Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([N+:26]([O-])=O)[C:20]=2[OH:29])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[OH:29])(=[O:17])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc(N)c2O)CC1

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (480 mg, 1.07 mmol) was reduced with hydrogen and 10% Pd/C (240 mg). The crude product (460 mg) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 6.86 (m, 2H), 4.00 (d, 2H), 2.83 (m, 2H), 2.78 (m, 2H), 1.60 (m, 3 H), 1.44 (s, 9H), 1.00 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=O)[CH2:7][C:6]1([CH3:15])[CH3:14])[CH2:2][CH3:3].C([O-])(=O)C.[NH4+].[BH3-]C#[N:23].[Na+]>>[NH2:23][CH:8]1[CH2:9][C:10]([CH3:12])([CH3:11])[N:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]([CH3:15])([CH3:14])[CH2:7]1
Reactant: CCCON1C(C)(C)CC(=O)CC1(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCON1C(C)(C)CC(N)CC1(C)C
Yield: 61.2 %

Procedure:
4-Amino-N-propoxy-2,2,6,6-tetramethylpiperidine (1.6 g, 62%) is prepared from N-propoxy-4-oxo-2,2,6,6-tetramethylpiperidine (12.2 mmol, 2.60 g) by the same method as described above, with the exception of the addition of ammonium acetate (122 mmol, 9.40 g), 6 g molecular sieves (10−10 m) and 95% NaBH3CN (12.2 mmol, 0.8 g). 1H-NMR (CDCl3); δ=3.61 (t, J=6.6 Hz, 2H, CH2—O), 2.99 (m, 1H, NH2—CH), 1.58 (d, J=11.4 Hz, 2H, NH2), 1.46 (m, 2H, CH2—CH3), 1.20 (m, 4H), 1.16 (s, 6H, CH3), 1.13 (s, 6H, CH3), 0.93 (t, J=7.4 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3): δ=78.3, 59.8, 49.9, 41.4, 33.2, 21.9, 20.9, 10.9.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH2:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH:23][CH2:35][C:32]1[CH:33]=[CH:34][C:28]2[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=2[N:31]=1
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@H](F)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](F)C3)c2n1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
To a stirred solution of (±)-[(trans-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.25 g, 0.77 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.24 g, 1.15 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.23 g, 60%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.25 (d, J=9.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.25 (d, J=9.1 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.43 (s, 2H), 4.19 (s, 3H), 3.90 (m, 2H), 3.77 (m, 4H), 3.65 (m, 4H), 3.57 (m, 2H), 3.32 (app s, 2H). LC-MS (ES) m/e 501 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N+:6]([O-])[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][C:7]1[N:6]=[C:5]2[NH:12][C:2]([CH3:1])=[N:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C)cc[n+]([O-])c2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(C)cc(Cl)nc2[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-4-oxide (4.45 g), chloroform (4.5 ml) and phosphorus oxychloride (25.4 ml) was stirred at 80° C. for 3 hr and concentrated to dryness under reduced pressure. The residue was poured into ice (75 g) and neutralized with aqueous ammonia under ice-cooling. After stirring at room temperature for 30 min, the precipitated solid was collected by filtration and washed with water to give 5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine as a gray powder (3.66 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11])[CH:13]=[CH2:12]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(CO)nc2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-methanol (501 mg, 3.38 mmol) and allyl bromide (0.29 mL, 3.38 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (0.71 mL, 4.06 mmol). The reaction mixture was stirred at 60° C. overnight. Then the mixture was cooled to room temperature and quenched with saturated NaHCO3 (25 mL). Then it was extracted with CH2Cl2 (3×25 mL). The combined organic layer was washed with brine (2×25 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (180 mg, 28%). 1H NMR (CDCl3) δ 4.85 (br s, 5H), 4.98 (d, 1H, J=17.1 Hz), 5.17 (d, 1H, J=10.5 Hz), 5.88-6.01 (m, 1H), 7.20-7.26 (m, 3H), 7.66 (t, 1H, J=3.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH3:24])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Yield: 55.1 %

