Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1.Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O>[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[N:20]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1
Reactant: ClCc1cccc2ccccc12
Reactant: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
Sodium hydride (1.1 mg, 0.306 mmol) and 2 ml of tetrahydrofuran was added to a previously dried reaction vessel. To the mixture were added 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid methyl ester (50 mg, 0.153 mmol) and 1-chloromethylnaphthalene (69 μl, 0.459 mmol), which was then stirred at 60° C. for 45 minutes. Water was added thereto, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-((5,6-dimethyl-1-(1-naphthylmethyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (yield 32%).
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.[CH3:36][O-:37].[Na+].Cl.[CH3:40][OH:41]>>[C:36]([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)([O:41][CH3:40])=[O:37]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cnc2cccc(CN(CCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 581 mg (1.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 5.0 ml of methanol was added 0.46 ml (2.00 mmol) of a 25% methanol solution of sodium methylate. The mixture was stirred for 10 minutes at room temperature. The reaction mixture was poured into ice-water, which was neutralized with 1N HCl. The mixture was extracted with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 462 mg of the desired compound (93.4%, a pale yellow liquid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=4)=[S:28])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: Nc1ccc(Sc2nc3cc(Cl)ccc3s2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4cc(Cl)ccc4s3)cc2)ccc1Cl
Yield: 24 %

Procedure:
2-(4-aminophenylthio)-5-chlorobenzothiazole (5.5 mmoles, 1.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (5.5 mmoles, 1.3 g) were reacted according to procedure C to yield the title compound 0.7 g, 24%. Mass Spec (FD) 529. Calculated for C21H12Cl2F3 S3 : C, 47.55; H, 2.28; N, 7.92. Found: C, 47.55; H, 3.32; N, 7.87.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CC4)c3n2)cn1
Reaction time: 4 h
Yield: 103.3 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (75.3 mg, 0.19 mmol) and morpholine (65.8 μl, 0.75 mmol) was heated at 140° C. and stirred for 4 hours. Morpholine (32.9 μl, 0.38 mmol) was added at room temperature and the resulting mixture was further stirred at 140° C. for 2 hours. The resulting mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=15:1) to give the title compound (85.9 mg, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1F.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Reactant: Nc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1Nc1ccccc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 84.4 %

Procedure:
4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0° C. in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH2Cl2 and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (−) m/z 320.3 (M−1) detected.
Reaction SMILES: Cl.CO[C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]=[C:23]=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]2[C:4](=[O:5])[C@H:6]3[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]3[C:23]2=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(N2C(=O)[C@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 1A and compound 23E in a manner similar to that described in Example 19. mp 237-238° C.; HPLC: 100% at 2.11 and 2.36 min (retention time) (Conditions: Phenomenex Luna C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=15.9 min (100%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 306 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1
Yield: 25.3 %

Procedure:
p-Anisoyl chloride (10 g, 58.5 mmol) and methylene chloride (500 mL) were combined under Ar. Aniline (8.0 mL, 87.7 mmol) was added dropwise with stirring. Diisopropylethylamine (10.0 mL, 58.5 mmol) was added dropwise to give a white suspension. After 3 h the contents of the reaction flask were washed with 5% potassium bisulfate then sat. sodium bicarbonate. The organic portion was dried with sodium sulfate (anh.), filtered and evaporated in vacuo to give a solid. Trituration with ethyl acetate gave 108 as a white solid (3.37 g, 14.8 mmol, 25.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]1([C:20]2[C:28]([CH:29]=O)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:20]2[C:28]([CH:29]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 60 °C
Yield: 53.5 %

Procedure:
A solution of trimethyl phosphonoacetate (4.0 g) in toluene (10 ml) was added to a mixture of sodium hydride (63%., 880 mg) in toluene (45 ml) with stirring and cooling and then heated at 60° C. for 20 minutes. To the mixture 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g) was added and heated at 60° C. for 8 hours. A saturated sodium bicarbonate solution (30 ml) was added to the reaction mixture and extracted with ethyl acetate (30 ml, 2 times). The extract was washed with brine (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isopropyl alcohol to give crystals of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (1.34 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:27]=[N:28][C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([NH:32][C:33]2[C:41]3[CH:40]=[CH:39][S:38][C:37]=3[CH:36]=[CH:35][CH:34]=2)[N:31]=1>C1COCC1>[S:38]1[CH:39]=[CH:40][C:41]2[C:33]([NH:32][C:30]3[N:31]=[C:26]([NH:14][C@@H:13]4[CH2:12][CH2:11][O:10][CH2:9][C@@H:8]4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[N:27]=[N:28][C:29]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=[CH:36][C:37]1=2
Reactant: CCOC(=O)c1nnc(Cl)nc1Nc1cccc2sccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(N[C@@H]2CCOC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (26 mg) and diisopropylethylamine (0.050 ml) were added to a solution of ethyl 3-chloro-5-(benzo[b]thiophen-4-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (34 mg) in THF (1 mL), and the reaction solution was stirred at 80° C. for 30 minutes. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C(O)(=O)C.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl>[Br:22][C:7]1[S:8][CH:9]=[CH:10][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: BrCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
3-(4-bromobutyl)thiophene (8 g, 36.5 mmol) was dissolved in 250 ml CHCl3, and glacial acetic acid (250 ml) was added in the dark. NBS (6.5 g, 36.5 mmol) was added, and the mixture was stirred for 20 minutes at room temperature in the dark. The reaction mixture was washed with water, saturated NaHCO3, dried over magnesium sulfate and the solvent was removed under vacuum. Purification by column chromatography afforded the title compound (7.4 g, 68% yield) as a light yellow oil. 1H-NMR (ppm, CDCl3): 1.71-1.77 (2H, m), 1.85-1.89 (2H, m), 2.6 (2H, t, J=7.44 Hz), 3.43 (2H, t, J=7.32 Hz), 6.78 (1H, d, J=5.6 Hz), 7.19 (1H, d, J=5.6 Hz); 13C-NMR (ppm, CDCl3): 27.5, 29.4, 32.9, 33.9, 109.2, 125.5, 128.4, 141.8; GC-MS (m/z): 295.89.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[NH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C(N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)N1CCCc2ccccc21

