Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=[O:10])[CH2:3][CH2:2]2.[BH4-].[Na+].O>CO>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CCN2CCCC1C2
Temperature: -10 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
1-Aza-bicyclo[3.3.1]nonan-4-one (11.92 g, 85.6 mmol) is dissolved in 160 ml MeOH and cooled to −10° C. NaBH4 (1.69 g, 42.9 mmol)) is added portionwise so that the inner temperature does not exceed 0° C. The reaction mixture is stirred at −10° C. for 1 h. Water is added and the solvents are evaporated. The remaining solid is dissolved in MTBE/MeOH, filtered over hyflo and the filtrate is evaporated to give 19.28 g of crude product which is purified by chromatography over aluminum oxide (400 g, eluent: MTBE/MeOH 95:5 to 80:20) to give 10.96 g (91%) (4SR,5RS)-1-aza-bicyclo[3.3.1]nonan-4-ol.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl[C:12]([O:14][CH2:15][Cl:16])=[O:13].C(N(CC)CC)C>O1CCCC1>[C:12](=[O:13])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[O:14][CH2:15][Cl:16]
Reactant: O=C(Cl)OCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCCl)Oc1ccc([N+](=O)[O-])cc1
Yield: 94.2 %

Procedure:
p-Nitrophenol (100 g, 0.72 moles) was dissolved in anhydrous tetrahydrofuran (3 L) and stirred vigorously. To this solution was added chloromethyl chloroformate (70 mL, 0.79 moles) at room temperature followed by triethylamine (110 mL). After stirring for 1 hour, the reaction mixture was filtered and the filtrate was concentrated and then diluted with ethyl acetate (1 L). The organic solution was washed with 10% potassium carbonate (3×500 mL) and 1N HCl (2×300 mL), brine (2×300 mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave 157 g (95%) of the title compound (52) as a solid. The compound was unstable to LC-MS. 1H NMR (CDCl3, 400 MHz): 5.86 (s, 2H), 7.44 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: COc1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) and (bromomethyl)cyclohexane (0.20 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.45 g), N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:12])[N:4]([CH3:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: Oc1nc2ccccc2cc1Br
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a solution of 3-bromo-2-hydroxyquinoline (50 mg, 0.223 mmol) in DMF (1 mL) was added methyl iodide (0.017 mL, 0.268 mmol) and potassium carbonate (46.3 mg, 0.335 mmol.) at room temperature. The reaction mixture was stirred for 16 hours at room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water then aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=/1) to give 3-bromo-1-methylquinolin-2(1H)-one (52 mg, MS: 238.1 [M+H+].)
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=O)[CH:8]=1)([O-:3])=[O:2].[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH2:21]([NH:23][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:22]
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reactant: CCN
Solvent: CCO
Product: CCCCCCC(C(=O)NCC)n1cnc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl 2-(4-nitro-1H-imidazol-1-yl)octanoate (17 moles, 5.0 g) and ethylamine (20 ml) were stirred in 150 ml ethanol at room temperature for 16 hours. The reaction was added to ice water, extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The oil crystallized upon standing to yield 3.9 g of N-Ethyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:31]1([CH2:37][S:38][CH:39]([C:43](O)=[O:44])[C:40](O)=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:44][C:43]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[O:15][C:40](=[O:41])[C:39]=1[S:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(C(C)=O)c(OC)c1OC
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(OC)c1OC

Procedure:
The title compound was prepared by Method A using 2',3',4'-trimethoxyacetophenone (1.5 g, 7.13 mmol), lithium bis(trimethylsilyl)amide (1.43 g, 8.56 mmol), chlorotrimethylsilane (1.8 mL, 10.67 mmol) and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH:6]=[CH:7][CH:8]=1.[BrH:21].BrBr.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[Br:21][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=3)[CH:10]=2)[C:14]1=[O:18]
Reactant: Br
Reactant: O=C1CCc2cc(-c3cccc(C(F)(F)F)c3)ccc21
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3cccc(C(F)(F)F)c3)cc2CC1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.79 g of 5-(3-trifluoromethylphenyl)indan-1-one are dissolved in 10 ml of glacial acetic acid. 5.5 μl of a 48% strength solution of hydrobromic acid in water are added and a solution of 0.362 ml of bromine in 5 ml of glacial acetic acid is then slowly added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then poured into a mixture of 50 ml of water with 50 g of ice and 86 mg of sodium hydrogencarbonate. The aqueous suspension is extracted by shaking with 100 ml of dichloromethane, the organic phase is washed three times with 50 ml of water, dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel using toluene/ethyl acetate 25/1. 2-Bromo-5(3-trifluoromethylphenyl)indan-1-one of melting point 96° C. is obtained. 2,2-Dibromo-5-(3-trifluoromethylphenyl)indan-1-one of melting point 210° C. (dec.) is isolated as a by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:9]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.4 %

