Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(1-benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[S:26])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)NCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
To 10 ml of anhydrous xylene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and then slowly added 110 mg (1 mmol) of benzylamine (MW 107) under ice-cooling and stirring over 30 minutes. The mixture was then stirred at room temperature for 1.5 hours, during which crystals were deposited and then filtered off. Recrystallization from ethanol gave colourless needles melting between 126° and 128° C. (uncorrected). Yield: 198 mg (40%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2([OH:12])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]3[CH2:21][CH2:22][CH2:23][CH2:24][N:2]=[C:3]23)[CH:18]=[CH:17][CH:16]=1
Reactant: NC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: BrCCCCBr
Agent: Cl
Solvent: CCO
Product: OC1(c2cccc(Cl)c2)C2=NCCCCN2c2ccccc21

Procedure:
2-Amino-3-(m-chlorophenyl)-3H-indol-3-ol hydrochloride (8.66 g) was converted to its oily base then heated under reflux with 1,4-dibromobutane (6.35 g) in ethanol (20 ml) for 4 hours. On cooling the title compound was obtained as its hydrobromide salt (2.41 g) m.p. 270°-275° C (decomp.) after recrystallization from methanol/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1>O1CCOCC1>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29]/[N:30]=[C:11]2\[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\2=3)[CH2:25][O:24]1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC1(C)OC[C@H](CON)O1
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1/C(=N/OC[C@H]1COC(C)(C)O1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 30 %

Procedure:
A 4 mL vial charged with (R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine-5-thione (31I (Example 31), 107 mg, 0.28 mmol), (R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (247 mg, 1.68 mmol), and dioxane (2 mL) was heated to 100° C. for 12 h. The crude mixture was purified by preparative reverse phase HPLC (10-70% H2O—AcCN, 0.035% TFA) to afford the product (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime (32A) in modest yield (40 mg, 30% yield). ESI-MS: m/z 480.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)/[CH:16]=[CH:17]/[CH3:18].N>O>[CH:16]([C:15]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)=[CH:17][CH3:18]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: C/C=C/C(=O)O
Agent: N
Solvent: O
Product: CC=Cc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 11, 0.95 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.43 g. crotonic acid are heated with 10 ml. polyphosphoric acid for 30 minutes at 170° C. (bath temperature). The cooled reaction mixture is dissolved in 40 ml. water and neutralised with concentrated aqueous ammonia solution. Insoluble material is filtered off with suction, washed with water and dissolved in 100 ml. hot ethanol. After treatment with active charcoal, the hot filtrate is evaporated in a vacuum and the evaporation residue is triturated with diethyl ether. There is thus obtained 0.7 g. of the title compound which contains 0.5 mole of water per mole of substance; m.p. 252°-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:23][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (107.6 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide (16.3 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.I[CH2:16][CH2:17][CH2:18][CH3:19]>[Cu]I.O1CCCC1>[CH2:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCc1ccc2c(c1)C(C)(C)CCCC2
Temperature: -15 °C

Procedure:
The corresponding Grignard compound was prepared under argon from 304 mg of Mg shavings and 2.50 g of 2-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene in 25 ml of abs. tetrahydrofuran. After cooling to -15° C. 206 mg of CuI and 1.78 ml of 1-iodobutane were added in succession. The mixture was left to react at room temperature for 2 hours and then poured into ice/ammonium chloride solution. The solution was extracted with diethyl ether, washed with water, dried and evaporated. After filtration over SiO2 with hexane as the eluent there were obtained 2.27 g of 2-butyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo-cycloheptene (contaminated with 4% regioisomers and 6% 5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyloheptene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2ccc(NCc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dichlorobenzaldehyde (1.28 g, 7.3 mmol) was added to a solution of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]propionate (2.1 g, 7.3 mmol) in ethanol (20 mL), and the resulting solution was stirred for 2 hours at 40° C. To the resulting reaction solution was added sodium borohydride (0.55 g, 15.7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. To the solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 2.71 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=O.P(Br)(Br)[Br:21].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:21][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c[nH]c2c(F)cc(OC)cc2c1=O
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(F)cc(OC)cc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 8-fluoro-6-(methoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (12 g, 45 mmol) in DMF (56 ml) was added dropwise phosphorus tribromide (4.5 ml, 47 mmol) over fifteen minutes (slightly exothermic). The reaction was held at 0° C., with an ice bath, for one hour and allowed to warm to room temperature then stirred for a further 2 hours. The mixture was then diluted with water (400 mL). A solution of sodium bicarbonate was added to reach pH 7. The reaction mixture was stirred for one hour at 0° C. then filtered. The precipitate was washed with water and dried in vacuo to afford the product as a yellow solid (12.2 g, 82%).
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(SCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(SCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.43 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1.5 mL of methanol and 1.5 mL of tetrahydrofuran containing 0.16 g of methyl 2-(benzamido)-4-(benzylthio)benzoate while ice-cooled and stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.14 g of 2-(benzamido)-4-(benzylthio)benzoic acid as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:20]1[CH:21]=[C:16]([F:15])[C:17](=[O:23])[NH:18][C:19]1=[O:22])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 3-t-butoxycarbonylaminopropyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(3-t-butoxycarbonylaminopropyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reaction time: 1.25 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 ml) (2.7 mL, ˜0.2 mmol) containing disiopropylethylamine (174 μL, 1 mmol) was added to 4-fluoro-phenyl sulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m+H=533.0; 1H NMR (400 MHz, CDCl3): δ 8.62-8.63 (m, 1 H); 7.85-7.86 (m, 2 H); 7.69-7.70 (m, 2 H); 7.44-7.45 (m, 3 H); 7.28 (s, 1 H); 7.14 (dt, J=12.9, 8.5 Hz, 4 H); 6.48 (d, J=2.2 Hz, 1 H); 5.51 (dd, J=12.2, 2.1 Hz, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 3.82-3.86 (m, 1 H); 2.84-2.86 (m, 2 H); 2.72 (d, J=12.2 Hz, 1 H); 2.46-2.51 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[C:35]([F:42])[N:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:3][C:2]([C:38]2[C:33]([F:32])=[N:34][C:35]([F:42])=[CH:36][CH:37]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1ccncc1
Reactant: OB(O)c1ccc(F)nc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccc(F)nc2F)cc1-c1ccncc1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-[4,4′-bipyridin]-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 5 mg (0.03 mmol) of (2,6-difluoropyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 2 mg (19% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH:21](Br)([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:14][CH:15]1[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]1
Reactant: CC(C)Br
Reactant: Cc1c[nH]c(=O)c2cc(F)c(OC3CCNCC3)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)c2cc(F)c(OC3CCN(C(C)C)CC3)cc12

