Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][C@@H:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=1)=[O:3].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[O:3][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][C@@H:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=1)=[O:1]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CC1=C[C@H](OC2CCCCO2)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC1=C[C@H](OC2CCCCO2)CC1=O)Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
5 g of 2-hydroxycarbonylmethyl-4(R)-tetrahydropyranyloxy-2-cyclopenten-1-one (21 mmol) obtained from Example 44, 2-naphthol (4.7 g, 32 mmol), dichloromethane (50 ml), and 0.2 g 4-(dimethylamine)pyridine were added together to a 50 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g, 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of diluted hydrochloride solution, water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give the titled compound as white solid (3.8g, 64%). MP: 75° C.; [α]D+29.3° (c 1.0, CH3CN); 1H-NMR (CDCl3/TMS): δ 7.10˜7.90 (m, 8H), 4.72˜5.11 (m, 2H), 3.90 (m, 1H), 3.60 (m, 3H), 2.89 (m, 1H), 2.35˜2.60 (m, 1H), 1.40˜1.92 (m, 6H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 82.3 %

Procedure:
A mixture of (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (150 mg, 0.41 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (118 mg, 0.49 mmol) and DIPEA (280 μL, 1.65 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (166 mg, 82%). LCMS (Method B): RT 3.57 min [M+H]+ 492.0/493.8.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.BrC1C([N+]([O-])=O)=CC=C[N:13]=1.N>[Cu]>[NH2:13][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: Brc1nccc2cc[nH]c12
Agent: [Cu]
Agent: N
Product: Nc1nccc2cc[nH]c12

Procedure:
7-Bromo-1H-pyrrolo[2,3-c]pyridine (600 mg, 3.05 mmol) prepared from 2-bromo-3-nitropyridine in a similar manner to that of Preparative Example 1, powdery copper (194 mg) and cuprous chloride (603 mg) were added to 84 ml of a concentrated aqueous solution of ammonia. The obtained mixture was kept at 120° C. by heating in a sealed tube for 15 hours and treated to give 170 mg of 7-amino-1H-pyrrolo[2,3-c]pyridine. This product was reacted and treated in a similar manner to that of Examples 1 and 2 to give 57 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>CN(C=O)C>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([O:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:39][CH:38]=2)[CH:34]=[CH:35]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 16.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), potassium carbonate (215 mg, 1.56 mmol) and 5-hydroxyindole (147 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallised from ethyl acetate, filtered and washed with diethyl ether to give 4-(indol-5-yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (77 mg, 17%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[C:15]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Temperature: 170 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-benzoic acid ethyl ester (0.175 g, 0.466 mmol) was combined with CuO (3.71 mg, 0.046 mmol), potassium carbonate (0.0805 g, 0.582 mmol) and 3-bromopyridine (0.229 mL, 2.33 mmol) in DMF (250 μL) and the reaction was heated to 170° C. overnight. After cooling the reaction was submitted to standard aqueous workup and the residue was purified by silica gel chromatography (0-100% (EtOAc:MeOH 98:2) in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccc(C=O)c(C)c1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,4-dimethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 497.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=4)[C:23]=3[CH3:24])=[O:18])=[CH:12][C:11]=2[CH3:35])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>O1CCOCC1.C(O)C.[C].[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][N:26]=4)[C:23]=3[CH3:24])=[O:18])=[CH:12][C:11]=2[CH3:35])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)N1CCC(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 54.2 %

Procedure:
N-{6-[1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl]-5-methylpyridin-3-yl}-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (180 mg) described in Example K39 was dissolved in 1,4-dioxane (2 ml) and ethanol (2 ml), 10% palladium-carbon (containing ca. 50% water; 90 mg) was added, and stirred at room temperature under hydrogen atmosphere for 8.5 hours, then ethanol (1 ml) was added and stirred at 40° C. for two days. The reaction solution was filtered through Celite, washed with chloroform and ethanol and the solvent was evaporated in vacuo. The precipitated solid was washed with ethyl acetate and ethanol to give the titled compound (98 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: Nc1cccc2[nH]c(=O)oc12
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc3[nH]c(=O)oc23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A mixture of 0.247 g of 7-amino-3H-benzooxazol-2-one (1.6 mmol, 1 eq) and 0.36 ml of 3,4-diethoxycyclobut-3-ene-1,2-dione (2.5 mmol, 1.5 eq) in 9 ml of ethanol was stirred at ambient temperature for 2 days (formation of a precipitate). Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. 0.35 g of product was obtained in the form of a light khaki solid. Yield=78%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.Cl.[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH:34]5[CH2:37][N:30]([CH2:36][CH2:35]5)[CH2:31][CH2:32]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1CN2CCC(C2)N1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCN3CCC2C3)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 1,4-diazabicyclo[3.2.1]octane dihydrochloride (102 mg, 552 μmol), propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) and N,N-diisopropylethylamine (469 μl, 2.76 mmol) in tetrahydrofuran (4.5 ml) was stirred overnight at 25° C. The mixture was applied on basic silica gel and purified by column chromatography using dichloromethane/methanol 19:1 as eluent to give 4-(1,4-diaza-bicyclo[3.2.1]octane-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (45 mg, 35.7%) as a white solid. mp: 110.1, MS: m/z=457.2 (M+H+).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[C:12]([C:19]([OH:21])=O)[CH:11]=2)[CH:2]=1.Cl.[CH3:24][O:25][C:26]([C:28]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1([NH:35][C:19]([C:12]2[CH:11]=[C:10]([O:9][CH2:8][CH2:7][C:3]3[CH:2]=[C:1]([CH3:22])[CH:6]=[CH:5][CH:4]=3)[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:27]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: Cc1cccc(CCOc2cc(C(=O)O)cc3c2OCO3)c1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)CCCCCC1

