Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:32]/[C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cccc(Cl)c2)COC1(C)C

Procedure:
In analogy to example 83c. from (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 3-chloro-benzaldehyde. Off-white solid. MS (ISP): 340.2 ([{37Cl}M+H]+), 338.2 ([{35Cl}M+H]+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:1][CH:2]2[CH2:3][CH2:4][C:5]([C:8]([O:10][CH3:11])=[O:9])([CH3:12])[CH2:6][CH2:7]2)=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1(C)CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a solution of methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate (5.8 g, 33.68 mmol, 1.00 equiv) and 4-nitrobenzoic acid (11.26 g, 67.38 mmol, 2.00 equiv) in 80 mL of anhydrous THF was added PPh3 (17.67 g, 67.37 mmol, 2.00 equiv) at room temperature. Then DIAD (13.62 g, 67.36 mmol, 2.00 equiv) was added dropwise and the resulting solution was stirred for 2 h at room temperature. The reaction was quenched water, extracted with 3×150 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/50) to give 4-(methoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate (5.5 g, 51%) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][C:17](=O)[CH3:18])[CH:11]=3)=[CH:6][C:5]=12.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>CO>[N:21]1([CH:17]([CH3:18])[CH2:16][C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)[CH:15]=[CH:14][N:13]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(=O)Cc1cc(-c2ccn3ccnc3c2)ccn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(Cc1cc(-c2ccn3ccnc3c2)ccn1)N1CCOCC1
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Dissolve 1-(4-imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (3.9 g, 15.5 mmol) in methanol (400 mL) under nitrogen. Add morpholine hydrochloride (38.4 g, 20 equiv.) followed by 3 {acute over (Å)} Sieves (7.8 g, powdered and dried in a vacuum oven at 100° C. overnight). Stir five minutes then add sodium cyanoborohydride (1.0 M in THF, 28 mL, 1.8 equiv.) via syringe and stir at room temperature for 5 days. Filter to remove insoluble material, washing with methanol. Concentrate to dryness then make basic with 20% NaOH (aq) and extract with ethyl acetate. Wash organics with aqueous saturated sodium chloride then dry over MgSO4. Filter and concentrate then purify by silica gel (Ethyl Acetate→5% Methanol:DCM→10% Methanol:DCM→5% 2M NH3 in methanol:DCM→10% 2 M NH3 in Methanol:DCM) to give product as a tan solid (3.7 g, 74%). MS (ES), m/z 323 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.CC(O)=O.CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1ccc(N2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
A solution of 4-(4-morpholinyl)benzoic acid (1.00 g, 4.83 mmol) and 4-methylmorpholine (0.53 mL, 4.8 mmol) in tetrahydrofuran (25 mL) at −10° C. was treated with ethyl chloroformate (0.46 mL, 4.8 mmol). After 0.25 h, the mixture was treated with sodium borohydride (550 mg, 14.5 mmol) followed by MeOH (50 mL) slowly. The mixture was then treated with 5% HOAc in water and the mixture was concentrated. The residue was purified by chromatography (SiO2, EtOAc:hexanes) yielding 164 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH2:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([CH3:16])[C:14]=1[F:15].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH:6][C:11]1[CH:12]=[C:13]([CH3:16])[C:14]([F:15])=[C:9]([CH3:8])[CH:10]=1)[CH3:5]
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1cc(B(O)O)cc(C)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 39 h
Yield: 37.5 %

