Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[C:4]([F:11])[CH:3]=1.P(Br)(Br)[Br:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:13])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
A solution of 1-(4-bromo-2-fluorophenyl)ethanol (8.95 mmol) in dichloromethane (40 mL) at 0° C. was treated dropwise with a solution of phosphorus tribromide (3.58 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was concentrated to a residue in vacuo. Purification of the residue by silica gel chromatography (hexanes) yielded the title compound as a clear oil (1.47 g, 58.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (d, J=6.82 Hz, 3 H) 5.58 (q, J=7.07 Hz, 1 H) 7.47 (dd, J=8.34, 1.77 Hz, 1 H) 7.57-7.65 (m, 2 H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+:13]>O>[C:1]([O-:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:13]
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
1.24 g (8.37 mol) of cinnamic acid and 0.37 g (8.37 mol) of sodium hydroxide are added to 120 ml of ion-exchange water while being stirred, to provide an aqueous solution of sodium cinnamate. The pH value of this aqueous solution is adjusted to 10 by the use of an aqueous solution of 0.1N sodium hydroxide.
Reaction SMILES: [H][H].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]>[Pd]>[ClH:4].[Cl:4][C:5]1[CH:6]=[C:7]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: [H][H]
Reactant: Clc1ccc(C2=CCNCC2)cc1Cl
Agent: [Pd]
Agent: Cl
Product: Clc1ccc(C2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 144.6 %

Procedure:
A balloon filled with hydrogen was charged into a solution of 4-(3,4-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (107 mg, 0.41 mmol) in the presence of 5% Pd/C (5% mmol) after the system was degassed. The reaction was stirred at rt for 2 h, filtered, rinsed with MeOH and then concentrated to give 4-(3,4-Dichlorophenyl)piperidine hydrochloride (79 mg, 72% yield) as an oil. MS found: 266.4 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([F:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.[C:20](=[O:22])=[O:21].[OH-].[Na+]>C(OCC)C.CCCCCC.O>[F:10][C:4]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH3:9])[C:20]([OH:22])=[O:21]
Reactant: CSc1ccc(Br)c(C(F)(F)F)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1ccc(C(=O)O)c(C(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
21.0 g (72.98 mmol) of 1-bromo-3-fluoro-4-(methylsulfanyl)-2-(trifluoromethyl)benzene were dissolved in 275 ml of absolute diethyl ether and cooled to −78° C. 54.8 ml (87.59 mmol) of a 1.6M solution of n-butyllithium in hexane were slowly added dropwise, and the resulting solution was stirred at −78° C. for 60 minutes. The reaction mixture was then added to freshly ground dry ice and slowly warmed to RT. Water was added, and the reaction mixture was made alkaline using 2M NaOH solution and washed with diethyl ether. The aqueous phase was then acidified with 51M HCl solution, causing the product to precipitate. The precipitate was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].ClCCl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:11]3[C:12]([O:14][CH3:15])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:17])[CH2:38][CH2:37]2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCNCC2)CC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: ClCCl
Solvent: CC#N
Product: COc1c(N2CCC(NC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 62.5 °C
Yield: 17.9 %

