Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+].O>CS(C)=O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=[C:3]1[CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1cc2ccccc2o1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(O)c1cccc(OCc2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
2-Bromomethylbenzofuran (5 g, 0.024 mol) and 1-(3-hydroxyphenyl)-1-hexanol (4.7 g,0.024 mol) were dissolved in DMSO (75 ml). To this clear, homogeneous solution was added an aqueous solution of sodium hydroxide (12.5 ml, 2N solution; 0.025 mol NaOH). Immediately after the sodium hydroxide solution was added, the reaction mixture became warm (45°-50° C.). This clear, homogeneous solution was stirred at room temperature for 6 hours, and then poured into water (300 ml). The organics were extracted thoroughly with ethyl acetate (3×50 ml), and the combined organic extract was washed with water, 1N sodium hydroxide solution (to remove excess phenol), water, 0.1N hydrochloric acid solution, water and finally brine. After drying over anhydrous magnesium sulfate, all volatiles were removed from the ethyl acetate extract to leave a clear liquid (7.2 g) which was chromatographed on silica gel using 10% ethyl acetate in hexanes as eluent to obtain the pure compound as a clear, colorless liquid (4.4 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Br:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>O1CCCC1>[Br:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br)c1cccc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
Using N-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (178 mg, 0.46 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol), triethylamine (0.14 mL, 1.00 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (67 mg, 24%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1O
Temperature: 50 °C

Procedure:
To 62 mmol 2-hydroxy-5-sulfamoyl-benzoic acid in 80 ml THF was added 80 mmol CDI and the mixture heated at 50° C. for 1 h. 616 mmol methanol was then added, and the mixture was heated at 50° C. for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: dichloromethane/methanol 20:1). The product containing fractions were concentrated in vacuo and the residue suspended in ethyl acetate and washed with aq NaHCO3 solution. The organic phase was dried with Na2SO4 and concentrated in vacuo to afford the title compound. MS (m/e): 230.2 ([M−H]−, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1)=[O:19]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: Cc1cc(N)cc(C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C=CC(=O)Nc2cc(C)c(O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Under argon gas stream, to a solution of 600 mg of 4-amino-2,6-dimethylphenol in 20 ml of tetrahydrofuran is added under ice-cooling 779 mg of 3-methoxycinnamic acid, and then 902 mg of dicyclohexylcarbodiimide and 118 mg of 1-hydroxybenzotriazole are added, followed by stirring at room temperature overnight. After ethyl acetate is added to the reaction mixture, the mixture is washed successively with 10 % hydrochloric acid, water, 5 % sodium hydrogen carbonate and water, and dried, followed by concentration. The residue is recrystallized from ethyl acetate-n-hexane to give 890 mg of 4-(3-methoxycinnamoyl)amino-2,6-dimethyl-phenol.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Si:12]([O:19][CH2:20][C:21]([CH3:63])([CH3:62])[CH2:22][N:23]1[CH:32]=[C:31]([S:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:47]3[CH:52]=[C:51]([C:53](=[O:58])[NH:54][CH:55]4[CH2:57][CH2:56]4)[CH:50]=[C:49]([F:59])[C:48]=3[CH3:60])[CH:29]=2)[C:24]1=[O:61])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][CH2:20][C:21]([CH3:63])([CH3:62])[CH2:22][N:23]1[CH:32]=[C:31]([S:33]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[O:9])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:47]3[CH:52]=[C:51]([C:53](=[O:58])[NH:54][CH:55]4[CH2:56][CH2:57]4)[CH:50]=[C:49]([F:59])[C:48]=3[CH3:60])[CH:29]=2)[C:24]1=[O:61])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
mCPBA (0.025 g of 77% Max) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 58d, 0.1 g) in DCM (2 mL). The reaction was stirred at room temperature for 1 h. The reaction was washed with saturated NaHCO3 solution (3×5 mL), then brine (3×5 mL). The organic layer was concentrated under reduced pressure to give the subtitle compound (0.060 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Sn](C)(C)C)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O>[Pd]>[CH2:1]([O:8][C:9]1[NH:10][CH2:11][C:12]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1ccc(OCc2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC=C(C2=CC=C(OCc3ccccc3)NC2)CC1

