Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][S:71]([CH3:74])(=[O:73])=[O:72])=[C:66]([F:75])[CH:65]=1>C1COCC1>[F:75][C:66]1[CH:65]=[C:64]([CH:69]=[CH:68][C:67]=1[NH:70][S:71]([CH3:74])(=[O:73])=[O:72])[CH2:63][NH:62][C:17]([CH:14]1[CH2:13][CH2:12][C:10]2([O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:16][CH2:15]1)=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C2CCC3(CC2)CC(c2ccccc2)=NO3)cc1F
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (400 mg, 1.54 mmol) was slowly added to a solution of N-ethyldiisopropylamine (662 g, 4.6 mmol), 1-hydroxybenzotriazole hydrate (206 mg, 1.54 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (496 mg, 1.54 mmol) and N-(4-aminomethyl-2-fluorophenyl)methanesulphonamide (336 mg, 1.54 mmol) in abs. THF (11 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (75 ml). The precipitate formed was removed by suction-filtration, washed with a small amount of ether and dried. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-3-fluoro-4-methanesulphonylaminobenzylamide was obtained as a cis isomer (89 mg, 13% of the theoretical amount). The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The residue was boiled up in EtOAc (2.5 ml) and DCM (1 ml). The precipitate formed was removed by suction-filtration and washed with a small amount of ether. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-3-fluoro-4-methanesulphonylaminobenzylamide was obtained as a trans isomer (138 mg, 19% of the theoretical amount).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([Br:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Br:10])[C:5]=1[O:9][CH3:11])[NH2:1]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Br:14][C:15]1[C:24]([CH:25]([O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][OH:27])=[C:23]([CH3:36])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2>C(Cl)Cl>[C:3]([O:27][CH2:26][CH:25]([C:24]1[C:15]([Br:14])=[C:16]2[C:21](=[CH:22][C:23]=1[CH3:36])[N:20]=[CH:19][CH:18]=[CH:17]2)[O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:31])([F:33])[F:32])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Cc1cc2ncccc2c(Br)c1C(CO)OC(C)(C)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ncccc2c(Br)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (19 μL, 0.15 mmol) in pyridine (0.4 mL, 4.95 mmol) was added 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (29.8 mg, 0.08 mmol) in CH2Cl2 (0.4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C21H26BrF3NO3: 476.11; Found: 476.2.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][CH:28]4[CH2:29][CH2:30][C:25]([F:32])([F:24])[CH2:26][CH2:27]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(F)(F)CC1
Temperature: 110 °C
Yield: 82.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.433 g, 1.28 mmol), 4,4-difluorocyclohexyl amine hydrochloride (0.242 g, 1.41 mmol), diisopropylethylamine (0.491 ml, 2.82 mmol) in propan-2-ol (10 ml) was heated at 110° C. in a microwave reactor for 20 min. The mixture was then cooled to 25° C. and was partitioned between water (50 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the resulting yellow solid by column chromatography on silica gel (gradient: 0 to 60% EtOAc in heptanes) afforded (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,4-di fluoro-cyclohexyl)-amine (0.46 g, 82%) as a yellow solid. LCMS (Method G, ESI): RT=1.21 min, m+H=437; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 7.17 (d, J=4.3 Hz, 1H), 4.39-4.26 (m, 1H), 2.29-1.98 (m, 6H), 1.83-1.68 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][C:11]3[C:12]([CH3:29])=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:32](C([Sn])=C(CCCC)CCCC)[CH2:33]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][C:11]3[C:12]([CH3:29])=[CH:13][C:14]([CH:32]=[CH2:33])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(C)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Temperature: 90 °C

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-(((trifluoromethyl) sulfonyl)oxy)benzoate (1.12 g) in DMF (25.0 mL) were added tributylvinyltin (1.08 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.09 g) and lithium chloride (0.77 g), and the mixture was stirred at 90° C. 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.73 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=3[CH:20]=2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To t-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), 4-ethoxyphenyl borate (2.35 g), 1M potassium carbonate solution (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (0.55 g), and the mixture was refluxed under argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1OS(C(F)(F)F)(=O)=O)[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36](=[O:55])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:33]([O:35][C:36](=[O:55])[CH2:37][C:38]1[CH:39]=[C:40]([C:16]2[CH:17]=[CH:18][C:19]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:20][C:15]=2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH3:13])[C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[CH3:34]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(S(C)(=O)=O)ccc1OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(S(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
