Azzindani/Open_Reaction_Data huggingface dataset:
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].[CH2:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>C(O)C>[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([N:23]2[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]2=[NH:2])=[CH:24][CH:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(N)cc1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCc1ccc(-n2cc(Cl)cc(C(N)=O)c2=N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.2 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in ethanol (10 ml) was added 4-butylaniline (0.95 g) (Table 1-2, amine 69), and the mixture was stirred at room temperature for 17 hr. Triethylamine (0.65 g) was added, and the mixture was further stirred at room temperature for 5 hr. The reaction mixture was concentrated and dissolved in a mixture of dimethyl sulfoxide (5 ml)-water (5 ml), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, the residue was purified by preparative HPLC, and the obtained fraction was treated with PL-HCO3 MP (200 mg cartridge, Polymer Laboratories) to give the title compound (0.15 g). HPLC purity 94%. MS m/z 304 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].C(N(CC)CC)C.[CH3:24][OH:25]>>[Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:25][CH3:24])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc(SCCCl)c([N+](=O)[O-])c1
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SCCCl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of 4-(2-chloroethylthio)-3-nitrobenzoyl chloride (22 mg, 0.080 mmol) in MeOH (5 mL) was added triethylamine (0.112 mL, 0.800 mmol). The reaction mixture was allowed to stir for 1 h. TLC analysis of the reaction mixture indicated consumption of starting material. The reaction was concentrated under reduced pressure to provide methyl 4-(2-chloroethylthio)-3-nitrobenzoate (22 mg, 0.080 mmol) as a crude semi-solid, which was used without further purification.
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:21][CH2:20][C:19](=O)[CH:18]=[CH:17]2)=[CH:12][CH:11]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17][C:18]3[NH:2][N:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]=3[CH:20]=[CH:21]2)=[CH:14][CH:15]=1
Reactant: O=C1C=CC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1n[nH]c2c1C=CC(c1ccc(F)cc1)(c1ccc(F)cc1)C2
Temperature: -70 °C
Reaction time: 3 h

Procedure:
1.4 cm3 of ethyl diazoacetate are added dropwise to a solution, cooled to −70° C., of 3 g of 4,4-bis(4-fluorophenyl)cyclohex-2-enone in 75 cm3 of tetrahydrofuran, followed by slow addition of 37.9 cm3 of lithium diisopropylamide solution prepared from 10.5 cm3 of 1.6 M n-butyllithium and 2.4 cm3 of diisopropylamine in solution in 25 cm3 of tetrahydrofuran. After stirring the reaction mixture at a temperature in the region of −70° C. for 3 hours, 1.9 cm3 of glacial acetic acid are added and the temperature is allowed to rise to the region of 20° C. 250 cm3 of ethyl acetate are added and the organic phases are then washed with twice 150 cm3 of distilled water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is dissolved in 100 cm3 of toluene and heated at a temperature in the region of 110° C. for 3 hours and then concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (35–70 μm), eluting with a dichloromethane/diisopropyl ether (50/50) mixture; 1.2 g of ethyl 6,6-bis(4-fluorophenyl)-6,7-dihydro-1H-indazole-3-carboxylate are thus obtained in the form of a beige-coloured foam, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1cccc(CBr)c1
Yield: 31 %

