Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([I:19])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Clc1nc(Cl)c2c(I)c[nH]c2n1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.6 mmol) in DCM (32 mL) was added NIS (2.4 g, 10.6 mmol) at room temperature. After stirring for 1 h, the resulting precipitate was collected by filtration to give 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: Cc1cc(C)c(-c2cccc(Br)n2)c(C)c1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
2,6-Dibromopyridine (9.47 g, 40 mmol) was dissolved in 80 mL of 1,2-dimethoxyethane (1,2-dimethoxyethane). Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.00 mmol) was added and the mixture was heated at 50° C. for 15 min. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (6.56 g, 40 mmol) dissolved in 40 mL of 1,2 dimethoxyethane was added. Finally, potassium t-butoxide (8.97 g, 80 mmol) was added as a solution in 40 mL of t-butanol. The reaction was heated for 0.5 h at 90° C. The solution was cooled and filtered through celite. Flash chromatography (2% ethyl acetate/hexanes) gave 7.48 g (68% yield) of the title compound.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:26][C:27]([F:36])([F:35])[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46]([CH3:49])=[CH:47][CH3:48])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38].O>ClCCl>[CH:37]([C:40]1[CH:45]=[CH:44][C:43]([C:46](=[CH:47][CH3:48])[CH2:49][C:28]([OH:34])([C:27]([F:35])([F:36])[F:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:42]([O:50][CH3:51])[CH:41]=1)([CH3:39])[CH3:38]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: CC=C(C)c1ccc(C(C)C)cc1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(C(C)C)cc1OC

Procedure:
Ytterbium(III) trifluoromethanesulphonate (3.25 g, 5.23 mmol) in 116 ml of dichloromethane is admixed dropwise at room temperature with ethyl trifluoropyruvate (9.55 ml, 78.5 mmol). Following the addition of 4-isopropyl-2-methoxy-1-(1-methylpropenyl)benzene (10.7 g, 52.37 mmol), in solution in 29.5 ml of dichloromethane, the reaction mixture is stirred at room temperature for two days. In parallel a second batch is carried out with the same quantities and under the same conditions. Water (100 ml) is added to each of the two reactions. For further working up, the two batches are combined. The dichloromethane phase is separated off and the aqueous phase is extracted a further time with dichloromethane (300 ml). The combined organic extracts are washed with water (100 ml) and brine (100 ml) and then dried (Na2SO4). After removal of the solvent on a rotary evaporator, the residue is purified by repeated chromatography on silica gel (eluent: ethyl acetate/hexane). The yield of ene product, which is used in the next stage, is 9.08 g, only 40% being the described compound and 60% being the corresponding ethyl 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pent-4-enoate.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[SH:14])[C:7]([O:9][CH3:10])=[O:8].Br[CH2:16][C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]2([CH3:32])[CH3:31])=[CH2:18].Cl>CN(C=O)C.C(OCC)C>[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[S:14][CH2:18][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)=[CH2:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=C(CBr)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(S)c(I)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(CSc1ccc(C(=O)OC)cc1I)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.33 h

Procedure:
75% NaH (115 mg, 3.58 mmol) is added to a solution of methyl 3-Iodo-4-mercaptobenzoate (531 mg, 3.25 mmol) in DMF (20 ml) at 0° C. Stirring is continued for 20 min at ambient temperature, then a solution of 6-(1-bromomethylvinyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (1 g, 3.25 mmol) in DMF (5 ml) is added dropwise. The mixture is stirred for 2 h at ambient temperature, and treated with an aqueous hydrochloric acid solution and ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The product is purified by flash chromatography on a silica column (CH2Cl2 50% heptane 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][C:14]=1[F:21].[CH3:22][O-].[Na+]>CO>[Cl:12][C:13]1[CH:20]=[C:19](/[CH:22]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:16]=[CH:15][C:14]=1[F:21]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C[O-]
Reactant: N#CCc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1ccc(F)c(Cl)c1)c1ccc(Cl)cc1F
