Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
Add 3-phenyl-2,3-dihydro-1H-indole (Yamamoto, Y et al. Bull Chem. Soc. Jpn 44, 1971, 541-545) (0.158, 0.81 mmol), 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.266 g, 0.81 mmol), Et3N (0.161 g, 0.23 mL, 1.5 mmol) and DMAP (0.011 g, 0.09 mmol) to CH2Cl2 (25 mL) and stir at ambient temperature under N2 overnight. Dilute the reaction to 150 mL with CH2Cl2 and pour into saturated NaHCO3 (50 mL). Separate the organic layer and extract with 1M HCl (2×75 mL). Wash with brine, separate dry (MgSO4) filter and evaporate the filtrate. Chromatograph the residue on the ISCO using a gradient EtOAc-hexane system (0-100%) to give 0.167 g of the title compound. Mass spectrum (m/e) (M+1) 487.1492; Found: 487.1479.
Reaction SMILES: I[CH:2]1[C:11](=[O:12])[N:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][C@@H:9]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:8][CH2:7][CH2:6][C@H:5]3[N:10]2[C:11](=[O:12])[CH:2]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH2:3][CH2:4]3)=[CH:14][CH:15]=1
Reactant: COc1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(OC)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-3-iodo-6-(4-methoxyphenyl)octahydroquinolizin-4-one (34 mg) with triethyl phosphite (1 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 35 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([O:38][C:39](OC3C=CC([N+]([O-])=O)=CC=3)=[O:40])[CH2:34][CH2:33]2)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[O:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([N:32]2[CH2:33][CH2:34][CH:35]([O:38][C:39]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:40])[CH2:36][CH2:37]2)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCCCO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of triethylamine (65.5 mL, 0.47 mol) and 6-aminohexanol (13.2 g, 0.11 mol) in 300 mL of methylene chloride was added dropwise under nitrogen to a solution of the carbonate (45.0 g, 0.09 mol) produced in Example 3 in 500 mL of methylene chloride at room temperature. After the addition the solution was stirred at room temperature overnight. The reaction was extracted one time with 1N HCl and then multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 47.0 g of an off-white solid. Recrystallization from methylene chloride-diisopropyl ether gave 35.5 g (83%) of the title compound as a white crystalline solid, mp 69-72° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](C(O)=O)=[CH:4][CH:3]=1>[Cu-]=O.CN(C)C=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Temperature: 150 °C
Yield: 83.4 %

Procedure:
A mixture of 20 parts of 4-chloroanthraquinone-1-carboxylic acid, 200 parts of dimethylformamide and 3 parts of copper (I) oxide is heated for four hours at 150°C. The end product is precipitated by pouring the mixture into 400 parts of water and filtered. 14 parts (83.4% of theory) of 1-chloroanthraquinone is obtained having a melting point of 154° to 157°C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[C:18][CH2:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)C.O1CCCCC1OC1CCCCO1.C(O)(=O)C(O)=O>C(OCC)(=O)C>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][CH2:19][C:18]#[C:17][CH2:16][C:15]#[C:14][CH2:13][C:12]#[C:11][CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCC#CCC#CCC#CCC#CCSc1ccc(C)cc1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(SCC#CCC#CCC#CCC#CCCCC(=O)O)cc1
Reaction time: 18 h

Procedure:
1.7 g of 16-(p-methylthiophenoxy)hexadeca-5,8,11,14-tetraynoic acid ethyl ester was mixed with 168 ml of the pH 6.7 buffer solution prepared in accordance with Example 1. The mixture was vigorously stirred and 16.24g of Sigma Lipase, Type VII, from Candida cylindracea were added, stirring was continued for 18 hours at room temperature; the reaction mixture was then transferred to a separatory funnel with 200 ml ethyl acetate and acidified with saturated solution of oxalic acid. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combinedorganic extract was dried over sodium sulfate and the solvent removed undervacuo. The residue was purified by TLC on silica gel with a Chromatotron using hexane-ethyl acetate (60:40) as the eluant, to yield 16-(p-methylthiophenoxy)hexadeca-5,8,11,14-tetraynoic acid, which was recrystallized from methylene chloride-hexane. M.P. 87°-88° C. (dec).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]=O)[CH:7]=[CH:8][CH:9]=1.I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:27]=[N:28][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=N)NN)cc1
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(OC(F)(F)F)c3)n2)cc1