Procedure:
To a stirred solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (295 mg, 1.0 mmol) in acetonitrile (5 mL) was added 4-(piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, 1.2 mmol) followed by the addition of 8-diazabicyclo[5.4.0]undec-7-ene (DBU, 182 mg, 1.2 mmol). The resulting stirred solution was then heated in a 60-65° C. oil bath for two days. The cooled reaction mixture was filtered through a fritted funnel. The filtrate was condensed to dryness. Dichloromethane was added into this residue and washed with water twice. The resulting organic layer was washed one more time with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give crude material as light brown syrup. This crude product was further purified with 10% methanol in dichloromethane by preparative TLC plate to afford pure title product as yellow solid (100 mg). ESI MS m/z 559 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.76 (d, J=12.4 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.51 (d, J=12.1 Hz, 2H), 3.17 (t, J=12.3 Hz, 2H), 2.76 (br s, 1H), 1.92 (d, J=11.8 Hz, 2H), 1.83 (d, J=11.6 Hz, 2H), 1.49 (q, J=8.6 Hz, 2H), 1.38 (s, 9H), 1.20 (q, J=7.9 Hz, 2H), 1.15 (d, J=7.1 Hz, 2H), 0.94 (d, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[C:17]([C:22]2[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Cl)CCl.ClCCl.O1CCCC1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([NH:40][S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[O:29])=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-benzyloxy-5-chloro-[1,1′;2′,1″]terphenyl-2″-carboxylic acid (100 mg, 0.24 mmol), benzenesulphonamide (46 mg, 0.29 mmol), EDC (56 mg, 0.29 mmol), and 4-dimethylaminopyridine (5 mg, 0.03 mmol) in 1:1 dichloromethane/tetrahydrofuran (4 ml) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (10 ml) and washed with aq. sodium bicarbonate (5 ml), dilute hydrochloric acid (5 ml), water (5 ml), and brine (5 ml). The organic phase was dried and evaporated. Purification by prep. HPLC gave the title compound. (27 mg 20%).
Reaction SMILES: [C:1]([C:3]1[N:4]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH:5]=[C:6]([CH:8]([OH:18])[C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])[N:7]=1)#[N:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[N:4]([S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH:5]=[C:6]([C:8](=[O:18])[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([Cl:16])=[CH:13][C:14]=2[Cl:15])[N:7]=1)#[N:2]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2c(Cl)cc(Cl)cc2Cl)nc1C#N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cc(C(=O)c2c(Cl)cc(Cl)cc2Cl)nc1C#N
Reaction time: 11 h

Procedure:
2-Cyano-1-(dimethylsulphamoyl)-4-(2,4,6-trichloro-α-hydroxybenzyl)imidazole (15.7 g) was dissolved in dichloromethane and pyridinium dichromate (28.9 g) and silica gel (230-400 mesh; 58 9) added and the mixture stirred for 11 hours. The mixture was filtered and the precipitate washed with dichloromethane. The filtrate and washings were evaporated under reduced pressure and the residue washed with diisopropyl ether and dried under reduced pressure to give 2-cyano-1-(dimethylsulphamoyl)4-(2,4,6-trichlorobenzoyl)imidazole, m.p. 142°-151°. (Compound 5).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:32]([NH2:34])=[O:33])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH:17]=4)=[CH:7][C:6]=1[Cl:35].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:35][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:32]([NH2:34])=[O:33])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH:17]=4)[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 75 °C
Yield: 97 %

