Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOCCOc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of diethyleneglycol monophenyl ether (1.56 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-ethyl acetate; 50:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-[[2-(phenoxy)ethyl]oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 75°-76° C.
Reaction SMILES: [P:1](=[O:7])([NH2:6])([S:4][CH3:5])[O:2][CH3:3].[C:8](OC(=O)C)(=[O:10])[CH3:9]>S(OC)(OC)(=O)=O>[C:8]([NH:6][P:1](=[O:7])([S:4][CH3:5])[O:2][CH3:3])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COP(N)(=O)SC
Solvent: COS(=O)(=O)OC
Product: COP(=O)(NC(C)=O)SC
Yield: 138.1 %

Procedure:
19.1 Grams of dimethyl sulfate were gradually added to 296 g(purity 86.3%) of O,O-dimethylphosphoramidothioate at 40° C. in 30 min and to the resultant were further added 1180 g of O,O-dimethyl phosphoramidothioate and 76.1 g of dimethyl sulfate at the same temperature over 2 hours separately. The resultant reaction mixture was further maintained at the temperature for 8 hours to obtain 1562 g of O,S-dimethyl phosphoramidothioate(purity: 79.1%). To 1562 g of obtained O,S-dimethyl phosphoramidothioate was added 1218 g of acetic anhydride and 41 g of dimethyl sulfate at 40° C. over an hour. The resultant was maintained at the temperature for an hour to complete the reaction to give 2799 g of crude O,S-dimethyl N-acetylphosphoramidothioate(purity: 49.13%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[NH:12][N:11]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.Cl.N>C(#N)C.O1CCOCC1.O>[Cl:23][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:11][N:12]=1
Reactant: Cc1ccc(CCc2n[nH]c(=O)c3ccccc23)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(CCc2nnc(Cl)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
Under N2-atmosphere, 217 mg (0.818 mmol) 4-[2-(6-methylpyridin-3-yl)ethyl]phthalazin-1(2H)-one in 3.3 ml acetonitrile is mixed with 187 μl (2.04 mmol) phosphoryl chloride and 0.41 ml 4 N HCl in dioxane and stirred for 9 h at 60° C. After cooling to RT, 2.6 ml H2O, followed by a solution of 0.5 ml sat. NH3 and 5 ml H2O is added. Immediate extraction with 3 portions of EtOAc, washing of the organic layers with water and brine, drying (Na2SO4) and evaporation yield the title compound; FAB-MS (M+H)+=284.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[CH2:14][C@@H:13]3[O:15][C:16]4[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C@H:12]3[CH2:11]2)=CC=1.Cl.O.C(Cl)(Cl)[Cl:37]>C(O)=O>[ClH:37].[N+:23]([C:22]1[C:16]2[O:15][C@@H:13]3[C@H:12]([CH2:11][NH:10][CH2:14]3)[O:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2C[C@@H]3Oc4cccc([N+](=O)[O-])c4O[C@H]3C2)cc1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: O=[N+]([O-])c1cccc2c1O[C@H]1CNC[C@@H]1O2

Procedure:
A solution of (±)-(trans)-2-[bis(4-methoxyphenyl)methyl]-2,3,3a,9a-tetrahydro-5-nitro-1H-[1,4]benzodioxino[2,3-c]pyrrole (1.12 g) in formic acid (10 ml) was heated under reflux with 10M hydrochloric acid (0.5 ml), water (1 ml) and chloroform (5 ml) for 70 minutes. The maroon mixture was cooled and partitioned between chloroform (20 ml) and water (10 ml). The chloroform layer was re-extracted with water (10 ml) and the aqueous solutions were sequentially washed with chloroform (20 ml), combined and evaporated to ca. 2 ml, when crystals formed. These were triturated with warm propan-1-ol (5 ml), cooled to 20° for 1 hour and harvested to give a first crop of the title compound (0.58 g). Concentration of the mother liquor gave a small second crop (0.03 g). Recrystallisation of the first crop from slightly aqueous propan-1-ol gave purer title compound (0.54 g) m.p. ca. 280° (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[CH2:4].COCCOC.[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16]>C(OCC)C.[Zn]>[C:2]([CH:3]1[CH2:4][C:15](=[O:16])[C:14]1([Cl:19])[Cl:13])([CH3:6])([CH3:5])[CH3:1]
