Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].BrC1C=CC(N)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC(C1C=CC(=O)N(C)C=1Cl)=O>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:15]([F:21])[CH:16]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: COC(=O)c1ccc(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To a solution of 4-bromo-2-fluorophenylamine (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. 2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a while crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32 g (0.20 mol) 2-chloro-5-nitropyridine in 120 mL toluene were combined with 200 mL (0.20 mmol) of a 1M sodium benzylate solution in benzylalcohol and stirred overnight at RT. The organic phase was washed with water and saturated sodium chloride solution, dried on sodium sulphate and the toluene was eliminated by distillation. The residue was cooled with ice, the precipitate formed was suction filtered and washed several times with tert.-butylmethylether.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.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:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The mixture of 6-bromo-1-methyl-1H-indole (0.216 g, 1.03 mmol), 4-trifluoromethylbenzeneboronic acid (0.216 g, 1.14 mmol), tetrakis(triphenylphosphine)palladium (0.0541 g, 0.0468 mmol) and sodium carbonate (0.438 g, 4.13 mmol) in water (2.5 mL), ethanol (1 mL) and toluene (5 mL) was refluxed for 1.6 hours. The mixture was cooled to room temperature then evaporated to dryness. The residue was partitioned in methylene chloride and water. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 0-0.2% ethyl acetate in hexane as an eluant to give the title compound (0.144 g, 51%) as a white solid, mp: ˜100° C.; 1HNMR (200 MHz, DMSO-d6): δ 8.0 (d, 2H, J=6.6 Hz), 7.8 (d, 3H, J=8.7 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.35-7.5 (m, 2H), 6.45 (d, 1H, J=2.6 Hz), and 3.8-3.95 ppm (m, 3H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>O.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:5]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.8 %

Procedure:
Add NaOH (3.6 g, 90.2 mmol) as solution in H2O (14 mL) to a solution of 4-chloroazaindole 24 (0.84 g, 5.50 mmol), TsCl (1.154 g, 6.053 mmol) and Bu4NHSO4 (16 μL, 50% in H2O) in toluene (16 mL). After stirring the reaction medium for 2.5 h at room temperature, the two-phase reaction medium is then extracted with EtOAc (2×), dried (MgSO4) and concentrated under vacuum. Flash chromatography gives 25 (1.33 g, 78%) as a white solid: 1H NMR (CDCl3) δ 8.28 (d, 1H, J=5.1 Hz), 8.04 (dd, 2H, J=8.5, 2.0 Hz), 7.75 (d, 2H, J=4.0 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=5.1 Hz), 6.67 (d, 1H, J=4.2 Hz), 2.37 (s, 3H), TLC (EtOAc at 40%/heptane) Rf=0.50, m/z obs.=307 (M+1), 308.9.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].O.[O:21]=[C:22]1[O:26][C@H:25]2[CH2:27][C@@H:28]([O:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[C@H:29]([CH:30]=O)[C@H:24]2[CH2:23]1>COC(C)(C)C>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:30]/[C@@H:29]1[C@@H:24]2[C@@H:25]([O:26][C:22](=[O:21])[CH2:23]2)[CH2:27][C@H:28]1[O:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.378 g, 1.50 mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate (60.8 mg, 1.45 mmol) was added and the mixture was stirred for one hour at room temperature. Water (0.15 ml) and (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydro cyclopenta[b]furan-4-carbaldehyde (10) (0.274 g, 1.00 mmol) were added thereto and the mixed solution was stirred for approximately 3 hours at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=1:2), to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (0.201 g; 0.495 mmol; yield: 49.5%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2,4-Dimethoxybenzoic acid (30.0 g) was suspended in acetic acid (180 mL). A bromine (27.6 g)/acetic acid (60 mL) solution was slowly added dropwise to the suspension and, after completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hrs, and the termination of the reaction was confirmed by HPLC. An aqueous solution of sodium sulfite (2.10 g) and water (360 mL) was added dropwise to the reaction mixture. After completion of the dropwise addition, the mixture was stirred at 25° C. for 1 hr. Precipitated crystals were collected by filtration, washed 4 times with water (150 mL), and vacuum dried to give 5-bromo-2,4-dimethoxybenzoic acid as white crystals (41.2 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]>C(O)(=O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(N)cc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
Iron (33 g, 0.59 mol) was added to 2-fluoro-1-methylsulfanyl-4-nitro-benzene (18.5 g, 99 mmol) in a mixture of acetic acid (350 mL) and water (70 mL). The mixture was stirred for 2 h with periodic swirling, and then the solvents were evaporated. Ethyl acetate and aqueous sodium bicarbonate solution were added and the mixture was filtered through Celite. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/hexanes to give 3-fluoro-4-methylsulfanyl-phenylamine (15.1 g, 97%).
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].IC.[CH2:15](N(CC)CC)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1.C(Cl)Cl.O>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:15])([CH3:5])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: COc1ccccc1C(C)C
Reaction time: 5 h
Yield: 94 %

