Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:23][CH:24](C)C)[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=2[O:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:8].Cl[CH2:35]Cl>>[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:35])=[CH:17][C:12]=2[O:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Reactant: ClCCl
Agent: ClB(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(OC)cc12
Reaction time: 20 h
Yield: 100 %

Procedure:
Preparation of compound 29(a) (2-(4-fluoro-phenyl)-5-hydroxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide). Boron trichloride (60 mL of 1M dichloromethane) was added for 10 minutes to 2-(4-fluoro-phenyl)-5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (7.10 g, 16.9 mmol, which can be prepared according to one of the procedures described in Example 21), in dichloromethane (200 mL). The mixture was stirred for 20 hours, and then carefully quenched with 1N HCl (10 mL). An additional amount of 4N HCl (100 mL) was added, and the reaction mixture was stirred for 24 hours. The precipitated solid was filtered off, washed with water, dried, and triturated with ethyl acetate/hexanes to provide 6.39 g (100%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](/[Cl:25])\[C:18]([O:20]C(C)(C)C)=[O:19])=[C:13]([O:26][CH3:27])[C:12]([CH3:28])=[C:11]2[C:7]=1[C:8](=[O:29])[O:9][CH2:10]2)(=[O:4])=[O:3]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](/[Cl:25])\[C:18]([OH:20])=[O:19])=[C:13]([O:26][CH3:27])[C:12]([CH3:28])=[C:11]2[C:7]=1[C:8](=[O:29])[O:9][CH2:10]2)(=[O:3])=[O:4]
Reactant: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)C(=O)OC(C)(C)C)C(=O)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
t-Butyl (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-chlorobut-2-enoate (2.7 g) was dissolved in freshly distilled trifluoroacetic acid (25 ml) and stirred at room temperature for 90 minutes. The mixture was diluted with CH2Cl2 (25 ml) and evaporated to dryness and repeated until a cream solid was obtained. The solid was recrystallized from a 4:1 mixture of hexanes-CH2CH2 (25 ml) affording 2.11 g of (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-2-chlorobut-2-enoic acid as white crystals, mp 200°-203° (d).
Reaction SMILES: [NH:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:2]([NH:1][C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(=O)Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 30.8 %

Procedure:
1-[1-(4-Acetaminophenethyl)piperidin-4-yl]indoline (135 mg) was dissolved in tetrahydrofuran (5 ml). After adding lithium aluminum hydride (28 mg) at room temperature, the resultant mixture was heated under reflux for 2 hr. After adding water, the reaction solution was extracted with ethyl acetate. Then the organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (40 mg) as an oil.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1O
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 1.22 g (4.49 mmol) of 4-hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 20 mL of phosphorous oxychloride is heated at reflux temperature for 3 hours, then cooled to room temperature. The solid is collected by filtration, then washed with hexane followed by water. The solid is dried to give 947 mg (73%) of a dark brown solid, mp softens at 270° C.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[CH3:18][C@H:19]([NH:22][C:23](=[S:41])[C@H:24]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][OH:21]>C(#N)C>[CH3:18][C@H:19]([NH:22][C:23](=[S:41])[C@H:24]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][O:21][N+:6]([O-:8])=[O:7]
Reactant: O=[N+]=O
Reactant: C[C@@H](CO)NC(=S)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H](CO[N+](=O)[O-])NC(=S)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
In 25 ml of dry acetonitrile were dissolved 1.24 g of nitronium tetrafluoroboron (85% content), 1.12 g of 2,4,6-collidine was added thereto with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Then, a solution obtained by dissolving 2.5 g of N-[(1S)-1-methyl-2-hydroxyethyl]-(2R)-2-t-butoxycarbonylamino-3-t-butoxycarbonylthiopropanamide in 25 ml of dry acetonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the thus obtained residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (4:1) as an eluent to obtain 1.39 g of the desired compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]([F:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH2:17]([C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=[CH:21][C:20]=1[F:34])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[CH2:17]([C:19]1[C:20]([F:34])=[CH:21][N:22]=[CH:23][C:24]=1[C:2]1[C:3]([F:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2)[CH3:18]
Reactant: CCc1c(F)cncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc2n1-c1ccc(Br)c(F)c1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(F)cncc1-c1ccc2c(c1F)CCc1nnc(C)n1-2
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-6-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (146-7; 0.2 g, 0.00704 mol) and 4-ethyl-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.21 g, 0.0084 mol) in the mixture of 1,4-dioxan (5 mL) and water (5 mL) was added sodium carbonate (0.186 g, 0.0176 mol). Reaction mass was purged with argon for the next 20 min. Catalyst Pd(dppf)2Cl2.dichloromethane (0.28 g, 0.00352 mol) was added and again purged with argon for 10 min and allowed to stir at 100° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography followed by preparative HPLC (analytical conditions: column: ZORBAX XDB (150 mm×4.6 mm×3.5 μm), mobile phase (A): water, mobile phase (B): methanol, flow rate: 1.0 mL/min, gradient T/% B:0/20,8/70,25/70,27/20,30/20) to obtain title compound. 1H NMR (400 MHz, CDCl3-d6) δ 8.451 (s, 1H), 8.238 (s, 1H), 7.427-7.406 (d, J=8.4 Hz, 1H), 7.297-7.278 (d, J=7.6 Hz, 1H), 3.219-3.184 (t, J=6.4 Hz, 2H), 3.132-3.097 (t, J=7.6 Hz, 2H), 2.812 (s, 3H), 2.604-2.586 (d, J=7.2 Hz, 2H), 1.130-1.093 (t, J=7.6 Hz, 3H). MS (M+1): 327.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:20](C(C(C)C)C)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=4)[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:20]([N:12]([CH:11]([CH3:20])[CH3:8])[CH3:13])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=4)[N:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nc(C)c4c3)c(C(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1n[nH]c2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.3 %

