Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCC/C(=C\c1ccc(-c2cccc(NC)c2)cc1)C(=O)OCC
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CCC)C(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
172 μL (1 mmol) of heptyl isocyanate are added to 251 mg (0.8 mmol) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]pentanoate (prepared according to Example 8a). The reaction mixture is heated at 100° C. in an Emrys Optimizer microwave oven for 20 minutes. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 361 mg (100%) of ethyl 2-[1-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]pentanoate are obtained in the form of a yellowish oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[S:35][C:32]1[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: Cc1ccc(S)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of D-mannose pentaacetate (16.0 g, 0.041 mol) and p-thiocresol (7.6 g, 0.0615 mol) in CH2Cl2 (200 mL), boron trifluoride diethyl etherate (6.8 mL, 0.0533 mol) was added. The mixture was stirred overnight. The reaction mixture was then diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3 (2×120 mL) and water (100 mL). The organic layer was dried over Na2SO4. The solvent was removed, and the residue was purified by column chromotography on silia gel (hexanes/EtOAc 3:1) to give product (16.2 g, 87%) as a syrup: 1HNMR (500 MHz, CDCl3), δ 7.38 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.49 (dd, 1H, J=2.5, 1.5 Hz), 5.42 (d, 1H, J=1.0 Hz), 5.30–5.35 (m, 2H), 4.54–4.58 (m, 1H), 4.30 (dd, 1H, J=12.5, 6.0 Hz), 4.11 (dd, 1H, J=12.0, 2.5 Hz), 2.33 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); HRMS (M+Cs) calcd for C21H26O9SCs 587.0352. found 587.0331.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:20]3[C:28]([O:29][CH3:30])=[CH:27][C:26]([CH3:31])=[C:25]4[C:21]=3[CH:22]=[CH:23][N:24]4C(OC(C)(C)C)=O)([NH:13]S(C(C)(C)C)=O)[CH3:12])=[N:8][C:7]=2[CH:39]=1)#[N:2].Cl>O1CCOCC1>[NH2:13][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:39][C:7]=2[N:8]=1)([C:20]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([CH3:31])=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2)[CH3:12]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C)c2[nH]ccc2c1C(C)(N)c1nc2cc(C#N)ccc2o1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (120 mg, 0.218 mmol) in dioxane (1 mL) was added 4M HCl in dioxane (2.2 mL, 8.72 mmol) and the mixture was stirred at 60° C. After 2 hours the reaction was cooled in an ice bath and quenched with 30% aq. NH4OH (2.18 mL). Water was added, the layers were separated and the aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc:Heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (br. s., 1H) 8.29 (dd, J=1.39, 0.88 Hz, 1H) 7.72-7.85 (m, 2H) 7.28 (t, J=2.84 Hz, 1H) 7.05-7.16 (m, 1H) 6.64 (s, 1H) 3.19 (s, 3H) 2.59 (br. s., 2H) 2.43 (s, 3H) 1.90 (s, 3H). HRMS calcd. for C20H18N4O2 (M+H)+ 347.1503. found 347.1486.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH2:25]=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1.CO>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CO
Solvent: CCO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Following the same procedure as described for (−) (18), cinchonidine (8.61 g, 29.3 mmol) in hot ethanol (175 mL) was added to a solution of (±)20 (10.0 g, 29.3 mmol) in hot ethanol. The solution was allowed to cool to room temperature and a portion of the solvent was removed under reduced pressure. Crystals obtained were collected by filtration, 6.6 g, mp 204-205° C. The optical rotation was measured at 21° C.: [α]D−73.3° (c=0.5, methanol). The salt was recrystallized from ethanol to give fluffy white crystals, 3.7 g, mp 206-207° C. The optical rotation was measured at 21° C.: [α]D−74.2° (c=0.5, methanol). The acid was recovered from salt, as described previously for (−)18, to obtain a white solid, 1.7 g. mp 150-15 1° C. The optical rotation was measured at 21° C.: [α]D−28.4° (c=1.2, methanol). Anal:(C20H23NO4); Calculated C 70.36, H 6.79, N 4.10; found C 70.17, H 6.86 and N 4.05
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[C:5]=1[OH:24].BrC1C=CC=CC=1O.[CH2:34]([N:36]([CH2:49][CH3:50])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41](F)=[C:40]([N+]([O-])=O)[CH:39]=1)[CH3:35].FC1C=C(C=CC=1[N+]([O-])=O)C#N>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:24][C:42]3[C:41](=[CH:40][CH:39]=[C:38]([C:37](=[O:48])[N:36]([CH2:49][CH3:50])[CH2:34][CH3:35])[CH:43]=3)[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)[C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:25]
Reactant: COC(=O)c1cccc(NC2CCN(Cc3ccccc3)CC2)c1O
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Oc1ccccc1Br
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(C(=O)OC)cccc1N2C1CCN(Cc2ccccc2)CC1

