Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]CC)=O.[CH3:18][O:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.C(OCC)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:36][CH:35]=1)[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:15]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(O)c3ccccc3[nH]c2=O)cc1
Temperature: 115 °C
Yield: 94.2 %

Procedure:
Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 67) (3.58 g, 15.4 mmol) and bis(4-methoxybenzyl)amine (4.54 g, 17.6 mmol) were suspended in toluene (36 mL) and heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether was added (50 mL), and the resultant precipitate was collected by filtration to give crude 4-hydroxy-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (6.45 g, 95%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH3:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[N:20]([CH2:36][CH3:37])[S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CS(=O)(=O)N(CC)c1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 0.387 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl]sulfamoyl]acetate in 5 mL of N,N-dimethylformamide were added 0.131 g of potassium carbonate and 0.169 g of ethyl iodide at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.342 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl](ethyl)sulfamoyl]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:21])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under Argon atmosphere, Intermediate 3 (147.08 mg; 0.65 mmol) was stirred in anhydrous DCM (5 mL). Oxalyl chloride (57.75 μL; 0.68 mmol) was added followed by DMF (0.50 μL; 0.01 mmol). The reaction mixture was stirred 3 hours at RT. Solvents were evaporated to give 2,2′-dimethylbiphenyl-4-carbonyl chloride as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 46 (136.62 mg; 0.65 mmol) and DIEA (221.08 μL; 1.30 mmol) were added under argon. The mixture was heated in the microwave at 150° C. for 15 min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4Cl, NaHCO3 and NaCl sat. solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method A): 398.9 (M−H)−, 400.8 (M+H)+. HPLC (Method A) Rt 6.37 min (Purity: 98.8%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(Oc2ccccc2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Yield: 98.5 %

Procedure:
200 g (1.025 mols) of 3-phenoxybenzonitrile is placed together with 1 liter of methanol, 200 g of liquid ammonia and 50 g of Raney nickel into a steel autoclave. This is then heated to 60° C., and stirring is maintained for one hour with an initial hydrogen pressure of 120 bars. After removal of the mixture from the autoclave, the catalyst is filtered off, the solvent is distilled off at normal pressure, and the residue is distilled in an oil-pump vacuum to obtain 200.3 g (1.01 mols) of 3-phenoxybenzylamine (98.7% strength), corresponding to a yield of 94.7% of theory; b.p. 94° C./3 Pa; nD20 =1.5946.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:3]1=2.[CH3:20][C:21]1([CH3:29])[C:23]([CH3:25])([CH3:24])[CH:22]1[C:26](O)=[O:27]>>[O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][N:8]([C:26]([CH:22]3[C:23]([CH3:25])([CH3:24])[C:21]3([CH3:29])[CH3:20])=[O:27])[CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:3]1=2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1C(C)(C)C1(C)C)C3

Procedure:
The product was prepared from methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and 2,2,3,3-tetramethyl cyclopropanecarboxylic acid according to the same procedure described as in Example 16 (step 1)
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH:23]([NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4])[CH3:26]
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: CC(N)CO
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC(C)CO)s1
Yield: 44 %

Procedure:
To a stirred solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (170 mg, 0.55 mmol) in toluene (0.5 mL) was added rac-2-amino-1-propanol (83 mg, 1.1 mmol) and TBD (23 mg, 0.017 mmol). After 15 h the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give the title compound (85 mg, 44%) as a pale yellow oil.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:23]3[CH2:25][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC1CC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 17 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (537 mg, 1.5 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (85 mg, 17%) which was obtained as a white solid after purification by chromatography (silica, 0 to 50% ethyl acetate in heptane). MS: m/e=330.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:7]1[CH2:6][CH2:5][N:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]2[C:2]1=[O:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2n(c1)CCNC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(c1)CCN(Cc1ccccc1)C2=O
Temperature: 70 °C

Procedure:
To a solution of ethyl 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (29.8 mg, 0.143 mmol) in acetonitrile (1 mL) was added cesium carbonate (60.6 mg, 0.186 mmol) and benzyl bromide (36.7 mg, 0.215 mmol). The reaction mixture was heated at 70° C. overnight. Upon cooling to room temperature all insolubles were removed by filtration and the solvent evaporated to dryness to afforde crude Intermediate 34.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([CH3:24])[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([CH3:24])[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.05 mmol of 1-methylpiperazine was dissolved in 10 ml of N,N′-dimethylformamide (DMF), and 1.0 mmol of 1,3-di-p-tolylcarbodiimide was added. After 0.5 h. of stirring at room temperature, a small precipitation was removed by filtration and washed twice with 1 ml of DMF. The filtrates were collected and kept at room temperature overnight. 50 ml of water was added to the solution. An oil precipitated after 0.5 h which transformed into a solid. The solid residue was collected by filtration, washed twice with water and dissolved in 20 ml of methanol. 0.2 ml of conc. HCl was added was added to the methanol solution. After evaporation of the methanol, the residue was redissolved in methanol, and pure product was precipitated from the solution with ethyl ether. Yield=78%.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([N:13]([C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])[C:14](=[O:18])[C:15](Cl)=[O:16])[C:9]([CH3:12])([CH3:11])[CH3:10].O>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:15](=[O:16])[C:14]([N:13]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])=[O:18])[CH:2]=[CH2:3]
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Reactant: C=CCNCC=C
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)N(CC=C)CC=C
Yield: 85.8 %