Procedure:
Using General Procedure B, to a solution of COMPOUND 249(0.1331 g, 0.43 mmol) in CH3CN (5 mL) was added Ac2O (0.05 mL, 0.51 mmol), Et3N (0.09 mL, 0.65 mmol), and KI (0.0116 g, 0.04 mmol). Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 83.5 mg (53%) of COMPOUND 251 as a white solid. 1H NMR (CDCl3) δ 1.53-1.69 (m, 2H), 1.78-1.85 (m, 2H), 2.08 (s, 9H), 2.35 (t, 1H, J=13.0 Hz), 2.72 (t, 1H, J=12.0 Hz), 2.91 (t, 1H, J=12.0 Hz), 3.73-3.90 (m, 5H), 4.69 (d, 1H, J=24.0 Hz), 7.06-7.11 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.35, 21.86, 27.09, 28.19, 42.05, 46.79, 54.99, 57.78, 122.82, 133.77, 138.43, 146.31, 157.49, 169.14. ES-MS m/z 353 (M+H). Anal. Calcd. for C21H28N4O.H2O: C, 69.43; H, 8.10; N, 15.42. Found: C, 69.52; H, 7.82; N, 15.28.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1.O>[F:15][C:10]1[CH:9]=[C:8]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(Br)cc1F
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(C)c(F)c2)c1
Yield: 75.6 %

Procedure:
A mixture of toluene (22.7 mL) and water (22.7 mL+7.5 mL) was degassed with nitrogen for 30 min. A mixture of cesium carbonate (3.3 g, 1.04 mmol), 4-bromo-2-fluoro-1-methyl-benzene (1.0 g, 5.2 mmol), 3-methoxyphenylboronic acid (0.8 g, 5.2 mmol) and tetrakis triphenyl phosphene palladium (0.294 g, 0.26 mmol) was added to the above degassed aq. toluene and the resulting mixture was refluxed for 5 h. After the reaction was completed, it was cooled and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulphate and concentrated. The residue was purified by column chromatography using 10% ethyl acetate in hexane to obtain the title compound (0.85 g, 74%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[N:12]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:31])([F:30])[F:32])=[O:23])=[CH:17][CH:16]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of dioxane (10 mL) that was saturated with hydrogen chloride gas was added to 4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.581 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then the volatiles were evaporated under reduced pressure. The residue was triturated with diethyl ether to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride as a white powder (226 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH:6]=1.CS(OC1CCOC1)(=O)=[O:13]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH2:9][O:13][CH2:8]2)[CH:6]=1
Reactant: Brc1cnn(C2CCC2)c1
Reactant: CS(=O)(=O)OC1CCOC1
Product: Brc1cnn(C2CCOC2)c1

Procedure:
The title compound was prepared in the same manner as 4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-yl methanesulfonate (prepared according to procedures known in the art).
Reaction SMILES: [C:1]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[C:1]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=O
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 2-(1-tridecynyl)benzaldehyde (6.42, 22.6 mmol from example 3) was condensed with diethyl malonate (3.72 g) as described in example 1 to give 2.00 g (21%, 36% on the basis of unrecovered starting material) of the title compound identical with that prepared in example 6 above.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.C(#N)C.CS(Cl)(=O)=O.[NH2:25][C:26]1[C:34]([CH3:35])=[CH:33][C:32]([Cl:36])=[CH:31][C:27]=1[C:28](O)=[O:29]>C(N(CC)CC)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([Cl:36])[CH:33]=[C:34]([CH3:35])[C:26]=3[N:25]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
To a mixture of 0.44 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 6 ml of acetonitrile and 0.20 g of triethylamine was added 0.125 ml of methanesulfonyl chloride. After the resulting mixture was stirred at room temperature for 15 minutes, 0.27 g of 2-amino-5-chloro-3-methylbenzoic acid was added and the mixture was stirred at room temperature for 20 minutes. To the mixture, 0.40 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.13 ml of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filter cake was washed with methyl tert-butyl ether. The resulting filter cake was dissolved in ethyl acetate, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.098 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one. In addition, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.093 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][OH:18])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][CH3:29])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CI
Reactant: COc1ccc(C2C(CO)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 216 %

