Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][CH3:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][CH3:43])[CH2:2][CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCNCCO[Si](C)(C)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reaction time: 11.5 h
Yield: 61.7 %

Procedure:
To a solution of (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 3.98 g, 8.25 mmol) and 2-(tert-butyldimethylsilyloxy)-N-ethylethanamine (INTERMEDIATE 63, 1.68 g, 8.25 mmol) in 1,2-dichloroethane (27.5 ml) was added sodium triacetoxyborohydride (2.62 g, 12.37 mmol). The resulting mixture was stirred in the dark for 11.5 h and was then quenched with 0.5 M aqueous sodium hydroxide (50 ml). After vigorous stirring for 10 min, the opaque mixture became clear. The layers were diluted with ethyl acetate and then separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride before being dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ISCO, 330 g SiO2, 50→100% ethyl acetate in hexanes for 20 mins then 0→20% methanol in ethyl acetate for 20 mins followed by 0→20% methanol in ethyl acetate over 20 min) to afford the title product (3.41 g, yield: 62%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].C(N(CC)CC)C.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-3 step (ii) (240 mg), triethylamine (0.12 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (204 mg) were dissolved in acetonitrile (5 ml), and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 35 mg (9%); mp 218-219° C., MS APCI+ve 493 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][NH:36][S:33]([C:29]1[CH:28]=[CH:27][CH:32]=[C:31]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:30]=1)(=[O:34])=[O:35]
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-methyl-benzenesulfonamide (example B.32) (225 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 68%). MS (ISP) 525.2 [(M+H)+]; mp 213-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and (aminomethyl)cyclopropane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[N:17]=1
Reactant: OCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: OCCc1ccc(Oc2nccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-4-(trifluoromethyl)pyrimidine. LC-MS (ESI): m/z 285 [M+H]+; 2.66 min (ret time).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH3:20])[N:14]=1)C.[OH-].[Na+].Cl>CO.O>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:5][C:4]([OH:27])=[O:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(CCCCCCc1cccc(NC)n1)c1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cccc(CCCCCCC(CC(=O)O)c2cncnc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 6-13a (0.215 g, 0.580 mmol) in TBf/MeOH/H2O 3:1:1 (10 mL)) was added NaOH (1.16 mL of 1N solution in water, 1.16 mmol). After 30 minutes, the mixture was neutralized with HCl (1.16 mL of 1N solution in water, 1.16 mmol) and the solvents were evaporated. The residue chromatographed on silica gel (15% MeOH/CHCl3) to give 6-14a as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15].O>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[C:14]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)=[O:15]
Reactant: Cc1cc(C)nc(N)c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 57% sodium hydride in mineral oil (38.0 gm, 0.90 mole) in dry toluene (600 ml) at 75° under nitrogen atmosphere is added in small portions 2-amino-4,6-dimethylpyridine (52.5 gm, 0.43 mole). The reaction is heated to 100° for one hour and then cooled to 90°. A solution of dimethyl carbamoyl chloride (47.0 g, 0.43 m) in toluene (150 ml) is added dropwise over a one and one-half hour period. Stir for two hours and then cool to ambient temperature. Water (150 ml) is added, the organic layer separated, dried over anhydrous sodium sulfate filtered through charcoal and evaporated. The residue is triturated with cyclohexane (50 ml) and filtered to give analytically pure product (74.0 g., 85% yield), m.p. 105°-108° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[N:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].CC(C)([O-])C.[K+]>O1CCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:6]2[N:7]=[C:2]([NH:22][C:21]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:3]=[CH:4][C:5]=2[CH:10]=[CH:9]1
Reactant: Clc1ncc2ccn(-c3ccccn3)c2n1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3ccn(-c4ccccn4)c3n2)cc(OC)c1OC
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-7-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine in 1,4-dioxane is added 3,4,5-trimethoxy aniline (3 equivalents) followed by adding potassium tert-butoxide solution (1.0 M in tetrahydrofuran, 3 equivalents) dropwise. After addition, the reaction mixture is heated at 80° C. for 2 hours. The solvent is removed after cooling to room temperature. Purification by reverse phase HPLC gives (7-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@:10]4([OH:21])[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22]>CS(C)=O>[OH:21][C@:10]12[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C@:15]1([CH3:16])[C@@H:17]1[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:22])[CH2:4][CH2:5]3)[CH2:8][CH2:9]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1CC[C@@H]2O
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Reaction time: 0.25 h

Procedure:
A solution of androstane-3β,5α,17β-triol (0.48 g) and IBX (0.72 g) in DMSO (8 mL) was stirred at −15° C. overnight and then quenched at room temperature by addition of H2O (40 mL). After stirring for 15 min, the mixture was filtered and the cake was washed with EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give the title compound II-ad (0.36 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.48 (s, 1H), 2.72 (d, 1H), 2.60-1.18 (m, 20H), 1.23 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.OS(O)(=O)=O.[CH3:19]O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:5][N:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)nc1
Yield: 100 %

Procedure:
To a solution of 6-(trifluoromethyl)nicotinic acid (3.82 g, 20 mmol) in 120 mL of methanol was added 5 mL of concentrated H2SO4 and the mixture was refluxed for 5 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to about 7 by 1N HCl. The mixture was extracted with ethyl acetate (100 mL×3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound (4.1 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[CH3:9][O:8][C:5]1[CH:4]=[N:3][C:2]([O:10][C:11]2[CH:12]=[C:13]([CH3:21])[C:14]([C:18](=[O:20])[CH3:19])=[C:15]([CH3:17])[CH:16]=2)=[N:7][CH:6]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COc1cnc(Cl)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc(Oc2cc(C)c(C(C)=O)c(C)c2)nc1
Temperature: 120 °C
Yield: 24 %

