Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-dimethylethane-1,2-diamine (0.20 mL, 1.81 mmol) was added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3x with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 295(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:41])[CH:16]=2)([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(CN)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(CNC(=O)OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred mixture of 4-(3-Aminomethyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester (0.30 g, 0.99 mmol), methylene chloride (10 mL) and water (10 mL) was added potassium carbonate (0.28 g, 2.02 mmol) followed by benzylchloroformate (0.34 g, 2.02 mmol). The reaction stirred overnight at room temperature. The reaction was extracted with methylene chloride (3×30 mL). The organic extracts were combined, dried over sodium sulfate and evaporated to give a tan oil. Purification by flash chromatography 40% Ethyl acetate: Heptane yielded 4-[3-(Benzyloxycarbonylamino-methyl)-phenyl]-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester (0.40 g). 1H NMR [(CDCl3: δ 7.45-7.18 (m, 9H), 5.15 (s, 2H), 5.08 (br.s., 1H, NH), 4.40 (d, 2H), 4.15-3.93 (m, 2H), 3.35-3.15 (m, 2H), 2.08-1.90 (m, 2H), 1.75-1.62 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[C@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: C[C@H]1C(=O)NCCc2c1[nH]c1cc(F)ccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CNCCc2c1[nH]c1cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To an oven-dried flask containing dry THF (10 mL) under argon at −78° C. was added a 1 M solution of (iBu)2AlH in CH2Cl2 (16.3 mL). This mixture was stirred at −78° C. for 5 min. To this was (R)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.236 g, 1.02 mmol) in dry THF (16 mL). The reaction mixture was stirred at rt for 72 h, cooled to 0° C., then quenched by the addition of MeOH (4.5 mL). The mixture was partitioned between CH2Cl2 and 1 M aq NaO2CCH(OH)CH(OH)CO2K. The CH2Cl2 extracts were washed with brine, and dried, filtered and concentrated to give an oil. The oil was purified by silica chromatography to give the amine. To a solution of this amine (0.105 g, 0.48 mmol) in dry MeOH (4 mL) was added fumaric acid (0.028 g, 0.24 mmol) in MeOH (2.2 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in hot MeOH from which crystalline product was recovered: mp 256-258° C.; MS (ESI+) m/z 219.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.83 (1H), 9.3-8.5 (2H), 7.35 (1H), 7.01 (1H), 6.78 (1H), 6.43 (1H), 3.22-2.70 (8H), 1.30 (3H); Anal. C 64.94, H 6.27, N 10.07.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[NH:17][CH2:16][C@@H:15]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:14]2[CH2:13]1>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:17]2[C:12](=[O:11])[CH2:13][C@H:14]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:15]3[CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)C[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC(=O)N(c3ccc([N+](=O)[O-])nc3)C[C@@H]2C1
Yield: 85 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine and cis-tert-butyl 6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate were combined and gave after purification cis-tert-butyl 5-(6-nitropyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.0 g) in 85% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (d, J=2.53 Hz, 1H), 8.28 (d, J=8.59 Hz, 1H), 8.07 (dd, J1=8.84, J2=2.27 Hz, 1H), 4.18-3.61 (m, 4H), 3.29 (m, 2H), 2.85 (m, 3H), 2.55 (m, 1H), 1.47 (s, 9H)
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([O:19]C)=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:5]>C(O)C>[CH3:5][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([OH:19])=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:3]
Reactant: COC(=O)c1ccc(OC)c2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)c2ccn(C(C)C)c12
Yield: 92.7 %

Procedure:
Added 1 N sodium hydroxide (6.47 mL, 6.47 mmol) to a solution of methyl 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylate (400 mg, 1.618 mmol) in ethanol (30 mL) and heated at reflux for 3 h. The EtOH was removed in vacuo and the residue dissolved in 20 ml of water. Acidified solution by addition of 1 N HCl and extracted with DCM. the combined DCM extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give 350 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (d, 6 H), 4.03 (s, 3 H), 5.47 (dt, J=13.39, 6.69 Hz, 2 H), 6.70 (d, J=8.34 Hz, 2 H), 7.23 (d, J=3.28 Hz, 2 H), 7.37 (d, J=3.03 Hz, 2 H), 7.99 (d, J=8.34 Hz, 2 H). MS(ES) [M+H]+ 234.0.