Procedure:
In an analogous manner to that described above, by a palladium catalyzed coupling of 2-benzyloxy-5-trimethylstannyl-pyridine with tert-butyl 4-trifluoromethylsulphonyloxy-3,6-dihydro-2H-pyridine-1-carboxylate [Example 126 (c)] there was obtained tert-butyl 6-benzyloxy-3',6'-dihydro-2H-[3,4']bipyridine-1'-carboxylate as a colourless solid MS: 367 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12].[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8]
Reactant: COc1ccsc1
Reactant: CC(C)=CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccsc1C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxythiophene (21.3 g, 0.187 mol) [S. Gronowitz, Arkiv. Kemi., 1958, 12, 239] in dichloromethane (50 mL) was slowly added to a solution of 3,3-dimethylacryloyl chloride (22 mL, 0.195 mol) and tin(IV) chloride (23 mL, 0.195 mol) in dichloromethane (350 mL) at 0°-5° C. After stirring at 0°-5° C. an additional 1 h, the solution was poured into ice water (1 L). The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography using dichloromethane as the eluant to give the product, 29.6 g (81%): mp 49°-51° C.; IR (KBr): 1671, 1628 and 1430 cm-1 ; MS: m/z 197 (MH+); 1H NMR (CDCl3): δ1.98 (d, J=1.2 Hz, 3H), 2.23 (d, J=1.1 Hz, 3H), 3.98 (s, 3H), 6.85 (d, J=5.5 Hz, 1H), 6.89 (dd, J=1.1 Hz, J=1.2 Hz, 1H) and 7.47 (d, J=5.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.ClCCl>[Br:17][CH2:18][CH2:19][CH2:20][O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(CO)c(=O)c(OCCCBr)c1
Temperature: 80 °C
Yield: 14 %

Procedure:
60% oily sodium hydride (292, mg, 7.3 mmol) in small portions were added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.29 g, 6.64 mmol) in dimethylformamide (5 ml) with stirring. After addition of 1,3-dibromopropane (1.35 ml, 13.3 mmol), the solution was heated at 80° C. for 4 hours. The solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1:1)] to give 293 mg of 2-(3-bromopropoxy)-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow crystal (yield: 14%).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:26][S:27]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)(=[O:29])=[O:28]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1

Procedure:
A solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol), methanesulfonyl chloride (16 mg, 0.14 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) in CH2Cl2 (3 mL) was stirred overnight. The solvent was evaporated under reduced pressure and the resulting residue purified by trituration from methanol-diethyl ether to 2-(methylsulfonyl)-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (43 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][N:10]([C:12](OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.ClC1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Cl:31][C:28]1[CH:29]=[N:30][C:12]([N:10]2[CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([OH:19])[CH2:11]2)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Product: COC(=O)c1cc(Cl)cnc1N1CC(O)(c2ccc(F)cc2)C1
Yield: 60.3 %

Procedure:
The title compound (D81) (0021/074/1) (75.9 mg) was prepared according to the experimental procedure described in Description 80 starting from tert-butyl 3-(4-fluorophenyl)-3-hydroxyazetidine-1-carboxylate (D29) (100 mg, 0.374 mmol) and methyl 2,5-dichloronicotinate (77.32 mg, 0.374 mmol).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:36].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([NH2:36])[C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: [NH4+]
Reactant: C[C@H]1COCc2nc3cnc4cc(CCS(C)(=O)=O)ccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCS(C)(=O)=O)ccc4c3n21
Temperature: 25 °C

Procedure:
A 200-mL, round-bottomed flask was charged with (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.45 g, 1.31 mmol) and CH2Cl2 (75 mL). The mixture was stirred at ambient temperature and MCPBA (0.45 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (25 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (0.27 g, 1.44 mmol). The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (100 mL) and vigorous stirring was maintained for 2 hours. The layers were then separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 0.12 g of (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white, crystalline solid, mp 205-206° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:15])=[S:14])[CH:10]=[CH:9][C:8]=1[CH3:16])C.Cl[CH2:25][C:26](=O)[CH3:27]>C(O)C.CN(C)C=O>[CH3:16][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:25]=[C:26]([CH3:27])[N:15]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:3])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=S)ccc1C
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (0.70 g, 2.1 mmol) obtained in step A was dissolved in a ethanol (14 ml)-N,N-dimethylformamide (4 ml) mixed solvent. Then, chloroacetone (0.18 ml, 2.3 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloromethane, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a crude oil of the title compound containing N,N-dimethylformamide. Using this oil and according to the method of Reference Example 62, step B, the title compound (0.56 g, yield 83%) was obtained as a pale-yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 4-methylsulfonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (41%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[I:16]I.OO.S(=O)(=O)(O)O>O.C(O)(=O)C.O>[I:16][C:7]1[CH:6]=[CH:5][C:4]2[N:3]([CH2:1][CH3:2])[C:15]3[C:10]([C:9]=2[CH:8]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: II
Reactant: CCn1c2ccccc2c2ccccc21
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCn1c2ccccc2c2cc(I)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.9 %