Procedure:
To a mixture of p-chlorophenol (19.0 g, 147.8 mmol) and tert-butanol (21.9 g, 295.6 mmol) was added concentrated sulfuric acid (15 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into ice water (300 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 95:5) to give the title compound (14.3 g, yield 54%) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:31]I>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=3)(=[O:18])=[O:17])[CH3:31])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
Starting with [(R)-4-(3-fluoro-5-trifluoromethyl-benzene-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared by a method described above for example 1-1) and methyl iodide, using the method analogous to the one described for example 2-1, {(R)-4-[(3-fluoro-5-trifluoro-methyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (500 mg, 94%) was prepared as a white solid. LC-MS cald. for C19H21F4N3O4S 463, obsd. (ESI+) [(M+H)+] 464.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:37]1([Zn])[CH:42]=[CH:41][CH:40]=[CH:39][NH:38]1>C1COCC1.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>[CH:8]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:4]1[CH:5]=[CH:6][C:2]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:3]1)([CH3:10])[CH3:9]
Reactant: [Zn]C1(Br)C=CC=CN1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccccn2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-iodo-1-(triisopropylsilyl)-1H-pyrrole (11.0 g, 2.87 mmol), triphenylphosphine (27 mg, 0.103 mmol), and tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) in THF (20 mL) was degassed with Ar (g) for 15 min, then 2-bromo(pyridin-2-yl)zinc (1.5 mL of 0.5M solution, 5.74 mmol) was added and degassing continued a further 15 min. The reaction was stirred at 70° C. for 5 h and monitored by LC/MS. The reaction mixture was quenched with H2O (40 mL) then extracted with EtOAc (3×25 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:9) to afford 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyridine as a clear oil which was used below without further purification.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:10]([C:20]#[N:21])=[C:9]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([OH:5])[CH:7]=2)[N:12]=[C:11]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:10]=1[C:20]#[N:21]
Reactant: CC(C)Cc1nc2ccc(OC(C)(C)C)cc2c(-c2ccccc2F)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Cc1nc2ccc(O)cc2c(-c2ccccc2F)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 6-tert-butoxy-4-(2-fluorophenyl)-2-isobutylquinoline-3-carbonitrile (0.22 g, 0.58 mmol) in tetrahydrofuran (1 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 4(2-fluorophenyl)-6-hydroxy-2-isobutylquinoline-3-carbonitrile (0.17 g, yield 92%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH3:15].O.NN>C(O)C.[Pd]>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:14][CH3:15])[NH2:9]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1OC
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)cc(OC)c1OC
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 1,2,3-trimethoxy-5-nitrobenzene (6.64 g, 31.2 mmol) in ethanol (250 mL) was added palladium on carbon (10%, 300 mg) and hydrazine hydrate (85%, 5.7 mL). After emission of gas has ceased, the reaction mixture was heated at refluxed for 1 hour, cooling to room temperature, filtered and evaporated to afford the product 3,4,5-trimethoxyaniline as a white solid (5.5 g, yield 96.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.86 (s, 2H), 4.82 (br, 2H), 3.64 (s, 6H), 3.50 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[CH:1]1([CH2:6][C:7]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:12][C:11](=[O:13])[C:10]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([OH:14])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1C=C(O)CC(CC2CCCC2)(c2ccccc2)O1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1OC(CC2CCCC2)(c2ccccc2)CC(O)=C1Cc1ccccc1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 6-cyclopentylmethyl-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (0.300 g, 1.10 mmol), Et3N (0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.10 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2) to provide a solid (0.188 g, 53°-55° C.). 1H NMR (400 MHz, DMSO-d6) δ 10.849 (bs, 1 H), 7.371-7.284 (m, 5 H), 7.040-7.004 (m, 3 H), 6.747-6.724 (m, 2 H), 3.395 (s, 2 H), 3.117 (AB, 2 H, JAB=17.5 Hz), 2.059-1.950 (m, 2 H), 1.652-1.578 (m, 2 H), 1.561-1.289 (m, 5 H), 1.021-0.844 (m, 2 H).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:33]4[C:34]([CH3:47])=[N:35][N:36]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=5)[C:37]=4[CH3:38])=[CH:31][N:30](C(OC(C)(C)C)=O)[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.O1CCOCC1>[CH:27]1([C:26]2[N:25]=[C:24]3[NH:30][CH:31]=[C:32]([C:33]4[C:34]([CH3:47])=[N:35][N:36]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=5)[C:37]=4[CH3:38])[C:23]3=[CH:22][C:21]=2[C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:14]=2)[CH2:28][CH2:29]1
Reactant: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cccc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cccc(F)c5)c4C)c[nH]c3nc2C2CC2)cc1NS(C)(=O)=O
Yield: 18.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (60 mg, 0.078 mmol) was deprotected in HCl in 1,4-dioxane (2 ml). This afforded 8 mg (18.1% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.1-9.0 (b, 1H), 7.679-7.673 (d, 1H), 7.52 (s, 1H), 7.14-7.13 (d, 1H), 6.99-6.96 (m, 3H), 6.85 (m, 2H), 5.28 (s, 3H), 3.93 (s, 3H), 2.99 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 0.89-0.85 (m, 4H). MS: m/z=559.9 (M+1), HPLC: 85.5% in method B.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37].[CH:38](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[NH:33][CH:38]=[N:34][C:29]=3[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1ccc(CC(NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(=O)N2CCc3ccsc3CC2)cc1[N+](=O)[O-]
Reactant: O=CO
Agent: [Pd]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCc3ccsc3CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-6-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1F
Solvent: ClCCl
Product: C[C@@H](O)c1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 336.3 %

