Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][C:4]=1[F:31])[CH3:2].[NH:32]1[CH2:37][CH2:36][S:35][CH2:34][CH2:33]1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)=[O:17])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][C:4]=1[F:31])[CH3:2]
Reactant: C1CSCCN1
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1F
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1F

Procedure:
According to General Method 5A, 2.2 g (5.0 mmol) of 3-methyl 1-(4-nitrophenyl) 5-(4-ethyl-3-fluorophenyl)piperidine-1,3-dicarboxylate and 2.8 ml (3.1 g, 30.0 mmol) of thiomorpholine were reacted. Yield: 1.2 g (57% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 57.5 %

Procedure:
Following General Procedure H, (S)-tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (500 mg, 1.08 mmol) was reacted with NCS (175 mg, 1.29 mmol)) to afford the desired product (310 mg, 58%) as a yellow solid: ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO[CH2:6]/[C:7](=[CH:9]\[CH2:10][CH2:11][CH:12]([CH2:14][CH:15]=O)[CH3:13])/[CH3:8]>CO>[CH3:1][O:2][C:7]([CH3:6])([CH3:8])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH:15]=[CH:13][C:12]1[CH:14]=[CH:15][C:9]([CH:7]([CH3:8])[CH3:6])=[CH:10][CH:11]=1
Reactant: COC/C(C)=C\CCC(C)CC=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)CCCC(C)CC=Cc1ccc(C(C)C)cc1

Procedure:
reacting said methanol solution with sodium methoxide, followed by methoxycitronellal to produce 8-methoxy-4,8-dimethyl-1-(4-isopropylphenyl)-1-nonene, and
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3](Cl)=[O:4].[CH3:9][NH2:10]>C(Cl)Cl.O>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([NH:10][CH3:9])=[O:4]
Reactant: CN
Reactant: O=C(Cl)C(Br)CCBr
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15° C., then warmed to 30° C. and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to afford the product (16.3 g, 98%). 1H NMR δ (400 MHz, CDCl3) 2.35-2.45 (m, 1H), 2.57-2.67 (m, 1H), 2.81 (d, 3H), 3.44-3.54 (m, 2H), 4.46 (q, 1H), 6.34 (s, 1H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)C>[CH2:25]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:13][CH2:4][CH2:5][CH3:6])[CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc2ccccc2c1-c1c(OCCCC)ccc2ccccc12
Reaction time: 4 h
Yield: 92.3 %

Procedure:
1.0 g NaOH, 20 ml water and 2.8 g 2,2′-dihydroxy-1,1′-binaphthyl prepared in the step a) of the Example 19 are added to a round bottom flask with the volume of 100 mL and are then stirred to be dissolved, 4.1 g n-butyl bromine, 0.2 g tetrabutylammonium bromide and 10 ml ethanol are dropwise added to the round bottom flask, the temperature of the water bath is maintained at 70° C., and after the reaction is performed for 4 hours, the reaction product is poured, while hot, into 50 g crushed ice, followed by stirring to further separate crystal out. The crystal is filtered the filter cake is washed with alkali solution and icy water to obtain light yellow granular solid. The solid is recrystallized with ethanol to obtain yellow-white crystal 2,2′-dibutoxy-1,1′-binaphthyl with the yield of 92.3%, the melting point of 85° C. and the content, according to HLPC detection, of 96.6%.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:9]([O:10][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: BrCCCOC1CCCCO1
Reactant: O=Cc1cccc(O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCOC2CCCCO2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (5.18 g, 25.0 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (5.1 mL, 30 mmol) in DMF (60 mL) was added sodium hydride (1.20 g, 30.0 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for overnight. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (9:1 to 3:1 hexane/ethyl acetate) to give 2-bromo-3-[3-(tetrahydropyran-2-yloxy)propoxy]benzaldehyde (8.75 g, quantitative).
Reaction SMILES: N[C:2]1[C:11](F)=[C:10](F)[C:9](OC)=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2C1CC1.N1CCCCC1>>[O:22]=[C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[NH:7][CH:6]=[C:5]1[C:19]([OH:21])=[O:20]
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCNCC1
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and isomers were prepared by a procedure described in Method 1 by using 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and appropriate {4-(amino/substituted amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)} piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C@@H:5]([CH3:39])[CH2:6][CH:7]([NH:22][C:23]([C:25]1[N:26]=[N:27][N:28](CC2C=CC(OC)=CC=2)[N:29]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:40])[C@H:5]([CH3:39])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[N:29]=[N:28][NH:27][N:26]=1)=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn[nH]n1

