%) were concentrated, dissolved in 50 ml of ethanol-diethyl ether (1:1). To this was added 0.25M of fumaric acid in ethanol (3.4 ml, 0.85 mmole) and then a minimum amount of hexane to precipitate the title compound as a light tan solid, (2:1) fumarate salt, m.p. 186°-188° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:1][CH:2]1[CH2:5][N:4]([C:20]([C:19]2[CH:23]=[CH:24][N:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=[C:9]([CH:6]3[CH2:8][CH2:7]3)[N:14]=2)=[O:16])=[O:21])[CH2:3]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: OC1CNC1
Product: O=C(Nc1cnccc1C(=O)N1CC(O)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 8 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-hydroxy-azetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (8%) as light yellow powder.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)C(OCCc1ccc(OC)c(OC)c1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCOC(c2ccccc2)(c2ccccc2)C(O)C(=O)O)cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
12 g (27.5 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate were dissolved in 110 ml of dioxane, and 55 ml of 1 N NaOH solution were added. The mixture was stirred at 80° C. for 2 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ether/n-hexane, and 10.2 g (87%) of colorless crystals were isolated.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15][O:16]CC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:23]O.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][O:16][N:23]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nocc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (4 g) is suspended in 10 mL of ethanol treated with 1.5 g of hydroxylamine hydrochloride in 10 mL of water which has been adjusted to pH 5 with sodium hydroxide. The mixture is stirred and warmed to 40° C. for 2 hours, then cooled to room temperature and the precipitate collected by vacuum filtration. Sodium hydroxide (1 g) is added to the filtrate which is stirred for 30 minutes. The mixture is acidified to pH 2 with 6 N hydrochloric acid and the precipitate collected by vacuum filtration. The filtrate is then diluted with 100 mL of water and allowed to stand at 4° C. overnight. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 300 mg of crude 3-methyl-4-[4-(trifluoromethyl)-phenylaminocarbonyl]isoxazole. The crude is purified on a column of silica gel eluting with ethyl acetate:hexane 1:4 to give 100 mg of 3-methyl-4-[4-(trifluoromethyl)phenylaminocarbonyl]-isoxazole, an off-white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1>>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:25])([F:27])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromo-4-methylpyridine
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)=[N:12][N:11]=[N:10]1.Br[C:31]1[S:35][C:34]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[N:33][CH:32]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18]([C:31]3[S:35][C:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[N:33][CH:32]=3)[CH:19]=2)=[N:12][N:11]=[N:10]1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(Br)s2)CC1
Product: Nc1ncc(-c2cnc(C3CCNCC3)s2)cc1-c1nnnn1-c1cccc(F)c1F

Procedure:
Using the same protocol used to prepare compound I-A-492, 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate were reacted together in a PdCl2(dppf)-2-mediated coupling to produce 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(piperidin-4-yl)thiazol-5-yl)pyridin-2-amine; 1H NMR (DMSO-d6): 8.46 (d, J=2.3 Hz, 1H), 7.90-7.48 (m, 5H), 3.40-3.22 (m, 3H), 3.11-2.92 (m, 2H), 2.22-2.10 (m, 2H), 1.99-1.83 (m, 2H); ES-MS: m/e=441.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(=O)C)(=[O:24])C>>[OH:24][C:6]1[C:5]2[N:4]=[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:2]([CH3:1])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cn1c(-c2ccccc2)nc2c[n+]([O-])c3ccccc3c21
Reactant: CC(=O)OC(C)=O
Product: Cn1c(-c2ccccc2)nc2c(O)nc3ccccc3c21

