Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([F:19])=[CH:13][CH:12]=3)=[CH:5][CH2:4]1>Br.C(O)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:6]1[CH2:7][CH2:8][C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([N:2]([CH3:26])[CH3:1])[CH2:4][CH2:5]1)=[C:17]2[CH3:18]
Reactant: Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccc(F)cc12
Agent: Br
Solvent: CCO
Product: Cc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccc(F)cc12
Reaction time: 1 h

Procedure:
(±)-2-(4-(Dimethylamino)-4-phenylcyclohex-1-enyl)-3-methyl-5-fluoro-1H-indole (free base from Example 28) (420 mg, 1.2 mmol) was dissolved in HBr/glacial acetic acid (33% HBr, 25 ml). Sn powder (1.4 g, 12 mmol) was then added to the mixture in portions in the course of 40 min. When the addition had ended, the reaction mixture was stirred for a further 60 min.—For working up, the mixture was concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (40 ml). Methylene chloride was added to the solution obtained and the mixture was extracted (4×20 ml). The combined organic phases were dried with MgSO4 and then concentrated. The residue obtained (360 mg) was boiled up in ethanol (30 ml), the substance only partly dissolving. The mixture was left at 5° C. for 1 h and the solid was then separated off. 4-(5-Fluoro-3-methyl-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine (less polar isomer) was obtained in this way in a yield of 256 mg (60%, melting point: 199-205° C.).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1)[CH3:20]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
3-Formylindol (10 g, 69 mmol) was dissolved in N,N-dimethylformamide (100 mL) and under an atmosphere of nitrogen and with external cooling, keeping the temperature below 15° C., sodium hydride (60% in mineral oil, 3.0 g, 76 mmol) was added in portions. Then a solution of ethyl bromoacetate (8.4 mL, 76 mmol) in N,N-dimethylformamide (15 mL) was added dropwise over 30 minutes and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride (100 mL), dried (MgSO4) and concentrated in vacuo to afford 15.9 g (quant.) of (3-formylindol-1-yl)acetic acid ethyl ester as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:61])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:57][CH2:56][C@@H:55]([C:58]([CH3:60])=[CH2:59])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:54])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH2:53][C:37]5([CH2:40][C:39]([C:47]([O:49]C(C)C)=[O:48])([C:41]([O:43]C(C)C)=[O:42])[CH2:38]5)[CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.CO>[O:61]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:57][CH2:56][C@@H:55]([C:58]([CH3:60])=[CH2:59])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:54])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH2:53][C:37]5([CH2:38][C:39]([C:41]([OH:43])=[O:42])([C:47]([OH:49])=[O:48])[CH2:40]5)[CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 12 h
Yield: 2.5 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (90 mg, 0.104 mmol) in dioxane (3 mL) and MeOH (2 mL) was added 1N NaOH (2 mL, 2 mmol). The mixture was stirred at 50° C. for 12 h. The crude product was purified by preparative HPLC using method 14. The fractions containing the expected product were combined and concentrated to give 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid as a white solid (2 mg, 2.46%). MS: m/e 779.5 (M+H)+, 2.31 min (method 2). 1H NMR (400 MHz, DMSO-d6) δ 6.02 (s, 1H), 5.48 (d, J=4.5 Hz, 1H), 4.71 (s, 1H), 4.60 (s, 1H), 3.12 (d, J=4.8 Hz, 5H), 3.01 (br. s., 4H), 2.91 (br. s., 5H), 2.72-2.64 (m, 1H), 2.57-2.49 (m 6H), 2.17-1.96 (m, 2H), 1.82 (d, J=5.8 Hz, 5H), 1.67 (m, 8H), 1.53-1.17 (m, 12H), 1.13 (s, 3H), 1.05 (m, 6H), 0.97 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[CH3:28][O:29][CH2:30][C:31]([N:23]1[CH2:24][CH2:25][C:26]2[N:27]=[C:19]([NH:18][C:8]3[CH:9]=[CH:10][C:11]([N:12]4[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]4)=[C:6]([O:5][CH3:4])[CH:7]=3)[S:20][C:21]=2[CH2:22]1)=[O:32]
Reactant: COCC(=O)O
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: Cl
Product: COCC(=O)N1CCc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)sc2C1

