Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:16][CH2:15][CH:14]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I.CS[C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[NH:31]>CCO>[CH2:25]([N:17]([CH:14]1[CH2:15][CH2:16][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:30]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[NH:31])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)=[CH:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(N)ccc23)CC1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Reaction time: 24 h
Yield: 75 %

Procedure:
A solution of above compound 130 in dry EtOH (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.29 g, 1.037 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 131 (0.18 g, 75%, over two steps) as a yellow solid. mp 110-112° C.; 1H NMR (DMSO-d6) δ 1.09 (t, 3H, J=6.6 Hz), 1.42 (s, 9H), 1.82-1.93 (m, 2H), 2.22-2.64 (m, 4H), 3.12-3.18 (m, 2H), 4.06 (brs, 1H), 6.10 (s, 1H), 6.32 (s, 2H), 6.60 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 7.09 (t, 1H, J=4.5 Hz), 7.23 (s, 1H), 7.59 (d, 1H, J=4.8 Hz), 7.68-7.73 (m, 2H), 10.84 (s, 1H); ESI-MS (m/z, %) 465 (MH+, 100).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([C:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:12]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reaction time: 20 h
Yield: 41.3 %

Procedure:
To a stirred solution of 23.5 g (0.35 mole) of imidazole in 425 mL of ethyl acetate was added 48.0 g (0.32 mole) of triphenylmethyl chloride. The mixture was stirred for 20 hours and then 500 mL of water was added. After being stirred for an additional 2 hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO4) and concentrated. Recrystallization of the residue from xylene gave 41 g of white crystals, mp 222°-225° C..
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(n1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C)ccc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al., Chem. Pharm. Bull., 32, 2522, (1984)] (2.73 g, 0.0184 mol) in CH2Cl2 (30 ml) and triethylamine (5.1 ml, 0.0368 mol) was added acetyl chloride (1.57 ml, 0.0221 mol) at 0° C. The reaction mixture was stirred for 24 h at room temperature, after which time the reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate, H2O, saturated brine, dried over MgSO4 and evaporated under reduced pressure to afford the subtitle compound (3.27 g, 93%). Rf 0.5 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 191 (MH+).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9](S(C)(=O)=O)[N:10]([CH3:22])[C:11](=[O:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])[CH3:3]>C(#N)C>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([NH2:1])[N:10]([CH3:22])[C:11](=[O:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: N
Solvent: CC#N
Product: CCOC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Gaseous ammonia was bubbled at 25° C. in a solution of 2-methanesulfonyl-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.200 g, 0.55 mmol) in acetonitrile (4 ml). After 30 min, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate, 6:4 to 1:1) to give 0.099 g (59% yield) of the title ester as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.19 (3H, t, J=7.1 Hz, CH3), 3.29 (3H, s, NCH3), 4.18 (2H, q, J=7.1 Hz, OCH2), 4.89 (2H, s, OCH2), 7.21 (2H, broad s, NH2), 7.31–7.37 (5H, m, aromatics). Anal. Calcd for C15H17N3O4: C 59.39; H, 5.64; N, 13.85. Found: C, 59.31; H, 5.46, N 13.72.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[C:22]([CH:25]([CH3:27])[CH3:26])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.C(N(CC)C)C>S(Cl)(Cl)=O.CO>[CH3:24][N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:32][CH:28]4[CH2:31][CH2:30][CH2:29]4)=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)c1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Reactant: O=S(=O)(O)Cl
Reactant: NC1CCC1
Agent: CCN(C)CC
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(C)c1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC4CCC4)cc3)n2)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71; 158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclobutylamine (100 μl, 1.08 mmol) and diethylmethylamine (1 ml, 15 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Trituration with water results in a solid which was washed water (3×20 ml) collected by filtration and dried under vacuum at 60° C. to yield the title compound (151 mg, 65%) as a solid. NMR: 1.24 (d, 6H), 1.45 (m, 2H), 1.70 (m, 2H), 1.90 (m, 2H), 3.17 (m, 1H), 3.58 (m, 1H), 3.98 (s, 3H), 7.19 (d, 1H), 7.70 (m, 4H), 7.92 (d, 2H), 8.41 (d, 1H), 9.90 (brs, 1H); m/z 427.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[K+].Br[CH:13]([Br:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20]O>CC(C)=O>[CH3:20][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][CH2:13][Br:19])=[CH:3][CH:8]=1
Reactant: CO
Reactant: CCCCCC(Br)Br
Reactant: COc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(CCCBr)Oc1ccc(C)cc1
Yield: 62 %