Procedure:
Next, a solution of (S)-5-(3′-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester (212 mg, 0.377 mmol) in TFA (5 mL) is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is purified by chiral HPLC on a Chirapak IA column using heptane/ethanol (80:20) (0.1% TFA) to elute the title compound; HPLC Retention time 1.59 minutes (condition C): MS 442.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.10 (m, 3H) 1.10-1.16 (m, 3H) 1.69-1.79 (m, 1H) 1.88 (ddd, J=13.89, 9.98, 3.92 Hz, 1H) 2.77-2.87 (m, 1H) 2.87-2.96 (m, 1H) 3.91-4.05 (m, J=10.72, 7.14, 7.14, 3.66, 3.66 Hz, 2H) 4.24 (br. s., 1H) 6.85-6.85 (m, 0H) 7.30 (d, J=8.34 Hz, 2H) 7.37-7.42 (m, 1H) 7.46 (t, J=7.83 Hz, 1H) 7.56-7.64 (m, 3H) 7.68 (t, J=1.77 Hz, 1H) 9.18 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:10](=[O:12])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: Cl
Product: CCOc1ccc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)cn1

Procedure:
In analogy to Example 83, step a) using 6-ethoxy-3-pyridinecarboxylic acid (CAS 97455-65-7) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (+)-(R)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Off-white solid. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:46]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40]([NH2:46])=[O:41])[CH2:37][CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(=O)O)CCC3)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxylic acid (0.4 g), 1-hydroxybenzotriazole ammonium salt (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (100 mg, 0.54 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (140 mg, 0.64 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (220 mg, 0.58 mmol) in DMF (2 mL) was added DIEA (280 μL, 1.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 148-1 (210 mg, 100%). MS m/z 388.1 (M+1).
Reaction SMILES: ClC1C=C(C(F)(F)F)C=C(Cl)C=1N.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](C(CC#N)C(=O)C)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClC1C=CC(S([C:41]([N:48]=[N:49][C:50]2[C:55]([Cl:56])=[CH:54][C:53]([C:57]([F:60])([F:59])[F:58])=[CH:52][C:51]=2[Cl:61])([CH2:45][C:46]#[N:47])[C:42](=[O:44])[CH3:43])(=O)=O)=CC=1>>[C:42]([C:41]1[C:45]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:46]([NH2:47])[N:49]([C:50]2[C:51]([Cl:61])=[CH:52][C:53]([C:57]([F:58])([F:60])[F:59])=[CH:54][C:55]=2[Cl:56])[N:48]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)C(CC#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(=O)C(CC#N)(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
A process according to claim 1, comprising reacting the hydrogensulfate diazonium salt of 2,6-dichloro-4-trifluoromethylaniline with 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, and then subjecting the resultant 3-(4-chlorophenylsulfonyl)-3-(2,6-dichloro-4-trifluoromethylphenylazo)-4-cyanobutan-2-one to rearrangement to afford 3-acetyl-5-amino-4-(4-chlorophenyl)sulfonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[N:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:28]([O:27][C:23]1[CH:22]=[N:21][N:20]([CH2:19][CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[C:25](=[O:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(OCc2ccccc2)cnn1CCc1ccc2c(c1)CNCC2

