Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:16])[CH:3]=1.[C:17]([NH:20][C:21]1[S:22][C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:20][C:21]1[S:22][C:23]([S:27]([NH:1][C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[C:4]([CH3:16])[CH:3]=2)(=[O:28])=[O:29])=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(N)nc(NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2cc(C)cc(NC(=O)OC(C)(C)C)n2)s1
Temperature: 24 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl (6-amino-4-methylpyridin-2-yl)carbamate (1.2 g, 6.0 mmol) in pyridine (30 mL) was added 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (1.5 g, 6.0 mmol). The resulting mixture was stirred at 24° C. for 16 hours. The reaction was concentrated in vacuo (˜25 mm Hg). Purification by high performance flash chromatography (0→5% methanol in dichloromethane) provided the intermediate (2.1 g, 80%). 1H NMR (400 MHz, CDCl3), δ: 7.43 (br s, 1H), 6.99 (s, 1H), 5.31 (s, 1H) 2.34 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 1.54 (s, 9H); LRMS (ESI) m/z: 342 [M-CO2C(CH3)3]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:23][OH:24])=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 126 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+].C=O.O>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 mL of anhydrous tetrahydrofuran, add potassium tert-butoxide (161 mg, 1.4 mmol) and paraformaldehyde (66 mg, 2.2 mmol) in one portion, the result mixture is heated to reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 15 mL of water, extract with toluene, the organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to obtain the crude product which is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:10]2[C:11](=[O:12])[N:6]([C@H:4]3[CH2:5][C@H:2]([O:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3]3)[C:7]3[N:8]([N:31]=[CH:32][N:33]=3)[C:9]=2[CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)#[N:27]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g), rhodium(I) acetate (0.0028 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.056 g, 17%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[I:14]N1C(=O)CCC1=O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:14][C:12]1[S:11][CH:10]=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=1
Reactant: CCOP(=O)(OCC)c1ccsc1
Reactant: O=C1CCC(=O)N1I
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1csc(I)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
In 5 ml of a mixed solvent of chloroform:acetic acid=1:1, 0.1101 g (0.5 mmols) of 3-(diethoxyphosphoryl)thiophene was dissolved, to which 0.2362 g (1.05 mmols) of commercially available N-iodosuccinimide was added at room temperature. Thereafter, the reaction mixture was stirred at room temperature for 4 days. After the reaction, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added, followed by extraction with chloroform. The organic phase was washed with a 0.2N sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane 1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.1263 g (yield: 73%). The thus obtained substance was used as it is for reaction in Example 12(9).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.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>[F:10][C:3]1[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(F)c(-c2cccnc2)c1F
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 ml) and water (50 ml) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 ml), extracted with ethyl acetate (300 ml), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)] afforded 5.8 g (47%) of the title compound as a cream-coloured solid: 1H NMR (400 MHz, CDCl3) δ 3.69 (2H, br s), 6.72–6.88 (2H, m), 7.39 (1H, dd, J 8, 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5, 1), 8.72 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[O:8].C([Li])CCC.CCCCCC.[C:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.[Ag]=O>[CH3:23][C:20]([C:24]1[CH:29]=[C:28]([CH2:30][CH:4]2[S:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:8])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:21])[CH3:22]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN1CCSCC1=O
Agent: O=[Ag]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCSC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