Procedure:
To a suspension of (R)-2-amino-propionic acid methyl ester (0.200 g, 1.940 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.652 g, 3.880 mmol), Cu(OAc)2 (0.388 g, 2.134 mmol), and molecular sieves 4 Å (1.456 g) in 15 mL of dichloromethane, was added triethylamine (0.54 mL, 3.880 mmol). After stirring at room temperature under O2 for 39 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as brown oil (0.164 g, 38% yield). LC-MS: tR=8.1 min; m/z 226 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(#N)C.[Br:18]N1C(=O)CCC1=O>C(OCC)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Br:18])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)c1cc(Br)c(C(F)(F)F)cc1N
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a mixture of 11.6 g of 1-[2-amino-4-(trifluoromethyl)phenyl]ethanone, 60 mL of acetonitrile, and 230 mL of diethyl ether was added 2.85 g of Amberlyst (registered trademark) 15, and 10.1 g of N-bromosuccinimide was added thereto in three times in an ice bath. After stirring for 30 minutes in an ice bath, the mixture was stirred at room temperature overnight. The insoluble material was filtered and washed with ethyl acetate. To the filtrate were added water and ethyl acetate, and the aqueous layer was separated. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate, and then solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 10.36 g of 1[2-amino-5-bromo-4-(trifluoromethyl)phenyl]ethanone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[NH:5][C:6]=1[CH2:7][O:8]CC1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:17][CH2:18]2)[NH:5][C:6]=1[CH2:7][OH:8]
Reactant: Clc1nc(C2CC2)[nH]c1COCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: OCc1[nH]c(C2CC2)nc1Cl
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-cyclopropyl-5-{[(phenylmethyl)oxy]methyl}-1H-imidazole (1.02 g, 3.9 mmol) and methanesulfonic acid (9.7 mL, 149 mmol) in chloroform (22 mL) was stirred at RT for 1 h. The reaction mixture was poured into ice (˜50 g) and the solution was neutralized by addition of 5N NaOH until the pH was 10. The solution was extracted with methyl tert-butyl ether (2×40 mL) and then with n-butanol (3×20 mL). The combined n-butanol extracts were concentrated, azeotroped with toluene, and dried in vacuo to provide crude (4-chloro-2-cyclopropyl-1H-imidazol-5-yl)methanol as a brown solid. A solution of this solid and manganese dioxide (2.1 g, 24.8 mmol) in CH2Cl2 (12 mL) and 1,4-dioxane (6 mL) was heated under reflux for 6 h. The reaction mixture was cooled to RT, filtered through Celite and washed thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide the title compound (0.282 g, 41%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.05 (br. s., 1H), 9.49 (s, 1H), 1.95-2.04 (m, 1H), 1.09-1.17 (m, 2 H), 1.03-1.09 (m, 2H). ES-LCMS: m/z 171.0 (M+1).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][C@@H:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])(=O)=O.O>CS(C)=O>[CH3:29][C@@H:22]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][CH2:19][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: CC(C)=CCC[C@H](C)CCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC[C@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a suspension of sodium theobromine (4.05 g, 20.0 mmol) in dimethylsulfoxide (50 mL) was added 1-methanesulfonyl-4-(S)-methyl-8-methylnon-7-ene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The organic portions were combined, dried using magnesium sulfate, and evaporated to give a residue which was purified by column chromatography (ethyl acetate/hexane) to yield 1.83 g (30% yield) 1-(4-(S)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (inventive compound no. 2536S) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][C:5](=[O:12])[NH:4][CH:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:9])[CH2:6][C:5](=[O:12])[NH:4][CH:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(=O)NC(Cc2ccccc2)C1=O
Reactant: OCc1ccccc1
Product: O=C1CC(C(=O)OCc2ccccc2)C(=O)C(Cc2ccccc2)N1

Procedure:
3,6-Dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, methyl ester, 4 g (0.015 mole) was added to benzyl alcohol, 8.1 g (0.075 mole), and the mixture warmed to 170° for three hours. The mixture was cooled and the residue chromatographed using 200 g of silica gel and eluting with 500 ml of dichloromethane-methanol (98:2) to give (±)-3,6-dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, phenylmethyl ester, 4.5 g; mp. 119°-120.5°.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.S(OCC)(O[CH2:27][CH3:28])(=O)=O.[OH-].[Na+]>CN(C=O)C>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([N:7]([CH2:27][CH3:28])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
To a mixture of 4′-chloro-2′-nitro-p-toluenesulfonanilide sodium salt (1046 g (3.00 mol)) and DMF (1100 ml), heated in an oil bath kept at 100° C., was added diethyl sulfate (733.8 g (4.50 mol)) over a period of one hour. The resulting mixture was further stirred for 1.5 hours at the same temperature to complete the reaction, and then left to cool to room temperature. A 1.5% aqueous sodium hydroxide solution was added and the mixture was stirred for one hour. The resulting solid was then filtered, washed with water, dried and recrystallized from 1450 ml of ethyl acetate to give 858 g (81%) of the title compound as pale yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:18][C:17]3=[N:19][NH:20][CH:21]=[C:16]3[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:14]=2[C:29]#[N:30])[CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]1[C:14]([C:29]#[N:30])=[C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[NH:18][C:17]2=[N:19][NH:20][CH:21]=[C:16]12
Reactant: CC(C)(C)OC(=O)N1CCC(C2=C(C#N)C(c3ccccc3Cl)c3c[nH]nc3N2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1=C(C2CCNC2)Nc2n[nH]cc2C1c1ccccc1Cl
Reaction time: 2 h
Yield: 85.2 %

Procedure:
6-(1-tert-Butoxycarbonylpyrrolidin-3-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (706 mg) was added to 4N-HCl dioxane solution (5 mL) at room temperature and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was washed by ethanol-ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (460 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:4]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[O:5][C:6]2[CH:23]=[CH:22][C:9]([CH2:10][NH:11][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15](I)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:24][CH3:25])[CH2:3][CH2:2]1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH:1]1([CH:4]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[O:5][C:6]2[CH:23]=[CH:22][C:9]([CH2:10][NH:11][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:24][CH3:25])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a stirred solution of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amine (2.20 g, 3.91 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.896 g, 4.30 mmol), and potassium carbonate (1.10 g, 7.95 mmol) in toluene (10 mL) and water (1 mL) was added (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.143 g, 0.20 mmol). The resulting mixture was heated to 100° C. and stirred under a nitrogen atmosphere. After 16 h, the mixture was allowed to cool to room temperature and was diluted with water (15 mL). The mixture was extracted with ethyl acetate (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. Chromatographic purification of the residue (silica gel, 33% ethyl acetate in petroleum ether elute) afforded 1.10 g (55%) of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[CH:23][N:22]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[CH:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2ccc3cccnc3n2)CC1

