Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([F:21])[CH:14]=2.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([NH:9][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cc(F)ccc2c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cnc2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.4 mL, 46.2 mmol) was added to a suspension of 3-amino-7-fluoro-4-quinolinol hydrochloride (3 g, 14.0 mmol) in tetrahydrofuran (50 mL). Butyryl chloride (1.6 mL, 15.4 mmol) was added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. Aqueous sodium bicarbonate was added and the reaction mixture was allowed to stir at ambient temperature for about 1 hour. The resulting biphasic mixture was filtered to remove solids. The solids were rinsed with diethyl ether to provide a slightly pink powder. The tetrahydrofuran layer was concentrated under vacuum to provide a dark pink solid. This solid was triturated with ether and then oven dried. The solids were combined to provide 3.0 g of N-(7-fluoro4-hydroxyquinolin-3-yl)butanamide. A 300 mg portion was recrystallized from ethyl acetate/ethanol to provide a light gray fluffy solid, m.p. 306-308° C. Analysis: Calculated for C13H13FN2O2: %C, 62.90; %H, 5.28; %N, 11.28; Found: %C, 62.95; %H, 5.34; %N, 11.14.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[C:6]4[CH2:5][C:4]5[S:3][C:2]([C:42]6[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=6)=[CH:9][C:8]=5[C:7]=4[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[N:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5cccnc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.25 g, 2.3 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.70 g, 3.4 mmol), Na2CO3 (2 M, 5.0 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give the corresponding intermediate 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 67% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[CH3:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH3:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]1
Reactant: Cc1cccc(C=O)c1C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CN2CC[C@@H](N)C2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.6 %

Procedure:
1H-NMR (300 MHz, CDCl3) δ 0.77-0.97 (2H, m), 1.05-1.30 (3H, m), 1.36 (3H, t, J=7.1 Hz), 1.40-1.86 (10H, m), 1.97-2.25 (3H, m), 2.37-2.64 (3H, m), 3.84-4.08 (1H, m), 4.30 (2H, q, J=7.1 Hz), 5.59 (1H, br peak), 6.35 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.74 (1H, d, J=2.0 Hz). Preparation 372 1) To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (1.00 g), 2,3-dimethylbenzaldehyde (720 mg), N,N-diisopropylethylamine (1.87 mL), and ethanol (10 mL) was added sodium triacetoxyborohydride (2.28 g). After stirring for 3 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated NH4Cl. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. 2) To a mixture of above product and ethyl acetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (8.40 mL) at 4° C. After stirring at room temperature for 5 hours, the reaction mixture was neutrized with saturated NaHCO3. The resulting mixture was evaporated in vacuo. The residue was added chloroform, dried over Na2SO4, filtered, and evaporated in vacuo to give (3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinamine (193 mg). 1H-NMR (300 MHz, CDCl3) δ 1.41-1.53 (1H, m), 2.12-2.46 (3H, m), 2.27 (3H, s), 2.29 (3H, s), 2.64-2.77 (2H, m), 3.42-3.51 (1H, m), 3.58 (2H, s), 7.00-7.14 (3H, m), MS (ES+) m/z 205 (M+1). Preparation 373
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)[C:9]([CH3:23])([CH3:22])[CH2:8]2)(=[O:4])=[O:3].[CH3:24][O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:31])[C:27]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:10]2[C:9]([CH3:23])([CH3:22])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)[NH:11]2)[CH:16]=1)([CH3:29])[CH3:28]
Reactant: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 7.7 %

Procedure:
A mixture of 3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1 g, 3 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.65 g, 9 mmol) and potassium carbonate (2.07 g, 15 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 10 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (100 mg, 7%) as a brown oil: LC/MS m/e calcd for C23H30N2O4S (M+H)+: 431.57, observed: 431.1.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])=[C:9]([CH:28]1[CH2:30][CH2:29]1)[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:34][C:32](=[O:33])[C:31]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]=1[CH:28]1[CH2:29][CH2:30]1)=[O:35]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C(=O)c1c(C2CC2)n(Cc2ccccc2-c2ccccc2)c2cccc(OCC(=O)O)c12
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A mixture of 175 mg (0.36 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 4 mL of 1N NaOH and 10 mL of MeOH was stirred for 0.5 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and extracted with EtOAc. The EtOAc solution was dried (MgSO4), evaporated and the residue stirred with EtOAc/ether. The insoluble material was filtered to give 105 mg (62% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid, mp, 172-174° C.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:13](=[O:18])[C:14]([F:16])([F:15])[F:17])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN(Cc2cc3c(cn2)OCCO3)C(=O)C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N(Cc1cc2c(cn1)OCCO2)CC1CCCNC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.6 %

