Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:16][N:17]([CH3:19])[N:18]=2)[NH:6][C:7]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:24][N:25]1[CH2:30][CH2:29]N[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([Cl:15])=[CH:10][C:8]2[N:9]=[C:3]([N:2]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:4]3[C:5](=[N:16][N:17]([CH3:19])[N:18]=3)[NH:6][C:7]=2[CH:13]=1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(Cl)c(Cl)cc1N2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cc(Cl)c(Cl)cc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-6,7-dichloro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (0.84 g) was added to a mixture of dry dimethylsulphoxide (5 ml), toluene (5 m) and N-methylpiperazine (1 ml), which had been purged with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil bath) under nitrogen for 16 hours, cooled to room temperature, and distilled water (10 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow-brown solid which was recrystallised from ethyl acetate/n-hexane to give a yellow crystalline solid, melting point 217.5°-218.5° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][NH:13][CH2:14][C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][N:13]([CH3:12])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CNCc1ccco1
Solvent: CCO
Product: CN(Cc1ccco1)c1ccc2c(c1)CCC2=O

Procedure:
A solution of 5-fluoro-1-indanone (1.0 g, 6.66 mmol) and N-methylfurfurylamine (2.0 g, 18.0 mmol) in ethanol (10 mL) was heated to about 80° C. for about 2 days. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (2:1) as the mobile phase to provide the desired product. MS (ESI): m/z 242 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl.[CH2:10]([O:12][C:13](=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)[CH3:11].C([BH3-])#N.[Na+]>CO>[ClH:22].[CH2:10]([O:12][C:13]([C:14]1[N:6]([CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:16]=1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18]2)=[O:31])[CH3:11]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g. of 2-diethylaminoethylamine in 10 ml. of methanol is treated with 2 ml. of 5-N methanolic hydrochloric acid. Then, there are added successively under argon at 20°-25° C. a solution of 1.6 g. of o-benzoyl-p-chlorophenylglyoxylic acid ethyl ester in 5 ml. of methanol and 0.2 g. of sodium cyanoborohydride and the mixture is stirred for an additional 7 hours at room temperature. While cooling with ice, the mixture is made acidic with concentrated hydrochloric acid, stirred for an additional 0.5 hour at room temperature and evaporated to dryness under reduced pressure. The residue is made alkaline with 1-N sodium hydroxide with addition of ice and extracted with 50 ml. of ether. The ethereal extract is treated with 20 ml. of 0.5-N hydrochloric acid, and the mixture shaken thoroughly. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[2 -(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18]([O:22]COCCOC)=[C:19]([F:21])[F:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18](=[O:22])[CH:19]([F:20])[F:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCOCOC(=C(F)F)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3-chloro-7-{2,2-difluoro-1-[(2-methoxyethoxy)methoxy]vinyl}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (50 mg, 0.12 mmol) in a mixture of methanol (0.6 mL) and dichloromethane (0.6 mL) was added chlorotrimethylsilane (0.08 mL, 0.61 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.84 (d, 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.93 (dd, 1H), 7.76 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 5.79 (t, 1H). LRMS (APCI) calc'd for (C16H9ClF2NO2) [M+H]+, 320.0; found 320.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c[nH]1
Temperature: 0 °C
Yield: 53.6 %

Procedure:
Ethylpyrrole-2-carboxylate (2.0589 g, 14.80 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.9913 g, 29.93 mmol) and 4-fluorophenylacetyl chloride (5.1338 g, 29.75 mmol) in dichloroethane (22 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 3.5 h. 20.6195 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. When 6.5 mL of 80:20 Hexanes:EtOAc were added, the organic liquid turned yellow, leaving behind a tan solid. The solid was removed by filtration, rinsed with 80:20 Hexanes:EtOAc, and dried to obtain pure 71 (2.1838 g, 53.6%). 1H (CDCl3, 400 MHz): δ 10.03 (1H, broad s), 7.54 (1H, s), 7.32 (1H, s), 7.23 (2H, dd, J=8.6, 5.3 Hz), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, q, J=7.1 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.81, 161.84 (d, J=244 Hz), 160.95, 130.89 (d, J=7.8 Hz), 130.37 (d, J=3.2 Hz), 126.72, 126.36, 124.30, 115.40 (d, J=21.4 Hz), 114.96, 61.02, 45.63, 14.29 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.29; CH2 carbons: 61.02, 45.63; CH carbons: 130.89 (d, J=7.8 Hz), 126.72, 115.40 (d, J=21.4 Hz), 114.96 ppm. HPLC: 9.689 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:6]([NH:8]C(=O)C(F)(F)F)[CH:7]=1.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([CH2:30][C:31]2[CH:32]=[C:33]([O:46][CH2:47][CH3:48])[C:34](I)=[C:35]([O:37][S:38]([CH:41]([CH2:43][CH3:44])[CH3:42])(=[O:40])=[O:39])[CH:36]=2)=[CH:25][N:24]=1>>[NH2:8][C:6]1[CH:7]=[C:2]([C:34]2[C:33]([O:46][CH2:47][CH3:48])=[CH:32][C:31]([CH2:30][C:26]3[C:27]([NH2:29])=[N:28][C:23]([NH2:22])=[N:24][CH:25]=3)=[CH:36][C:35]=2[O:37][S:38]([CH:41]([CH2:43][CH3:44])[CH3:42])(=[O:39])=[O:40])[CH:3]=[CH:4][C:5]=1[CH2:15][N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=C(Nc1cc(Br)ccc1CN1CCOCC1)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1-c1ccc(CN2CCOCC2)c(N)c1
Yield: 57.7 %