Procedure:
3.88 g (0.4 mole) of diallylamine are added dropwise to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene. During this addition, the internal temperature is kept at 20° C. by external cooling with ice. When the dropwise addition has ended, 30 ml of water are added, the organic phase is separated off and the latter is washed twice with water, dried over sodium sulphate and finally concentrated in vacuo. 5.5 g (86% of theory) of N,N-diallyl-N'-neopentyl-N'-2-propinyloxycarbonyl-oxalic acid diamide of refractive index nD20 =1.4878 are obtained.
Reaction SMILES: CN(C)C=O.O.[NH2:7][NH2:8].Cl([O-])(=O)(=O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][CH2+:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH:24]=[C:23]([CH3:34])O1>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][C:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH2:24][C:23]([CH3:34])=[N:8][N:7]=1
Reactant: COc1cc(C=C[CH2+]2OC(C)=Cc3cc4c(cc32)OCO4)ccc1O
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)ccc1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 12.5 ml of dimethylformamide and 2.1 ml (42 mM) of 100% hydrazine hydrate is cooled to 5° to 6° C. with ice-water, then 6.14 g (14 mM) of 1-(3-methoxy-4-hydroxystyryl)-3-methyl-6,7-methylenedioxy-2-benzopyrylium perchlorate (m.p. 300° C. carboniz.) are added at stirring during 15 minutes. The orange solution is stirred for a further 15 minutes, then 12.5 ml of distilled water are added at cooling which initiates the precipitation of the end-product. The crystal mash is stored for 12 hours at 5° C., filtered, washed with 3×20 ml of distilled water and dried at 80° to 100° C. Yield 4.81 g, m.p. 210° to 213° C. d. For further purification this product is refluxed with 24 ml of 99.5% ethanol, cooled, filtered, washed with 3×20 ml of ethanol and dried. Yield 4.59 g (93.7%), m.p. 214° to 216° C. (decomp.)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:7]=[CH:6]/[CH2:5][C:4]([CH:3]([O:2][CH3:1])[O:17][CH3:18])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(OC)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(OC)OC

Procedure:
A mixture of 10.0 g. (36.7 moles) of 4-dimethoxymethyl-4-trimethylsiloxy-1-octyne, 12.82 g. (44 moles) of tri-n-butylstannyl hydride and 100 mg. of azobisisobutyronitrile is heated to 140° C. under argon for 2 hours. The excess hydride is distilled off and the residue is purified by molecular distillation (bath temperature=170°-175° C., 0.2 mm.) to give 20.5 g. of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8](C)[S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:32]=[CH:31][C:20]3=[N:21][CH:22]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:24]=[C:19]3[C:18](=[O:33])[C:17]=2[CH:34]=1)(=[O:11])=[O:10].N[C:37]1[CH:42]=[CH:41]C=[CH:39][CH:38]=1>O1CCOCC1.O>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[CH:24]=[C:19]3[C:18](=[O:33])[C:17]4[CH:34]=[C:13]([CH2:12][S:9]([NH:8][C:7]5[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=5)(=[O:10])=[O:11])[CH:14]=[CH:15][C:16]=4[CH:32]=[CH:31][C:20]3=[N:21][CH:22]=2)[CH:26]=[N:27]1
Reactant: Nc1ccccc1
Reactant: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)Nc5ccccc5)cc4c(=O)c3c2)cn1
Temperature: 180 °C

Procedure:
Cesium carbonate (80 mg, 0.245 mmol) was added to a solution of N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide (50 mg, 0.122 mmol) and aniline (559 μL, 6.12 mmol) in dioxane (1113 μl) and water (111 μl) in a 0.5 ml to 2 ml microwave vial. The vial was then sealed and the mixture was heated to 180° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.84 (br s, 1H); 9.22 (d, 1H); 8.51 (d, 1H); 8.48 (s, 1H); 8.15 (s, 1H); 8.04 (d, 1H); 7.76 (d, 1H); 7.63 (dd, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.27 (m, 2H); 7.16 (dd, 2H); 7.00 (m, 1H); 4.68 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 457.1; found 457.1.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32]([O:34]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:37]>C1COCC1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32](=[O:34])[NH2:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Yield: 19 %