Procedure:
An oven dried 500 mL flask, was charged under nitrogen with (S)-2-methyl-CBS-oxazaborolidine 1M in toluene (5.02 mL) and dissolved in CH2Cl2 (250 mL). Me2-BH3 (30 mL, 60.27 mmol) was then added and cooled to −30° C. and reaction stirred for 15 minutes. (1-(4-Bromo-2-fluoro-phenyl)-ethanone (10.9 g, 50.23 mmol) from step 2 below was dissolved in CH2Cl2 (10 mL) and slowly added via addition funnel to the previous solution. The resulting reaction was stirred at 25° C. overnight. The solution was carefully quenched with MeOH, the solvent was removed in vacuo and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide the desired product (9 37 g, 90%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.49 (d, J=6.6 Hz, 3H), 5.15 (q, J=12, 6.4 Hz, 1H), 7.15-7.45 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[S:35]1[C:39]([NH2:40])=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:39]4[S:35][N:36]=[CH:37][N:38]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ncns1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE XXXX, 150.33 mg, 0.291 mmol), 1,2,4-thiadiazol-5-amine (35.4 mg, 0.350 mmol), and cesium carbonate (285 mg, 0.874 mmol). acetonitrile (1457 μl) was added, and the mixture was stirred for 1.5 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from MeOH. The residue was taken up in MeOH, sonicated, and filtered on a membrane filter. The collected solid was washed with MeOH (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(5-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100.0 mg, 0.231 mmol, 79% yield) as a cream-colored solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.49 (s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.59 (dd, J=2.7, 8.9 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 3.65 (s, 3H). m/z (ESI) 432.9 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([OH:18])=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:41]([N:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:38]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:39])[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: O=C(O)C1CNCCN1C(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 79 mg (0.24 mmole) of (±)-1-(diphenylacetyl)piperazine-2-carboxylic acid (from Example 2, Step A) and 2 ml of THF was treated with 49 mg (0.48 mmole) of triethylamine to give a solution which was cooled to 0° C. With stirring a solution of 61 mg (0.25 mmole) of dipentylcarbamoyl chloride (from Step A) in 0.5 ml of THF was added and the solution was briefly warmed to 50° C. and then stirred at 25° C. for 16 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in 0.5 ml of methanol and was chromatographed over an 85×0.9 cm. LH-20 column with 1.7 ml fractions of methanol. Fractions 21-25 were combined and concentrated in vacuo to 70 mg (57%) of oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:18]=2)O)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[CH:26]1([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)=[N:18]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1nn(C2CCCC2)c2ccccc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Oc1cccc(Cc2nn(C3CCCC3)c3ccccc23)c1
Yield: 484.5 %

Procedure:
A mixture of [3-(benzyloxy)phenyl](1-cyclopentyl-1H-indazol-3-yl)methanol (0.24 g, 0.6 mmol) and 10% palladium on carbon in ethanol/cyclohexene (3:1, v/v) was heated at reflux for 1 hour. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give 0.85 g of product as a white solid.