Procedure:
Combine [6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-yl]-methanol (0.084 g, 0.24 mmol), NaH (0.014 mg, 0.29 mmol), and DMF (3.0 mL) and stir under nitrogen atmosphere at −10° C. After 1 hour, add MeI (50 uL, 0.072 mmol) and stir at room temperature for 18 hours. Concentrate reaction under vacuum then add ethyl acetate and water, separated the organic phase and wash 2× with brine. Dry the organic phase over anhydrous sodium sulfate. Concentrate the organic phase under vacuum and flash chromatograph using 0% to 25% ethyl acetate/hexanes to yield the titled compound (0.057 g, 65%) as a white solid. TLC Rf=0.40 in 3:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.58 (d, 1H, J=8.8 Hz), 7.25 (d, 2H, J=8.8 Hz), 6.93 (m, 3H), 6.81 (dd, 1H, J=8.4, 2.6 Hz), 3.85 (m, 6H), 3.66 (m, 1H), 3.38 (m, 2H), 3.23 (m, 4H), 3.11 (dd, 1H, J=11.9, 3.1 Hz), 2.48 (d, 1H, J=13.7 Hz), 1.92 (m, 1H), 1.42 (m, 2H), 1.18 (m, 3H), 1.77 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#N)=[C:4]([F:11])[C:3]=1[Br:12].C(O)=[O:14]>[Ni]>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:14])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: O=CO
Reactant: N#Cc1cc(F)c(N)c(Br)c1F
Agent: [Ni]
Product: Nc1c(F)cc(C=O)c(F)c1Br
Temperature: 85 °C
Yield: 83 %

Procedure:
Raney nickel (5.3 g, 50% slurry in water) was added to a solution of 4-amino-3-bromo-2,5-difluoro-benzonitrile (4.0 g, 17.2 mmol) in formic acid (60 mL). After heating for 1 h at 85° C., the reaction mixture was filtered through Celite, washed with DCM and evaporated to dryness. The residue was suspended in DCM and neutralized carefully with saturated sodium hydrogencarbonate. The aqueous phase was extracted with DCM and the combined organic phases were dried over sodium sulfate and evaporated to yield 4-amino-3-bromo-2,5-difluorobenzaldehyde (3.4 g, 14.3 mmol, 83%). 1H NMR (d6-DMSO) δ 9.91 (d, J=3.0 Hz, 1H), 7.45 (dd, J=11.0, 6.0 Hz, 1H), 6.96 (br s, 2H).
Reaction SMILES: [BH4-].[Na+].C([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)C.[CH2:12]([OH:14])[CH3:13]>>[OH:14][CH:12]([C:9]1[CH:8]=[N:7][CH:6]=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCO
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium borohydride (1.75 g) was added in portions to a stirred solution of acetylpyridine (12.1 g) in ethanol (100 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 min, then concentrated under reduced pressure to remove ethanol. The thick residue was diluted with 300 mL of dichloromethane, 25 mL of water and 5 mL of 20% NaOH. The aqueous layer was saturated with sodium chloride, and extracted with ethyl acetate (4×150 mL). The combined organic extracts were dried (MgSO4) and concentrated. Evaporative distillation of the crude oily product (14.0 g) at 1 mm, oven temperature 85°-95° C. gave 11.4 g of 3-(1-hydroxyethyl)pyridine as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:29])[F:30])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 356, methanesulfonyl chloride (6.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([O:17][CH3:18])=[C:11]([C:12]([F:16])=[C:13]([F:15])[CH:14]=1)[CH:26]=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl-silane (5.2 g, 18.95 mmol) in tetrahydrofuran (60 mL) cooled to −78° C. was added n-butyllithium (9.096 mL, 22.74 mmol) dropwise over a period of 15 minutes. At the end of the addition, the reaction mixture was stirred at −78° C. for 1 hour. Dimethylformamide (1.737 mL, 22.74 mmol) was added and the reaction mixture was stirred at −78° C. for 2 hours. Saturated solution of ammonium chloride (˜5 mL) was added, and then the mixture was diluted with 100 mL of water. The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 4% ethyl acetate in hexanes) yielded 3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-benzaldehyde as clear oil (3.96 g, 69%). LR-MS (M+) 302.2.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:20]=[N+:21]=[N-:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1nc2ccccc2n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1nc2ccccc2n1Cc1ccccc1
Yield: 72.5 %