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 1,2,3,4-tetrahydro-quinoline. MS (ESI): 474.4 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH:1]([N:14]1[CH2:17][CH:16]([NH:18][C:25]2[CH:24]=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[CH:21][C:20]=2[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(NC2CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1

Procedure:
A solution of 7.96 g of 1-benzhydrylazetidin-3-ylamine (33.41 mmol), 3.69 ml 3,4-difluoronitrobenzene (33.41 mmol) and 4.65 ml triethylamine (33.41 mmol)) in 50 ml ethyl acetate was stirred for 2 weeks at 60° C. The reaction was diluted with water and the product extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[C:27]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:25])=[CH:22][CH:23]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.26 g (1.2 mmol) of 4-biphenylcarbonyl chloride was added under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to yield the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][S:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)=[C:14]([CH2:16][S:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(CSc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c(CSc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 34b (347 mg, 0.627 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved. TFA (2 mL) was added dropwise and then the reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure and then the residue was dissolved in DCM (10 mL) and MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was triturated with MeOH (10 mL) to afford a white precipitate that was isolated by filtration. The residual solvent was removed under reduced pressure to afford the title compound 116. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 13.05 (br. s., 1H), 8.12-8.20 (m, 2H), 8.06 (d, J=8.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 3H), 7.59-7.71 (m, 2H), 7.47-7.53 (m, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.40 (d, J=5.6 Hz, 1H), 4.82 (s, 2H), 3.85-3.98 (m, 4H), 3.66-3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H23N5O3S: 498.2 (M+H). Found: 498.4.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([SH:13])=[N:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([S:13][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[N:11][N:12]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Methyl 2-chloroacetate (0.73 mL, 8.3 mmol) was added dropwise over 5 mins to a suspension of 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.24 g, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in DMF (40 mL) at room temperature. The reaction was stirred at room temperature for 24 h and slowly poured into a stirred ice-cold water solution. The tan precipitate was collected by vacuum filtration and dried under high vacuum at 50° C. for 16 h in the presence of P2O5 to yield methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (2.24 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]O>>[OH:11][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:12])=[O:7])[NH2:1]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)c(O)c1
Product: COC(=O)c1ccc(N)cc1O

Procedure:
A solution of 4-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) in MeOH (15 mL) and concentrated sulfonic acid (1 mL) was refluxed overnight. The reaction mixture was quenched with NaHCO3 aqueous solution (60 mL) and EtOAc (60 mL). The organic layer was separated, dried, evaporated to give 3-hydroxy-4-methoxycarbonylaniline.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:21]=[CH:22][C:15]1=2)=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[C:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]4)[C:15]=3[CH:22]=[N:21]2)=[CH:24][CH:25]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cn1cc(C(F)(F)F)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 65 °C
Yield: 113.7 %

Procedure:
A mixture of 4-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.025 g, 0.085 mmol) and K2CO3 (0.060 g, 0.43 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 65° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.038 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 5.20 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)[CH3:4])=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH2:5]([N:3]1[CH:1]=[CH:11][C:10]([C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4]1)[CH3:6]
Reactant: CN(C=O)CC(=O)O
Reactant: C#CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(CC)c1
Yield: 65.3 %

Procedure:
Using 117.1 g (1 mol) of N-formylsarcosine, 98.1 g (1 mol) of ethyl propiolate and 638 ml of acetic anhydride, a reaction and post treatment were conducted in a similar manner as in Referential Example 1. The resulting brown oil was distilled under reduced pressure and a 103-104° C. fraction was collected under 4 mmHg, whereby 109.19 g of the title compound were obtained (yield: 71.3%).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[C:23]1([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.C(O)(=O)C>CS(C)=O>[F:1][C:2]1[C:21]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:34]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 20 °C
Yield: 68.3 %

Procedure:
A suspension of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g) and (RS)-2-phenylpiperazine (2.1 g) in dimethyl sulphoxide (30 cc) is heated with stirring for 15 minutes to approximately 50° C. After cooling to approximately 20° C., the reaction mixture is poured into water (100 cc) and treated with acetic acid (1.2 cc). The insoluble matter is drained, washed with water (3×10 cc) and recrystallized in dimethylformamide (80 cc). (RS)-7-Fluoro-1-methoxy-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g) is obtained in the form of a yellow solid, decomposing at 284° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>O1CCCC1>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:13]
Reactant: O=C=NCCCl
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: O=C(NCCCl)N(CCO)CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
2.1 g of diethanolamine are dissolved in 30 ml of tetrahydrofuran, and 2.1 g of 2-chloroethyl isocyanate is added dropwise thereto at 0° to 5° C. The solution is stirred at room temperature for 2 hours. Then, the reaction solution is condensed under reduced pressure. 4.2 g of 1-(2-chloroethyl)-3,3-bis(2-hydroxyethyl)urea are obtained as a colorless oil.