Procedure:
100 mg (0.383 mmol) ketone (21), 47 mg (0.383 mmol) 2-aminopyridine-3-carbaldehyde and 22 mg (0.192 mmol) proline were refluxed in ethanol for 3 days. The solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate/hexane) to yield 4-[1,8]naphthyridin-2-yl-piperidine-1-carboxylic acid benzyl ester as an oil. 210 mg (0,605 mmol) of this intermediate were dissolved together with 50 mg 10% Pd/C in 50 ml methanol and stirred under an atmosphere of hydrogen for 18 h. Removal of the catalyst by filtration through a pad of Celite followed by evaporation of the solvent under reduced pressure gave the desired amine (22).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:15])[C:9]2[N:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][C:26]=2[F:35])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:35][C:26]1[CH:27]=[C:28]([C:31]([OH:34])([CH3:32])[CH3:33])[CH:29]=[CH:30][C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:15])[C:9]3[N:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[N:3]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cn1cc(C(F)c2cccc(Br)n2)nn1
Product: Cn1cc(C(F)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was synthesized from 2-bromo-6-[fluoro(1-methyl-1H-1,2,3-triazol-4-yl)methyl]pyridine (111 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].Cl.[NH2:45][C:46]1([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:48][CH2:47]1.C(N(CC)CC)C>ClCCl>[CH2:52]([O:51][C:49]([C:46]1([NH:45][S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:48][CH2:47]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)C1(N)CC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 600 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 390 mg of ethyl 1-aminocyclopropane carboxylate hydrochloride, 0.27 mL of triethylamine, and 6.0 mL of dichloromethane was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 523 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a pale yellow solid. ESI+: 730
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[C:15](=[O:16])[CH:14]2[CH2:17][CH:11]1[CH2:12][CH2:13]2)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(O)(=O)C>CO>[C:3]([NH:10][C@@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:15][OH:16])[CH2:17]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1

Procedure:
2.7 g (0.0714 mol) of sodium borohydride are added in portions to a solution of 3.8 g (0.018 mol)of N-BOC-2-azabicyclo[2.2.1 ]heptan3-one in 125 ml of methanol in the course of 20 minutes, while stirring and cooling in an ice-bath. The reaction mixture is further stirred at 0° C. for 1 hour and at room temperature for 1 hour, a solution of 4.08 ml (0.0714 mol) of acetic acid in 8 ml of methanol is then added dropwise and the mixture is evaporated to dryness in vacuo. The crystalline residue is partitioned between methylene chloride and water. After the organic phase has been washed with brine, dried over sodium sulfate and evaporated in vacuo, the title compound is obtained as crystalline residue, m.p. 73°-74° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:27]([O:26][CH3:25])=[O:36])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6]
Reactant: C#Cc1cc(C(=O)OCC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OCC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2-dimethylpropyl ester (Intermediate 48, 0.227 g, 0.70 mmol), 4-iodo phenyl acetic acid methyl ester (0.23 g, 0.83 mmol), triethyl amine (3 mL), copper(I)iodide (0.07 g, 0.39 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.21 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.198 g, 60%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N+:24]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a 100 mL round-bottom flask containing MeOH (25 mL) was added 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (5.3 g, 11.81 mmol), tin(II) chloride dihydrate (8.00 g, 35.4 mmol) and hydrochloric acid (4.92 mL, 59.1 mmol). The resultant suspension was heated to 50° C. and monitored by LC/MS. By LC/MS the reaction was complete in 30 minutes. After the reaction had cooled to room temperature, the majority of the MeOH was removed in-vacuo and 6N aqueous sodium hydroxide solution was added to adjust the pH to pH>10 and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with H2O and brine then dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude solid was purified by chromatography on silica gel eluted with chloroform/(solution of 2N ammonia in methanol) [95:5]. The fractions corresponding to product were combined, then concentrated in vacuo to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine (3.78 g, 9.03 mmol, 76% yield) as a light yellow solid. MS (ES+) m/e: 419.0, 420.0 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (d, J=8.08 Hz, 1H) 6.95-7.05 (m, 2H) 6.21-6.32 (m, 2H) 5.39 (s, 2H) 3.84 (s, 2H) 2.49 (s, 3H)