Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([N:28]1[CH2:33][CH2:32][C:31]([F:38])([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[OH-].[Na+]>CO.O>[F:44][C:42]([F:43])([F:45])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:41]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([N:28]1[CH2:33][CH2:32][C:31]([F:38])([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(F)(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(F)(C(=O)O)CC1
Yield: 406.7 %

Procedure:
To a solution of methyl 1-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl]-4-(trifluoromethyl)phenyl]propyl}-4-fluoropiperidine-4-carboxylate (example 204) (0.23 g, 0.33 mMol) in methanol was added 1N sodium hydroxide (1.8 mL.) and the solution was microwaved for 30 minutes at 100° C. The reaction mixture was diluted with water and the pH was adjusted to 3 and was extracted with dichloromethane. The organic extract was dried, concentrated and purified by flash chromatography to afford the title compound (0.9 g., 40%), 1HNMR (400 MHz. CDCl3) δ 7.90 (t, 1H), 7.80 (s, 1H), 7.60 (m, 37.15 (m, 1H), 4.70 (dd, 4H), 4.6 (m, 2H), 4.40 m, 2H), 4.10 (s, 3H), 3.80 (m, 1H), 2.90 (m, 1H), 3.60 (m, 2H), 2.40(m, 2H), 2.15 (m, 1H), 2.10 (m, 2H), 1.9 (m, 1H), 0.5 (t, 3H). MS (ES+) Calc 670.55, Found 671.4 (M+1)
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=3)[N:15]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1
Reactant: COc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
2-(dibenzo[b,d]thiophen-4-yl)-6-(3-methoxyphenyl)pyridine (3.8 g, 10.3 mmol) was dissolved in 120 mL dichloromethane. The solution was cooled to 0° C. under nitrogen. BBr3 (22.8 mL, 1M in hexane) was slowly added in at 0° C. and then was slowly brought up to room temperature. The mixture was stirred at room temperature overnight. A brown solid was observed to form. The reaction was quenched by adding 100 mL water slowly. The dichloromethane was removed by rotovap. Then the mixture was refluxed for three hours. Saturated sodium bicarbonate solution was added to neutralize the mixture, which was extracted by dichloromethane and ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 4 gram glassy dark brown solid. The product was used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:25][CH2:26][O:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:25][CH2:26][O:27][CH3:28])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a stirred solution of crude methyl 5-bromo-3-(ethyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methylbenzoate (25 g, 65.44 mmol), 1-bromo-2-methoxyethane (18.19 g, 130.8 mmol) in acetonitrile (250 mL), K2CO3 (18.06 g, 130.8 mmol) and KI (6.51 g, 39.21 mmol) were added. The resulting reaction mass was stirred at 65° C. for 16 h. On completion, reaction mixture was diluted with water (300 mL) and extracted with DCM (500 mL×3). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the title compound (20 g, 69.3% yield).
Reaction SMILES: [C:1]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[C:9]([F:15])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Oc1ccc(C#N)c(F)c1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[Si](Oc1ccc(CN)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of the 4-(t-butyl-diphenyl-silanyloxy)-2-fluoro-benzonitrile (2.07 g, 5.52 mmol) in ether (17 mL) was added a solution of lithium aluminum hydride (6.6 mL, 1M in THF) slowly. The reaction was heated at reflux for two hours and allowed to stir overnight at ambient temperature. The reaction was quenched with 1.17 mL of water, then 1.17 mL of NaOH (15%), and 1.17 mL of water. The white solid was filtered, washed with methylene chloride. The filtrate was dried (Na2SO4), and concentrated in vacuo to give the benzylamine (1.66 g,) as a yellow oil, which was used directly in the next step.