4-methyl-3-thiomorpholinone (1.88 g, 14.3 mmol) dissolved in tetrahydrofuran (72 ml) was cooled to 0° C. and treated with 1.37M n-butyl lithium in hexane (20.9 ml, 28.7 mmol). After five minutes, the cold bath was removed. Ten minutes later a solution of 2,6-di-t-butyl-quinone methide, prepared by adding silver oxide (33.2 g, 143 mmol) to 2,6-di-t-butyl-4-methyl-phenol (BHT) (3.16 g, 14.3 mmol) in tetrahydrofuran (72 ml) stirring for 30 minutes and filtering, was added dropwise over 20 min. The reaction was stirred for three hours, quenched with 1N hydrochloric acid, and evaporated to an aqueous suspension. The crude product was extracted into ethyl acetate, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel eluting with 8 L of a 0-50% ethyl acetate in hexane gradient yielded desired product (2.0 g, 40%):
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([NH:11][C:12]([N:14]1[C:18]2[CH2:19][CH2:20][O:21][CH2:22][C:17]=2[C:16](C2C=CC(F)=C(F)C=2)=[N:15]1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:42])=[C:37]([CH:41]=1)C(Cl)=O>>[Cl:32][C:33]1[CH:41]=[CH:37][C:36]([F:42])=[C:35]([C:16]2[C:17]3[CH2:22][O:21][CH2:20][CH2:19][C:18]=3[N:14]([C:12]([NH:11][C@@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:31])=[O:13])[N:15]=2)[CH:34]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2cc(Cl)ccc2F)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 86 was prepared according to the procedure for the synthesis of compound 36 by replacing 3,4-difluorobenzoyl chloride with 5-chloro-2-fluorobenzoyl chloride. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.81 (d, J=9.1 Hz, 1H), 7.60-7.62 (dd, J=2.7, 6.21 Hz, 1H), 7.27-7.32 (m, 1H), 7.07 (t, J=9.3 Hz, 1H), 6.56 (br, 1H), 4.57 (s 2H), 4.12 (d, J=9.2 Hz, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.66 (s, 3H), 3.36-3.41 (m, 2H), 3.08-3.12 (m, 2H), 1.03 (s, 9H). Purity: 97%.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15](OC)=[O:16].O>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:28][CH:29]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15]([NH:4][C:3]([NH2:5])=[NH:2])=[O:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(CCN(C)C)cc2)cc1Cl
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(Oc2cc(Cl)c(C(=O)NC(=N)N)cc2S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
268 mg of guanidine hydrochloride were dissolved in 3 ml of DMF and a solution of 286 mg of potassium t-butoxide in 3 ml of DMF is added. The mixture was stirred at RT for 3 hours, then a solution of 210 mg of methyl 2-chloro-4-(4-(2-dimethylaminoethyl)phenoxy)-5-methylsulfonylbenzoate in 4 ml of DMF was added. The mixture was stirred at RT for 3 hours and allowed to stand at RT for 18 hours. The mixture was poured onto 150 ml of water and extracted 3 times using 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. 230 mg of a glassy solid were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[CH:24](=[O:26])[CH3:25]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:24]([OH:26])[CH3:25])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a 250-mL 3-neck flask was added a THF solution (20 mL) of 2-bromo-5-fluoropyridine (8.80 g, 50 mmol). At −78° C., to the solution was added LDA (25.0 mL, 50 mmol, 2.5 M in THF) dropwise. After stirring for 5 min, diisopropylamine (7.0 mL, 50 mmol) was added dropwise via a syringe and the mixture was stirred at −78° C. for 4 h. A THF solution of acetaldehyde (11 mL, 55 mmol, 5M in THF) was added dropwise via a syringe. The contents were removed from the cold bath and stirred with warming to room temperature overnight. The mixture was diluted with water (150 mL) and vigorously stirred for 5 min. The contents were concentrated under reduced pressure and the residue was extracted with ethyl ether (3×150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford yellow oil, which was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 5:1) to afford 325b (8.0 g, 72.7%) as a yellow solid. MS-ESI: [M+H]+ 220.1. 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=1.5 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 5.17 (d, J=6.5 Hz, 1H), 2.18-2.16 (m, 1H), 1.52 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1
Yield: 33.9 %

Procedure:
To a solution of aniline (27.9 g, 0.30 mol) and tert-butyl acrylate (38.4 g, 0.30 mol) in dry benzene (500 ml) was added tin tetrachloride (2 ml) and the resulting solution was heated under reflux for 18 8 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo giving a residue which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (22.53 g, 34%) as an oil. 1H NMR (300 MHz, CDCl3) δ7.12 (2H, t), 6.71 (1H, m), 6.62 (2H, d), 3.40 (2H, t), 2.54 (2H, t), 1.44 (9H, s).