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH:21]=O>C(O)C>[CH3:17][C:18]1[CH:25]=[C:24]([CH:26]=[N:10][CH2:9][CH2:8][P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=[C:20]([CH3:21])[CH:19]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: NCCP(c1ccccc1)c1ccccc1
Solvent: CCO
Product: Cc1cc(C)cc(C=NCCP(c2ccccc2)c2ccccc2)c1
Yield: 98 %

Procedure:
Under argon, a solution of 2-diphenylphosphino-ethylamine (652.2 mg, 2.84 mmol) and 3,5-dimethyl-benzaldehyde (387.4 mg, 2.89 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless oil (993.2 mg, 2.8 mmmol, quantitative).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:41][C:42]([C:44]2([NH:59]C(=O)OC(C)(C)C)[CH2:49][CH2:48][N:47]([C:50]3[C:51]4[CH:58]=[CH:57][NH:56][C:52]=4[N:53]=[CH:54][N:55]=3)[CH2:46][CH2:45]2)=[O:43])[CH2:16][C:17]2[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1>O.CO>[NH2:59][C:44]1([C:42]([NH:41][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[O:43])[CH2:49][CH2:48][N:47]([C:50]2[C:51]3[CH:58]=[CH:57][NH:56][C:52]=3[N:53]=[CH:54][N:55]=2)[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(Cc2ncc[nH]2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
Trifluoroacetic acid (5 mL, 64.90 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 89) (310 mg, 0.38 mmol) at room temperature and the resulting solution stirred for 30 minutes. Water (5-6 drops) was then added and stirring continued for a further 30 minutes. The resulting solution was diluted with methanol and applied to a 10 g SCX column which was then eluted with MeOH followed by 2N NH3 (in MeOH). Product-containing fractions were combined and concentrated by evaporation then triturated with MeCN/DMF (1:1) to give a pale yellow ppt. The precipitate was collected by filtration, washed with MeCN and dried under vacuum to afford 4-amino-N-(1-(4-chlorophenyl)-2-(1H-imidazol-2-yl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (130 mg, 72.8%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH2:25][CH3:26])([CH3:23])[CH3:24])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)CC)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(C)(C)c1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionate (6.650 g, 17.10 mmol), sodium hydroxide (1.37 g, 34.2 mmol), methanol (20 ml), water (20 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionic acid as a white solid.
Reaction SMILES: [F:1][C:2]([CH3:16])([CH3:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1.[NH2:36][C:37]([NH2:39])=[S:38]>CC#N>[NH2:39][C:37]1[S:38][C:4]([C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:6])=[C:3]([C:2]([F:1])([CH3:16])[CH3:15])[N:36]=1
Reactant: NC(N)=S
Reactant: CC(C)(F)C(=O)CC(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(F)c1nc(N)sc1C(=O)c1ccc(F)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-Fluoro-1-(4-fluoro-phenyl)-4-methyl-pentane-1,3-dione (900 mg) and Koser's reagent (4.2 g) in MeCN (20 mL) was heated at 80° C. for 50 min. The mixture was cooled to RT, and thiourea (820 mg) was added. The mixture was heated at 80° C. for 3 h., cooled to RT and partitioned between ethyl acetate and aq. KOH. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 283.2 (MH+). 1H NMR (DMSO-d6) 7.81 (dd, J=8, 4 Hz, 2H), 7.73 (s, 2H), 7.32 (t, J=8 Hz, 2H), 1.61 (d, J=20 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][N:28]=[C:29]=[O:30]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][CH3:27])=[O:30])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Reactant: CN=C=O
Product: CNC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedures of Example 76, 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide and methyl isocyanate gave 167. MS: (ESI+) 442.1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][CH2:8][C:9](=O)[CH3:10].CC[CH2:15][CH2:16][CH2:17][CH3:18].[CH2:19](Cl)Cl>>[CH3:15][C:16]1[CH:17]=[CH:18][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]2[C:19]=1[CH:10]=[CH:9][CH2:8]2
Reactant: CC(=O)CCC(=O)c1ccco1
Reactant: CCCCCC
Reactant: ClCCl
Product: Cc1ccc(-c2ccco2)c2c1C=CC2
Yield: 70 %

Procedure:
16.6 g (100 mmol}of 1-(2-furyl)-1,4-pentanedione were reacted analogously to Example 8. Column chromatography with hexane/methylene chloride (7:1) as the mobile phase gave 13.7 g (70 %) of the indene 13. For the NMR data, see Table 1.
