Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+:3].[Na].O.[CH3:6][O:7][Si:8]([O:13]C)([O:11][CH3:12])[O:9][CH3:10]>CO>[CH3:6][O:7][Si:8]([O:11][CH3:12])([O:9][CH3:10])[O-:13].[Na+:3]
Reactant: CO[Si](OC)(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CO[Si]([O-])(OC)OC
Yield: 96.4 %

Procedure:
A solution of 81 gm (1.5 mol) of sodium methylate in methanol, prepared by reacting 34.0 gm (1.5 mol) of sodium with 500 ml methanol, was mixed with 27.0 gm (1.5 mol) of water and subsequently with 1000 gm (6.6 mols) of tetramethoxy-silane. The mixture was heated for about 15 minutes under reflux. Then methanol and excess tetramethoxy-silane were distilled off under water jet-vacuum. 231.5 gm of sodium trimethoxy-silanolate were obtained. Theoretically 240.3 gm (1.5 mol) of this compound should have been formed.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:3][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1
Reactant: Cc1ccccc1CN(C)CC(O)c1ccc2ccccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1CN(C)CC2c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 62 %

Procedure:
The product from Step A (1.25 g, 4.1 mmol) was dissolved in trifluoroacetic acid (TFA, 7.5 mL), then trifluoroacetic anhydride (TFAA, 7.5 mL) was added. After stirring for 24 h, the solvents were removed in vacuo, the residue was dissolved in MeOH, and the solvent was removed in vacuo. The residue was dissolved in aqueous NH4OH, then extracted twice with CH2Cl2. The extract was dried over Na2SO4, filtered, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (40 g) eluting with 5% to 30% EtOAc/hexanes with 1% Et3N to give 2,8-dimethyl-4-naphthalen-2-yl-1,2,3,4-tetrahydroisoquinoline (0.73 g, 61%) as a clear, dark yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.88 (m, 4H), 7.38-7.48 (m, 2 H), 7.26 (dd, J=8.3, 1.6 Hz, 1 H), 6.93-7.04 (m, 2 H), 6.74 (d, J=7.2 Hz, 1 H), 4.45 (t, J=6.9 Hz, 1 H), 3.75 (d, J=15.4 Hz, 1 H), 3.51 (d, J=15.4 Hz, 1 H), 3.06 (ddd, J=11.2, 5.6, 0.9 Hz, 1 H), 2.67 (ddd, J=11.4, 8.5 Hz, 1 H), 2.48 (s, 3 H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24]C)[CH:20]=4)[C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.[OH-].[Na+]>Br>[CH3:1][N:2]([CH3:28])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)c(F)c1)C2=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1
Temperature: 100 °C

Procedure:
A mixture of 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (9.3 g) and hydrogen bromide (48% strength in water; 140 mL) was heated at 100° C. for 12 hours. The cooled reaction solution was adjusted to pH 10 with sodium hydroxide solution (4N). The precipitate was filtered off with suction, washed with water until neutral and dried. The product with the molecular weight of 369.44 (C21H24FN3O2) was obtained in this way; MS (ESI): 370 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])[CH:8]([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:24])=[O:5])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(C)C(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.250 g (0.700 mmol) of the product of Example 5 in 1.0 mL of dichloromethane was added 0.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of ethyl acetate/hexanes (1:3) to (1:1) to provide 0.211 g (100%) of the carboxylic acid as a colorless oil. Electrospray Mass Spec 300.0 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C@H:9]([C:11](=[O:26])[NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:25])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6](=[O:27])[N:7]([C@H:9]([C:11](=[O:26])[NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:14]1=[O:25])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: BrCc1cccc2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2N(Cc2cccc3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Reaction time: 36 h
Yield: 83.8 %

Procedure:
To a solution of (S)-1-((R)-9-amino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylcarbamoyl)-ethyl-methyl-carbamic acid tert-butyl ester (1.5 g, 3.9 mmol) in DMF (25 mL) was added K2CO3 (2.6 g, 19.0 mmol) and 1-bromomethyl-naphthalene (631 mg, 2.9 mmol) in DMF (10 mL) was added dropwise. After 36 h, the mixture was diluted with sat. aq. citric acid and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.3 g, 81%).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:3]3[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc3[nH]ncc3c2)[nH]c1=O
Temperature: 80 °C
Yield: 88 %