Procedure:
(3-Trifluoromethoxyphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (2.39 g, 8.16 mmol) using the method described in Example 1 to give 3-(4-methoxyphenyl)-5-(3-trifluoromethoxyphenyl)-[1,2,4]triazine as a yellow solid (1.10 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.45-7.49 (1H, m), 7.64 (1H, t, J 8.2 Hz), 8.14-8.18 (2H, m), 8.59-8.63 (2H, m), 9.53 (1H, s); m/z (ES+) 348.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[C:7]([NH:26][C:47](=[O:48])[CH2:46][C:43]3[CH:42]=[CH:41][C:40]([O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])=[CH:45][CH:44]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc(-c4cccs4)s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc(-c3cccs3)s2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Under an argon atmosphere, to a mixture of 3-(2,2′-bithiophen-5-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7m) (350 mg, 752 μmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11m (298 mg, crude) as a brown oily substance. Rf=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.22 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.64 (s, 2H), 6.76-6.85 (AA′BB′, 2H), 6.98-7.05 (AA′BB′, 2H), 7.06-7.13 (m, 2H), 7.19-7.27 (AA′BB′, 2H), 7.33 (d, 1H, J=3.6 Hz), 7.36 (d, 1H, J=3.6 Hz), 7.54-7.59 (m, 1H), 8.05-8.11 (AA′BB′, 2H), 8.91 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:53])([F:52])[C:17]1[CH:18]=[C:19]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:20][N:21]([C@H:28]1[CH2:34][CH2:33][CH2:32][NH:31][C:30]2[C:35]([CH3:44])=[C:36]([C:40]([F:43])([F:42])[F:41])[C:37]([CH3:39])=[CH:38][C:29]1=2)[C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH:67]=O)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55].C(O)(=O)C>ClCCCl.ClCCl>[F:53][C:16]([F:15])([F:52])[C:17]1[CH:18]=[C:19]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:20][N:21]([C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1)[C@H:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:67][CH:64]2[CH2:65][CH2:66][N:61]([C:59]([O:58][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:60])[CH2:62][CH2:63]2)[C:30]2[C:35]([CH3:44])=[C:36]([C:40]([F:41])([F:42])[F:43])[C:37]([CH3:39])=[CH:38][C:29]1=2
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCN(C(=O)OC(C)(C)C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 24 h

Procedure:
Add sodium triacetoxyborohydride (0.374 g, 1.76 mmol) portionwise to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 148, Step 2) (0.250 g, 0.441 mmol), tert-butyl-4-formylpiperidine-1-carboxylate (0.282 g, 1.32 mmol) and glacial acetic acid (0.2 mL) in 1,2-dichloroethane (3 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a white crushable foam (0.272 g, 81%). 1H NMR (CDCl3, 500 MHz) δ 0.87-1.14 (m, 3H), 1.24-1.34 (m, 1H), 1.45 (s, 9H), 1.61-1.97 (m, 7H), 2.30-2.33 (m, 6H), 2.65-2.75 (m, 2H), 2.86-2.89 (m, 2H), 2.95-3.11 (m, 1H), 3.25-3.28 (m, 1H), 4.13 (s, 3H), 4.81-4.88 (m, 1H), 5.21 (br s, 1H), 5.60 (br s, 1H), 6.57 (s, 1H), 7.77 (s, 3H); ESI MS m/z 764 [C35H42F9N7O2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([C:36](O)=[O:37])[CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][C@:2]12[CH2:14][CH2:13][NH:12][C@H:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C@H:3]2[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[C:20]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[C:35](O)=[O:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[CH3:1][C@@:2]12[CH2:14][CH2:13][N:12]([C:35]([C@H:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]3[NH:28][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:36])[C@@H:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C@@H:3]2[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Reactant: C[C@]12CCN[C@H]1c1ccccc1N[C@H]2c1ccsc1
Agent: CCOC(=O)OC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@]12CCN(C(=O)[C@H]3CCCC[C@H]3NC(=O)c3ccccc3)[C@@H]1c1ccccc1N[C@@H]2c1ccsc1
Reaction time: 0.17 h
Yield: 7.9 %

Procedure:
To a mixture of (3aS*,4R*,9bR*)-3a-methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (750 mg, 2.77 mmol), (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (685 mg, 2.77 mmol), triethylamine (606 mg, 6.10 mmol), acetonitrile (14 ml) and tetrahydrofuran (14 ml) was added DEPC (500 mg, 3.05 mmol) under ice-cooling, and the mixture was stirred for 10 min. The mixture was allowed to return to room temperature and stirred for 12 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (4:1-1:1, v/v) to give the title compound (3aR,4R,9bR) (110 mg, 8%) as an amorphous form from the first eluted fraction.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:36]1[C:48]2[NH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]=2[CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:45]3[C:46]4[NH:47][C:48]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:41]=4[CH:42]=[CH:43][CH:44]=3)=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(C(=O)c2ccccc2NC(Cc2ccc(OCCc3cccc4c3[nH]c3ccccc34)cc2)C(=O)O)cc1
Yield: 46.8 %