Procedure:
A solution of 1-Benzyl-2-chloromethylbenzimidazole hydrochloride (16 g, 0.055 mole) in N,N-dimethylformamide (80 ml) was stirred and a solution of sodium azide (17 g, 0.26 mole) in water (40 ml) was added. The resulting yellow solution was heated on a steam bath for 30 minutes, diluted with water (250 ml) and the crystalline product was filtered, dried in vacuo at room temperature, and recrystallized from 2-propanol to yield 10.5 g (73%) of product: mp 108°-110°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.I[CH3:17]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:17])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CI
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Yield: 88.9 %

Procedure:
8-Fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 3.13 g, 0.0149 mol) and iodomethane (1.39 ml, 0.0223 mol) in DMF (25 ml) are stirred at room temperature overnight. The reaction is diluted with water and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum to give the title compound as an orange solid (2.97 g, 89%); 1H NMR (300 MHz, CDCl3) δ 2.56–2.61 (m, 2H), 2.99–3.04 (m, 2H), 3.32 (s, 3H), overlapping 8.06 (s, 1H) and 8.08 (dd, 1H); [M+H]+=225.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[N:9]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9]
Reactant: O=N[O-]
Reactant: Nc1ccccc1I
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1I
Temperature: 0 °C
Yield: 44 %

Procedure:
21.9 g (100 mmol) o-iodophenyl amine was dissolved in 40 mL concentrated hydrochloric acid. At 0° C., 6.9 g (100 mmol) sodium nitrite (dissolved in 35 mL water) was added dropwise, and stirred at 0° C. for half an hour. Then, SnCl2.2H2O 64.7 g (300 mmol) (dissolved in 70 mL concentrated hydrochloric acid) was added dropwise slowly, and reacted for about 3 h until complete. It was filtered to obtain a white solid, washed with a saturated solution of sodium chloride, and then washed with a mixed solvent of petroleum ether and diethyl ether (1:1). Then, the solid was adjusted to be basic with sodium hydroxide solution. The solid impurity therein was filtered, the aqueous phase was extracted with dichloromethane several times, the organic phases combined, dried, rotate evaporated to dryness to obtain a colorless oil 10.3 g, at a yield of 44.0%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:23][CH:22]([CH3:24])[C:21]([N:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[N:15]1)=[O:25]
Reactant: c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)n1ccc(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1H-pyrazole (123 mg, 0.52 mmol) and NaH (28 mg, 0.70 mmol) in 5 mL of DMF was stirred at room temperature for 30 minutes. Neat isobutyryl chloride (80 μL, 0.75 mmol) was added and the reaction was stirred at room temperature. The reaction was then partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the pooled organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography (5% EtOAc/hexane) gave 127 mg (80%) of the title compound as a white solid, mp 49-51° C. 1H NMR (CDCl3): δ 8.30 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.39 (t, J=8.0 Hz, 2H), 7.17 (t, J=7.2 Hz, 2H), 7.12-7.08 (m, 4H), 6.75 (d, J=3.0 Hz, 1H), 4.03 (m, 1H), 1.78 (d, J=6.9 Hz, 6H).