Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:12](=N)(OCC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:13]([C:12]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=2[N:1]=1)[CH2:14][CH3:15]
Reactant: Nc1ccc(CO)cc1N
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cc(CO)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.9 parts of 3,4-diaminobenzenemethanol, 8.3 parts of ethyl butanimidate hydrochloride and 80 parts of ethanol is stirred first for 2 hours at room temperature and further for 2 hours at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated, yielding 6.2 parts of 2-propyl-1H-benzimidazole-5-methanol as a residue.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C#N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C#N)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (597 mg) obtained in Example 159-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto were tri-n-butyl(2-cyano-5-pyridyl)tin (590 mg), dichlorobis(triphenylphosphine)palladium(II) (70 mg) and copper(I) iodide (19 mg). The mixture was heated under stirring at 100° C. for 4 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (351 mg) as colorless powder. APCI-Mass m/Z 621 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (62 mg) was dissolved in a mixture of tert-butanol (3 ml)tetrahydrofuran (3 ml) and added thereto was sodium tert-butoxide (48 mg). The mixture was stirred at room temperature for 3.5 hours. Sodium tert-butoxide (19 mg) was further added thereto, and the mixture was stirred at room temperature for 1 hour. To the mixture was added a saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (23 mg) as colorless powder. APCI-Mass m/Z 470 (M+NH4).
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH2:16][CH:15]=[CH:14][CH:13]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:17][C:18]([CH3:20])=O.N1CCCC1>CO>[CH3:1][C:2]1([C:12]2[CH:16]=[CH:15][C:14](=[C:18]([CH3:20])[CH3:17])[CH:13]=2)[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]1[CH2:10]3)[CH2:11]2
Reactant: CC1(C2=CC=CC2)C2CC3CC(C2)CC1C3
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)=C1C=CC(C2(C)C3CC4CC(C3)CC2C4)=C1
Yield: 88.2 %

Procedure:
A flask containing 19.45 grams (90.74 mmol) of 2-methyl-2-adamantylcyclopentadiene was charged with 30 mL acetone, 100 mL methanol, and 10 mL pyrrolidine (120 mmol). The solution formed a yellow precipitate over 96 hours which was collected by suction filtration and rinsed with 50 mL methanol. The material was dried in vacuo to provide 20.36 grams of product as a yellow powder (88.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
311 mg (purity 90%, 0.55 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 6A. Yield: 312 mg (purity 87%, quant.)
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC=C)(=[O:21])[CH3:20]>C(COC)OC>[C:19]([O:17][C@H:13]1[C@@H:12]([OH:18])[C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:16][CH:15]=[CH:14]1)(=[O:21])[CH3:20]
Reactant: C=COC(C)=O
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@H]1O)c1ccccc1
Solvent: COCCOC
Product: CC(=O)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@@H]1O
Yield: 80 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylgalactal is taken up in 10-15 ml of dimethoxyethane (DME) and 20-25 ml of vinyl acetate and stirred with 1 g of lipase P at room temperature for 8 h, Filtering off the enzyme and crystallization or chromatography on silica gel (ether/hexane 1:1) yield 3-O-acetyl-6-O-benzoylgalactal in 80-85% yield,
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:17])=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:17][CH3:18])=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCc2cc(S)c(C(F)(F)F)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cc2c(cc1C(F)(F)F)N(C(C)=O)CC2
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of the thiol (D5) (26 g, 99 mmol), anhydrous K2CO3 (15.12 g, 109 mmol) and iodomethane (18.6 ml, 300 mmol) in dry DMF (100 ml) was heated at 80° C. for 1 h. The reaction mixture was cooled, evaporated in vacuo and partitioned between water (200 ml) and dichloromethane (3×200 ml). The combined organics were washed with water (400 ml), dried (Na2SO4) and evaporated to yield the title compound (26.3 g, 97%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])[CH3:2].Cl.[CH3:15]O>>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([OH:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: CCOc1cc(C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: CCOc1cc(C(=O)OC)ccc1O
Yield: 91 %