Yield: 50.9 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.3 g, 19 mmol) was reacted with 4-chloro-3-fluoro-benzaldehyde (Aldrich) (3.65 g, 23 mmol), methanolic solution (25 wt %) of sodium methoxide (4.8 mL, 21 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (3 g, 50%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[N:9]=[C:8]([Zn+])[CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:13]([C:24]2[CH:32]=[CH:31][C:30]3[C:26](=[CH:27][N:28]([CH3:33])[N:29]=3)[CH:25]=2)=[N:14][S:15][C:16]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]>O1CCCC1.COCCOC>[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:12]2[C:13]([C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH3:33])[N:29]=4)[CH:25]=3)=[N:14][S:15][C:16]=2[NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Reactant: COc1cccc([Zn+])n1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cccc(-c2c(-c3ccc4nn(C)cc4c3)nsc2NC(=O)[C@@H]2C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add a 0.5M solution of 6-methoxy-2-pyridylzinc bromide in tetrahydrofuran (6.13 mL, 3.07; mmol) to a solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide (0.24; g, 0.61; mmol) in anhydrous 1,2-dimethoxyethane (3.1; mL) and degas by bubbling with nitrogen for 20 min. Add bis(tri-t-butylphosphine)palladium (0) (0.01; g, 12.27; μmol), stir at room temperature under nitrogen overnight and then heat at 55° C. for 48; h. Dilute with brine and extract with ethyl acetate. Dry the ethyl acetate layers over magnesium sulfate, filter and concentrate. Purify by silica gel chromatography, gradient eluting from 0:100; to 30:70; eluting using ethyl acetate:chloroform and then further purify by reverse phase HPLC (water w/ammonium bicarbonate (pH=9)/acetonitrile) to give the title compound (29.6; mg). 1H NMR (CD3OD) δ 0.85; (m, 1H), 1.18; (d, 3H), 1.35; (m, 1H), 1.44 (m, 1H), 1.62; (m, 1H), 4.11; (s, 3H), 4.24; (s, 3H) 6.57; (d, 1H), 6.62; (d, 1H), 7.27; (m, 1H), 7.34; (t, 1H), 7.65; (d, 1H), 7.91; (d, 2H), 12.17; (bs, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[C:17]([O:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([NH:24][N:25]=[CH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(C=NNC(=O)OC(C)(C)C)cc12
Yield: 98.1 %

Procedure:
A 100 ml flask is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Reference Example 9; 2.16 g, 10 mmol), hydrazinecarboxylic acid tert-butyl ester (1.32 g, 10 mmol), and methanol (10 ml). This mixture is heated at reflux for 18 hours, and then the solvent is removed on the rotavapor to leave the hydrazone (3.24 g, 98%). 1H-NMR (CDCl3, 300 MHz) δ 1.55 (s, 9H, C(CH3)3); 2.30 (s, 6H, N(CH3)2); 2.59, 2.87 (2 m, 2H each, CH2CH2NHMe2); 6.94 (d, 1H, J=2 Hz, H-2); 7.17 (d, 1H, J=8.5 Hz, H-7); 7.52 (dd, 1H, J=1.5 Hz, H-6); 7.68 (d, 1H, H-4); 7.84 (br s, 1H, N═CH); 8.42 (br s, NH); 9.10 (s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 23.89 (CH2); 28.83 (C(CH3)3); 45.66 (N(CH3)2); 60.47 (CH2NMe2); 81.23 (OCMe3); 111.94 (C-7); 114.77 (C-3); 119.30 (C-4); 120.76 (C-6); 122.91 (C-2); 125.37 (C-5); 127.48 (C-9); 137.54 (C-8); 146.13 (N═CH); 153.13 (NC═O).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15](O)[C:14]([C:23]3C=CO[CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(OS(C(F)(F)F)(=O)=O)C(CC)=CC=2)(=O)=O)C=CC=CC=1.[CH3:58][N:59]1[C:63](B2OC(C)(C)C(C)(C)O2)=[CH:62][CH:61]=[N:60]1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:63]3[N:59]([CH3:58])[N:60]=[CH:61][CH:62]=3)[C:14]([CH2:23][CH3:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1-c1ccnn1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 127) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[K+].[NH4+:20]>C(#N)C.O.C1(C)C=CC=CC=1>[NH2:20][C:2]1[N:4]=[C:5]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:8]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:1]=1
Reactant: CCCCN
Reactant: [NH4+]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCNc1nc(N)nc(NCCCC)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 185.5 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride was dissolved in 150 mL of acetonitrile. The solution was cooled to 0° C. and the cooled solution was dropwise added, while stirring, with a solution of 7.3 g (0.1 mol.) of butylamine in 20 mL of water over one hour in such a manner that the reaction temperature did not raise over 5° C. While further continuing the stirring, a solution of 10.0 g (0.1 mol.) of potassium hydrogencarbonate in 100 mL of water was dropwise added to the mixture at the same temperature and stirred for three hours. After the completion of the conversion of the resulting product into 2-butylamino-4,6-dichloro-1,3,5-tirazine was recognized by a high-performance liquid chromatography, 24.3 g (0.4 mol.) of an aqueous 28-% ammonium solution were added. The temperature was raised to 50° C. and the reaction was carried out for five hours. After the cooling, an obtained product was separated through filtration and washed fully with a large amount of water. An obtained crude product was suspended in 100 mL of water and added with 29.2 g (0.4 mol.) of butylamine and reacted for six hours under heating and refluxing. After the completion of the cooling, the resulting product was added with 200 mL of toluene and vigorously stirred and then, the aqueous layer was separated. Further, after the toluene layer was thrice washed with each 150 mL of water, toluene was distilled off from the organic layer under heating and reduced pressure to obtain 22.1 g of 2-amino-4,6-bis-(n-butylamino)-1,3,5-triazine (yield: 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31].O>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (27.5 g, 0.08 Mol) was suspended in ethyl acetate (0.193 L) and 1,1-carbonyidimidazole (13.3 g, 0.082 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 15 minutes and then the reaction was stirred for a further 60 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (16.5 g, 0.078 Mol) was added to the cooled mixture, and the reaction stirred for a further 17 hours under reflux. The solution was cooled and water (0.07 L) and ethyl acetate (0.17 L) added. The slurry was warmed to 40° C. and the organic separated. The organic was concentrated to by evaporating 0.23 L solvent. The slurry was cooled, granulated at 0-−10° C. filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)nicotinamide as an off white crystalline solid, 38.7 g, 89%. m.p.