Procedure:
Using an adaptation of the method described in Procedure 1, substituting 3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester, 2l for 2-bromophenol, and N,N-diethyl-4-fluoro-3-nitrobenzamide for 3-fluoro-4-nitrobenzonitrile, the title compound 10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxylic acid methyl ester, 3l was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=O)[CH2:13][Cl:14])[C:3]=1[C:4]([OH:6])=O.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(N(CC)CC)C.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[C:12]([CH2:13][Cl:14])=[N:11]2
Reactant: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Reactant: NCc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Temperature: 110 °C
Yield: 58.8 %

Procedure:
To a stirred mixture of compound (7a) (7.50 g, 27.4 mmol), 2-chlorobenzylamine (5.00 mL, 41.05 mmol) and triethylamine (5.70 mL, 41.1 mmol) in toluene (250 mL) was added a solution of phosphorus trichloride (2.60 mL, 30.1 mmol) in toluene (250 mL) dropwise over 1 hr. The reaction mixture was heated to 110° C. for 24 hr, whereupon the hot solution was decanted and concentrated in vacuo. The residue was triturated with propan-2-ol (50 mL) to afford the title compound (8) (6.41 g, 59%) as a yellow solid: m/z 397/399 (M+H)+ (ES+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C)C=O>[CH2:19]([C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:11]=[CH:12][C:7]=1[C:29]#[C:28][C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCN1c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCCN1c1ccc(C#C[C@@]2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 200 mg of 2-benzyl-4-[2-pyrrolidinon-1-yl]phenyl trifluoromethanesulfonate (Production Example 5), 80 mg of (3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 30 mg of tetrakis(triphenylphosphine)palladium (0), 5 mg of copper (I) iodide and 0.2 ml of triethylamine was added 1 ml of N,N-dimethylformamide, followed by heating under stirring under nitrogen atmosphere in an oil bath at 80° C. for 3 hours. After standing to cool, aqueous ammonia was added to the reaction mixture, which then was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by NH-silica gel column chromatography with ethyl acetate, to give 66 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[NH:14]1[C:22]2[C:17](=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.C(N(CC)CC)C.CN(C=O)C>O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH:16]=[CH:15][NH:14]3)[CH2:24][CH2:25]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1NCCCl
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCCN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A mixture containing 0.49 g of N-(2-chloroethyl)-2-nitroaniline, prepared according to the procedure described by Ramage G. R. et al. in J. Chem. Soc. 4406-4409 (1952), 0.55 g of 1-(4-indolyl)piperazine (prepared according to WO 95/33743), 1 mL of triethylamine and 3 mL of DMF was heated at reflux while stirring under nitrogen for 2.5 h. After cooling at room temperature, the mixture was poured into H2O, extracted with CH2Cl2, and the organic phase dried on anhydrous Na2SO4 and evaporated to dryness. The residue was purified via flash chromatography (EtOAc-petrolium ether 3:7) giving 0.35 g (40%) of the title compound.
Reaction SMILES: [C:1]([N:6]=C=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)[C:14]=1[OH:24])(C)(C)C.[CH3:25][SH:26]>ClCCCl>[C:1]([NH:6][C:25](=[S:26])[O:24][CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)N=C=O
Reactant: CS
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=S)OC