Procedure:
A solution of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbomethoxy carbazole (1.10 g, 2.31 mM) in 35 ml THF and 140 mL concentrated aqueous ammonium hydroxide was sonicated for 6 hours at 30-40° C. The precipitated solid was filtered and washed with water. Trituration with Et2O, then with 2:1 Et2O/CH2Cl2 afforded 0.20 g (19%) of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ 10.8 (s, 1H), 8.9 (bs, 1H), 8.45 (bs, 1H), 8.0 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 7.6 (s, 1H), 7.5 (m, 2H), 7.3-7.1 (m, 6H), 7.0 (s, 1H), 5.8 (s, 2H). MS (ES) m/e 444, 461.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[CH:11](O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: O=CO
Product: Cc1cc2[nH]cnc2cc1Cl
Temperature: 100 °C

Procedure:
4-Chloro-5-methyl-benzene-1,2-diamine (560 mg, 3.6 mmol, Maybridge Chemical Co. Ltd., Cornwall, UK) was dissolved in formic acid (10 mL) and the solution was refluxed at 100° C. for 18 hr. The reaction was allowed to cool and then evaporated to dryness in vacuo to give 5-chloro-6-methyl-1H-benzoimidazole as a tan solid (quantitative yield) that was used without further purification. The solid obtained above (410 mg, 2.4 mmol), di-tert-butyl dicarbonate (1.6 g, 7.4 mmol), and DMAP (29 mg, 0.24 mmol) were dissolved in CH3CN (20 mL). To the mixture, DIEA (1.3 mL, 7.4 mmol) was added and the reaction was stirred for 18 hr at rt. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (75 mL). The aqueous layer was separated and washed with EtOAc (100 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude residue was purified using flash SiO2 chromatography (20% EtOAc in hexanes) to give 620 mg (97%) of the title compound as a 1:1 mixture of regioisomers that were used without separation. 1H-NMR (CDCl3; 400 MHz, 1:1 mixture of isomers) δ 8.35 and 8.36 (s, 1H), 7.89 and 7.99 (s, 1H), 7.62 and 7.75 (s, 1H), 2.48 and 2.50 (s, 3H), 1.698 and 1.700 (s, 9H). ESI-MS (m/z): Calcd. for C13H15ClN2O2: 266.7; found: 266.9, 167.2 (M−Boc).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3][NH:2]1.[C:11](N1CCNCC1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>N1C=CC=CC=1>[C:11]([C:3]1[NH:2][O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: C1=Cc2ccccc2ON1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1=Cc2ccccc2ON1
Temperature: 70 °C
Yield: 58.1 %

Procedure:
To a solution of 2.1 g of the benzoxazine (E) (R8 =CH3, R9 =C2H5, R10 =C6H5, X=F), in 30 ml pyridine is added 8 g of N-carbobenzoxypiperazine. The mixture is heated at 70° C. for 18 hours. The solvent is removed by evaporation under reduced pressure. The residue is washed with ether, water and ether. It is dried, yielding 2.45 g of the carbobenzoxy-benzoxazine (F) (R8 =CH3, R9 =C2H5, R10 =C6H5, Z=carbobenzoxy-piperazin-1-yl).
Reaction SMILES: C1(C2N=C(/C=C/[C:12]3[CH:13]=[C:14]([CH:18]=[O:19])[CH:15]=[CH:16][CH:17]=3)SC=2)CCC1.CC(C)([O-:23])C.[K+].C(O)(C)(C)C>C(O)(=O)C>[C:18]([OH:19])(=[O:23])[C:14]1[CH:13]=[CH:12][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture composed of 3.15 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzenecarboxaldehyde, 1.44 g of potassium tert-butoxide and 100 ml of tert-butanol was heated to reflux for 2 hr while exposed to air. The mixture was then diluted with 100 ml of ice water. This mixture was then acidified with acetic acid and extracted with methylene chloride. The combined extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield (E)-3-[2-(4-cyclobutyl)-2-thiazolyl)ethenyl]benzoic acid; m.p. 172°-175° C. from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C>CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1CCCC2
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-Nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [from 3-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.150 g , 6.78 mmol) and PCl5 (0.190 g, 8.48 mmol) in EtOAc (1.5 mL) as described in T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984)] was dissolved in EtOAc (2 mL) and added to a stirred solution of N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.3075 g, 0.678 mmol), triethylamine (0.124 mL, 0.892 mmol) and EtOAc (3.1 mL) and the mixture stirred overnight at ambient temperature. The reaction mixture was washed with 10% aqueous HCl, 5% aqueous NaOH and brine solutions, dried (MgSO4) and the solvent removed in vacuo to yield the title compound (0.168 g, 38%) which was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.2.0H2O: calculated: C, 54.30; H, 5.81; N, 4.75; found: C, 54.10; H, 5.55; N, 4.55.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:9]=1[C:10]([OH:12])=O.CN(C=O)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:8]([F:7])=[C:9]([CH:13]=1)[C:10]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(C(=O)Nc2ccccc2)c1
Yield: 92.6 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 2-fluoro-5-nitrobenzoic acid (5.00 g, 27.01 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (5.0 mL, 54.88 mmol) to afford the pure product (5.76 g); m.p. 120-122° C.