Reactant: C=CC(C)(C)C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)C1CC(=O)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Suspend 3,3-dimethyl-1-butene (10 mL, 80.8 mmol), ethylene glycol dimethyl ether (11.5 mL, 106 mmol), and freshly activated zinc (13.8 g, 211 mmol) in dry diethyl ether (100 mL) under a nitrogen atmosphere. Add to this suspension a solution of trichloroacetyl chloride (11.5 mL, 103 mmol) in dry diethyl ether (50 mL) dropwise over 20 minutes. Heat to reflux for 24 hours. Cool to room temperature and filter off the residual solid materials. Concentrate the filtrate and triturate the residue with hexanes. Filter the mixture to remove solid materials. Wash the filtrate solution with saturated aqueous sodium bicarbonate solution (3×), saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the pure fractions and concentrate. Isolate the desired compound by vacuum distillation to give a clear liquid (7.59 g, 48%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Cl-].[Zn+2].[Cl-]>[CH2:25]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([OH:11])=[CH:2][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCO
Reactant: Oc1cccc2ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCc1ccc(O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
In a one liter three-neck flask provided with agitating means were charged and stirred 216 g (1.5 mole) of α-naphthol and 171 g (1.26 mole) of zinc chloride, 278 g (1.26 mole) of tetradecyl alcohol was added dropwise to the flask kept at 160° C. Stirring was continued for 8 hours after the completion of the addition at the same temperature. The reaction product was cooled to room temperature (i.e., 20°-30° C), and then washed with water after the addition of 500 ml of petroleum ether and 500 ml of water with stirring. This washing operation was repeated twice. The petroleum ether layer was separated, which was distilled under a reduced pressure after being dried with anhydrous sodium sulfate. 183 g of 4-tetradecyl-α-naphthol (yield: 42.7%) having boiling range of 188° to 194° C at 0.15 mmHg was obtained.
Reaction SMILES: O[C@H:2](C)[CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@@H:6]([CH3:17])[CH2:5]1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:41]([O:45][C:46](=[O:54])[NH:47][CH:48]1CCNCC1)([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([O:45][C:46]([NH:47][CH:48]1[CH2:25][CH2:24][N:21]([CH2:19][C@@H:3]([N:4]2[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[C@@H:6]([CH3:17])[CH2:5]2)[CH3:2])[CH2:22][CH2:23]1)=[O:54])([CH3:44])([CH3:43])[CH3:42]
Reactant: C[C@@H](O)CN1CC[C@H](OC(=O)C(C)(C)C)[C@@H](C)C1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of alcohol 57 (1.26 g, 5.16 mmol) and triethylamine (1.43 ml, 10.32 mmol) in 80 ml of DCM is cooled to −78 C. Triflic anhydride (0.85 ml, 5.16 mmol) is slowly added and stirring continued for 1 hour. The mixture is then allowed to warm up to 0 C and cooled back to −78 C after 15 minutes. A solution of piperidin-4-yl-carbamic acid tert-butyl ester, 3, (1.03 g, 5.16 mmol) in 40 ml of DCM is slowly added at −78 C. After complete addition, the cooling bath is removed and the dark solution is allowed to warm up to room temperature. The mixture is washed twice with water, dried over sodium sulphate, filtered and evaporated. The crude is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (1%).