Procedure:
Into 5.0 g (25.6 mmol) of 9-ethylcarbazole, 40 ml of a 9:1 acetic acid-water mixture, 3.3 g (13.0 mmol) of iodine, 2.5 g of a 30% hydrogen peroxide solution, and 1.8 g of 97% sulfuric acid were added, and the mixture was stirred at 60° C for 2 hours. After natural cooling, the mixture was diluted with water and then extracted with toluene. After the toluene layer was concentrated, the residual component was purified with a silica gel column. As a result, 5.3 g of 3-iodo-9-ethylcarbazole was obtained (corresponding to a 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccc(Cl)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(Cl)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-chloro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2B) (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (0.047 g, 0.35 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-chloro-benzyl ester. M.S. (M+1): 379.26
Reaction SMILES: F[C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[OH:11].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:3]2[CH2:4][N:5]3[CH:9]=[CH:8][CH:7]=[C:6]3[CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:2]=2[CH:22]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C2Oc3cc(F)ccc3Cn3cccc32)CC1
Temperature: 50 °C

Procedure:
To a solution of [1-(2,4-difluorobenzyl)-2-pyrryl]-(1-methylpiperidin-4-yl)methanol(28.1 g; 0.088 mole) in 320 ml of tetrahydrofuran was added potassium tert-butoxide (11.3 g; 0.10 mole). The reaction mixture was warmed (50° C.) for 15 minutes, diluted with ethyl acetate and washed with water (2×). The organics were then dried (saturated NaCl solution, anhydrous MgSO4). This was concentrated to a solid, m.p. 115°-120° C.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([P:1]([Cl:4])[Cl:2])=[CH:12][CH:11]=1
Reactant: ClP(Cl)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Product: Fc1ccc(P(Cl)Cl)cc1
Temperature: 73 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A mixture of 3.4 mol of PCl3 and 1.2 mol of AlCl3 (98% pure) was placed under an argon atmosphere in a 1 l flask which was provided with a thermostated jacket, mechanical stirring, thermometer and reflux condenser at 73° C. 0.8 mol of fluorobenzene was subsequently added over a period of 30 minutes, with a gentle stream of argon being passed through the reaction flask. The reaction mixture was stirred for 3 hours, cooled to 60° C. and 1.25 mol of pyridine were slowly added over a period of 45 minutes. The reaction was exothermic and mist was formed. The mixture was subsequently stirred for another 30 minutes at 60° C. A nonuniform solid in the form of large lumps precipitated, and this could not be separated off via a suction filter but only by filtration. The filtration residue was washed with petroleum ether. The filtrate and the washings were combined and distilled, giving 73.3 g of p-fluorophenyldichlorophosphine in a yield of 47% of theory.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.BrC1C=CC([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=C(C=1)C=O>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1ccc(Sc2ccc(Br)cc2C=O)cc1
Product: Cc1ccc(Sc2ccc(C=O)cc2C(F)(F)F)cc1
Yield: 100 %

Procedure:
Using 4-fluoro-5-(trifluoromethyl)benzaldehyde (0.20 g, 1.0 mmol), 4-[(4-methylphenyl)thio]-3-(trifluoromethyl)benzaldehyde (0.30 g, 100%) was obtained in a manner similar to the synthesis of 5-bromo-2-[(4-methylphenyl)thio]benzaldehyde.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[N:12]=[C:11]1[CH3:28]>CN(C)C=O>[CH3:28][C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][S:2][CH3:1])[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[N:12]=1
Reactant: C[S-]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
Sodium thiomethoxide (1.5 g, 21 mmol) was added to a solution of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (7.00 g, 19 mmol) in anhydrous N,N-dimethylformamide (80 mL). The reaction mixture was stirred at ambient temperature for 1.5 hours, then it as quenched with water and extracted with ethyl acetate (250 mL). The extract was washed with water (5×50 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 6.73 g of 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-4-phenoxy-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=4[F:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,5-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white powder (53% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 8.0, 7.17-7.11, 7.03, 4.02-3.92, 3.85-3.83, 3.59-3.5, 1.52, 0.74-0.69, 0.46-0.40, 0.09-0.04.