Procedure:
2-Chloro-5-methoxypyrimidine (8-1, 5.13 g, 35.6 mmol) and 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 6.10 g, 37.2 mmol) were suspended in DMF (80.0 ml) and added with copper powder (0.78 g, 7.8 mmol) and potassium carbonate (15.31 g, 0.11 mol). The reaction was heated at 120° C. for 16 h. The reaction was cooled to room temperature and diluted with EtOAc (90 mL). The organic phase was washed with 15% NaOH and water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (8-2, 2.33 g) as light yellow solids in 24% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 2 H), 6.86 (s, 2 H), 3.86 (s, 3 H), 2.47 (s, 3 H), 2.18 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([CH3:9])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:10][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:9])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(F)cc1N
Yield: 102.1 %

Procedure:
To a solution of 49.0 g of 5-fluoro-o-toluidine in 600 mL of dichloromethane was added 69.7 g of N-bromosuccinimide at 0° C., and stirred at this temperature for an hour. Then sodium thiosulfate aqueous solution was added, and the reaction solution was evaporated and diluted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. Then the solvent was evaporated, and the precipitated crystals were washed with diethyl ether:n-hexane=1:10, to afford 81.6 g of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]2[CH:23]=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.37 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-ethoxycarbonylmethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.56 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 117–118° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>CN1C(=O)CCC1>[Cl:10][C:8]1[N:9]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Yield: 82.5 %

Procedure:
TEA (0.20 ml, 1.44 mmol) and 2,6-dichloroisonicotinonitrile (0.25 g, 1.44 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.28 g, 1.44 mmol) in NMP (2 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 10 minutes. The crude mixture was partitioned between water and EtOAc and washed (×2) with water. The extracts were combined dried over MgSO4 and concentrated to give the title compound (400 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse -phase preparative liquid chromatography (20.6 mg, 0.0635 mmol, 31.8%). ESI-MS m/z calc. 294.1, found 295.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[C@H:13]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)[CH2:14][N:3]1[C:4]=23.[ClH:30].CO>C(Cl)(Cl)Cl>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C@H:13]2[N:5]3[C:4]4[N:3]([C:2](=[O:1])[CH:11]=[CH:10][C:9]=4[CH:8]=[CH:7][C:6]3=[O:12])[CH2:14]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.2 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(1R)-4,9-dioxo-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl]methyl}-4-piperidinyl)carbamate (see Example 1 (i) above) (4.282 g, 10.69 mmol) in CHCl3 (20 ml) under Ar at room temperature was treated with HCl (4M solution in 1,4-dioxane, 20 ml, 80 mmol) and stirred at rt for 15 min, MeOH (20 ml) was then added. After stirred for 15 min, the reaction was evaporated and triturated with Et2O (20 ml). The obtained solid was dried in vacuo to give (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (4.55 g, 12.21 mmol, 100%) as a yellow powder.
Reaction SMILES: C1([C@@H]([N:9]([C@H:21]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:23]=3[CH2:22]2)[CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C)C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:37]([O:36][C:34]([CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:24]2[CH2:25][CH2:26][CH2:27][C@H:21]([NH:9][CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][C:23]=2[CH:31]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N(C[C@H](O)COc1ccccc1)[C@@H](C)c1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)COc1ccccc1)CCC2
Yield: 82.8 %

Procedure:
A mixture of (2S)-1-[N-((S)-1-phenylethyl)-((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.65 g) and 10% palladium on activated carbon (50% wet, 0.20 g) in ethanol (6 ml) and tetrahydrofuran (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour, and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel to afford (2S)-1-[((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (430 mg). (2S)-1-[((6S)-3-Ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (190 mg) was treated with 4N hydrogen chloride in ethyl acetate to afford (2S)-1-[((6S)-3-ethoxycarbonyl-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (103 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:41][C:38]2[CH:37]=[CH:36][C:35]([C:34]([O:33][CH3:32])=[O:43])=[CH:40][CH:39]=2)([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (30.12 mmol; 9.62 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 39.16 mmol; 19.58 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethylbenzoic acid methyl ester (30.12 mmol; 6.90 g) was added and the resulting solution was stirred at −78° C. for 2 hours and allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester. MS (ESI) m/z 468.20 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[I:12].CO.[OH-].[K+]>O>[I:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)c(I)c1

Procedure:
205 G. of 2-iodo-4methoxy-benzoic acid methyl ester, 400 ml. of methanol, 390 ml. of water and 95 g. of potassium hydroxide are stirred at 48° C. for 30 minutes. The solution is then concentrated under reduced pressure and acidified with aqueous hydrochloric acid. The yellow crystalline 2-iodo-4-methoxy-benzoic acid obtained is removed by filtration, washed neutral with water and dried, melting point 185° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18](N3CC[C@@H](NC(NCC4C=CC=C(O)C=4)=O)C3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:37]2[CH2:41][C@H:40]([NH:42]C(=O)CO)[C@@H:39]([OH:47])[C@H:38]2[OH:48])=[CH:4][CH:3]=1.[ClH:56]>CO.O1CCOCC1>[NH2:42][C@H:40]1[CH2:41][C@@H:37]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([Cl:56])=[N:19][C:11]=3[NH:10][CH2:9][CH:8]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[C@H:38]([OH:48])[C@@H:39]1[OH:47]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 7 step 1 (3.45 g, 5.80 mmol) in methanol (7 ml) is treated with 4M HCl in dioxane (3 ml) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between saturated sodium bicarbonate solution and DCM. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound.