Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:35])=[C:8]([CH:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:14][CH:13]2[C:32](O)=[O:33])[CH:9]=[CH:10][CH:11]=1.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[NH:41][C:40]2=[O:47]>C(N(CC)CC)C>[O:46]=[C:42]1[C:43]2[C:39](=[CH:38][C:37]([NH:36][C:32]([CH:13]3[CH:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=4[F:35])[C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])[NH:14]3)=[O:33])=[CH:45][CH:44]=2)[C:40](=[O:47])[NH:41]1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc3c(c2)C(=O)NC3=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of thionyl chloride (2 mL), rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (110 mg, 0.24 mmol) was added and the mixture was stirred at rt for 2 hrs. The excess thionyl chloride was removed and the residue was dissolved in methylene chloride (5 mL) and 5-amino-isoindole-1,3-dione (Aldrich, 0.30 mmol) was added followed by the addition of triethylamine (0.2 mL). The mixture was stirred overnight. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a pale yellow solid. 10 mg.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].[Cl:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[CH:21][C:20](F)=[CH:19][C:18]=2[F:25])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1>CS(C)=O.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([C:17]2[C:18]([F:25])=[CH:19][C:20]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:21][C:22]=2[F:23])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1
Reactant: CN(C#N)c1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NCC(F)(F)F)n1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(N(C)C#N)nc2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) in 2 mL of dimethylsulfoxide is added 3-dimethylamino-1-propanol (27 μL, 0.23 mmol). The mixture is then stirred at room temperature for 1 h. 4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide (60 mg, 0.152 mmol) is then added, and the reaction mixture is heated at 60° C. for 4 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate to methyl alcohol. Concentration provides 4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide as a light yellow semisolid solid (20 mg). MS: m/z 479.3(M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[N:24]=1>>[C:29]([C:25]1[N:26]=[C:27]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:28]=[CH:23][N:24]=1)#[N:30]
Reactant: N#Cc1nccc(Cl)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(C#N)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (113 mg, 0.36 mmol) and 4-chloropyrimidine-2-carbonitrile (51 mg, 0.36 mmol) as starting materials.
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Yield: 73 %

Procedure:
A solution of ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (0.50 g, 2.05 mmol), trimethyl orthoformate (0.25 mL, 2.28 mmol) and p-toluenesulfonic acid monohydrate (10 mg) in methanol (10 mL) was subjected to microwave irradiation for 10 minutes at 90° C. (30 psi). The solvent was removed in vacuo and the residue was suspended in dichloromethane. The solid was collected by filtration, washed with saturated sodium bicarbonate and water, and dried to afford the title compound in 73% yield (0.38 g): 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 4.32 (q J=6.9 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); MS (ES+) m/z 255.2 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 86.7 %

Procedure:
1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1) (50.0 g, 128 mmol) was dissolved in N,N-dimethylformamide (120 ml) at room temperature and cooled in an ice bath. To this solution was added ammonium acetate (20.0 g, 260 mmol), the ice bath was removed, and the mixture was stirred at room temperature for 21.5 hours. Since the remainder of the starting material was confirmed by thin layer chromatography (TLC), the reaction mixture was cooled in an ice bath, and ammonium acetate (5.0 g, 65 mmol) was added. Then, the ice bath was removed, the reaction mixture was stirred at room temperature for 3 hours, and the disappearance of the starting material was confirmed by TLC. The reaction container was cooled in an ice bath, water (600 ml) was added slowly, and the ice bath was removed. The mixture was extracted 5 times with diethyl ether (400 ml) at room temperature. The combined organic layer was washed with 15% brine (100 ml), dried over magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient; ethyl acetate:n-hexane=40:60→68:32) to give 2,3,4,6-tetra-O-acetyl-D-glucopyranose (2) (38.5 g, 111 mmol, yield 86%) as a colorless transparent oil. As a result of 1H-NMR analysis, it was a mixture of α form:β form at a ratio of about 3:2.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3]1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([N:7]1[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3][C@H:2]1[CH3:1])(=[O:34])=[O:33])(=[O:25])=[O:24]
Reactant: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N(S(=O)(=O)c3ccccc3S(C)(=O)=O)[C@@H](C)C2)c1C

Procedure:
The title compound was prepared from the product of step (i) (0.503 mmol) and 2-methanesulphonylbenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 6 mg
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(=O)([O-])O.[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:22](=[O:23])[CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cc1cccs1
Yield: 80 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 10 ml of tetrahydrofuran and 5 ml of 1N-sodium hydrogen carbonate, which is previously stirred under ice-cooling, is added dropwise a solution of 0.32 ml of 2-thienyl acetyl chloride in 10 ml of tetrahydrofuran. To the mixture, after being stirred for 10 minutes, are added 100 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium chloride, followed by stirring, and the organic layer is separated. The aqueous layer is subjected to extraction with 30 ml of ethyl acetate, and the extract is combined with the organic layer. The whole organic layer is washed with a saturated aqueous solution of sodium chloride (20 ml×2), dried and concentrated under reduced pressure. To the residue is added 4 ml of a mixed solution (ethyl acetate:hexane=1:2), and the resulting crystals are collected by filtration and dried to afford 430 mg (80%) of cis-3 -(2-thienylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1