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (358 mg, 1.671 mmol) and 1H-indazol-5-amine (222 mg, 1.671 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (HGN-0042) (441 mg, 88% yield).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](OC)=[O:16]>C1COCC1>[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(F)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(F)C(=O)CP(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
Dimethyl methylphosphonate (8.38 g) was dissolved in dry THF (250 ml) and cooled to -78° C. n-Butyllithium (1.6-M, 42 ml) was added dropwise, and the reaction was stirred for 10 minutes. The above methyl fluorocaproate (200 g) in THF (10 ml) was added dropwise. After addition, the mixture was stirred at -78° C. for 45 minutes, and then at room temperature for additional 45 minutes. The crude product obtained after the conventional work-up was chromatographed (hexane/ethyl acetate=1/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:34]C(=O)C)=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:34])=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Yield: 68.4 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline (0.060 g, 0.110 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.037 g, 0.0752 mmol, 68%).
Reaction SMILES: [CH3:1][N:2]([CH2:34][C@H:35]([OH:44])[C@@H:36]([OH:43])[C@H:37]([OH:42])[C@H:38]([OH:41])[CH2:39][OH:40])[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=4)=[C:22]([CH3:32])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:54](OCC)(=[O:56])C>ClCCl>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([N:2]([CH2:34][C@@H:35]([C@@H:36]5[C@@H:37]([C@H:38]([OH:41])[CH2:39][OH:40])[O:42][C:54](=[O:56])[O:43]5)[OH:44])[CH3:1])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:33])=[CH:21][C:22]=2[CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@H]4OC(=O)O[C@@H]4[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-amide of Example 5 (0.190 g, 0.315 mmol), and N,N-diisopropylethylamine (0.110 mL, 0.315 mmol) were dissolved in anhydrous dichloromethane (6.3 mL) and the solution cooled to 0° C. N,N′-Carbonyldiimidazole (0.051 g, 0.315 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirring continued for 12 hours. The solution was diluted with ethyl acetate and washed with water, 0.1 N hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue by flash column chromatography on silica gel eluting with ethyl acetate, afforded 0.140 g of the title compound as a white, partially crystalline solid, m.p. 166-175° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([N:29]=[CH:30][C:31]([S:35][CH2:36][CH:37]=O)=[N:32]2)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:10][CH2:9][N:8]([CH2:37][CH2:36][S:35][C:31]2[CH:30]=[N:29][C:28]3[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[N:32]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc2ncc(SCC=O)nc2c1
Reactant: CCOC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Product: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
The title compound is prepared as an off-white solid (232 mg, 70% yield) following Scheme 3 and in analogy to Example 35 using (3S,4R)-4-benzyloxycarbonylamino-piperidine-3-carboxylic acid ethyl ester (200 mg, 0.63 mmol, 1.0 eq) (prepared according to procedures described in WO2005/066176) and (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (158 mg, 0.63 mmol 1.0 eq) as starting materials.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CO.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1ncnc2[nH]cnc12
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 20 mL of a 40% methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120° C. for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90%) of methyl-(9H-purin-6-yl)amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=O.C1(C)C(C)=CC=CC=1.[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CO>[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:5](=[O:7])[C:4]3[CH:9]=[C:10]([Cl:17])[C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:12][C:3]=3[O:2][CH3:1])[CH2:35][CH2:34]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: NC1CCN(CC2CCCCC2)CC1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Yield: 64 %

Procedure:
A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1-cyclohexylmethyl-4-aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2 N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 2, m.p. 219°-221° C.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCCCC1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g), 1-[5-fluoro-2-(piperidin-1-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (1.58 g) and potassium carbonate (1.76 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.75 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]([CH3:24])[CH3:23])[S:14]1(=[O:26])=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[CH3:27][NH2:28]>>[Cl:12][C:7]1[CH:6]=[C:5]([C@H:4]([N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH3:23])[CH3:24])[S:14]2(=[O:25])=[O:26])[CH2:3][CH2:2][NH:28][CH3:27])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: CN
Reactant: CC(C)N1c2ccccc2N([C@H](CCCl)c2cc(F)cc(Cl)c2)S1(=O)=O
Product: CNCC[C@H](c1cc(F)cc(Cl)c1)N1c2ccccc2N(C(C)C)S1(=O)=O
Yield: 70 %