Procedure:
A solution of 62 g of methoxy phenol in 50 ml of methanol was added into a solution of 33.75g of potassium hydroxide in 100 ml of methanol. The resulting solution was added dropwisely and slowly into 1 mole of α, -dibromohexane in 200 ml of acetone within 1 hour. After a reflux of the mixture for 1 hour, the mixture was concentrated and then diluted with water. The oil layer of the mixture was extracted with ethyl ether. Then, the ethyl ether layer was filtered and the filtrate was extracted with water. The solution was dried by calcium chloride, and 4-(4'-methoxyphenoxy) hexylbromide (compound 1, with a yield of 62% was obtained by distillation under reduced pressure.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:20][N:19]=4)=[CH:14][CH:13]=3)=[N:9][CH:8]=2)=[CH:3][CH:2]=1.[S:29](=[O:33])(=[O:32])([OH:31])O>>[C:12]1([C:10]2[O:11][C:7]([C:4]3[CH:3]=[CH:2][C:1]([S:29]([OH:33])(=[O:32])=[O:31])=[CH:6][CH:5]=3)=[CH:8][N:9]=2)[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([OH:31])(=[O:33])=[O:32])=[CH:25][CH:24]=3)=[CH:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(-c2cnc(-c3ccc(-c4ncc(-c5ccccc5)o4)cc3)o2)cc1
Product: O=S(=O)(O)c1ccc(-c2cnc(-c3ccc(-c4ncc(-c5ccc(S(=O)(=O)O)cc5)o4)cc3)o2)cc1
Reaction time: 8 h

Procedure:
One hundred milliliters of 20% fuming sulfuric acid (oleum) is charged into a 500 mL flask. Stirring is begun, and 50.0 g of POPOP is added in small portions. The reaction is exothermic. After the addition is complete, the reaction mixture is heated at about 90°-100°C. with stirring for two hours. The reaction is then quenched by pouring the reaction mixture onto 500 g of crushed ice with stirring. A bright-yellow product precipitates as a very fine powder. The resulting suspension is allowed to stand overnight. The product is then collected on a medium-porosity fritted-glass Buchner funnel. It should not be washed at this point, nor should the filter cake be disturbed. As much liquid is removed from the filter cake as possible. The pasty filter cake is then washed by stirring it in 200 mL of 2/1 (v/v) water/methanol or 1/20/10 concentrated hydrochloric acid/water/methanol. Water alone should not be used, as a very thick paste will form. Stirring is continued until the product is finely dispersed. The suspension is then allowed to settle briefly, and the solid is collected by vacuum filtration. The washing process should be repeated once. The product is then dried in a vacuum oven at 60°-70° C. Typical yields are 67-73 g (90-94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](Cl)=[O:30]>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:29]([C:21]1[N:20]([CH3:19])[C:28]2[C:23]([CH:22]=1)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:30]
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.1 %

Procedure:
To a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.01 mmol, 1 g) and 4-dimethylaminopyridine (0.401 mmol, 0.049 g) in dichloromethane (5 ml) and pyridine (5 ml) was added 1-methyl-1H-indole-2-carbonyl chloride (5.22 mmol, 1.010 g) and this solution was stirred at room temperature for four days. The reaction mixture was concentrated and coevaporated with toluene. To the residue dichloromethane and water were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo. Purification using flash chromatography (silica gel, dichloromethane) yielded N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (1.5 g).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]4)=[C:26]([F:39])[C:25]=3[F:40])=[C:20]([F:41])[C:19]=2[F:42])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(O)=O>[CH2:8]([CH:11]1[O:16][CH:15]([OH:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]4)=[C:26]([F:39])[C:25]=3[F:40])=[C:20]([F:41])[C:19]=2[F:42])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4=O)c(F)c3F)c(F)c2F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CC1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Toluene (50 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-one (16) (4.18 g) prepared in the first step. A diisobutylaluminum hydride-toluene solution (0.99 M; 12.5 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (50 ml) to give two layers. The water layer was extracted with toluene (20 ml) twice and the combined organic layer was washed with water. The solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (17) (4.2 g) in 99% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([N:19]([CH2:20][C:21]2[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 4) (1.30 g, 2.55 mmol) was dissolved in anhydrous dichloromethane (100 mL), and pyridine (2.05 mL, 25.5 mmol) was added. The mixture was cooled to 0° C., and methyl chloroformate (1.97 mL, 25.5 mmol) was slowly added over 20 min. The reaction was stirred at 0° C. for 1 h, then at room temperature for 18 h. The reaction mixture was then diluted with chloroform, and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10% ethyl acetate/hexanes as eluent afforded the title compound (1.00 g). MS m/z 558 (M+); 1H NMR (CDCl3) δ1.1(d, 3H), 2.9 (m, 4H), 3.8 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[N:4][CH:5]=[CH:6][CH:7]=1>ClCCl.C(O)C.[Pt]=O>[F:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ncccc2F)c1
Agent: O=[Pt]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(F)c(-c2ncccc2F)c1
Reaction time: 4 h