Procedure:
A 22 L three-necked round bottom flask equipped with mechanical stirring was charged with KOH (1154 g, 20.56 moles), tetrabutylammonium hydrogen sulfate (140 g, 0.411 mole), and deionized water (5.6 L). The mixture was cooled to a temperature of approximately 20° C. to 25° C. Methylene chloride (5.6 L) was added to the flask, then 2-isopropylphenol (590 g, 4.33 moles). The mixture was stirred for 0.5 h before iodomethane (741 g, 5.22 moles) was added. The stirring was continued at room temperature until the reaction was observed to be complete by HPLC, typically after approximately 5 h. Stirring was discontinued and the reaction mixture was allowed to settle into aqueous and organic layers, which were then separated. Triethylamine (185 mL, 1.33 moles) was added to the organic phase with stirring for at least 15 min. Solvent was then removed by vacuum distillation to afford a white solid. Cyclohexane (41) was added to the white solid, which was filtered and washed with further cyclohexane to remove the reaction product as a solvate. The cyclohexane solution was washed with aqueous HCl (2N), then half-saturated aqueous NaCl, and finally saturated aqueous NaCl. The cyclohexane was removed by vacuum distillation to afford 1-isopropyl-2-methoxybenzene as a light yellow oil of medium viscosity (612 g, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=1.[CH2:13](O)[CH2:14][OH:15].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[O:15][CH2:14][CH2:13][O:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C2OCCO2)c1
Yield: 100.5 %

Procedure:
A solution of 3-formyl-benzoic acid methyl ester (9.48 g, 57.8 mmol), ethylene glycol (8.97 g, 144.5 mmol, 2.5 eq.) and conc. sulfuric acid (0.18 g, 1.8 mmol) in toluene was heated under Dean-Stark reflux for 3 hrs. After cooling, satd. NaHCO3 (100 ml) was added. The aqueous phase was extracted with EtOAc, the combined organic phases were dried over Na2SO4 and evaporated to afford the title compound (12.1 g, 101% yield) as a yellow liquid. MS: m/e=164 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:67][CH:68]=[CH2:69].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:69][CH:68]=[CH2:67])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (90 mg in 3 ml 33% methylene chloride in cyclohexane) allyl trichloroacetimidate (27 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (20 mg).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C=C>C(Cl)Cl>[C:2]1([CH2:1][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: C=CC(=O)O
Solvent: ClCCl
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
To a solution of benzhydrol (184 mg, 1 mmol) in methylene chloride (1 mL) is added 0.2 g 90 weight percent HF/10 weight percent acrylic acid polymer, 100,000 m. wt., and the solution stirred until complete by TLC. The liquid is decanted and the gel washed with 2×1 mL methylene chloride. The organic layers are combined and washed with 1 mL water, 1 mL NaHCO3, dried through MgSO4 and evaporated. Diphenylmethane is afforded.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-acetoxybenzoic acid (516 mg) and oxalyl chloride (0.5 ml) was stirred for 30 minutes. The mixture was concentrated under reduced pressure to give 4-acetoxybenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C1C=CN=CC=1)C>[CH3:32][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([O:8][C:6]1[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=[C:2]([NH2:1])[N:7]=1)(=[O:29])=[O:30]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Agent: CN(C)c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from step (iii) (3.4 g), 2-mesitylenesulfonyl chloride (3.51 g), TEA (5.59 ml) and DMAP (82 mg) was stirred at rt for 18 h. The mixture was partitioned between DCM/water, the organics separated, washed with aq. NaHCO3 soln, water, dried and evaporated under reduced pressure. The residue was triturated with ether/ethylacetate and filtered to afford the subtitle compound, 5.08 g.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:6]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[O:3][C:4]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-chloro-4-(3,4-dichlorophenyl)-5-oxazolepropionate (1.00 g), 2-methylimidazole (0.82 g), potassium carbonate (0.69 g), and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 1 hour. The reaction mixture was poured into ice water (100 ml). The precipitated crystals were filtered, washed in sequence with water and isopropyl ether, and air-dried to give crystals of methyl 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate. Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prisms (0.82 g, 72%). Melting point 116-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2c(c1)NCC2
Reaction time: 1 h
Yield: 98.6 %