Procedure:
A solution of 3-ethoxy-4-hydroxy-benzoic acid (5.5 g, 30.19 mmol, 1.0 equiv) in methanol (300 mL) was saturated with anhydrous HCl gas and heated to reflux overnight. Evaporation of the solvent and purification of the crude reaction product over a short plug of silica eluting with dichloromethane yielded 5.4 g (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.37 (t, J=7.0 Hz, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 6.11 (s, 1H), 6.86 (d, J=8.3 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.54 (dd, J=8.3 Hz, J=1.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.69, 51.85, 64.74, 112.67, 114.05, 122.21, 124.05, 145.46, 150.20, 166.88. MS (ISN): 195.0 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C(Cl)CCl.[CH:30]1[CH:35]=[N:34][C:33]2N(O)N=[N:38][C:32]=2[CH:31]=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[O:1]=[C:2]1[N:6]2[C:7]([C:11]([NH:38][C:32]3[CH:33]=[N:34][CH:35]=[CH:30][CH:31]=3)=[O:13])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=C(O)c1cccc2nn(CCc3ccc4ccccc4n3)c(=O)n12
Reactant: On1nnc2cccnc21
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cccc2nn(CCc3ccc4ccccc4n3)c(=O)n12
Temperature: 40 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a 1-dram vial was placed 8-1 (15 mg, 0.045 mmol) in anhydrous DMF (0.45 mL). To this solution was added EDC (8.0 mg, 0.045 mmol), HOAT (6.0 mg, 0.045 mmol), diisopropylethylamine (0.008 mL, 0.045 mmol), and 3-aminopyridine (0.001 g, 0.049 mmol). The reaction mixture was heated at 40° C. and stirred for 16 h. The crude reaction mixture was then directly purified by reversed phase HPLC to give 15.0 mg (80%) of 8-2. 1H NMR (500 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.84 (s, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.40 (d, J=5.0 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.64-7.55 (m, 2H), 7.53 (t, J=6.5 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.85 (d, J=6.5 Hz, 1H), 4.39 (t, J=7.6 Hz, 2H), 3.46 (t, J=7.6 Hz, 2H). HRMS (ES) 411.1546 (M+H) found, 411.1567 required.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Agent: Cl
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-naphthalen-1-yl-piperazine hydrochloride according to the above procedure. MS: APCI: M+1: 449.1 (Exact Mass: 448.23).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].B(F)(F)F.CCOCC>O1CCCC1.CCCCCC>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[S:8][CH3:9])[CH:23]=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CSc1ccc(Br)cc1OC1CCCC1
Reactant: CN(C)C=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene (13.2 g) in dry tetrahydrofuran (100 mL) under nitrogen is treated at -70° C. with a solution of butyllithium in hexane (20.24 mL; 2.5M) and the resulting solution is stirred for 1 hour at this temperature. It is then treated with dimethylformamide (7.12 mL), followed by boron trifluoride diethyl etherate (11.32 mL), keeping the temperature at -65° C. When the addition is complete the reaction mixture is allowed to warm to room temperature and is then poured into ice-water (450 mL) and extracted with dichloromethane (3×400 mL). The combined extracts are dried over magnesium sulfate and concentrated to give an oil, which is subjected to flash chromatography, eluting with a mixture of dichloromethane and cyclohexane (3:7 v/v), to give 3-cyclopentyloxy4-(methylthio)-benzaldehyde (6.2 g). [NMR (DMSO): 9.91(S,1H),7.53(dd,1H),7.36(d,1H), 7.33(d,1H),5.01 (m,1H),2.44(s,3H),2.01.5(m,8H)].
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[CH3:21])=[CH:14][CH:15]=1
Reactant: C[C@H](Oc1ccc(F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(F)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-fluoro-pyridine 310 mg (0.75 mmol) dissolved in toluene (5 mL) were added 0.10 mL (0.98 mmol) of 1-chloroethyl chloroformate and 0.17 mL (0.98 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 230 mg (85%) of the title compound as a light yellow oil. ES-MS m/e: 321.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)=[CH:10][C:11]2[N:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15]C)=[O:14])=[CH:5][CH:4]=1.N>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:15][C:13](=[O:14])[C:12]3[CH:17]=[CH:18][CH:19]=[N:20][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)c1cccnc1C=C(O)c1ccc(OC)cc1
Agent: N
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3ncccc3c(=O)[nH]2)cc1
Temperature: 1700 °C
Yield: 76.1 %

Procedure:
2-[2-(4-Methoxyphenyl)-2-hydroxyethenyl]-N-methylnicotinamide (2.509 g) was added to a 29% aqueous solution of ammonia (100 ml) and dioxane (50 ml), which was then heated in a sealed tube at 1700° C. overnight. After cooling as it was, the resulting insoluble matters were collected by filtration, to give the title compound as a dark green solid (1.694 g, yield; 73%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3ccc(Br)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-bromo-phenylamine to give N1-(4-bromo-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 424(MH+).
Reaction SMILES: CN(C)C=O.Cl.Cl[CH:8]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.C(OCC)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:8]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1cccnc1C(Cl)c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a dimethylformamide (5 ml) solution of the 2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94 mg, 0.32 mmol) obtained in Referential Example 4 were added 4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg, 1.92 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (103 mg, 89%) as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)nnnc12