Reaction SMILES: [Cl:1]C(OCC)=O.C(N(CC)CC)C.C(OC([NH:21][CH:22]1[CH2:24][CH:23]1[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](O)=[O:40])=[CH:27][CH:26]=1)=O)(C)(C)C.COC([O:48][NH2:49])(C)C>O1CCCC1>[ClH:1].[NH2:21][CH:22]1[CH2:24][CH:23]1[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([NH:49][OH:48])=[O:40])=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cl
Reactant: COC(C)(C)ON
Reactant: CC(C)(C)OC(=O)NC1CC1c1ccc(NC(=O)CCCCCCC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cl
Product: NC1CC1c1ccc(NC(=O)CCCCCCC(=O)NO)cc1
Reaction time: 0.17 h

Procedure:
Ethyl chloroformate (0.384 mmol, 0.04 mL) and triethylamine (0.42 mmol, 0.06 mL) were added to a cooled (0° C.) solution of 8-(4-(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxooctanoic acid (0.32 mmol, 130 mg) in dry tetrahydrofuran (5 mL), and the mixture was stirred for 10 min. The solid was filtered off, and O-(2-methoxy-2-propyl)hydroxylamine (0.96 mmol, 0.7 mL) was added to the filtrate. The solution was stirred for 15 min at 0° C., then a 6 N HC1 solution (10 mL) was added, and the stirring was continued for further 12 h. Therefore the precipitate was filtered and washed with diethyl ether (3×10 mL) to give the pure N1-(4-(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide hydrochloride (9).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)c(N3CCCCC3)nc2n1
Reactant: C1CNCCN1
Product: Clc1nc2c(N3CCCCC3)nc(N3CCNCC3)nc2nc1N1CCCCC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4,7-dipiperidino-pteridine and piperazine.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH:3]1[C:6]([CH3:8])=[CH2:7].CC1(CC=[O:22])CCC1C(C)=C.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:1][C:2]1([CH2:9][C:10]([OH:22])=[O:11])[CH2:5][CH2:4][CH:3]1[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C1CCC1(C)CC=O
Reactant: C=C(C)C1CCC1(C)CCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C=C(C)C1CCC1(C)CC(=O)O

Procedure:
A four gram sample of racemic 1-methyl-2-(1-methylethenyl)-cyclobutaneethanol (grandisol I) [2] (Bedoukian, Inc.) was oxidized to the corresponding racemic aldehyde, 1-methyl-2-(1-methylethenyl)-cyclobutaneacetaldehyde (grandisal) using pyridinium chlorochromate (Webster) (3.4 g, % yield 86.1). The racemic aldehyde was distilled under vacuum and a 3 gram sample was subsequently oxidized to racemic 1 using AgNO3 and NaOH (Pickett): nearly colorless oil (1.23 g, % yield 32.2); eims m/z (rel. int. %) 168 (1), 125 (12), 109 (14), 108 (35), 93 (9), 91 (3), 81 (6), 79 (11), 77 (10), 69 (11), 68 (100), 67 (86), 55 (11), 53 (30), 43 (35), 41 (41); H NMR (CDCl3) δ 2.61 (1H, m, H-2), 1.83 (1H, m, H-3a), 1.95 (1H, m, H-3b), 1.71 (1H, m, H-4a), 1.95 (1H, m, H-4b), 1.31 (3H, s, Me-5), 2.03 (1H, dd, J=14.6,H-6a), 2.54 (1H, d, J=14.6, H-6b), 4.85 (1H, m, H-9a), 4.65 (1H, m, H-9b), 1.64 (3H, s, Me-10); 13C NMR (CDCl3) δ 41.1 (C-1), 51.9 (C-2), 18.7 (C-3), 29.0 (C-4), 27.9 (C-5), 38.5 (C-6), 179.7 (C-7), 144.1 (C-8), 110.3 (C-9), 22.8 (C-10).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N:31]1(CC#N)CCN[CH2:33][CH2:32]1.C(OC(N1CCN(CC#N)CC1)=O)(C)(C)C.Cl.C12NC(CC1)CN(C(=O)C)C2>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([CH2:33][C:32]#[N:31])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: N#CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CC(=O)N1CC2CCC(C1)N2
Agent: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: Cl
Product: N#CCN1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 284 is synthesized from Intermediate C and piperazin-1-yl-acetonitrile (prepared from 4-Cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure used to synthesize Intermediate U from U-1) according to General Method F. (LC/MS method 16: ES+ m/z 351.3 [M+H]+, Rt=2.68 min)