Reaction SMILES: C(N(N=O)[C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:47])C>O1CCCC1.O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:20]2[N:19]([CH:10]([CH:11]3[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:9]([OH:47])=[O:37])[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:35][CH:34]=1
Reactant: O=NN(Cc1ccccc1)C(=O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CC(=O)O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 2 h
Yield: 49 %

Procedure:
To a suspension of 3.05 g (5.46 mmol) N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 15 ml tetrahydrofuran and 10 ml water were added dropwise over 5 min. a solution of 2.29 g (54.57 mmol) lithium hydroxide monohydrate in 11.14 ml (109 mmol) 30% hydrogen peroxide solution and 10 ml water. The reaction mixture turned into a turbid solution and became slightly warm (cooled temporarily using an ice-bath). After stirring for 2 h the pH was adjusted to pH 4 using 12.48 ml (218 mmol) acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated. The remaining yellow foam was treated with 100 ml tert-butyl methylether and the resulting light yellow suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum to give a first batch of compound (yellow solid). The mother liquor was purified on a preparative HPLC system (Phenomenex Gemini column) eluting with a gradient of acetonitrile and water. to give another batch of compound (colorless solid). Overall yield 49%. MS (Turbo Spray): m/z=441.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[CH:3]=1.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:9][C:6]1[CH:5]=[C:4]([F:12])[CH:3]=[C:2]([Br:1])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Br)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JH-F =8.4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:6]=2[CH:18]=1.[C:19]([O:23][C:24](=[O:30])[NH:25][C:26](=O)[CH2:27]Cl)([CH3:22])([CH3:21])[CH3:20]>CC(N(C)C)=O>[C:19]([O:23][C:24](=[O:30])[NH:25][C:26]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:7]3[C:6]4[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=4[N:9]=[N:8]3)=[N:16][N:15]2[CH:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Reactant: Nc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 135 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of compound 10G (1.0 g, 3.28 mmol), (2-chloro-acetyl)-carbamic acid tert-butyl ester (1.0 g, 5.0 mmol) and Na2HPO4 (1.4 g, 10 mmol) in DMA (50 mL) was stirred at 135° C. for four hours. Solvent was removed under reduced pressure. The residue was sonicated in ethyl acetate/water, and the precipitate was filtered off. Ethyl acetate solution was separated and concentrated and loaded on silica gel. The silica column was eluted with hexane/ethyl acetate (1/2) to give 0.45 g of desired product (10H). ESI-MS:m/z 444.1 (M+H)+.
Reaction SMILES: [ClH:1].[C:2](N)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O-].[Na+].[CH3:15][N:16]([CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][NH2:25])=O)[CH3:17].Cl.CCOCC>C(O)C>[ClH:1].[CH3:15][N:16]([CH3:17])[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:21]([C:22]2[N:9]=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)[CH:20]=1
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred ethanolic suspension of benzamidine hydrochloride salt (235 mg, 1.5 mmol, 1.5 eq.), was added 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) over 3 minutes, the mixture was further stirred for 30 min. at r.t. To this was added 3-dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol at 20° C. and the mixture heated to reflux for 24 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution (1.0 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (84 mg, 0.27 mmol, 27% yield) as a yellow foam. MS: m/e=279.4 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)CCC>[N+:12]([C:11]1[C:2]2[NH:19][CH2:16][CH2:17][NH:18][C:4](=[O:6])[C:3]=2[CH:8]=[CH:9][CH:10]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NCCN
Solvent: CCCCO
Solvent: O
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 parts of 1,2-ethanediamine monohydrate and 40 parts of 1-butanol was stirred for 1/2 hour at reflux temperature. The reaction mixture was evaporated and the residue was diluted with 50 parts of water. The precipitate was filtered off and washed with water and 2-propanol. It was then recrystallized from 2-methoxyethanol, yielding 6.5 parts of 2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; mp. 191°-195° C. (interm. 1)
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].[CH3:14][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1)([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH:29]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:24][CH:23]=1)([CH3:14])[CH3:16]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccc(OCCNC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCCOc1ccc(C(=O)C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of 2.55 g of indole-4-carboxaldehyde and 4 ml of 50% sodium hydroxide solution was added with stirring under an inert atmosphere to a solution of 3.5 g of the product of Step B in 40 ml of ethanol and after stirring for 24 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and the wash water was reextracted with an 8-2 chloroform-methanol mixture. The extract was washed with water and aqueous sodium chloride solution and the combined organic phases were dried over a deshydrant and were evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 4.3 g of 1-[4-{-2-(1,1-dimethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E) melting at ≃162° C.