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][CH2:15][C:16]([C:31]([O:33][CH3:34])=[O:32])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a chilled solution of diisopropylamine (3.5 mL, 24.7 mmol) in THF (20 mL) at −78° C. was added n-BuLi (2M in hexane, 14.8 mL, 1.2 equiv.). The reaction mixture was stirred for 1 h. A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (5 g, 20.6 mmol, 1 equiv.) in THF (15 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 h. Methyl chloroformate (1.7 mL, 22.6 mmol, 1.1 equiv.) was added to the above mixture. The reaction mixture was warmed to rt slowly while stirring. After 3 h, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate (6.2 g, quant.), which was used without further purification. LRMS (M+H+-Boc) m/z 202.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC.C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(F)cc(F)c2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
A solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-ol (0.96 g) in dichloromethane was added to a stirred mixture of pyridinium chlorochromate (0.83 g) and powdered molecular sieve (4A) in dichloromethane at 20° C. After 18 hours, ether and charcoal were added, the mixture filtered through hyflo and evaporated to give 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (0.59 g) as a beige solid, m.p. 156.8-157.8° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O-:9])[N:3]=[CH:2]1.[Na+].[Cl-].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16]>>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: [O-]CCCc1c[nH]cn1
Reactant: CCCC(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)CCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1H-imidazol-4-yl)propanolate and 5 mmol of 4-methylpentane chloride are treated as described in Example 5.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:20]2[CH:21]=[CH:22][C:18]([C:17]([F:24])([F:23])[F:16])=[N:19]2)[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Product: COc1ccc2c(Cl)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of compound 220d (5 g, 19 mmol) and 3-trifluoromethylpyrazole 233a (7.76 g, 57 mmol) was heated at 120° C. for 4-6 hrs and the reaction was followed by LCMS and TLC. The reaction mixture was purified by silica gel column (mono and dipyrazole were separated) using DCM and heptane as mobile phase to yield compound 235a (3.5 g) in 51% yield.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([CH2:13][CH:14]([O:31]C(=O)C)[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([CH2:13][CH:14]([OH:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(OCC(Cn2ccc(C(=O)OC(C)(C)C)c2)OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.104 g (0.221 mmol) tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate is dissolved in 10 ml absolute methanol, mixed with 0.88 ml (0.440 mmol) of a 0.5M sodium methanolate solution and stirred at room temperature for 15 min. Following concentration to half the volume on the rotary evaporator, the batch is diluted with diethyl ether. Washing of the organic phase with semi-saturated and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7](=[O:22])[C:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][CH:9]=2)[CH:5]([CH2:23][CH2:24][CH3:25])[N:4]([CH3:26])[C:3]1=[O:27].[H][H]>C(O)C>[CH3:1][N:2]1[CH:6]([C:7](=[O:22])[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH:5]([CH2:23][CH2:24][CH3:25])[N:4]([CH3:26])[C:3]1=[O:27]
Reactant: CCCC1C(C(=O)c2ccc(OCc3ccccc3)cc2)N(C)C(=O)N1C
Reactant: [H][H]
Solvent: CCO
Product: CCCC1C(C(=O)c2ccc(O)cc2)N(C)C(=O)N1C