Procedure:
To a solution of 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.26 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.14 g, 47%). HRMS calcd for C40H38N2O4: 610.7496. Found: 610.7493. MA calcd for C40H38N2O4: C, 78.66%; H, 6.27%; N, 4.59%. Found: C, 78.85%; H, 6.24%; N, 4.61%.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20](SC)[N:19]=3)=[CH:16][C:15]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]3)=[CH:14][N:13]=2)=[CH:7][CH:6]=1.CC(O)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:2][CH3:1])[N:19]=3)=[CH:16][C:15]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:32][CH2:33]3)=[CH:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Reactant: CN
Solvent: CC(C)O
Product: CNc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc(OC)nc2)n1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Methylamine was bubbled through a mixture of N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (33 mg, 0.064 mmol) in IPA (1.50 mL, 19.47 mmol) for 15 min and then allowed to stand overnight. The resulting precipitate was collected by filtration and washed with a minimal amount of IPA to give 4-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,6-dimethyl-1,3,5-triazin-2-amine (17.1 mg, 1.761 mmol, 54.7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) mixture of rotamers δ 11.26-12.03 (m, 1H); 8.73 (d, J=13.69 Hz, 1H); 8.38-8.63 (m, 1H); 7.96-8.38 (m, 3H); 6.83 (d, J=8.41 Hz, 1H); 3.84 (br. s., 3H); 3.50 (d, J=12.72 Hz, 2H); 3.11 (br. s., 4H); 2.90-3.03 (m, 3H); 2.86 (br. s., 3H); 2.47-2.50 (m, 4H); 2.44 (br. s., 3H). m/z (ESI, +ve ion) 500.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:19]([OH:21])[CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[N:9]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[C:10]([CH3:24])([CH3:25])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)[CH3:20])(=[O:28])[CH3:27]
Reactant: CC(O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Reaction time: 24 h

Procedure:
A solution of 2.5 g (7.34 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 10 ml of acetic acid anhydride and 10 ml of pyridine is left to stand at room temperature for 24 hours and then concentrated in vacuo. The residue is taken up in chloroform and the organic phase is washed successively with 2 N hydrochloric acid, 2 N sodium bicarbonate solution and water, dried and evaporated. The residue is chromatographed on 50 g of silica gel using chloroform as the elution agent. There is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ethyl acetate as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].Cl.[Cl:19][C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C(N(CC)CC)C.C(OC(=O)C)C>CN(C)C=O.C(Cl)Cl>[ClH:1].[Cl:19][C:20]1[N:25]=[C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=4[S:7]3(=[O:17])=[O:16])[CH2:30][CH2:31]2)[CH:23]=[N:22][CH:21]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCCl
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 48 h

Procedure:
The title compound is prepared by dissolving 2.5 g (0.008 mol) of 2-(4-chlorobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide in 50 ml of dimethylformamide and to that solution 2.5 g (0.01 mol) of 1-(6-chloro-2-pyrazinyl)piperazine hydrochloride and 5 ml of triethylamine are added. Stirring is continued for 48 hours. The solvent is removed under reduced pressure and the residue is partitioned between water and methylene chloride. The methylene chloride extracts are combined, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give crude base. Preparative HPLC (silica gel; ethylacetate:methylene chloride (9.1)) gives, following evaporation of the appropriate fractions (Rf 0.5), the title compound, which is converted to the hydrochloride salt; mp 246°-249° C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:23][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1cc(F)cc(F)c1
Product: Nc1nnc(Oc2cc(F)cc(F)c2)c(-c2ccccc2)n1
Yield: 16.9 %

Procedure:
6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (101 mg, 17%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,5-difluorophenol (0.31 g, 3.98 mmol) according to the general procedure of Example 3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N:18]([CH2:22][CH2:23][Cl:24])[CH2:19][CH2:20][Cl:21])[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH2:5][CH2:6][Cl:7]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N:18]([CH2:19][CH2:20][Cl:21])[CH2:22][CH2:23][Cl:24])[CH:17]=1)[C:11]([OH:13])=[O:12])[CH2:5][CH2:6][Cl:7]
Reactant: COC(=O)c1cc(N(CCCl)CCCl)cc(N(CCCl)CCCl)c1
Agent: Cl
Product: O=C(O)c1cc(N(CCCl)CCCl)cc(N(CCCl)CCCl)c1
Temperature: 50 °C
Yield: 65.7 %

Procedure:
A suspension of 1.59 g (3.82 mmol) of methyl 3,5-bis[N,N-bis(2-chloroethyl)amino]benzoate in 48 ml of concentrated hydrochloric acid was heated at 50° C. for 5 hours. After completion of the reaction, the suspension was extracted with methylene chloride. The extract was washed with an aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and was then concentrated. The resultant residue was purified by flush chromatography (methanol/chloroform=1/20), whereby 1.01 g of the title compound were obtained as colorless crystals.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6]>O.O1CCOCC1.C(OCC)(=O)C>[Cl:2][C:3]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: N
Reactant: O=C(Cl)c1cc(C(F)(F)F)cnc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of ammonia in water was treated with a solution of 2-chloro-5-(trifluoromethyl)nicotinoyl chloride (as prepared in the previous step, 1.18 g, 4.8 mmol) in dioxane. After stirring at ice bath temperature for 1 hour, the resulting precipitate was dissolved in ethyl acetate and the organic extract dried over anhydrous sodium sulfate. Concentration in vacuo followed by drying on the high vacuum afforded the product as a white solid.