Procedure:
To a solution of 0.43 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)methyl)piperidine-1-carboxylate in 3 mL of chloroform, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour 40 minutes. The solvent was distilled off under reduced pressure. The resultant residue was charged with chloroform and water, and adjusted to pH 8.0 with an aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.15 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamide as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of ice-cooled methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred for 2 hours with ice cooling. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59%) as powders.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[C:10]1([S:16]([N:19]2[C:27]3[CH:26]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=[C:23]([NH2:32])[C:22]=3[CH:21]=[N:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:32][C:23]2[CH:24]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:26]=[C:27]3[C:22]=2[CH:21]=[N:20][N:19]3[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-1,3-thiazole-4-carbonyl chloride (350 mg) in DCM (4 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (300 mg) in DCM (15 ml) and pyridine (0.167 ml). The reaction was stirred at RT overnight. Saturated sodium bicarbonate (aq) (25 ml) was added and the reaction vigorously stirred for 15 min. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM and purified on a silica cartridge, preconditioned with cyclohexane, washing with cyclohexane followed by elution with ether. The ether was evaporated to give title compound, 373 mg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:20]2[C:19]([CH3:21])=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Preparation 1, Procedure B, using 4-tert-butyl phenyl boronic acid and 3,5-dimethyl-phenol as starting materials.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[C:5]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:1]([CH:16]([OH:17])[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([C:5](=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=1)#[CH:2]
Reactant: C#C[Mg]Br
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 2 h

Procedure:
Ethynylmagnesium bromide (11.2 mmol) in tetrahydrofuran (20 cm3) was added dropwise to a stirred solution of 3-benzoylbenzaldehyde (2 g, 9.5 mmol, prepared as in Example 3(b) in tetrahydrofuran (30 cm3) through which purified acetylene was being passed. After 2 hours, saturated ammonium chloride solution (200 cm3) was added, and the mixture extracted with ether (3×50 cm3). The combined extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulphate, and the solvent removed in vacuo. The product was purified by thin layer chromatography on silica to give the title alcohol, yield 1.1 g (49%) nD20 1.6075.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH:20]([C:19]3[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=3)[OH:22])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 11.1 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (400 mg, 2.1 mmol), 4-methylstyrene oxide (2.1 g, 15.7 mmol) and NaH (252 mg, 6.3 mmol) were heated in DMF (5 mL) at 120° C. for 16 h to obtain 75 mg of racemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.C(N1C=CC(N)=N1)[CH2:43][CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:43][CH:44]([CH3:46])[CH3:45])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)CCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 192 mg, 0.58 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (211 mg, 0.64 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (155 μL, 1.34 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Iso-pentyl-1H-pyrazol-3-ylamine (89 mg, 0.58 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-iso-pentyl-1H-pyrazol-3-yl)-propionamide (153 mg, 57%) as a white foam: ESI-LRMS m/e calcd for C23H32ClN3O3S [M+] 465.2, found 466.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δppm 0.93 (t, J=6.6 Hz, 6H, 2×CH3), 1.05-1.20 (m, 2H, CH2), 1.42-1.96 (m, 11H, CH and 5×CH2), 2.14-2.34 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.52 (t, J=7.6 Hz, 1H, CH), 3.96-4.02 (m, 2H, NCH2), 6.63 (d, J=2.3 Hz, 1H, Ar), 7.25 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2Cl2 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (XIV) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 400 MHz), δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17](/[N:20]=[CH:21]/[C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:5][C:4]1=[O:30])[CH3:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][CH2:21][C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[O:5][C:4]1=[O:30])[CH3:2]
Reactant: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 86.8 %

Procedure:
3-Ethyl-5-[1-(4[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9c, 0.41 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-ethyl-5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10c, 359 mg, 87%).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[CH:18]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[NH:7][S:3](=[O:5])(=[O:4])[N:2]1[CH3:1]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2ccc3cccnc3c2N)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)c(OC)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 16 %

Procedure:
N-methylsulfamyl chloride (Intermediate 213) (504 mg, 3.88 mmol) was added dropwise to a solution of (8-amino-quinolin-7-yl)-(2,4-dimethoxy-phenyl)-methanone (Intermediate 379) (200 mg, 0.65 mmol) in dry pyridine (10 ml) at 0° C. and the mixture was stirred at room temperature for 36 h (additional equivalents of methylsulfamyl choride were added as required after 24 h). After completion of the reaction (monitored by LCMS), NaBH4 (95 mg, 2.58 mmol) was added and reaction was stirred at room temperature for 18 h. The reaction was quenched with water, concentrated in vacuo and the residue was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (40 mg, 16%).
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N:21]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[N:22]3)=[C:16]([CH3:30])[CH:15]=2)[NH:7]S(C(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31]>CO>[ClH:31].[CH:1]1([CH:6]([C:14]2[CH:15]=[C:16]([CH3:30])[C:17]([N:21]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[N:22]3)=[C:18]([CH3:20])[CH:19]=2)[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(NS(=O)C(C)(C)C)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(N)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1

Procedure:
To a solution of (+/−)-N-(cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)-2-methylpropane-2-sulfinamide (1.184 g, 2.680 mmol) in methanol (13.4 mL) was added hydrogen chloride (4 M in dioxane, 3.35 mL, 13.4 mmol) dropwise. The reaction was concentrated under reduced pressure to provide (+/−)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride. 1H NMR (400 MHz, CD3OD, δ): 8.33 (s, 1H), 8.07 (s, 1H), 7.31 (s, 2H), 4.05 (d, J=10.6 Hz, 1H), 2.35-2.51 (m, 1H), 2.10-1.98 (m, 7H), 1.89-1.39 (m, 6H), 1.20-1.14 (m, 1H).