Reaction SMILES: C([OH:6])CCC=C.N1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13](Cl)(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>C(Cl)Cl>[C:13]([O:24][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])(=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCCCO
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OCCCC=C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
A flask was charged with 10 g (116 mmol) of 4-pentenol, 200 ml of methylene chloride, 18.33 g (232 mmol) of pyridine and the mixture was ice-cooled. To the mixture was added dropwise 80 ml of a methylene chloride solution containing 23.51 g (116 mmol) of 10-undecenoyl chloride. The resulting mixture was stirred for 30 minutes and then at room temperature for 3 hours. The insoluble substance was filtered. 5% hydrochloric acid was added to the filtrate to separate an organic layer. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and water in this order, followed by drying using magnesium sulfate anhydride. After the drying, a solvent was distilled and the residue was subjected to vacuum distillation (121-123° C./2 mmHg) to obtain 25.3 g of an object material in a yield of 86.4%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:5]([CH:6]([OH:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:4]([OH:30])=[O:3])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 4.12 g (10.2 mmol) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester in 57 ml tetrahydrofurane were added 1.73 g (40.8 mmol) lithium hydroxide monohydrate dissolved in 10 ml water. The mixture was stirred at 60° C. overnight. Water was added followed by extraction with ethyl acetate. The waterphase was adjusted to pH 1 with 1 N aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol 9/1 yielded 3.40 g (89%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid, MS m/e (%): 376.5 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#N)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].[PH2]([O-])=[O:21].[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]=[O:21])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(C#N)ccc12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(Cl)ccc2cc(C=O)ccc12
Temperature: 100 °C

Procedure:
(2-Chloro-6-cyano-naphthalen-1-yl)-acetic acid ethyl ester (1.39 g, 5.07 mmol) is dissolved in a mixture of water (17 ml), pyridine (33 ml) and glacial acetic acid (17 ml). Sodium hypophosphite (4.30 g, 40.62 mmol) and Raney nickel (3.2 g) are then added at RT. The reaction mixture is heated to 100° C. for 1 h. TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT and filtered through Celite. After addition of silica gel, the solvents are removed on a rotary evaporator. Purification by FCC (hexane/EtOAc 5:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.17 (t, J=8 Hz, 3H), 4.10 (q, J=8 Hz, 2H), 4.24 (s, 2H), 7.52 (d, J=10 Hz, 1H), 7.82 (d, J=10 Hz; 1H), 7.94-7.98 (m, 2H); 8.26 (s, 1H), 10.09 (s, 1H). ES−-MS: 275.2, 277.3 [M−H]−.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].O.Cl.[NH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:7][C:2]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C)(C)N1CCC(=O)CC1
Reaction time: 17.5 h

Procedure:
A mixture of methyl 2-bromo-2-methylpropanoate (80.87 ml, 5 equiv), 4-piperidone hydrochloride monohydrate (19.6 g, 1 equiv), acetonitrile (200 ml) and potassium carbonate (69.1 g, 4 equiv) was heated at reflux under nitrogen with mechanical stirring for 17.5 h then cooled in an ice bath before adding diethyl ether (100 ml). Filtration through celite followed by flash chromatography (silica, 10-50% ethyl acetate in hexane) and evaporation of the product fractions gave the desired product as a yellow oil (14.28 g).