Procedure:
Compound 1 was prepared following general synthetic scheme 7 wherein 3-trifluoromethyl-benzylamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [348 (M+1)], 1HNMR (400 MHz, DMSO-d6): δ 9.36-9.33 (m, 2H), 8.55-8.49 (m, 2H), 8.04 (s, 1H), 8.02-7.98 (m, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.59-7.56 (m, 1H), 5.00 (d, 2H).
Reaction SMILES: [N:1]1[NH:2]N=N[C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:24](Cl)(=[O:34])[C:25]1[CH:33]=[CH:32][CH:31]=[C:27]([C:28](Cl)=[O:29])[CH:26]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:34][C:24]([C:25]3[CH:33]=[CH:32][CH:31]=[C:27]([C:28]4[O:29][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[C:14]([C:18]7[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=7)[N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:1][N:2]=4)[CH:26]=3)=[N:2][N:1]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3cccc(-c4nn[nH]n4)n3)n2)nc1
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3cccc(-c4nnc(-c5cccc(-c6nnc(-c7cccc(-c8cccc(-c9ccccn9)n8)n7)o6)c5)o4)n3)n2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
2.0 g of 6-(2H-tetrazol-5-yl)-2,2′:6′2″-terpyridine was dissolved in 50 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 30 ml was dehydrated by azeotropy. After cooling to 50° C., 0.68 g of isophthaloyl dichloride was added. Temperature was elevated to 110° C., and stirring was conducted for 3 hours under flux. After cooling to room temperature, the reaction solution was poured into 200 ml water, and a precipitated yellowish-brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 1.53 g (yield 67%) of TpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.12 ppm (1H), 8.85 ppm (2H), 8.62-8.73 ppm (6H), 8.37-8.51 ppm (6H), 7.79-8.12 ppm (7H), 7.35 ppm (2H).
Reaction SMILES: ClCCN(CCCl)C(Cl)=O.[Cl:11][CH2:12][CH2:13][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:16][Cl:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:17][CH2:16][CH2:15][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:13][CH2:12][Cl:11].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42][C:21]([NH:20][C:18]([N:14]([CH2:13][CH2:12][Cl:11])[CH2:15][CH2:16][Cl:17])=[O:19])=[S:22])=[CH:43][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)N(CCCl)CCCl
Agent: O=C(N=C=S)N(CCCl)CCCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(CCCl)CCCl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
[Di(2-chloroethyl)amino]methanoyl isothiocyanate was prepared using commercially available N,N-di(2-chloroethyl)carbamic chloride (80 mg) as a starting compound according to the description of the literature. [Di(2-chloroethyl)amino]methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 55%).
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]([N+:15]([O-])=O)=[CH:11][CH:10]=1)#[N:2]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(N)cc1
Reaction time: 2.5 h

Procedure:
6.0 g (26.8 mmol) of 2'-cyano-4-nitrobiphenyl (prepared according to B. Sain, J. S. Sandhu, J. Org. Chem. 1990, 55, 2545) were dissolved in a mixture of 60 ml ethanol and 60 ml ethyl acetate, and the solution was filled into an autoclave. After addition of 660 mg 10% Pd on charcoal the mixture was set under an atmosphere of hydrogen (2-3 bar). The reduction was carried out at room temperature, the course of the reaction monitored by thin layer chromatography, and it had completed after 2.5 h. The catalyst was filtered and the solvent distilled off in vacuo. The title amine was obtained by crystallization from hexane as a white powder, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br)([O-])=O.O>CN(C)C=O.[Pt](=O)=O.C(O)C.O1CCCC1>[NH2:16][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=[Pt]=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(N)c2)cc1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (5.10 g, 28.3 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (in oil, 1.20 g, 30 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 hr. 3-Nitrobenzylbromide (6.72 g, 31.1 mmol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (50 mL) and ethanol (50 mL) was added platinum dioxide (350 mg) and the mixture was stirred under a hydrogen atmosphere for 16 hr. Insoluble materials were filtered off, and the filtrate was concentrated to give the title compound (7.73 g, yield 96%, 2 steps) as pale-yellow crystals.