Procedure:
6-Chloroindole (1 g, 6.6 mmol) in glacial acetic acid (10 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) portionwise at room temperature with stirring. After 1 hour, the reaction was diluted with water (25 mL) and basified with 40% sodium hydroxide with cooling. The mixture was then extracted with dichloromethane (3×50 mL), dried and concentrated to give 1 g of 6-chloroindoline. It was used in the next step without further purification. 1HNMR (300 MHz, dimethylsulfoxide-d6) δ 6.95 (d, 1H), 6.46 (dd, 1H), 6.43 (d, 1H), 5.74 (br s, 1H, NH), 3.42 (t, 2H, CH2), 2.85 (t, 2H, CH2). MS m/z 349 [M+1].
Reaction SMILES: O.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:22]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: NCCCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 100 ml. of water and 120 ml. of tetrahydrofuran is added sequentially 12.4 g. of γ-aminobutyric acid, 10.4 g. of sodium bicarbonate, and 30 g. of N-benzyloxycarbonyloxysuccinimide. The reaction mixture is stirred for approximately 3.5 hours at room temperature and then the tetrahydrofuran is evaporated in vacuo. The residue is diluted with 200 ml. of water and extracted with (2×300 ml.) anhydrous ether. The aqueous layer is then acidified to pH 1-2 with 1 N hydrochloric acid and extracted with (3×400 ml.) methylene chloride. The methylene chloride extracts are collected and combined and then washed with (3×200 ml.) brine solution, dried with anhydrous magnesium sulfate and the solvent evaporated in vacuo at room temperature. The residue provides N-carbobenzoxy-γ-aminobutyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(Cl)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)C2CCCN2Cc2cc(Cl)ccc21

Procedure:
The above compound is obtained when (+)-7 -chloro-1,2,3,11a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] -benzodiazepin-5,11(10H)-dione (melting point 155°-157°C. is prepared from L-proline and 5-chloro-N-methylisatoic acid as described in Example 1) is treated with 1M borane in tetrahydrofuran as described in Example 1. The hydrochloride salt melts at 270°-272°C., [α]D 25 + 377° (1.03%) methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](OC)=[O:14])[CH:10]([C:17](OC)=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([CH2:17][OH:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
To a solution of dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (0.50 g) in THF (20 mL) was added LiAlH4 (3.0 eq) at 0° C. under N2. The reaction mixture was heated to the room temperature and stirred for 24 h. The reaction was quenched with water, 10% NaOH and water in turn. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH) to give the title compound (0.31 g, 63.79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 222.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reaction time: 72 h
Yield: 95.3 %

Procedure:
A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol, 14.95 g of trityl chloride and 40 ml pryridine was stirred for 72 hours, then diluted with chloroform, washed with two 100 ml portions of aqueous sodium bicarbonate, then water and dried. The solvents were evaporated under reduced pressure and the residue evaporated with toluene. This residue was then diluted with hexanes and the solid which formed collected giving 18 g of the desired compound.