Procedure:
The title compound was prepared in analogy to example 53 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 20 mg (0.22 mmol) methoxyacetic acid yielding 46 mg (56%) 2-methoxy-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-ethanone as a light yellow solid. MS ISP (m/e): 414.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.32 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.54 (br s, 2H), 4.20 & 4.14 (s, 2H), 3.78 (s, 3H), 3.78 & 3.68 (m, 2H), 3.32 (s, 3H), 2.73-2.60 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:16][OH:17])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].ClN1C(=O)CCC1=O.C(=O)([O-])O.[K+].[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[Cl:45]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:39][C:38]([C:36]4[CH:35]=[C:34]([Cl:44])[C:33]([Cl:45])=[C:32]([Cl:31])[CH:37]=4)([C:40]([F:43])([F:42])[F:41])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a stirred solution of 1-[4-(hydroxyimino-methyl)-phenyl]-azetidine-3-carboxylic acid methyl ester (Preparation 10, 2.36 g, 10.08 mmol) in DMF (25 mL) was added N-chloro succinimide (1.48 g, 11.09 mmol) at 0° C. Resulting reaction mixture was stirred at 0° C. for 1 hour and then at 10° C. for 1 hour. After complete consumption of starting material to chloro intermediate (red colored reaction mixture) potassium hydrogen carbonate (1.51 g, 15.12 mmol, 1.5 eq.) was added followed by of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)benzene (1.21 g, 12.10 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. After consumption of chloro intermediate, reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2×200 mL). Combined organic layer was washed with water (2×400 mL), brine (2×200 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford brown colored semi solid (2.5 g, crude). Crude compound was purified by column chromatography (silica gel, 100-200 mesh). Compound was eluted using 25% ethyl acetate in hexane to afford off white solid (1.91 g, 33%). 1H NMR (400 MHz, CDCl3): 3.58-3.63 (m, 2H), 3.75 (s, 3H), 4.03 (d, 1H, J=17.04 Hz), 4.07-4.15 (m, 4H), 6.39-6.42 (m, 2H), 7.46-7.49 (m, 2H), 7.63 (s, 2H); LC-MS (M+H): =506.90.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([Cl:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[Cl:32][C:29]([F:30])([F:31])[C:26]1[N:24]2[N:25]=[C:20]([N:15]3[CH2:16][CH2:17][CH2:18][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: FC(F)(F)c1cnc(N2CCCNCC2)c(Cl)c1
Product: FC(F)(F)c1cnc(N2CCCN(c3ccc4nnc(C(F)(F)Cl)n4n3)CC2)c(Cl)c1
Yield: 62 %

Procedure:
A mixture of 1-(3-chloro-5-trifluoromethyl-2-pyridyl)-1,4-diazepane and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,4-diazepan-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:6][C:5]=2[CH:4]=[C:3]1[C:21]([O:23]CC)=[O:22].[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:6][C:5]=2[CH:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cc2c(n1C)CCN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCc3c(cc(C(=O)O)n3C)C2)cc1

Procedure:
A solution ethyl 1-methyl-5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1 eq) obtained from step I and NaOH (1.5 eq.) in ethanol was refluxed for 2 h Reaction mixture was concentrated under reduced pressure and neutralized to get 1-methyl-5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([Cl:22])[CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]2[C:21]([N:20]=1)=[C:12]1[C:13]([C:4]3[C:3]([S:8](=[O:10])(=[O:9])[NH:11]1)=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:15]=2
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3ccc(Cl)nc23)-c2ccccc21
Yield: 14.3 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(2-chloro-quinolin-8-yl)-benzenesulfonamide (Intermediate 283) (590 mg, 1.77 mmol), t-butyl nitrite (0.32 ml, 2.65 mmol) and AcOH:THF (5.9 ml: 5.9 ml) gave the title compound (80 mg, 16%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:20])[NH:7]2.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.[Cl-].[Na+]>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([O:12][C:9]1[C:8]2[NH:7][C:6](=[O:20])[CH2:5][CH2:4][C:3]=2[C:2]([OH:1])=[CH:11][CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[O:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:20]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCc2c(O)ccc(OCc3ccccc3)c2N1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C

Procedure:
10 g of 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril was dissolved in 100 ml of anhydrous tetrahydrofuran, and 100 mg of p-toluenesulfonic acid was added to the solution. 10 g of dihydropyran was slowly added dropwise thereto at room temperature while stirring. After completion of the addition, the mixture was stirred at room temperature for 12 hours, poured into a large volume of a saturated aqueous solution of sodium chloride and then extracted with chloroform. The extract was washed successively with a 5% aqueous solution of sodium hydroxide and water, and the chloroform layer dried over anhydrous potassium carbonate. The chloroform was evaporated under reduced pressure, and the residue was crystallized from petroleum ether. Recrystallization from ethanol-water afforded 9.5 g of 8-benzyloxy-3,4-dihydrocarbostyril-5-ol-tetrahydropyranyl ether (IV) as colorless needle-like crystals having a melting point of 113.5°-114° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.CN(C=O)C.CS(O[CH2:23][C:24]1([CH3:35])[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1)(=O)=O>O>[CH3:23][C:24]1([CH2:35][S:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1
Reactant: Sc1nc2ccccc2o1
Reactant: CC1(COS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CSc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Sodium hydride (50 mg, 1.25 mmol) was added to a mixture of 2-mercaptobenzoxazole (200 mg, 1.3 mmol) and DMF (3 ml) followed by stirring at room temperature for 1 hour. To the reaction mixture, 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl methanesulfonate prepared in Example 41 (330 mg, 1.2 mmol) was added, and the resulting mixture was stirred at 60-70° C. for 5 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with 5% sodium hydroxyde solution and water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=1/1) to afford 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylthio)benzoxazole (37 mg, yield 9%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH:14]([N:17]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)([CH3:16])[CH3:15].Cl>N1C(C)=CC(C)=CC=1C>[CH:27]1([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([NH:6][C:5]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:21][CH:20]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Nc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyaniline (733 mg, 4.0 mmol) and p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SC4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of methanol, methylene chloride and ammonium hydroxide as the eluents to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.[F-].[Cs+].N>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: N
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid (66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol), and tetrakis-(triphenylphosphine)-palladium(0) (13.9 mg, 0.012 mmol) in DME (25 mL) were stirred at reflux for 6 hours TLC (1CH2Cl2:1 hexanes:1.5 ethyl acetate) indicated that all starting materials were consumed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (0.5:2.5:0.5 CH2Cl2/hexanes/ethyl acetate). A yellow powder was obtained (yield: 50 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 5.41 (s, 2H), 6.72 (dd, J=1.5 Hz, 9 Hz, 1H), 7.13 (dd, J=3 Hz, 3 Hz, 1H), 7.3–7.45 (m, 5H), 7.5–7.6 (m, 3H), 7.78 (s, 1H), 7.92 (d, 9 Hz, 2H). MS (DCI/NH3) n/z 423 (M+H)+. Anal. calc. for C22H18N2O3S2.0.5H2O: C, 6.23; H, 4.43; N, 6.49. Found C, 61.29; H, 4.40; N, 6.16.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)C.[BH4-].[Na+]>>[Br:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([CH2:5][CH2:4][OH:3])[S:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [BH4-]
Agent: [Na+]
Product: OCCc1nc2ccc(Br)cc2s1