Procedure:
20 ml of acetic anhydride was added to 1.0 g of Compound b obtained in Reference Example 2, followed by refluxing for 5 hours. After the reaction solution was concentrated under reduced pressure, methanol was added to the residues. The solution was adjusted to a pH of 9 to 10 with sodium methoxide. The precipitate was collected by filtration and washed with methanol, to afford 0.63 g of Compound c.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C:23]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:22][C:23]([CH2:29][CH3:30])([CH2:31][CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=413.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([C:4]1[C:5](=[O:19])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:7]([CH3:11])=[CH:8][C:9]=1[O:10][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)cc(C)n(-c2ccccc2Cl)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCc2ccccc2)cc(C)n(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.56 g, 2.02 mmol) in DMF (5.0 mL), benzyl bromide (0.3 mL) and potassium carbonate (0.3 g, 2.16 mmol) were added. The mixture was stirred at room temperature for 3 h, and at 65° C. for 1 h under argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The resulting residue was purified by silica gel flash chromatography using 50% EtOAc in hexanes to afford the title compound (0.58 g, 75%) as a pale yellow amorphous substance: 1H-NMR (CD3OD) δ: 7.65-7.3 (m, 9H), 6.5 (s, 1H), 5.31 (s, 2H), 2.42 (s, 3H), and 2.01 (s, 3H); ER-MS m/z=368 (MH +); HR-MS m/z calcd C21H19NO3Cl, 368.1060, found 368.1053.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:18])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:21])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc2cnn(CC(OC)OC)c12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc2cnn(CC(OC)OC)c12
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of methyl 1-(2,2-dimethoxyethyl)-5-hydroxy-1H-indazole-7-carboxylate (180 mg, 0.6 mmol) from Step F above in DMF (10 ml) was added cesium carbonate (313 mg, 1.0 mmol) followed by iodomethane (40 μL, 0.64 mmol) and the reaction was stirred overnight. The reaction mixture was extracted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to afford methyl 1-(2,2-dimethoxyethyl)-5-methoxy-1H-indazole-7-carboxylate (180 mg, 96%): 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 4.90 (d, J=5.0 Hz, 2H), 4.51 (d, J=5.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.27 (s, 6H); MS (ESI+) m/z 295 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:15]([F:16])([F:17])[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 1c (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with ether, and dried under vacuum. The crude compound 1d was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
Reaction SMILES: C(OC([N:8]([CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34])[CH2:9][CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCCC1.O1CCOCC1>[Cl:41][C:37]1[CH:36]=[C:35]([C@@H:33]([OH:34])[CH2:32][NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:30][CH:31]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)COc1cccc(COc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)COc1cccc(COc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of ethyl [3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenoxy]methyl]phenoxy]acetate (1.0 g) in tetrahydrofuran (5.0 ml) was added 4N hydrochloride in dioxane (4.3 ml). The mixture was stirred at room temperature for 8 hours and evaporated under reduced pressure. The residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/chloroform=1/20) to give ethyl [3-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-methyl]phenoxy]acetate (632 mg).
Reaction SMILES: C(=O)(O)O.[OH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:7][NH2:8].[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=2[CH3:32])=[CH:22][CH:21]=1)[C:17]([CH3:19])=O.C([BH3-])#N.[Na+]>CO>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:6]([OH:5])[CH2:7][NH:8][CH:17]([CH3:19])[CH2:16][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=2[CH3:32])=[CH:24][CH:25]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(C2=C(C)NC(=O)CC2)cc1
Agent: O=C(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1=C(c2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)CCC(=O)N1
Reaction time: 16 h

Procedure:
A mixture of 2-hydroxy-2-(3-chlorophenyl)ethanamine carbonate (0.34 g) and 3,4-dihydro-5-(4-acetonylphenyl)-6-methyl-2(1H)-pyridone (0.4 g) was dissolved in methanol (30 ml). Sodium cyanoborohydride (0.1 g) was added and the mixture was allowed to stand at room tempeature for 16 hr. The solvent was evaporated, the residue partitioned between ethylacetate and water, the organic layer separated, dried (MgSO4) and evaporated to give an oil which was chromatographed on Silica. Elution with methanol-chloroform (3:97) gave 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenyl]-3,4-dihydro-6-methyl-2(1H)-pyridinone as a 1:1 mixture of diastereoismers, m.pt. 103°-106° C. (ethyl acetate ether).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2]
Reactant: CCOc1nc(-c2ccnc(N)c2)sc1-c1ncn(C2CCCCO2)n1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(-c2nc(OCC)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-{4-ethoxy-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-amine (100 mg, 0.268 mmol) obtained by similar manner with Example 47-B(ii) in pyridine (2.7 mL), was added ethyl chloroformate (100 μL, 1.08 mmol) at 0° C., and the mixture was stirred for 3 h. The reaction mixture was diluted with water (20 mL), and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration and was washed with water and diethyl ether to give the title compound (99.1 mg, 83%) as a yellow solid.