Procedure:
3-(4-(2-Bromoethoxy)-3-chlorophenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide (48.6 mg, 0.076 mmol, Example 408C) was dissolved in DMF (5 ml). Morpholine (0.1 ml, 1.15 mmol) and K2CO3 (40 mg, 0.29 mmol) were added and the mixture heated to 75° C. for 2 hour. The mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC. Product containing fractions were evaporated to dryness to give 43.0 mg 3-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=583/585, m/e−=581/583 [1 Cl isotope pattern]. HPLC retention time 14.31 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.12 (s, 1H), 8.53 (d, 1H, J=1.2), 8.35 (b, 1H), 8.16 (d, 1H, J=1.5), 8.11 (d, 1H, J=8.8), 7.99 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.5, 2.2), 7.53 (b, 1H), 7.34 (d, 1H, J=2.0), 7.31 (d, 1H, J=8.8), 7.00 (dd, 1H, J=8.8, 2.2), 4.26 (t, 2H, J=5.8), 3.85 (b, 4H), 3.64-3.59 (m, 4H), 3.23 (b, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[C:1]([C:3]1([C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)OCC)cc(C2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 5-(cyanomethyl)benzene-1,3-dioate (500 mg, 1.9 mmol) in 18.6 mL THF was added potassium bis(trimethylsilyl)amide (1.1 g, 5.7 mmol) and the reaction was stirred at rt for 5 min. 1,4-Dibromobutane (0.25 mL, 2.1 mmol) was added, the mixture was stirred for 45 min and then quenched with 1N HCl. Ethyl acetate was added, the layers separated and the organic layer was washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0-15% EtOAc/hexanes) gave diethyl 5-(1-cyanocyclopentyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.63 (m, 1H), 8.31 (m, 2H), 4.43 (q, J=7.1 Hz, 4H), 2.56 (m, 2H), 2.14-1.99 (m, 6H), 1.43 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH:13]1(B(O)O)[CH2:15][CH2:14]1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCCc2cc(C3CC3)ccc21
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a round bottomed flask charged with 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (16.9 g, 74.7 mmol), cyclopropylboronic acid (9.45 g, 1.5 equiv), tricyclohexylphosphine (1.04 mg, 0.025 equiv), and K3PO4 hexahydrate (50 g, 2 equiv) in toluene (210 mL) and H2O (15 mL) was added Pd(OAc)2 (100 mg, 0.05 equiv). The combined mixture was heated for 4 h at 100° C. The reaction mixture was cooled, filtered and washed with toluene. The organic phase was partitioned and washed with water and brine, dried over Na2SO4, filtered and concentrated to an oil. Addition of hexanes produced 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one as a tan solid (13.6 g). MS (ESI) 187.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=4[F:40])[CH:31]=3)[N:26]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:25]=2)[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([F:40])[C:33]=1[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)[N:25]=[C:24]2[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[N:23]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.28 g, 1.32 mmol) in DMF (10 mL) was treated with NaH (0.056 g, 2.34 mmol) and stirred for 15 min. The reaction mixture was cooled to 0° C. and 3-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.17 mmol) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to obtain (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.2 g, 18%). MS (ESI, pos. ion) m/z: 591.1 (M+1). To a solution of (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.3 g, 0.5 mmol) in EtOAc (10 mL) was added EtOAc-HCl (10 mL) and stirred at RT for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse-phase preparative HPLC (using a AG/PP/C18-15/021 column, eluting with gradient, A: 5% TFE+0.01% TFA in Water; B: ACN). The title compound was obtained. MS (ESI, pos. ion) m/z: 407.2 (M+1).
Reaction SMILES: CO[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[CH2:18]([SH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:18]([S:24][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCS
Reactant: COC(=O)C(OC)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCCSC(C(=O)OC)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl α-methoxy-3,4-dimethoxyphenylacetate (0.39 g) in methylene chloride (5 ml) were added hexanethiol (0.35 ml) and 3 drops of concentrated sulfuric acid and the mixture was stirred for 30 minutes. Then it was washed with water and brine, dried (magnesium sulfate) and evaporated to give an oily residue. Purification by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane provided methyl α-hexylthio-3,4-dimethoxyphenylacetate (0.37 g), a compound of Formula 4 wherein X is S, R5 is 3,4-dimethoxyphenyl and R7 is hexyl.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C(F)(F)F
Agent: Cl
Solvent: CO
Product: NCc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 221.7 %