=159-161° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.Cl[C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CN1CCCC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2,6-lutidine and 0.9 ml of N-methylpyrrolidine to 360 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it was returned to room temperature, water was added, the precipitated solid was filtered out and washed with water and diethyl ether, and the collected solid was dried to obtain 112 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:16]([NH2:17])=[N:19][NH:20][C:14]=1[NH2:15]
Reactant: Cc1c(CC(C#N)C#N)cccc1C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Yield: 47.4 %

Procedure:
To a mixture of malononitrile (2.352 g, 35.6 mmol) in 95% Ethanol (50 mL) was added 2-methyl-3-(trifluoromethyl)benzaldehyde (6.7 g, 35.6 mmol). The reaction was stirred at rt for 18 h. Additional EtOH (20 mL) was added and the mixture was stirred for 20 minutes and cooled to 0° C. in an ice bath. Sodium borohydride (0.364 g, 9.61 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 77%). To a mixture of {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 27.3 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.68 mL, 54.6 mmol). The reaction mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (eluting with MeOH/DCM: 0˜10%) to give the product (3.5 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.47 (s, 3H) 3.69 (s, 2H) 7.11-7.37 (m, 2H) 7.51 (d, 1H); LC/MS: MS (ES+) m/e 271.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.[BH4-].[Na+]>CN(C=O)C.[Co](Cl)Cl>[NH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:19])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide (1 g, 2.6 mmol, 1.0 equiv.), cobalt chloride (0.5 g, 3.85 mmol, 1.5 equiv.) and sodium borohydride (0.295 g, 7.8 mmol, 3.0 equiv.) in DMF (20 mL) was stirred at 0° C. to rt for 2.5 hr. The reaction was quenched with ice cubes, diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4. filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (320 mg, 30%). MS found for C20H17ClN4O2 (M+H)+: 381.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:5]2=[CH:4][CH:3]=1.[Li][CH3:32]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])([CH3:32])[CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ketone 75-1 (210 mg, 0.497 mmole) in THF was added MeLi (0.466 mL, 1.5 eq, 1.6 M in THF) dropwise, at 0° C. The resulting mixture was stirred at RT overnight, then was heated at 50° C. for 2 hours. After cooling to RT, the reaction mixture was poured in water, extracted with dichloromethane, dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol, followed by a purification by prep HPLC on RP SunFire Prep C18 OBD-10 μm, 30×150 mm, and mobile phase (0.25% NH4HCO3 solution in water, CH3CN) to give 11 mg of the desired compound 75. LCMS m/z=441 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.05 (m, 2H), 1.11-1.22 (m, 2H), 1.17 (s, 6H), 1.43-1.53 (m, 2H), 1.74 (br. s., 1H), 1.79-1.91 (m, 2H), 2.82-3.05 (m, 1H), 4.40 (t, J=7.5 Hz, 2H), 5.39 (s, 2H), 7.11 (d, J=5.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.70 (s, 1H).
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][O:14]CC2C=CC=CC=2)[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.C[Si](I)(C)C.C(N(CC)CC)C>ClCCl.CO>[C:4]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][OH:14])[C:1](=[O:39])[C:2]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOCc2ccccc2)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-benzyloxy-4-aza-octane (9.5 g, 17.1 mM) and trimethylsilyl iodide (2.7 mL, 10% excess) in dry dichloromethane is stirred overnight at room temperature under nitrogen. Triethylamine (3 g) is added, and stirring is continued for 1 hour at room temperature. Following the addition of more dichloromethane, the reaction mixture is washed with 1N HCL (twice), aqueous NaHSO3 (twice), brine (twice), and dried (Na2SO4). The solvents are removed by evaporation to yield an oil. This oil is dissolved in methanol and 1 mL of a 9N solution of HCL in methanol is added. The mixture is evaporated and stripped twice with CCl4 to provide an oil, which upon scratching with ether/petroleum ether yields 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane as slightly violet crystals: 6.8 g (85%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@@H]2CCCC[C@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)c(F)c2)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@@H]2CCCC[C@H]2c2cn[nH]c2)cc1F
Yield: 86 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (62.2 mg, 0.0988 mmol) prepared in Example 169d, triethylsilane (0.080 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound (37.0 mg, 85%) as a colorless solid.