Trifluoro-methanesulfonic acid 2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4-methanesulfonyl-phenyl ester (1.3 g, 2.62 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.26 g, 3.93 mmol), and cesium carbonate (2.55 g, 7.85 mmol) were combined in DMF. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.213 g, 0.26 mmol) was added, and the reaction was immediately immersed in an oil bath pre-heated to 45° C. The reaction was stirred at 65° C. for 20 minutes, and then worked-up and purified to give the title compound, contaminated with a phenol by-product. The mixture was dissolved in CH2Cl2 (100 mL) and washed with 0.5N aqueous NaOH, and then concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]([CH3:23])[C:15]3([CH3:22])[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]([CH3:23])[C:15]4([CH3:22])[CH2:19][CH2:18][S:17](=[O:20])(=[O:21])[CH2:16]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CN(CCc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)C1(C)CCS(=O)(=O)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN(C)C3(C)CCS(=O)(=O)C3)n(C)c2n1
Temperature: 110 °C
Yield: 54.3 %

Procedure:
A mixture of [2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]methyl-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)amine (87 mg, 0.20 mmol), 2-ethylbenzimidazole (32 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 2.5 mol %), XPhos (9 mg, 10 mol %) and Cs2CO3 (96 mg, 0.30 mmol) in dioxane (2 mL) was purged with argon then heated at 110° C. for 20 h in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) affording 748 as an off-white solid (60 mg, 55%). LCMS (method I): RT 2.63 min, [M+H]+ 553.1. 1H NMR (CDCl3, 400 MHz): δ 8.01-7.98 (1 H, m), 7.75-7.74 (1 H, m), 7.30-7.23 (2 H, m), 4.34 (4 H, brd s), 3.87 (4 H, t, J=4.78 Hz), 3.78 (3 H, s), 3.37-3.30 (3 H, m), 3.01-3.00 (7 H, m), 2.40-2.30 (4 H, m), 2.08-2.08 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.29 (3 H, s)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>C(Cl)Cl>[Br:1][CH2:21][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(CO)cc1F
Solvent: ClCCl
Solvent: CSC
Product: N#Cc1ccc(CBr)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified chromatography (silica gel, 5-10% EtOAc/hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].C(C1C=CC(OC)=C(O)C=1C(O)=O)C(CO)O.[CH3:25][O:26][C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[O:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33].N1C=CC=CC=1.O>C(Cl)Cl>[OH:34][CH:31]([CH2:30][O:29][C:28]1[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=1[O:26][CH3:25])[CH2:32][O:33][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: COc1ccccc1OCC(O)CO
Reactant: CN(C)S(=O)(=O)Cl
Agent: COc1ccc(CC(O)CO)c(C(=O)O)c1O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1OCC(O)COS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a stirred solution of 21.9 g (152.5 mole) of the dimethylsulfamoyl chloride prepared in (a) above in 60 ml of methylene chloride was added a solution of 7.6 g (0.038 mole) of 3-(2-methoxyphenoxy)-1,2-propanediol (glyceryl guaiacolate) and 12.1 g (0.152 mole) of pyridine in 40 ml of methylene chloride at such a rate that the reaction temperature was maintained at ≤12° C. The reaction mixture was stirred at ambient temperature for 4 days. Water, 200 ml, was added to the mixture and the layers were separated. The organic layer was washed successively with two 200 ml portions of 2N hydrochloric acid and 200 ml of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 11.6 g of yellow liquid. The liquid was purified by high pressure chromatography using a Waters Associates Prep LC/System 500 A with PrepPak® silica. Eluting solvent used was 10:1 mixture of methylene chloride to ethyl acetate at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvents were evaporated under reduced pressure to give 3.9 g (33%) of title compound as a yellow, viscous oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[ClH:18]>O.CO.[OH-].[Na+]>[Cl:18][C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cccc(N)c1OC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(Cl)cccc1C(=O)O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 1.2 g of sodium nitrite in 3 mL of water was added dropwise to a solution of 2 g (0.011 mole) of methyl 3-amino-2-methoxybenzoate in 15 mL of conc. HCl kept below 10° C. After completing the addition, stirring was continued for 0.5 hour at 0° C. The cold solution was then added dropwise to a solution of 2.5 g of cuprous chloride in 6 mL of concentrated HCl at 80°-85° C. After stirring at this temperature for 0.5 hour, the solution was chilled to precipitate an oil which was taken up in methylene chloride. After drying and removing the solvent, the oil obtained above was dissolved in 75 mL of methanol containing 7 mL of 10% NaOH. The solution was heated under reflux for 0.5 hour. After evaporation, the oil was treated with 40 mL of dilute HCl. A white solid precipitated to give 0.5 g (24%) of 3-chloro-2-methoxybenzoic acid after crystallization from ethyl acetate-hexane.