Reaction SMILES: BrCCC1C([Cl:10])=C(Cl)C=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[C:14]=1CCBr.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[ClH:10].[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH2:5][CH2:6][NH:27][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Clc1ccc(Oc2ccc(Cl)c(Cl)c2CCBr)c(CCBr)c1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)NCCOc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
A solution of 36.18 g. (0.135 mole) of 2-bromoethyl-3,4-dichlorophenyl ether and 31.8 g (0.54 mole) of isopropyl amine in 200 ml of chloroform was heated at reflux for 72 hours. Solvent was removed in a rotary evaporator and the residue partitioned between water and chloroform. The chloroform layer was extracted with 1N sulfuric acid. The aqueous phase, which contained a dispersed white solid, was made alkaline with 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was concentrated under vacuum to an oil, the free base. A portion of the oil was dissolved in methanol and treated with ethereal hydrogen chloride. The precipitate was recrystallized from methanol-diethyl ether. Overall yield of white crystalline product was 62.4% of theory based on the proportion taken. The melting point was 186°-187° C.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([F:4])[CH3:3].[Cl:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(OCC)C>ClC1C=CC=CC=1>[ClH:12].[F:1][C:2]([C:5]1[CH:6]=[C:7]([N:8]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc(N)c1
Reactant: ClCCNCCCl
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: CC(F)(F)c1cccc(N2CCNCC2)c1
Product: Cl
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 2.5 g (15.9 mmol) of 3-(1,1-difluoroethyl)aniline and 2.8 g (15.9 mmol) of bis(2-chloroethyl)amine in 20 mL of chlorobenzene is refluxed overnight. After cooling to room temperature, diethyl ether is added and precipitation occurs. The solid is filtered, washed with diethyl ether and dried under reduced pressure to give 3.8 g (90%) of 1-[3-(1,1-difluoro-ethyl)phenyl]piperazine, hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][OH:13]>>[Cl:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:13][CH3:12])[N:3]=1.[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:13][CH3:12])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CO
Product: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A slurry of 2,6-dichloro-3-nitropyridine (92%, 9.9 g, 47 mmol) and K2 CO3 powder (6.5 g, 47 mmol) in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHCO3. The organic solution was washed with 60% sat. aq. NaHCO3 (2×), H2O , then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.31 (d, 8.3 Hz, 1H), 8.28 (d, 8.9 Hz, 1H), 7.10 (d, 8.3 Hz, 1H), 6.82 (d, 8.9 Hz, 1H), 4.15 (s, 3H), 4.06 (s, 3H).
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:26])[N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[NH:13][N:12]=2)[C:9](=[O:21])[C:8]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]12.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].[K]>O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][N:13]1[C:14]2[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[C:11]([N:10]2[C:9](=[O:21])[C:8]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]3[C:6]2=[O:26])=[N:12]1)[CH3:34]
Reactant: CCN(CC)CCCBr
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Agent: Br
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Yield: 59 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.54 g of 3-phthalimido-4-chloroindazole obtained in the same method as described in Example 1, 4.83 g of 3-bromopropyldiethylamine hydrobromide and 6.3 g of anhydrous potassium for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. After the pH of the layer was adjusted to 14 with potassium carbonate, the layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 3.70 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole having the following analytical values in a yield of 59 %.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=[O:14])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[OH:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 36 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (0.10 mg, 0.21 mmol) in a 9:1 mixture of dichloroethane in CH3CN (5 mL) was added sodium triacetoxyborohydride (181 mg, 0.854 mmol). After 36 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by silica gel chromatography using a gradient of 0-8% methanol in dichloromethane to afford the title compound as a white solid.