Procedure:
1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.75 g, 4.19 mmol) and ethanolic solution of methylamine (33% in ethanol, 30 mL) was heated at 85° C for 4 hours with stirring in a sealed reaction vessel. Upon cooling, all volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (50 mL), washed with aqueous potassium carbonate (20 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion column chromatography (silica gel, 0-15% methanol/dichloromethane, with 0.5% triethylamine additive) gave 1.22 g (70%) of (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothia diazol-1(3H)-yl)-N-methylpropan-1-amine as a white foam, which was dissolved in dichloromethane (20 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 3.3 mL, 3.3 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride as a white powder. MS (ES) m/z 411.9 ([M+H]30 ); HRMS: calculated for C19H23CIFN3O2S+H+, 412.1256; found (ESI, [M+H]30), 412.1266.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([OH:28])[CH2:4]1)[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:28][CH:5]1[CH2:6][CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH:3]([CH2:1][CH3:2])[CH2:4]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Solvent: ClCCl
Product: CCC1CC(OS(C)(=O)=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of the scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.5 g, 1.245 mmol) and TEA (0.347 mL, 2.49 mmol) in DCM (13 mL) was added MsCl (0.107 mL, 1.37 mmol) dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography using 10 to 70% EtOAc in DCM to yield 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.48 g, 80%) as a white amorphous solid. LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 480 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:25][CH2:26][CH:27]3[CH2:29][CH2:28]3)=[N:10][CH:11]=[C:12]([CH:24]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:22]\[OH:23])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:25][CH2:26][CH:27]3[CH2:28][CH2:29]3)=[N:10][CH:11]=[C:12]([CH:24]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:22]\[O:23][CH2:34][C:33]([F:44])([F:43])[F:32])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCCC/C1=N\O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCCC/C1=N\OCC(F)(F)F)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To a solution of 0.100 g 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-{(S)-2-[(E)-hydroxyimino]-cyclohexyl}-nicotinamide in 1.0 ml dimethylformamide was added 0.012 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added 0.037 ml (0.062 g, 1.1 equivalents) 2,2,2-trifluoroethyl-trifluoro-methanesulfonate and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.040 g of the title compound as light yellow oil. MS (EI): 496.3 (M+H).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C(Cl)Cl>[N:20]1([C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCCNCC1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Yield: 93.5 %

Procedure:
Benzyl (2R)-2-carboxymethyl-4-methylvalerate (1.35 g), hexahydro-1H-azepine (0.610 g) and WSCD.HCl (1.18 g) were reacted in methylene chloride (30 ml) in a similar manner to that of Preparation 1-1) to give benzyl (2R)-2-(hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvalerate (1.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2O)=[CH:5][CH:4]=1.[ClH:14]>>[Cl:14][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: Cl
Reactant: COc1ccc2c(c1)C(O)CCC2
Product: COc1ccc2c(c1)C(Cl)CCC2

Procedure:
35.6 g (0.2 mol) of 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (D. G. Thomas, A. H. Nathan J. Am. Chem. Soc. 79, 331, 1948) are stirred at ambient temperature for 3 hours in a liter of concentrated hydrochloric acid.
Reaction SMILES: [NH3:1].CO.[I:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]=2[CH:22]=1>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]2[CH:22]=[C:5]([I:4])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: N
Reactant: S=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc(I)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
60 ml of 25% aqueous ammonia solution and 30 ml of methanol were added to a suspension of 3.0 g of 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 200 ml of tetrahydrofuran. The mixture was stirred at room temperature for 16 h., with the solution which formed being concentrated to about 50 ml in a vacuum. The crystals were filtered off, washed with water, dried, stirred in 25 ml of dioxan at 100° C., cooled and filtered off. There were obtained 2.35 g of 2-amino-7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine of m.p. 228-229° C.