Procedure:
Starting from 308 mg (0.84 mmol) N-(5-bromo-2-morpholin-4-ylmethyl-phenyl)-2,2,2-trifluoro-acetamide and 214 mg (0.422 mmol) butane-2-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 139 mg of the title compound are obtained as pale brown crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:14][CH:13]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[OH:3][CH2:4][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C2=C(CO)CCCC2)cc1)c1c(F)cccc1F
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To the solution of Compound 99 (645 mg, 1.67 mmol) in THF (10 mL) was added LAH (320 mg, 8.4 mmol) at room temperature. After 10 min, the reaction was added 1N NaOH (5 mL) and H2O (10 mL) and extracted with ethyl acetate (EtOAc) (30 mL). The organic phase was collected, dried and concentrated. Column chromatography afforded Compound 22 (485 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.59-7.56 (m, 2H), 7.45-7.35 (m, 1H), 7.17-7.13 (m, 2H), 7.13-6.94 (m, 2H), 3.95 (s, 2H), 2.31-2.21 (m, 4H), 1.78-1.64 (m, 4H); ESMS cacld (C20H13F2NO2): 343.1; found: 344.1 (M+H).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([CH2:23][CH2:24][CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9]([CH2:23][CH2:24][CH3:25])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Yield: 87.6 %

Procedure:
A 2M aq. LiOH sol. (44 ml) was added to a solution of 4.3 g (13.7 mmol) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 44 ml) and the mixture was subsequently heated to 60° C. for 72 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with ether, set at pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 3.6 g (12.0 mmol, 88%) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: C(OC([N:8]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:14][CH2:13]1)[CH:9]([CH3:11])[CH3:10])=O)(C)(C)C.Cl>O1CCOCC1>[CH:9]([NH:8][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:16][CH2:17]1)([CH3:11])[CH3:10]
Reactant: COc1ccncc1CN1CCC(N(C(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccncc1CN1CCC(NC(C)C)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 4-(N-tert-butoxycarbonyl-N-isopropylamino)-1-(4-methoxypyrid-3-ylmethyl)piperidine (17.0 g, 0.047 mol) in dioxane (93 mL) was cooled to 5° C. in ice/water bath. To this solution was added concentrated hydrochloric acid (40 mL) and the resulting mixture was stirred 5° C. for 15 minutes. The ice/water bath was then removed and the reaction mixture was stirred for 12 hours. The reaction mixture was then concentrated in vacuo to dryness, diluted with dichloromethane (100 mL) and 10 N aqueous sodium hydroxide was added slowly (CAUTION: very exothermic) until the pH was 14. The mixture was stirred for 0.5 hours and the organic layer was then separated and the aqueous layer was washed three times with dichloromethane (200 mL). The organic layers were then separated and dried over sodium sulfate (10 g). The sodium sulfate was removed by filtration and the organic layer was concentrated in vacuo to give 7.8 g of the title intermediate as a yellow oil (65% yield; 83% purity by GC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:15][C:16]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:33])[CH:28]([NH2:32])[CH2:29][CH2:30][CH3:31])=[N:23][N:22]=1)([CH3:20])[CH2:17][CH2:18][CH3:19].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH3:20][C:16]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:33])[C@@H:28]([NH:32][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:29][CH2:30][CH3:31])=[N:23][N:22]=1)([CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)CCC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)CCC)s1
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (182 mg, 1.0 mmol), 2-amino-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide HCl (321 mg, 1.0 mmol) in methylene chloride (25 mL) was treated with triethyl amine (0.14 mL), then acetic acid (0.27 mL) and sodium sulfate. After stirring for 15 min, 95% pure sodium triacetoxy borohydride (424 mg, 2.0 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was quenched with dilute water and extracted with methylene chloride. The organic layer was washed with dilute sodium bicarbonate to pH 8, separated, dried and concentrated to give 394 mg of the title compound as a yellow glass foam, LC-MS, RT=2.6 min, M+1=451.0. The glass foam was purified by HPLC to give the trifluoroacetic acid salt of the title compound as a solid.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:13]([CH2:27][CH2:28][OH:29])[S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>C(Cl)(Cl)Cl>[CH2:7]([N:13]([CH2:27][CH2:28][O:29][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN(CCO)S(=O)(=O)c1cccc2cnccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 70 ml of pyridine were added 5.24 g of N-hexyl-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide and 3.39 g of p-toluenesulfonyl chloride. The resulting mixture was stirred at 60° C. for 4 hours. Then, the pyridine was removed under reduced pressure to obtain an oily residue. To the residue were added 50 ml of chloroform and 20 ml of an aqueous hydrochloric acid solution having a pH of 2, and the chloroform layer was dried with anhydrous magnesium sulfate. Then, the chloroform was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: a 3% methanol solution in chloroform) to obtain 2.60 g of N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([O:27][CH2:28][C:29](O)=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:32])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.F[P-](F)(F)(F)(F)F.[N:54]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:58]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][N:8]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[C:22]([O:27][CH2:28][C:29]([NH:54][CH3:58])=[O:30])[CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][C:18]4=[O:32])[CH2:11][CH2:10]3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(OCC(=O)O)cccc32)CC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 5 mL of an N,N-dimethylformamide solution containing 88 mg of (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid and 41 mg of methylamine hydrochloride, 183 mg of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and 0.11 mL of N,N-diisopropylethylamine were added, and stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with a mixture of ethyl acetate: toluene=5:1. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform: methanol=10:1], to give 89 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-((methylamino)carbonylmethyloxy)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:27]12CC(C=C1)C=[CH:28]2.C1(C)C(C)=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: C1=CC2C=CC1C2
Reactant: Brc1ccc(-c2nnc(-c3ccccn3)nc2-c2ccc(Br)cc2)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(-c3ccccn3)nc2-c2ccc(Br)cc2)cc1
Temperature: 140 °C
Yield: 59.6 %