Procedure:
To 30 mg (0.06 mmol) 7-[2-(4-benzyloxy-6-oxo-6H-pyridazin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 25.1a) in 2.0 mL DCM is added 50 μL trifluoroacetic acid at RT. The solvent is evaporated and the residue is purified via reverse HPLC chromatography (Waters SunFire, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.CCCCCC.C([Li])CCC.[I:28]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[CH:14]1([CH2:13][O:12][C:3]2[C:4]([O:8][CH2:9][O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=2[I:28])[CH2:16][CH2:15]1
Reactant: COCOc1cccc(Br)c1OCC1CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1cccc(I)c1OCC1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To 76 ml of diethyl ether solution containing 24.1 g (84 mmol) of 1-bromo-2-cyclopropylmethoxy-3-methoxymethoxybenzene obtained in Reference example 12-(a) was added dropwise 53.4 ml (84 mmol) of 1.58M n-butyl lithium hexane solution at −60° C. or lower under argon atmosphere. The mixture was stirred at the same temperature for further 30 minutes, raised to −30° C., and then, 50 ml of diethyl ether solution containing 21.3 g (84 mmol) of iodine was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then, gradually raised to room temperature. After completion of the reaction, to the reaction mixture was added 95 ml of 2% aqueous sodium thiosulfate solution, and the mixture was stirred for 1 hour. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 29.8 g of the title compound as a reddish oil substantially quantitatively.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:31]=1)([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([S:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:31][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A slurry of the compound prepared in Example 95A (0.7 g, 1.73 mmol) and 10% Pd/C (100 mg) in acetic acid (10 ml) and methanol (10 mL) was placed under a hydrogen balloon atmosphere with stirring for 20 hours at room temperature. The slurry was filtered and the solvent removed under vacuum to provide the title compound as an acetic acid salt (540 mg, 63%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=7.0 Hz, 6H), 1.91 (s, 6H), 3.27 (m, 1H), 6.55 (d, J=8.8 Hz, 2H), 6.62 (m, 1H), 6.69 (m, 1H), 6.95 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 8.75 (s, 1H), 8.99 (m, 1H), 9.52 (s, 1H), 11.57 (bs, 1H); MS (ESI+) m/z 404 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1
Reactant: NN
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccc(C(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (740 mg, 1.5 mmol) produced in Synthesis Example 15 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 291 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(3-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (364 mg, yield 50%).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl[CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].O.C(Cl)Cl.CCOC(C)=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:36]([CH:35]=[CH2:34])(=[O:38])=[O:37])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 0.224 g (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) and 25 mg of DMAP in 10 mL of pyridine was cooled to 0° C. and 0.122 g (0.75 mmol) of 2-chloroethanesulfonyl chloride was added dropwise over 5 min. The mixture was stirred at 0° C. for 2 hrs and water was added to give a precipitate which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 183 mg (31% yield) of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole: mp (MeOH) 242-244° C.; 1H NMR (CDCl3) δ 7.85 (dd, J=8.4, 0.7 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.43 (dd, J=16.6, 9.8 Hz, 1H), 6.29 (d, J=16.6 Hz, 1H), 6.07 (d, J=9.8 Hz, 1H), 4.05 (s, 3H), 4.01 (m, 4H), 3.87 (m, 4H), 3.78 (m, 4H), 3.26 (m, 4H); MS (APCI+) m/z 538.4; Anal. Calcd. for C22H26F2N8O4S: C, 49.25; H, 4.9; N, 20.9. Found: C, 49.1; H, 5.0; N, 20.4%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]=[C:4](Br)[CH:3]=1.[SH-:16].[Na+]>CO>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:16])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1)[CH3:14]
Reactant: CCOc1ccc2c(Cl)cc(Br)nc2c1
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc2c(=S)cc[nH]c2c1
Yield: 83 %

Procedure:
4-Chloro(bromo)-7-ethoxyquinoline (180 mg) and 70% sodium hydrosulfide (250 mg) were dissolved in methanol(50 ml) and refluxed for 15 hours. This reaction mixture was evaporated under reduced pressure and the residue was developed by silica gel column chromatography [Wako Gel™ C-200, mixed solution of methylene chloride with methanol (9 : 1)]. Fractions corresponding to yellow spots were collected and evaporated to obtain crude crystals. The obtained crude crystals were recrystallized from 40% aqueous ethanol solution to obtain 107 mg of the titled compound. Melting Point: 171°-174° C.; MS m/z: 205 (M+); NMR(DMSO-d6)δ: 1.40(3H, t, J=6.9 Hz), 4.15(2H, q, J=6.9 Hz), 7.02(1H, d, J=1.3 Hz), 7.09(1H, dd, J=2.3, 9.2 Hz), 7.15(1H, d, J=6.5 Hz), 7.73-7.78(1H, m), 8.58(1H, d, J=9.2 Hz), 12.68(1H, brs)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[C:13](O)=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:47]([CH3:49])[CH3:48])C2C=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:20][CH:21]=2)[C:13]([N:47]([CH3:49])[CH3:48])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccccn3)cc2)cc(OC)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccccn3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3,5-dimethoxyphenyl)-2-[4-(pyridin-2-yloxy)-phenyl]-acrylic acid, 65, (0.11 g, 0.3 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.15 g, 0.35 mmol), dimethylamine in THF (2M, 0.5 mL, 1.0 mmol), triethylamine ( 0.035 g, 035 mmol) in DMF (6.0 mL) was stirred for 3 h at room temperature. The reaction mixture was poured in water (50.0 mL) and extracted with ethyl acetate (2×50 mL). Solvent was evaporated under reduced pressure and residue was purified by silica gel chromatography to yield 66.