Procedure:
To a solution of methyl 2-(3-methyl-1H-indazol-5-yl)-3-(3-methylbutan-2-yl)quinoxaline-6-carboxylate (85 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (18 mg, 0.45 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 6 with 3N HCl and filtered to give 2-(3-methyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (50.1 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)C2CCC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)C1CCC1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-cyclobutyl-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give 5-[3-(4-bromo-phenyl)-3-cyclobutyl-propionyl]-1H-pyridin-2-one as a light yellow oil, which was directly subjected to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](O)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:46][C:47]([F:53])([F:52])[S:48]([NH2:51])(=[O:50])=[O:49]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH:51][S:48]([C:47]([F:53])([F:52])[F:46])(=[O:50])=[O:49])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NS(=O)(=O)C(F)(F)F)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 47 mg (0.10 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in DMF (4 mL) was added 64 mg (0.34 mmol) of EDC, 48 mg (0.36 mmol) of HOBt, and a catalytic amount of DMAP. After 30 min, 45.5 mg (0.30 mmol) of trifluoromethanesulfonamide was added. The resulting light yellow solution was stirred at room temperature for 3 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 50% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)O)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C(OC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[Cl:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)C(O)c1ccc(Cc2cccnc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(C)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 86 %

Procedure:
In 4.6 ml of methylene chloride was dissolved 910 mg of 3-[p-(3-acetoxy-1-hydroxy-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 0.48 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for one hour. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of methyl acetate and 10 ml of water, after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (5:1 by volume)] to obtain 740 mg (yield 86.0%) of colorless, oily 3-[p-(3-acetoxy-1-chloro-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[O:20].N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>O>[OH2:20].[OH2:20].[CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[S:29]
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=S)Nc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
A solution of 2.0 g (7.2 mmol) 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 35 ml. pyridine is heated for about 5 hours to 100° C. with 4 g. phosphorus pentasulphide (P4S10). Subsequently, the reaction mixture is decomposed with water, rendered alkaline and the desired product is extracted and purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). Yield: 1.7 g. (72% of theory); m.p. 205°-220° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:62][N:63]1[C:67]([NH2:68])=[CH:66][CH:65]=[N:64]1>CN(C=O)C>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:68][C:67]4[N:63]([CH3:62])[N:64]=[CH:65][CH:66]=4)=[O:19])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2]
Reactant: Cn1nccc1N
Reactant: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)Nc2ccnn2C)cc1C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
To a solution of 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (0.60 g, 1.521 mmol, Preparation # V.1) and DIEA (0.80 mL, 4.56 mmol), in DMF was added HATU (0.64 g, 1.67 mmol). The reaction mixture was stirred for about 30 min and 1-methyl-1H-pyrazol-5-amine (0.22 g, 2.28 mmol, Aldrich) was added. The reaction mixture stirred for about 5 h and was concentrated under reduced pressure. The residue was dissolved in DCM (15 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (Table 2, Method e), to afford 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide (0.30 g, 0.64 mmol, 42%) as a white solid. LC-MS (Table 1, Method g) Rt=2.01 min, m/z 474 (M+H)+; 1H NMR (DMSO-d6) δ 10.11 (s, 1H), 8.52-8.48 (m, 1H), 7.87-7.81 (m, 1H), 7.76-7.70 (m, 2H), 7.62 (dd, J=8.1, 1.8 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.24-7.18 (m, 1H), 6.89 (s, 1H), 6.19 (d, J=1.9 Hz, 1H), 5.83 (d, J=4.6 Hz, 1H), 4.31-4.00 (m, 2H), 3.76-3.68 (m, 1H), 3.65 (s, 3H), 3.06-2.95 (m, 1H), 2.77-2.62 (m, 2H), 2.60 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])([CH3:9])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)([Cl:18])=O>ClCCCl>[CH2:1]([Si:7]([CH3:10])([CH3:9])[Cl:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Si](C)(C)O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCC[Si](C)(C)Cl
Yield: 91.1 %