Procedure:
To a solution of methacryloyl isocyanate (4.9 g; 44 mmol) in 1,2-dichloroethane (12 ml), 2,6-di-t-butyl-4-methylphenol (50 mg) was added, and the resultant solution was ice-cooled. Methylmercaptan gas and nitrogen gas were blown into the solution. After completion of the reaction, the solvent was removed by evaporation under reduced pressure to give methyl N-methacryloylthiocarbamate (4.98 g), which was recrystallized from a mixture of hexane and benzene to give colorless prisms. M.P., 66°-68° C.
Reaction SMILES: B#B.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7][CH2:6][C:5]1=O.Cl.N>O1CCCC1.O>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:7][CH2:6][CH2:5]1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: B#B
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CN1CCNC(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 7.5 h
Yield: 94.9 %

Procedure:
To a solution of 50 ml of 1.07 M diborane in tetrahydrofuran was added with stirring 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one at room temperature, and the mixture was refluxed with stirring for 7.5 hours. After having been left standing overnight, 5 ml of water followed by 5 ml concentrated hydrochloric acid was added to decompose the excess diborane, and the mixture was refluxed for one hour. After cooling, the solution was neutralized with concentrated ammonia, and extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was ramoved under reduced pressure. The residue was recrystallized from n-pentane to obtain 1.30 g of 1-methyl-5-phenyl-7-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, melting at 66° to 68° C.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22]([O:24]C4C=CC([N+]([O-])=O)=CC=4)=O)[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH2:43].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH:43][C:22]([C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-fluoro benzyl)-1-methoxy-9H-4-carbazole carboxylate (50 mg, 0.106 mmoles) in dry DMF (4 ml) under nitrogen atmosphere, 3,5dichloro-4-amino pyridine (17.34 mg, 0.106 mmoles) was added followed by sodium hydride (60% suspension, 8.5 mg, 0.212 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 15 mg of the title compound as an off white solid, m.p: 222-225° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CN[CH:15]1[CH2:20][CH2:19]C[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:3]1([N:2]([CH:4]=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[OH:12])[CH3:1])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1
Reactant: CNC1CCCCC1
Reactant: CN(C)C=Nc1ccncc1O
Solvent: Cc1ccccc1
Product: CN(C=Nc1ccncc1O)C1CCCCC1
Yield: 83.8 %

Procedure:
A mixture of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (5.00 g), N-methylcyclohexylamine (5.20 g), and anhydrous toluene (50 mL) was heated at reflux under nitrogen for 17 hours. The solution was concentrated under reduced pressure and the crude product chromatographed on silica gel (10% methanol in dichloromethane) to afford 5.92 g of solid. Recrystallization from ethyl acetate/hexanes afforded 4.90 g of crystalline material, m.p. 127°-129° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][CH2:24][C:25](Br)=[O:26]>C(Cl)(Cl)Cl.O>[Br:21][CH2:22][CH2:23][CH2:24][C:25]([NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=[O:26]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CCCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCBr
Yield: 63.1 %