Procedure:
Compounds of formula (22) can be prepared from 6-bromobenzothiazolone as shown in Scheme 3. 6-Bromobenzothiazolone is heated in the presence of NaOH base to provide a mixture of 2-amino-5-bromothiophenol (15) and its disulfide (16). The mixture is treated with chlorocarbonyl-acetic acid ethyl ester to provide 6-bromo-benzothiazol-2-yl-acetic acid ethyl ester (17) and 7-bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (18), which can undergo rearrangement by treatment with zinc and ethyl acetate to provide compound (17). Compound (17) is reduced with NaBH4 to provide 2-(6-bromo-benzothiazol-2-yl)-ethanol (19). Compound (19) is treated with mesyl chloride in the presence of triethyl amine to afford the corresponding methanesulfonic acid 2-(6-bromo-benzothiazol-2-yl)-ethyl ester (20), which is treated with an amine of formula HNRaRb, wherein Ra and Rb each is as defined for R4 and R5, to provide compounds of formula (21). Compounds of formula (21) can be treated with a boronic acid, wherein Rc is aryl or heteroaryl, to provide compounds of formula (22).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH3:1])[CH2:6][N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Reactant: O=C1CCCc2[nH]ccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Temperature: 85 °C
Yield: 48.5 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (101 mg, 0.33 mmol) and 1,5,6,7-tetrahydroindol-4-one (74.9 mg, 0.56 mmol) in 0.75 mL of anhydrous ethanol was added sodium ethoxide (21 wt. % solution in ethanol, 103 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% to 60% ethyl acetate-hexanes) to give 80.0 mg (58% yield) of the title compound as a white solid, m.p. 207° C.-208° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][N:1]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:2]=1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-n2ccc(-c3ccccn3)n2)c1
Temperature: 145 °C

Procedure:
2-(1H-Pyrazol-3-yl)pyridine (435 mg, 3 mmol), 3-fluorobenzonitrile (0.32 mL, 3 mmol) and K2CO3 (830 mg, 6 mmol) were dissolved in DMF (10 mL) under Ar (g) and heated at 145° C. for 18 h. After cooling to ambient temperature, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were washed with brine (3×40 mL), dried over Na2SO4 and concentrated onto silica gel. The crude material was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (1:1) to afford a solid that was recrystallized from EtOAc-hexane to give 3-(3-pyridin-2-yl-1H-pyrazol-1-yl)benzonitrile as a solid. 1H NMR (CD3Cl, 300 MHz) δ 8.68-8.71 (1H, m), 8.18 (1H, m), 8.12-8.15 (1H, m), 8.02-8.06 (2H, m), 7.81 (1H, ddd), 7.60-7.62 (2H, m), 7.30 (1H, ddd), 7.20 (1H, d). MS (ESI) 247 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:2].[CH3:16][C:17]([C:20]1[CH:25]=[C:24]([SH:26])[CH:23]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]=1[OH:31])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:30][C:27]([C:22]1[CH:23]=[C:24]([S:26][CH2:14][CH2:13][C:12]([NH:11][C:4]2[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:15])[CH:25]=[C:20]([C:17]([CH3:19])([CH3:18])[CH3:16])[C:21]=1[OH:31])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Nc1c(CC)cccc1CC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method of Example 4 from N-(2,6-diethylphenyl)-2-propenamide (1.01 g, 0.005 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole) and triethylamine (0.5 ml) in methanol, m.p. ca. 150.5°-151.5° C.