Procedure:
The title compound was synthesized from 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to example 126, step 4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26](=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J11) (240 mg. 0.75 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example L9) (215 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (245 mg).
Reaction SMILES: C([NH:3][C:4]([NH:16][CH2:17][CH2:18][NH2:19])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#N.[ClH:20]>>[ClH:20].[ClH:20].[ClH:20].[NH2:19][CH2:18][CH2:17][NH:16][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])=[NH:3]
Reactant: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC(=N)NCCN

Procedure:
N-Cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (1.0 g) (see Example 10) for 1 N hydrochloric acid (20 ml) were refluxed together for 6 hours. Evaporation and crystallisation from methanol/isopropanol gave the title compound (0.6 g), m.p. 195°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH4+:13].[OH-]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(F)cc1S(N)(=O)=O
Yield: 98 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone (20 mL) was added, dropwise, concentrated NH4OH (3 mL) and the resulting mixture stirred for 5 min. Acetone was removed in vacuo and the precipitates were filtered, washed thoroughly with water and dried in vacuo to provide 3.7 g (Yield 98%) of the title compound as a white solid; 1H NMR (500 MHz, DMSO-D6) δ ppm: 2.55 (3H, s) 7.33–7.40 (1H, m) 7.40–7.46 (1H, m) 7.54 (2H, s) 7.59 (1H, dd, J=9.2, 2.7 Hz); LC/MS m/z 190 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:16]1[C:17]2[C:22]([C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:8][CH:7]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: FC(F)(F)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1

Procedure:
5.7 g (18 mmol) of 9-(4-trifluoromethylphenyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and stirred. A solution in which 3.2 g (20 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.9 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 84%.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[N-:26]=[N+:27]=[N-:28].[Na+]>C(O)C.C(Cl)Cl>[N:26]([CH2:3][C:4]1[N:5]=[CH:6][C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: [N-]=[N+]=NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A suspension of 3-chloromethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline hydrochloride (5.64 g, 15 mmol) and sodium azide (2.0 9, 30 mmol) in anhydrous ethanol (60 mL) was refluxed under nitrogen for 15 hours. The resulting suspension was cooled to room temperature, diluted with an equal volume of CH2Cl2, and washed with water (2×50 mL) and brine (2.5 mL), respectively. The organic extract was dried over anhydrous Na2SO4 and concentrated to give 5.70 grams (100%) of 3-azidomethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline as a pale yellow solid. 1H NMR (CDCl3) δ8.75 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.04 (s, 1H), 7.58 (t,J=7.5 Hz, 1H), 7.32-7.40 (m, 3H), 7.20 (dd, J=9.6, 2.5 Hz, 1H), 6.53 (d, J=2.3 Hz,1H), 5.52 (s, 2H), 4.20 (s, 2H); MS monoisotopic mass (calculated) 381.1, MH+ (observed) 382.0, (MH+−N2) 354.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: C1COCCN1
Product: O=C(c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1)N1CCOCC1
Yield: 63 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and morpholine following a procedure analogous to that described in Example 1. Yield: 63% of theory; LC (method 1): tR=2.05 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:18]=[CH:19][C:20]#[N:21])[CH2:17][CH2:16]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH:15]1([CH:18]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: N#CC=CC1CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 68.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.44 g, 12.6 mmol), 3-cyclopropylacrylonitrile (Preparation B; 2.34 g, 25.1 mmol) (as a mixture of isomers) and DBU (1.88 mL, 12.6 mmol) were suspended in MeCN (10 mL) and stirred at 40° C. for 3 days. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25-35% EtOAc/Hexanes) to furnish 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (2.48 g, 8.64 mmol, 68.8% yield). MS (apci) m/z=288.2 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13](I)[CH3:14].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:10][C:5]1[C:4]([O:11][CH3:12])=[CH:3][C:2]([I:1])=[CH:7][C:6]=1[O:8][CH3:9])[CH3:14]
Reactant: CCI
Reactant: COc1cc(I)cc(OC)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-iodo-2,6-dimethoxyphenol (JP61-207432A) (100.0 mg, 0.360 mmol) in dimethylformamide (1.0 mL) were added ethyl iodide (84.0 mg, 0.540 mmol) and a 50% dispersion of sodium hydride in mineral oil (19.0 mg, 0.40 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into 0.10 M hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 4-ethoxy-1-iodo-3,5-dimethoxybenzene as a colorless amorphous powder (102.0 mg, yield: 93%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][S:30]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:37][CH2:38]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(S(C)(=O)=O)CC3)ccc21
Yield: 73.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (42 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 1-methanesulfonyl-piperidin-4-ylamine (60 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 570. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (br, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.74 (br, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 3.92 (br, 1H), 3.63 (s, 3H), 3.58 (m, 2H), 2.87 (s, 3H), 2.82 (m, 2H), 1.83 (m, 2H), and 1.62 (m, 2H), 2 —NH proton signals were not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:35](=[O:36])[N:34]([CH3:37])[C:12]2[N:13]([CH3:33])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)=[CH:16][CH:15]=3.O.[NH2:39][NH2:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:35](=[O:36])[N:34]([CH3:37])[C:12]2[N:13]([CH3:33])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:39][N:40]=[C:22]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc(COC5CCCCO5)n[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with compound A, 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-(tetrahydropyran-2-yloxy)butane-1,3-dione and hydrazine monohydrate.