Procedure:
In a 500 mL three-neck flask were put 13 g (27 mmol) of 5,6-bis(4-bromophenyl)-3-(2-pyridyl)-1,2,4-triazine, 9.0 mL (83 mmol) of 2,5-Norbornadiene, and 150 mL of xylene. This mixture was refluxed at 140° C. for 5 hours under a nitrogen stream. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The extract was washed with a saturated saline together with the organic layer, and the organic layer was then dried with magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The solid was refined with silica gel column chromatography (toluene), so that a target substance, 7.5 g of light-yellow powder was obtained in a yield of 59%.
Reaction SMILES: NC1[N:11]=[C:10]([O:12]C)C2C(=NC=CN=2)N=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=C=O)(=[O:24])=[O:23]>C(Cl)Cl>[F:29][C:15]([F:14])([F:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:10](=[O:12])[NH2:11])(=[O:24])=[O:23]
Reactant: COc1nc(N)nc2nccnc12
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: NC(=O)NS(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
0.88 g (0.005 mol) of 2-amino-4-methoxypteridine and 1.30 g (0.0052 mol) of 2-trifluoromethylphenylsulfonyl isocyanate were reacted in 40 ml of methylene chloride according to Example 4 to obtain 2.0 g (94% of theory) of N-4-methoxypteridin-2-yl)-N'-(2-trifluoromethylphenylsulfonyl)-urea in the form of light yellow crystals melting at 187° C.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=O)=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([CH2:64][NH2:65])[OH:63]>CN(C=O)C>[OH:63][CH2:62][CH2:64][NH:65][C:26]([C:10]1[C:11](=[O:25])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:13]([CH3:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=2)[CH:9]=1)=[O:28]
Reactant: NCCO
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCCO)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1, 70 mg, 0.102 mmol), TBTU (37 mg, 0.115 mmol), DIPEA (40 μL, 0.234 mmol) in DMF (0.5 mL) is stirred for 15 min at room temperature. Ethanolamine (7 μL, 0.116 mmol) is added and the reaction mixture is stirred for 1.5 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 16 mg (34% of theory); ESI mass spectrum: [M+H]+=456; Retention time HPLC: 1.34 min (Z002—005).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.O1CCCC1.[Ni]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1F
Yield: 99.4 %

Procedure:
141 g of methyl 2-fluoro-4-nitrobenzoate was dissolved in 1000 ml of methanol and 400 ml of tetrahydrofuran, 20 g of Raney nickel was added to it, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain 119 g of methyl 4-amino-2-fluorobenzoate.