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CCCCCC.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][CH2:32][N:33]([CH2:41][CH3:42])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24]2.C[Si]([N-:47][Si](C)(C)C)(C)C.[Li+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:47][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][CH2:32][N:33]([CH2:41][CH3:42])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCN(CCN1CCCc2cc(Br)ccc21)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CCN1CCCc2cc(N)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
A suspension of tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.072 mmol) in anhydrous THF (3 mL) was treated with tri-t-butylphosphine in hexane (10% wt) (0.435 mL, 0.143 mmol) and the mixture stirred for 5 minutes at room temperature. A solution of tert-butyl 2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl(ethyl)carbamate (compound 5, 0.275 g, 0.717 mmol) in THF (7 mL) was added followed by Lithium bis(trimethylsilyl)amide (1M in THF, 1.435 mL, 1.435 mmol) and the mixture heated in a sealed reaction vial at 90° C. for 3 hours. The mixture was cooled to room temperature and treated with TBAF (1M in THF, 4 mL, 4 mmol) for 30 minutes. The mixture was partitioned between water (10 mL) and ethyl acetate (100 mL), transferred to a separatory funnel and the organic layer separated. The aqueous layer (pH=10) was further extracted with ethyl acetate and the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated to give a dark brown residue. Purification on silica gel eluting with 2.5% 2M NH3 in methanol/97.5% dichloromethane yielded a brown residue, 6 (171 mg, 74.6%). 1H-NMR ((DMSO-d6) δ 6.42 (d, 1H, J=8.5 Hz), 6.31-6.26 (m, 1H), 6.22 (br s, 1H), 4.20 (br s, 2H), 3.26-3.08 (m, 8H), 2.55 (t, 2H, J=6.3 Hz), 1.82-1.74 (m, 2H), 1.41 (s, 9H), 1.02 (t, 3H, J=7.0 Hz). MS (ESI+): 320 (MH+, 90), 264 (100).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:3]([N:29]2[CH2:30][C@@H:31]([F:32])[C@@H:27]([CH2:26][NH:25][CH:22]3[CH2:23][CH2:24]3)[CH2:28]2)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 20.5 %

Procedure:
Using 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (318 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a yellow solid (93.6 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[CH2:10]([N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: Oc1ccncc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc(=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (2.04 g) in N,N-dimethylformamide (50 ml) was added 4-hydroxypyridine (5 g) at room temperature. Octyl bromide (9.08 ml) was added thereto. The mixture was stirred for 2 hours at 50° C. The reaction mixture was added to a mixture of brine (100 ml), trtrahydrofuran (100 ml) and ethyl acetate (100 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-octyl-4-pyridone (14.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][NH2:6].C(O)(=O)C.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]3[C:23]4[S:30][C:29]([C:31]5[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=5)=[CH:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][NH:6][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:29]2[S:30][C:23]3[C:22]([NH:21][C:17]4[CH:16]=[C:15]5[C:20](=[CH:19][CH:18]=4)[NH:12][CH:13]=[CH:14]5)=[N:27][CH:26]=[N:25][C:24]=3[CH:28]=2)=[CH:38][CH:37]=1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: COC(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Yield: 66.3 %

Procedure:
3-Amino-propionic acid methyl ester (261 mg, 1.7 mmol) was dissolved in 3 mL of methyl alcohol and the pH was adjusted to 6 with concentrated acetic acid. 4-[4-(1H-Indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde (100 mg, 0.28 mmol) was added to the solution followed by sodium cyanoborohydride (11 mg, 0.17 mmol). After 14 hours the reaction mixture was poured into water and diluted with chloroform. The aqueous layer was separated and the pH was adjusted to 8.5 with 1N sodium hydroxide. The desired product was extracted from the aqueous layer with chloroform (3×20 mL), the combined organic extracts were dried over sodium sulfate, filtered, and dried in vacuo to afford 85 mg (41%) of 3-{4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzylamino}-propionic acid methyl ester. The product was converted to the HCl salt by stirring with 1 equivalent of 1N HCl in ether and the resulting yellow solid was dried in vacuo. M.P. 105-118° C.; LC-MS: 458 (MH+); HPLC RT: 3.86 minutes.