Procedure:
1,3-dimethyl-4-propyl-5-(4-benzyloxybenzoyl)-2-imidazolidinone (10 g) is dissolved in 100 ml ethanol and the reaction flask charged with 100 mg 10% pallidium on charcoal. The mixture is hydrogenated at atmospheric pressure until 1 equivalent of hydrogen is consumed. After filtration and evaporation of solvent the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][N:23]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:31]=[CH:30][C:25]([CH2:26][OH:27])=[CH:24][N:23]=1
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(CO)cn2)c1

Procedure:
To 110 mg of methyl 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate at 0° C. in 5 mL of EtOH was slowly added 148 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:32])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].C(Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:25]3[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([F:22])[CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 46.8 %

Procedure:
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (300 mg) and 3-fluoro-4-nitrophenol (785 mg) were dissolved in chlorobenzene (3 ml), and the solution was stirred at 130° C. for 5 hr. Chloroform and an aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was stirred for one hr. The reaction solution was extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with hexane/ethyl acetate (1/1) to give 197 mg (yield 47%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)Nc3ccccc3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), aniline (46 uL, 47 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 43 mg (50% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.58 (m, 4 H), 1.61 (s, 9 H), 2.21-2.38 (m, 1 H), 3.29-3.35 (m, 2 H), 3.85-3.93 (m, 2 H), 4.45 (d, J=7.62 Hz, 2 H), 6.96-7.04 (m, 1 H), 7.04-7.11 (m, 2 H), 7.11-7.21 (m, 2 H), 7.84-7.89 (m, 1 H), 7.91-7.98 (m, 1 H), 8.06 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=428.0; Anal. Calcd for C23H29N3O3S+1.10 TFA+0.30 EtOAc+0.2H2O (583.03): C, 54.39; H, 5.69; N, 7.21. Found: C, 54.43; H, 5.68; N, 7.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:27])[C:9]([C:11]1[S:26][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH2:25])=[O:29])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccccc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(2-chlorophenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 120 (120 mg) and K2CO3 (49 mg) in dry DMSO (2 mL) was added 33% hydrogen peroxide (40 μL). The resultant was stirred overnight at room temperature. Ice was added to the resulting solution and the solid formed was collected, washed with water and dried to give 119. NMR: (CDCl3): 3.04 (t, 2H, CH2, J=5.02 Hz), 3.42 (s, 3H, CH3), 4.28 (t, 2H, CH2, J=5.06 Hz), 5.75 (sbr, 2H, NH2), 6.71 (s, H, ArH), 7.03 (d, H, ArH, J=8.44 Hz), 7.39-7.45 (m, 3H, 3×ArH), 7.55-7.60 (m, 2H, 2×ArH), 7.99 (d, H, ArH, J=1.81 Hz). MS: (ESI+) MH+ 413.14
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:43])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH3:42])[CH3:41])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH3:41])[CH3:42])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:43])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N(C)C)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)nc(N(C)C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(2-dimethylamino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K49) (171 mg, 0.48 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (133 mg).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C:30]1[NH:34][N:33]=[N:32][N:31]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:9]1=2.CO.[C:46]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:39][C:38]([F:41])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:42])([F:1])[F:43])[CH:37]=1)[CH2:6][N:7]([C:30]1[N:31]=[N:32][N:33]([CH3:46])[N:34]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:9]1=2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (87 mg, 0.139 mmol), methanol (0.564 mL, 13.9 mmol), triphenyl phosphine (73 mg, 0.278 mmol) in dry dichloromethane (3.4 mL) at 0° C., under nitrogen, add diethyl azodicarboxylate (0.128 mL, 0.278 mmol). Stir the reaction mixture at room temperature for 3 h. Remove the solvents under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate to afford the title compound (47 mg, 53%). MS (ES+): 639 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][OH:19])[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2].N1C=CC=CC=1.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][O:19][C:36](=[O:37])[C:35]4[CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=4)[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
One gram of (±)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (I) and 500 mg of pyridine were suspended in 100 ml of anhydrous tetrahydrofuran (THF), and 1.6 g of 3,5-dinitrobenzoyl chloride was added thereto, followed by refluxing at 90° C. The suspension was once dissolved, and a colorless precipitate was then formed. The reaction was continued for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with methanol and diethyl ether and dried to obtain 1.2 g of (±)-9,10-difluoro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (II) as a colorless powder having a melting point of 240°-242° C. NMR (CDCl3 /5% DMSO-d6) δ(ppm); 1,30 (3H, t, J=7.0 Hz, --CH2CH3), 4.26 (2H, q, J=7.0 Hz, --CH2CH3), 4.4-4.5 (5H, m), 7.76 (1H, dd, J=11.0 Hz, 7.0 Hz, C8 -H), 8.8 (1H, s, C5 -H), 9.0 (2H, d, J=3.0 Hz, aromatic ring proton) and 9.2 (1H, t, J=3.0 Hz, aromatic ring proton).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[S:22][C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])=[N:25][CH:24]=3)=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 1-chloro-4-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 8.991 (s, 1H), 8.897 (s, 1H), 8.737-8.710 (d, 1H), 8.353 (s, 1H), 7.730-7.701 (d, J=8.7 Hz, 2H), 7.583-7.554 (d, J=8.7 Hz, 2H), 7.513-7.484 (d, J=8.7 Hz, 2H), 7.355-7.325 (d, J=9 Hz, 2H), 4.324-4.287 (t, J=7.2, 7.8 Hz, 1H), 3.681 (s, 3H), 2.342-2.242 (m, 1H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 487 (M+H)+.
Reaction SMILES: N1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[CH:17]1[CH:18]=[CH:19][CH:20]=[C:13]2[C:14]=1[C:15]1[NH:16][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]=1[C:2](=[O:3])[NH:12]2
Reactant: NCc1ccccc1N
Reactant: O=C1Nc2ccccc2C1=O
Product: O=c1[nH]c2ccccc2c2[nH]c3ccccc3c12

Procedure:
Specifically, as shown in Scheme 1, reaction of isatin (1) and 2-aminobenzylamine (2) gives 5,11-dihydro-indolo[3,2-c]quinolin-6-one (3), which may be treated with POCl3 to yield 6-chloro-11H-indolo[3,2-c]quinoline (4), which may be further reacted with either an amine of formula R—NH2 or a diamine of formula H2N—R—NH2 to give a corresponding compound of either formula (IA) or formula (IB).