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[Na+].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C(O)=O>CO.O>[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)NC(c1cccc(Cl)c1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At RT, 2.23 g (19.0 mmol) of tert-butyl carbamate and 6.25 g (38.1 mmol) of benzenesulphinic acid sodium salt were initially charged in 55 ml of methanol/water (1:2), and 5.00 g (28.6 mmol) of 2,3-dichlorobenzaldehyd and then 1.43 ml (37.9 mmol) of formic acid were added. The reaction mixture was stirred at RT for 2 days. The precipitated solid was filtered off with suction and washed with water and twice with diethyl ether. From the ethereal filtrate, 3.47 g of 2,3-dichlorobenzaldehyde were recovered after removal of the solvent on a rotary evaporator. The solid which was filtered off with suction was dried under high vacuum. This gave 2.22 g (19% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].Cl[C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]=1)[C:3](=[O:5])[CH3:4]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(=O)C(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)COc1ncc(C(F)(F)F)cc1Cl
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
3,3-Dimethyl-4-hydroxybutan-2-one (11.2 g) was dissolved in 50 ml of dimethyl sulfoxide, and nitrogen gas was passed therethrough for 20 minutes. Then, 21.6 g of 2,3-dichloro-5-trifluoromethylpyridine and 15 g of anhydrous potassium carbonate were added thereto, and the system was gradually heated to 115° C. and stirred for 4 hours at that temperature. After completion of the reaction, the product was put into ice water, extracted with methylene chloride, washed with water and dried over Glauber's salt. The solvent was distilled off to give 26.7 g of oily 3,3-dimethyl-4-(3-chloro-5trifluoromethylpyridine-2-yloxy)butan-2-one.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]2[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C@H:12]([CH2:23][Br:24])[O:11]1)C1C=CC=CC=1.[H][H]>[Pt].CO.C(OCC)(=O)C>[Br:24][CH2:23][C@H:12]1[C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:14]=2[CH2:15][C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: [H][H]
Reactant: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reaction time: 8 h

Procedure:
5% Platinum on carbon (1.0 g) is added to a solution of [1R,3S] 3-benzyloxymethyl-1-bromomethyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran (3.42 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethyl acetate. The reaction mixture is sealed under 4 atmospheres of hydrogen and shaken overnight. The reaction mixture is filtered to remove the catalyst and concentrated. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: C([CH:5]([O:27][C:28]1[CH:29]=[N:30][NH:31][C:32](=[O:35])[C:33]=1[Cl:34])[C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][CH:7]=1)(C)(C)C.[F-:36].[K+]>C(#N)C>[C:6]([N:31]1[C:32](=[O:35])[C:33]([Cl:34])=[C:28]([O:27][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][F:36])=[CH:25][CH:26]=2)[CH:29]=[N:30]1)([CH3:26])([CH3:7])[CH3:5]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)n1ncc(OCc2ccc(OCCCF)cc2)c(Cl)c1=O
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To a scintillation vial containing a suspension of Example 4F (4.5 mg, 8.64×10−3 mmol) in anhydrous acetonitrile (0.25 mL) was added a solution of potassium fluoride (1.6 mg, 4.07×10−2 mmol) and kryptofix (15.0 mg, 4.07×10−2 mmol) in anhydrous acetonitrile (0.25 mL). The vial was capped and lowered into a 90° C. oil bath. The reaction was allowed to stir for 40 minutes. The reaction was cooled and concentrated under reduced pressure. Preparatory thin layer chromatography [silica gel; eluent pentane-ethyl acetate (3:2)] provided the desired product (0.8 mg, 25%). 1H (CDCl3) δ(ppm): 1.62 (s, 9H); 2.14-2.20 (m, 2H); 4.09-4.11 (m, 2H); 4.60 (t, 1H); 4.68 (t, 1H); 5.24 (s, 2H); 6.92 (d, 2H); 7.32 (d, 2H); 7.72 (s, 1H); 19F(CDCl3, CFCl3 as internal standard) δ(ppm): −222.66 (t of t, J=28.2, −50.4)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][CH:18]=O)[CH2:6][CH2:5]2.P(Cl)(Cl)(Cl)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH:10]=1)[CH:18]=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]3[CH2:6][CH2:5]2