Procedure:
To a solution of 3-methylphenylacetic acid (125 g) in tetrachloro methane (1660 ml), N-bromosuccinimide (148 g) and 2,2′-azobisisobutyronitrile (AIBN; 1.37 g) were added. The mixture was refluxed with heating. After termination of reaction, the solution was cooled with ice. The white precipitate was filtered by glass-filter. The filtrate was washed by tetrachloro methane. The filtrate together with washing liquid was concentrated. The obtained residue was dissolved into ethyl acetate. Thereto, hexane was added. The mixture was crystallized to obtain the title compound (59 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:33](=[O:32])[CH2:34][OH:35])[CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CO)N1CCc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 88 (200 mg, 0.5 mmol), acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (200 mg, 83%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H), 7.3 (dt, J=2.4 and 7.2 Hz, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 5.1 (s, 2H), 4.8 (t, J=5.8 Hz, 1H), 4.1 (d, J=5.6 Hz, 2H), 3.9 (t, J=7.9 Hz, 2H), 3.1 (t, J=7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088 (M+H calcd for C23H20ClF2N2O4 requires 461.1074).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([NH:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COCCOC>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:31][CH2:30][CH2:29][NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]=1[CH3:16]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: Cc1c(NCCNc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 310 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:36])=O>>[Cl:36][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1cncn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Yield: 65 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.11 g, 3.86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8.5 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was triturated with ether, collected by filtration, washed with water and then ether, and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline (756 mg, 65%). 1H NMR Spectrum (DMSO d6) 3.97(s, 3H); 4.65(dd, 2H); 4.70(dd, 2H); 7.39(s, 1H); 7.52(s, 1H); 7.99(s, 1H); 8.57(s, 1H); 8.89(s, 1H) MS-ESI: 306 [MH]+
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)(=[O:34])=[O:35])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC(=O)OC(C)(C)C)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A solution of (1-{2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-2-phenyl-acetyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (254 mg, 0.39 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was dissolved in CH2Cl2 (30 mL) and treated with solid K2CO3. The reaction mixture was stirred at room temperature for 1 hour, filtered and concentrated in vacuo to afford 3-[2-(4-amino-piperidin-1-yl)-2-oxo-1-phenyl-ethyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (179 mg, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:22])[C:16](=[O:20])[NH:17]3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)c(F)c3)cc2[nH]c1=O
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)c(F)c3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(3,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethylpropanol employing methods similar to those described in Example 9 and was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 8.40 (1H, br s), 7.41-7.36 (3H, m), 7.12 (1H, br s), 4.70 (1H, br s), 4.07 (2H, s), 3.20-3.15 (4H, m), 0.83 (3H, s), 0.77 (3H, s); HRMS calcd for C21H21F2N3O4+H+: 418.1578. Found 418.1573.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:32])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(F)cc(C(=O)Cl)cc1Cl
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(F)cc(C(=O)N2CSc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (3 mL), and triethylamine (0.38 mL) and 3-chloro-5-fluoro-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 90 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (356 mg) as a pale yellow oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
2-Formylbenzoate (500 mg, 3.33 mmol) was dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (553 mg, 4.00 mmol) and benzyl bromide (0.396 mL, 3.33 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (795 mg; yield, 99%) as a colorless oily substance.
Reaction SMILES: NC1C2C(=NC=C(Cl)C=2N2CCC[C@@H:13]([N:17](C)[C:18](=O)[O:19]C(C)(C)C)C2)NC=1.C(Cl)(=O)CC.[Li+].[OH-].O.[CH3:35][N:36]1[C:40](=[O:41])[CH2:39][CH2:38][CH2:37]1>N1C=CC=CC=1.CC#N.O.C(Cl)Cl>[NH:36]1[CH2:37][CH2:38][CH2:39][CH:40]([O:41][C:18](=[O:19])[NH:17][CH3:13])[CH2:35]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Reactant: CN1CCCC1=O
Agent: CCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: CNC(=O)OC1CCCNC1
Reaction time: 0.17 h
Yield: 46 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.300 g, 0.790 mmol; Example 112, Step A) in NMP (2 mL), pyridine (1 mL) and propionyl chloride (0.365 g, 3.95 mmol) were stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the organic fraction was separated, dried, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-95% CH3CN/water) to give (R)-tert-butyl 1-(5-chloro-3-propionamido-1H-pyrrolo[2, 3-1)]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.160 g, 46% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCCc2sccc21

Procedure:
A solution of 20 g (0.13 mol) of 4,5,6,7-tetrahydro-4-oxo-benzo[b]thiophene in 300 ml absolute ethanol was stirred with 5.4 g (0.14 mol) NaBH4 at ambient temperature for 20 hours. Then 200 ml H2O was added and the ethanol was removed under reduced pressure. The resulting mixture was extracted with ether. The combined organic extracts were backwashed with H2O, dried (Na2SO4), filtered, and evaporated under reduced pressure. The resultant colorless solid was triturated with hexane yielding 19.03 g (95%) of product, mp 58°-60° C.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: OC1(c2cc(F)cc(F)c2)CCC1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 1-(3,5-difluorophenyl)cyclobutanol (1.0 equiv.) to give 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.23-1.25 (m, 12 H), 1.69-1.82 (m, 1 H), 2.05-2.12 (m, 1 H), 2.37 (br. s., 2 H), 2.47 (br. s., 2 H), 7.00 (d, J=8.80 Hz, 2 H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)OC1CCNCC1

Procedure:
A solution of piperidine 51 (35.99 g, 130.7 mmol) in methanol is hydrogenated with Pd/C in the presence of one equivalent of HCl (104.5 ml, 130.7 mmol, 1.25M in MeOH). After filtration and evaporation, the crude is taken up in ether and washed with 1N—NaOH and brine. Drying, evaporation and distillation (0.08 mbar, 75-90 C) gave a colourless oil. Yield: 17.98 g (74%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:9][CH:8]=1)(=O)C.[OH-].[Na+]>C(O)C>[Cl:20][C:18]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]2[N:25]=[C:26]([CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=3)[C:14]=2[CH:19]=1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2NC(=O)CCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCc1ccc(-n2c(CCCc3ccncc3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 54.4 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) was stirred at 40° C. for 7 h. The solvent was removed and the residue was added water (50 ml). The mixture was extracted with ethyl acetate(100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with dichloromethane:methanol (20:1) to afford 105 mg (54%) of the title compound as pale brown oil.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CNc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A mixture of methyl 4-((phenylamino)methyl)benzoate (800 mg, 3.2 mmol), lithium hydroxide monohydrate (72 mg, 3 mmol), tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 2 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give 4-((phenylamino)methyl)benzoic acid (600 mg, 80%). The product was used for the next step directly without further purification. LRMS (M+H+) m/z: calcd 227.09. found 227.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].CO.[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>CO>[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[N:5][OH:6])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: NO
Reactant: Cc1cc(COc2ccc(C=O)cc2)c2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of sodium methoxide/hydroxylamine hydrochloride/methanol (˜1.4 M)(10.4 mL) was added to 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde (2.0 g, 7.2 mmol) in methanol (20 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 3 h and concentrated in vacuo to give a solid. This was triturated with water saturated KH2PO4 solution and water and dried in vacuo to give 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime (1.75 g, 83%) as an off white solid. MS found: (M+H)+=293.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:41])([F:39])[F:40])=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: OC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (381 mg, 1.06 mmol, Example 264, step 1), 2-(6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (148 mg, 0.53 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (22 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (517 mg, 1.59 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (99 mg) as a white solid.