Procedure:
3-Fluoro-2-(2-fluoro-5-nitrophenyl)pyridine (1.0 g) was dissolved in dichloromethane (25 ml) and diluted with ethanol (50 ml). Platinum oxide (0.1 g) was added, and the mixture shaken on a Parr hydrogenation apparatus under an atmosphere of hydrogen at 45 psi for 4 h. The reaction was filtered and the filtrate evaporated, to afford 4-fluoro-3-(3-fluoropyridin-2-yl)phenylamine, which was used without further purification: 19F NMR (400 MHz, CDCl3) δ 128.48 (1F, d, J 36 Hz), 122.66 (1F, d, J 36 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[S:45][C:41]3[C:40]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C2CCCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:33]1[CH:38]=[CH:37][C:36]([Li])=[CH:35][CH:34]=1)=C.Br[CH:41]=[CH:42]C1C=CC=CC=1>CCOCC>[C:1]1([C:7]2[CH:8]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([CH:41]=[CH2:42])=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)C1c1ccccc1
Reactant: BrC=Cc1ccccc1
Reactant: [Li]c1ccc(C=C)cc1
Solvent: CCOCC
Product: C=Cc1ccc(C2=C(c3ccccc3)C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
1,2,4,5-Tetraphenyl-3-p-vinylphenylcyclopenta-1,3-diene was prepared from 37.8 g (0.098 mol) of 2,3,4,5-tetraphenylcyclopent-2-enone and 0.5 mol of p-vinylphenyllithium (from 7 g (1 mol) of Li and 91.52 g (0.5 mol of bromostyrene) in 300 ml of ether and was purified analogously to 1,2,3,4-tetraphenyl-5-p-vinylphenylcyclopenta-1,3-diene. (Yield: 37 g (80%))
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.11 g, 0.40 mmol) and 3-fluoro-5-piperidin-1-ylbenzoic acid (0.10 g, 0.40 mmol) according to conditions described in general procedures E and F. A light pink solid is produced (67 mg). Mp: 150-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.60 (bs, 6 H), 2.49-2.57 (m, 4H), 2.89 (bs, 2H), 3.30 (bs, 4H), 3.61 (bs, 4H), 4.32 (bs, 2H), 3.96 (d, J=12.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.15 (d, J=9.3 Hz, 1H), 7.40-7.45 (m, 2H), 7.54-7.57 (m, 2H), 7.83-7.87 (m, 1H), 8.23 (s, 1H), 10.24 (s, 1H); MS 478 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][OH:28])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7].C(N(C(C)C)C(C)C)C>C1COCC1>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CO)cc(OCC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride was added slowly at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxymethyl-phenyl)-acetate (200 mg, 0.564 mmol) obtained in Example 234.2 and N-ethyldiisopropylamine (88 mg, 0.68 mmol) in THF (3 ml). The mixture was stirred for 1.5 h. at 0° C. and for 1.5 h. at room temperature. The mixture was poured into ice-water/1M HCl and extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. There were obtained 232 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methanesulphonyloxymethyl-phenyl)-acetate as a yellow oil, which was used for the next reaction without additional purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 51.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (100 mg, 0.19 mmol) was coupled with N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65C) (62 mg, 0.19 mmol) using potassium carbonate (60 mg, 0.57 mmol) and Pd(PPh3)4 (11 mg, 0.0095 mmol) in toluene/ethanol/water (2/2/1 mL). This afforded 63 mg (51.4% yield) after purification by preparative TLC (silicagel-1000 micron) using 40% ethyl acetate in hexane as eluent. MS: m/z=646.2 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.CC(C)=O.C(OCC)(=O)C>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([S:16][C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Sc1cccc(Br)c1
Reactant: Oc1cccnc1Br
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1cccnc1Sc1cccc(Br)c1
Yield: 77.5 %

Procedure:
2-Bromo3-pyridinol (44 g, 250 mmol) and 3-bromothiophenol (30 g, 160 mmol) are dissolved in tetrahydrofuran (hereinafter, occasionally referred to as THF) (100 ml) and dimethylformaldehyde (hereinafter, referred to as DMF) (100 ml), and the mixture is heated under reflux for 5 hours. After being allowed to cool, ethyl acetate (1000 ml) is added to the mixture, and the mixture is washed with 5% aqueous sodium hydroxide solution (50 ml×2) and a saturated brine (100 ml×2), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give the title compound (35 g) as colorless crystals, m.p. 125-126° C.