Reactant: O=CNc1ccccc1N1CCc2cc(Cl)ccc21
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: Clc1cc2c3c(c1)CCN3c1ccccc1N=C2

Procedure:
A mixture of 9.40 g of 5-chloro-1-(2-formamidophenyl)indoline and 45 ml of phosphorus oxychloride is stirred under nitrogen. After a short time, a purple solution results. While heating this to reflux, a solid precipitates at 60° C. During the early stages of a 6 hour reflux period a solution is obtained again followed by heavy HCl (g) evolution and separation of a solid. The mixture is cooled and 45 ml of hexane is added to give a finely divided purple solid. This is filtered, washed repeatedly with hexane and dried. For purification, the solid is slurried in absolute ethanol, and tri-n-butylamine is added until a color change, indicating liberation of the free base of the product. The mixture is warmed to produce a solution, and the base allowed to crystallize at 0° C. The base is collected, washed with ethanol and dried. To reform the HCl salt, the base is dissolved in 15 ml of dimethylformamide without heating, and to the solution is added 35 ml of ethanol saturated with HCl gas. The product of 4-chloro-1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride crystallizes rapidly in the form of needles with m.p. 231°-233° C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].Cl>CO>[Cl:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1Cc1sc3ncccc3c1S(=O)(=O)Nc1noc(C)c1Cl)OCO2
Yield: 83.7 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[2methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (58 mg, 0.10 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization fronm chloroform and hexanes provided 40 mg (80%) of the title compound as a white solid, m.p. 189-191° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].CC(C)([O-])C.[K+].[F:38][C:39]([F:62])([F:61])[CH2:40][CH2:41][CH:42]([C:45]1[CH:46]=[N:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)=[CH:49][CH:50]=1)[CH:43]=O>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:43]/[CH:42]([C:45]2[CH:46]=[N:47][C:48]([C:51]3[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)[CH2:41][CH2:40][C:39]([F:38])([F:62])[F:61])=[CH:30][CH:31]=1
Reactant: O=CC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/C=C/C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
(4-Methoxycarbonyl-benzyl)-triphenyl-phosphonium chloride (6.7 g, 15 mmol) is suspended in anhydrous toluene (25 mL) and potassium tert-butoxide (1.7 g, 15 mmol) is added at room temperature in one portion. The mixture is allowed to stir under nitrogen for 1 h. Meanwhile, 5,5,5-trifluoro-2-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentanal (3.61 g, 10.0 mmol) is dissolved in another portion of the toluene (25 mL), and kept at room temperature. The mixture is then cooled to 0° C. with ice water, and then the ketone is transferred by cannula. The reaction is allowed to stir at 0° C. for 10 min, then the ice bath is removed. The reaction is allowed to warm to room temperature and monitored by HPLC. Upon complete conversion, the reaction is carefully quenched with saturated ammonium chloride solution, and diluted with ethyl acetate, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The cis and trans 4-{6,6,6-Trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoic acid methyl ester (2.0 g, 4.1 mmol) are isolated as pure regioisomers (1:1) after column chromatography, 31% total yield.