Procedure:
By alkylation of 50 mg of 7-fluoro-4-methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (22) with isopropylbromide in the presence of triethylamine in DMF at 60° C. 31 mg of 7-Fluoro-6-(1-isopropyl-piperidin-4-yloxy)-4-methyl-2H-isoquinolin-1-one were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(c3ccccc3n2Cc2ccc(F)cc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
The acid 2 (20.0 g, 63.2 mmol) in DMF (630 mL) was degassed and the flask was cooled in ice water bath. NaH (60% in mineral oil; 7.8 g, 196.0 mmol) was slowly added portionwise over 45 min at 0° C. and stirred for 1 hr. 4-fluorobenzyl bromide (8.7 mL, 69.5 mmol) was added dropwise over 45 min at 0° C. and stirred for 1.5 hr. The reaction quenched with water. The mixture diluted with water (1.8 L) and washed with EtOAc (1 L). The aqueous layer was acidified to pH 3-4 with solid citric acid. The mixture extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (900 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using 0-30% EtOAc/Hexane to give a solid. The solid was washed with 10% CH2Cl2/hexane to afford the acid 3 (19.5 g, 72%) as a white powder. 1H NMR (300 MHz, DMSO-d6): δ 12.81 (br s, 1H), 7.48-7.42 (m, 2H), 7.13-6.97 (m, 6H), 5.41-5.28 (m, 2H), 5.14-5.03 (m, 1H), 4.66-4.58 (m, 1H), 4.42-4.27 (m, 1H), 3.32-3.28 (m, 1H), 3.06-2.96 (m, 1H), 1.40 (s, 9×½H), 1.39 (s, 9×½H); LC-MS [M+H+ 425].
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O.Cl.[C:20]1([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:36]1([C:26]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:16](=[O:18])[CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)[CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccn3)CC12
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
Triethylamine (1.4 cc) is added to a suspension of 2-(2-pyridyl)acetic acid hydrochloride (1.73 g) in dry dichloromethane (30 cc). The solution is cooled to +5° C. and then treated with N,N'-carbonyldiimidazole (1.62 g). The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of ethyl acetate (100 cc) and water (75 cc). The organic phase is washed with water (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-pyridyl)acetyl]-4-perhydroisoindolone (1.6 g) is obtained in the form of white crystals melting at 195° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10]([F:19])=[CH:11][C:12]([F:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:8])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C([N:62]2[CH2:67][CH2:66][C:65]([C:88]3[CH:93]=[CH:92][CH:91]=[C:90]([F:94])[CH:89]=3)([CH2:68][CH2:69][N:70]3[CH:75]4[CH2:76][CH2:77][CH:71]3[CH2:72][CH:73]([N:78]3[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][C:81]=5[N:80]=[C:79]3[CH3:87])[CH2:74]4)[CH2:64][CH2:63]2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:17]=[C:13]([C:14]([N:62]2[CH2:63][CH2:64][C:65]([C:88]3[CH:93]=[CH:92][CH:91]=[C:90]([F:94])[CH:89]=3)([CH2:68][CH2:69][N:70]3[CH:71]4[CH2:77][CH2:76][CH:75]3[CH2:74][CH:73]([N:78]3[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][C:81]=5[N:80]=[C:79]3[CH3:87])[CH2:72]4)[CH2:66][CH2:67]2)=[O:16])[C:12]([F:18])=[CH:11][C:10]=1[F:19])(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)c(F)cc1F
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC(C)(C)C)c(F)cc2F)CC1
Yield: 40 %

Procedure:
Prepared from a mixture of 5-{[(1,1-dimethylethyl)amino]sulfonyl}-2,4-difluorobenzoic acid 882-3b 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide 1. The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford N-(1,1-dimethylethyl)-2,4-difluoro-5-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide (example 882) as a white solid (46 mg, 40% yield).