Procedure:
tert-Butyl 4-(3-(5-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (1.24 g, 3.26 mmol) from Step 4 was dissolved in CH2Cl2 (10 mL) and treated with HCl in dioxane (3.26 mL, 4.0 M, 13 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (1.48 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:10]([O-:16])[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O.O>CN(C)C=O>[CH3:23][N+:10]([O-:16])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccncc1[NH+]([O-])n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[N+]([O-])(c1cnccc1[N+](=O)[O-])n1cccc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A solution of 4-nitro-N-(1H-pyrrol-1-yl)-3-pyridinamine-N-oxide (3.9 g) in 50 ml of dimethylformamide was added to a cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, washed with hexanes) in 5 ml of dimethylformamide. After the anion formation, a solution of dimethyl sulfate (2.7 g) in 5 ml of dimethylformamide was added. After stirring twenty hours at ambient temperature, the reaction mixture was stirred with water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 4.5 g of oil. This oil was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 4 g of solid, mp 135°-140°. This material was purified by HPLC (silica, 20% ethyl acetate in dichloromethane) to give 3.5 g of solid, mp 140°-144°. This material was recrystallized from absolute ethanol to give 2.1 g of needles, mp 150°-151°.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:52]O)[CH2:50][OH:51])C1C=CC=CC=1.O.[C:55]1([CH3:65])[CH:60]=[CH:59][C:58](S(O)(=O)=O)=[CH:57][CH:56]=1>ClCCl>[CH2:65]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:50][OH:51])[CH2:52][O:31]2)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1i (2.49 g, 3.37 mmol) in dichloromethane (300 mL) was added p-toluenesulfonic acid monohydrate (0.32 g, 1.69 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and quenched with 30 mL of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=7/1 to give the title compound 1j as pale yellow oil (1.06 g, 44.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.45 (d, 1H), 7.40 (m, 12H), 7.30 (m, 3H), 7.09 (m, 2H), 6.91 (m, 2H), 6.78 (m, 2H), 4.88 (m, 3H), 4.78 (d, 1H), 4.29 (m, 2H), 4.11-3.96 (m, 6H), 3.88 (d, 1H), 3.80 (m, 2H), 3.71 (m, 2H), 1.85 (t, 1H), 1.41 (t, 3H).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C>[CH2:20]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[CH3:21]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
A mixture of 25.0 g (137 mmol) methyl vanillate, 38.87 g (274 mmol) potassium carbonate, 500 ml DMF, and 16.5 ml (206 mmol) ethyl iodide was heated to 100° C. under N2. At 2.5 hours, cooled and removed solids. Stripped solvent, and partitioned between water and methylene chloride. Stripped solvent and dried in vacuo, giving 25.85 g of white solid: mass spectrum (EI m/e): M=210.0.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COCCCCN
Solvent: CCN(CC)CC
Product: COCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybutylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-])=O)[C:15]=2[OH:24])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:24])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-[3-(4-morpholinyl)propyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.01 g) was reduced with hydrogen and 10% Pd/C (250 mg). The crude product (890 mg) was carried onto the next step without purification. 1H NMR (MeOD-d4): δ 6.86 (m, 2H), 3.87 (m, 4H), 3.15 (m, 6H), 2.98 (t, 2H), 1.92 (m, 2H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][Si:2]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])[CH3:3]
Reactant: OCc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (1.9 ml, 15 mmol) was added dropwise to a stirred solution of 4-bromobenzyl alcohol (2.0 g, 11 mmol) in toluene (25 ml) and pyridine (2 ml) at 0° C. The stirred mixture was heated to ambient temperature during 3 hours. The reaction mixture was filtered and the organic solution evaporated to yield pure 4-bromobenzyl trimethylsilyl ether. The silyl ether can be further purified by distillation (b.p. 73° C., 0.1 mm Hg). Yield after distillation: 1.49 g (50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:54]CC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:54])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O)cc2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-1(5,6-dihydro-5,5- dimethyl-8-(4-.((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1)50.0 mg (0.095 mmol) in 1.0 ml of THF at room temperature was added 73.2 mg (0.29 ml, 0.29 mmol) of tetrabutylamonium fluoride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.3 Hz), 7.41-7.20 (5H, m), 6.88 (2H, d, J=8.4 Hz), 5.96 (1H, t, J=4.5 Hz), 4.37 (2H, q, J=7.1 Hz), 2.34 (2H, d, J=4.5 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:22]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (14.3 g, 0.17 mol) in dry THF (150 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (38.0 mL, 2.5 M, 95.0 mmol) was then added dropwise over a course of 40 minutes. After addition, the reaction mixture was stirred at −78° C. for additional 2 hours, before a solution of n-C12H25Br (16.9 g, 67.8 mmol) in dry THF (25 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction was quenched by water (20 mL) and the mixture was poured into water (400 mL), and the resulting mixture was extracted with ether (400 mL). The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as eluent, leading to a colorless oil as the product. (8.68 g, 50.7%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[C:38]([CH2:40][CH2:41][N:42]([CH3:52])[C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)#[N:39]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:42]([CH2:41][CH2:40][C:38]#[N:39])[CH3:52])=[O:51])[CH2:46][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 16d) in an analogous manner as described in example 25. LR-MS: 748.3 [(M+H)+]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:31][CH3:32])[CH:37]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (144 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (297 mg, 97%) in an orange oily form.