Procedure:
To a solution of 2,6-diisopropylaniline (1.77 g, 10 mmol) in chloroform (30 ml) was added triethylamine (1.11 g, 11 mmole), then 4-bromobutyryl bromide (1.95 mg, 10.5 mmol) was slowly dropped thereinto with ice cooling and the mixture was made to react for 20 minutes. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with 0.5N HCl, water, aqueous solution of sodium bicarbonate and saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (120 g of silica gel; developing solvent, hexane:acetone=7:1→5:1) and the resulting crude crystals were recrystallized from hexane-acetone to provide 2.06 g (yield 63%) of 4-bromo-N-(2,6-diisopropylphenyl)butyramide as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:21]C(C)([O-])C.[K+].C1COCC1.IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: O=S(=O)(c1ccc(F)cc1)c1c[nH]c2ccc(Br)cc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred solution of 5-bromo-3-(4-fluoro-benzenesulfonyl)-1H-indole (0.315 g, 0.89 mmole) in tetrahydrofuran (4 mL) was added 1M potassium t-butoxide/THF (1.0 mL, 1.0 mmol). After 10 minutes iodomethane (0.16 g, 1.1 mmole) was added. The reaction mixture was stirred at room temperature overnight and then passed through a pad of silica gel (230–400 mesh) eluting with 50% ethyl acetate/hexane. The eluate was concentrated under reduced pressure to provide a residue that was crystallized from ethanol/hexanes to give 0.3 g of 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14](C(=O)C(Cl)(Cl)Cl)[CH2:13]2)(=[O:9])=[O:8].[OH-].[K+].C(O)(=O)C>CCO.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CNC2

Procedure:
2-(2,2,2-Trichloro-acetyl)-2,3-dihydro-1H-isoindole-5-sulfonic acid thiazol-2-ylamide (0.10 g, 0.23 mmol) and KOH (0.03 g, 0.46 mmol) were stirred in a mixture of EtOH (0.5 mL) and H2O (0.13 mL) for 19 h at room temperature. The solution was acidified with acetic acid and concentrated in vacuo. The white solid was used in the next step without further purification. LC/MS (10-99% CH3CN), M/Z: M+1 obs=282.3; tR=2.62 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:22]([CH3:34])=[N:21]1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[N:20]([CH3:19])[N:21]=[C:22]([CH3:34])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C)n1
Product: CCCNC(=O)c1nnc2c(-c3cc(C)nn3C)cccc2c1N
Yield: 21.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (200 mg, 0.647 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (288 mg, 1.297 mmol) were reacted to afford the title compound (45 mg, 21% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].S(=O)(=O)(O)O.CCOCC>O1CCOCC1>[O:14]=[C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([CH3:15])[CH:17]=3)[O:20][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cccc(-c2nc3c(o2)C(=O)c2ccccc2C3=O)c1
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a solution of 5 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 70 mL of dioxane, one adds, with protection from light, 32.00 mL (240 mmol) of 3-methylbenzoic acid chloride; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid is added. After 45 min of reflux and complete cooling, 200 mL of ether are added, and the precipitate that forms is eliminated by filtration. The red filtrate is evaporated to dryness, redissolved in dichloromethane, washed several times with water, dried and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals formed after evaporation of the solvent are uncolored and recrystallized in dichloromethane to produce 3 g of 4,9-dihydro-4,9-dioxo-2-(3-methylphenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)([O-:3])=[O:2].[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:31][C:28]([CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:20][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[O:7][C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: O=C(O)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCC(CNC(=O)c2cccnc2Oc2cccc([N+](=O)[O-])c2)CC1

Procedure:
A solution of 2-(3-nitro-phenoxy)-nicotinic acid (86.9 mg, 0.33 mmol), trans-2-(4-Aminomethyl-cyclohexyl)-propan-2-ol (57.2 mg, 0.33 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (148 mg, 0.33 mmol), and diisopropylethyl amine (0.29 mL, 1.67 mmol) in 10 mL of dry DMF was stirred overnight. The solution was then diluted with ethyl acetate and washed with water, 5% citric acid, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and concentrated to an oil. Purified through a pad of silica eluted with ethyl acetate to give a clear oil (120 mg.) 1HNMR (CDCl3) δ1.04 (4H, dd), 1.14 (6H, s), 1.55 (2 s), 1.88 (4. m), 3.37 (2H, t) 7.23 (1H, m), 7.51 (1H, d), 7.64 (1H, t), 8.07 (1H, t), 8.16 (2H, m), 8.63 (1H, dd); MS: m/e 414 (M++1).