Procedure:
To the same reactor as used in Example 1 were added 40.1 g (0.25 mole) of hexyldimethylsilanol, 160 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 40.7 g of hexyldimethylchlorosilane.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1(Br)[CH2:16][CH2:15]1.C(Cl)Cl>CN(C)C=O.O>[CH:14]1([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)[CH2:16][CH2:15]1
Reactant: O=Cc1cn[nH]c1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnn(C2CC2)c1
Temperature: 130 °C

Procedure:
Dissolve 1H-pyrazole-4-carboxaldehyde in N,N-dimethylformamide (1.9 mL). Add potassium carbonate (0.539 g, 3.90 mmol) and cyclopropylbromide (0.346 g, 2.86 mmol). Heat in a pressure tube to 130° C. for 18 hr. Cool to ambient temperature and add DCM and water. Separate layers and extract water layer 3 times with DCM. Wash combined DCM layers with brine, dry (magnesium sulfate), filter, and concentrated to give the free base of the title preparation. GC-MS: m/z=136 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[SH:27].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:27][C:19]2[S:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: Sc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Sc2nc3ccccc3s2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A charge of 269.1 g (1.00 mol) of 2,5-dichloro-4′-fluorobenzophenone, 175.6 g (1.05 mol) of 2-benzothiazolethiol, 152.0 g (1.10 mol) of potassium carbonate and 1.5 L of dehydrated N,N′-dimethylacetamide was weighed into a 3 L three-neck flask equipped with a stirrer, a thermometer, a cooling tube and a nitrogen gas introducing tube. The reaction solution was heated under nitrogen atmosphere to 110° C. for 2 hours using an oil bath. After the disappearance of raw materials was confirmed by thin layer chromatography, the reaction solution was left to cool to room temperature. The reaction solution was then gradually added to 3 L of water to coagulate a product, which was filtered. The product obtained by filtration was dissolved in 4 L of toluene. The organic layer was washed with brine until an aqueous layer became neutral. After the organic layer was dried over magnesium sulfate, the solvent was removed by an evaporator. A crude yield was 350.3 g. A 1.5 L aliquot of toluene heated to 80° C. was used for recrystallization to yield 325.4 g (0.782 mol) of a purified product in 78.2% yield.
Reaction SMILES: [H-].[Na+].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5].[C:12](=[O:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)OC1C=CC=CC=1.Cl>CN(C)C=O>[O:20]([C:12]([NH:5][C:4]1[N:6]=[C:7]([NH:8][C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[N:9]=[C:10]([NH:11][C:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])[N:3]=1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(N)nc(N)n1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc(NC(=O)Oc2ccccc2)nc(NC(=O)Oc2ccccc2)n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
1 g of 95% sodium hydride was placed in a two-neck flask equipped with a magnetic stirring bar, a reflux condenser with an argon inlet and a rubber septum. To it was added 40 ml of dimethylformamide (DMF) followed by 1.26 g of melamine. The contents were stirred at room temperature for 15 minutes and then 8.56 g of diphenyl carbonate was added to the flask. The reaction mixture was stirred at room temperature for 4 hours and then poured, with stirring, into 500 ml of 5% aq HCl. A white precipitate was formed which was filtered, washed with water, and dried under reduced pressure to give 4.4 g of crude 2,4,6-tris-phenoxycarbonylamino-1,3,5-triazine. The structure was confirmed by thin layer chromatography (TLC), 1H NMR and mass spectroscopy.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33]([O:35]CC)=O)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:46][NH2:47]>CO>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:32][C:33]([NH:46][NH2:47])=[O:35])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Solvent: CO
Solvent: O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)NN)Cc1ccccc1)C(C)C

Procedure:
100 mg (0.164 mmol) of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate were stirred at room temperature for 3 hours in a solution of 30% hydrazine hydrate in methanol. Thereafter, the reaction mixture was evaporated and the residue was chromatographed on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Crystallization of the crude product from methanol/methylene chloride/ether yielded (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]4-phenylbutyrohydrazide as white crystals, melting point 109°.