Procedure:
To a solution of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetamide (0.800 g) in methanol (20 mL) was added conc. HCl (2.0 ml). The reaction mass was refluxed for 18 h. Excess solvent was removed under vacuum to afford 0.700 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.18 (s, 1H), 7.35 (s, 1H), 7.52 (s, 1H), 7.86 (s, 2H), 8.28 (s, 1H), 8.72 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[CH2:14][N:13]([CH:17]([CH3:19])[CH3:18])[C:12]2=[O:20])=[C:4]([F:21])[CH:3]=1>C(O)(=O)C.O.C(OCC)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[CH2:14][N:13]([CH:17]([CH3:19])[CH3:18])[C:12]2=[O:20])[CH:6]=1
Reactant: CC(C)N1CC(=O)N(c2cc([N+](=O)[O-])c(Cl)cc2F)C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(C)N1CC(=O)N(c2cc(N)c(Cl)cc2F)C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred mixture of 4.4 g (0.014 mole) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-(1-methylethyl)hydantoin in 70 mL of acetic acid and 10 mL of water was added slowly 4.5 g (0.083 mole) of iron powder. The reaction mixture was heated briefly at 50° C, then was cooled to room temperature and was stirred for 0.5 hour. The mixture was diluted with diethyl ether and was filtered through a pad of Celite® filter aid. The filter pad was rinsed with diethyl ether. The filtrate, containing the diethyl ether wash, was transferred to a separatory funnel and was washed with water and an aqueous dilute sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 3.0 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-(1-methylethyl)hydantoin.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:29][CH2:30][CH3:31])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:28])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])[CH3:2].[OH:32][C:33]1[C:47]([O:48][CH3:49])=[CH:46][C:36]2[C:37](=[O:45])[N:38]3[CH2:44][CH2:43][CH2:42][C@H:39]3[CH2:40][NH:41][C:35]=2[CH:34]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:29][CH2:30][CH3:31])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:28])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:32][C:33]2[C:47]([O:48][CH3:49])=[CH:46][C:36]3[C:37](=[O:45])[N:38]4[CH2:44][CH2:43][CH2:42][C@H:39]4[CH2:40][NH:41][C:35]=3[CH:34]=2)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCBr)cc1[N+](=O)[O-]
Reactant: COc1cc2c(cc1O)NC[C@@H]1CCCN1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]

Procedure:
A solution of (2S)-N-[4-(4-bromobutoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (535 mg, 1 mmol), 8-hydroxy-7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrol[2,1-c][1,4]benzodiazepine-5-one (248 mg, 1 mmol) of the formula II and K2CO3 (414 mg, 3 mmol) in dry acetone (20 mL) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc, the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc:hexane (8:2) gave the pure (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)=[O:4].[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH:2]([CH3:16])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COC(=O)c1cc(C(=O)C(C)Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)ccc1O
Reaction time: 1 h

Procedure:
300 ml of methyl ethyl ketone containing 57.4 g of 2-bromo-4'-hydroxy-3'-methoxycarbonylpropiophenone, 35 g of 4-benzylpiperidine and 30.6 g of potassium carbonate are heated under reflux for 4 hours. The precipitate is filtered off hot, the filtrate is evaporated to dryness, the residue is taken up in 3N hydrochloric acid and the mixture is extracted with diethyl ether. The ether phase is stirred for one hour; the hydrochloride crystallizes and is filtered off, rinsed with diethyl ether and transferred to a beaker containing water rendered alkaline with 3N aqueous ammonia solution, and the base freed in this way is extracted with ethyl acetate. After washing, drying and evaporation of the organic phase, 52 g of product are obtained, which is used as such.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:14][Cl:15].ClCCCC>C(Cl)Cl>[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([NH:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1)=[O:28])(=[O:24])=[O:25])=[CH:14][Cl:15]
Reactant: Cc1nc(N)nc2c1CCO2
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: CCCCCl
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)nc2c1CCO2
Reaction time: 8 h

Procedure:
To 300 mg of 2-amino-5,6-dihydro-4-methylfuro[2,3-d]pyrimidine in 25 ml of methylene chloride was added 20 ml of 2-(1,2-dichloroethen-1-yloxy)benzenesulfonyl isocyanate in methylene chloride from the previous example. After heating to reflux, the mixture was stirred overnight at room temfperature. Removal of the solvent in vacuo yielded an amber oil. Trituration of this oil with 1-chlorobutane gave a tan solid. After filtration and washing with ethyl ether, a yield of 0.8 g of a tan solid melting at 208°-210° was obtained.