Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH2:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Yield: 99.2 %

Procedure:
Into a 1-neck round-bottom flask was added tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and tetrahydrofuran (20 mL) and triethylamine (1.0 mL, 7.2 mmol). The mixture was cooled in an ice bath and (3-nitrophenyl)methanesulfonyl chloride (1.1 g, 4.8 mmol) was slowly added. The resultant mixture was warmed to rt. The solvent was removed under vacuum and EtOAc and water added. The aqueous phase was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4 and the solvent removed under vacuum to give the desired product (1.94 g, 99%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 9.37 (s, 1H), 8.98 (s, 1H), 8.19 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.71 (dt, J=7.7, 1.3 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.10 (m, 1H), 6.81 (t, J=8.0 Hz, 1H), 6.78 (br, 1H), 6.75 (ddd, J=7.4, 2.2, 1.6 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[CH2:15]1[C@@H:18](C(O)=O)[NH:17][CH2:16]1>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:17]3[CH2:18][CH2:15][C@H:16]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c(F)c2C(=O)N2CC[C@@H]12
Yield: 68.3 %

Procedure:
A solution of 19.6 g (98.4 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 9.95 g (98.4 mmol) of L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 16 g (68%) of (S)-5,6-difluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione as colourless needles of m.p. >250°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=3[CH3:29])=[C:11]([C:15]([O:17]C)=O)[NH:12]2)=[CH:8][CH:7]=1.O.[NH2:32][NH2:33]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=4[CH3:29])=[N:33][NH:32][C:15](=[O:17])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: NN
Reactant: COCCOc1ccc2c(C(=O)c3cccc([N+](=O)[O-])c3C)c(C(=O)OC)[nH]c2c1
Solvent: O
Solvent: CCO
Product: COCCOc1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A yellow, homogeneous solution of methyl 6-(2-methoxyethoxy)-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (1.546 g, 3.75 mmol) and hydrazine hydrate (0.982 mL, 13.13 mmol) in ethanol (55.1 mL) under nitrogen was refluxed overnight. The reaction was cooled to room temperature and concentrated in vacuo. It was dissolved in EtOAc (150 mL) and washed with water (40 mL) and brine (40 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.7461 g, 1.892 mmol, 50.4% yield) as a light yellow solid.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.C(O)(=[O:22])C.[OH2:24]>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)(=[O:22])=[O:24])=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: O
Agent: OO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 75 °C

Procedure:
A 35% aqueous hydrogen peroxide solution (13.6 g) was added dropwise to a mixture composed of 14.0 g of 1-(4-chlorophenylthio)-4-nitrobenzene and 47 mL of acetic acid. The mixed solution was stirred with heating at 70 to 80° C. for 1.5 hr. Thereafter, this reaction solution was cooled and was poured into water, and the precipitated crystals were collected by filtration to give 22.0 g of 1-(4-chlorobenzene sulfonyl)-4-nitrobenzene.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 90 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H2O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H2O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cc(CN)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CNS(C)(=O)=O)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
To a solution of 5-aminomethyl-2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (0.382 g, 0.944 mmol) and Et3N (0.191 g, 1.89 mmol) in dry THF (20 mL) was added MsCl (0.162 g, 1.42 mmol) at room temperature. After the addition the mixture was stirred at room temperature for 2 h saturated aqueous NaHCO3 (20 mL) was added. THF was then removed, and the aqueous residue was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over MgSO4. After filtration the solvent was removed to afford 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-(methanesulfonylamino-methyl)-benzoic acid methyl ester as a pale yellow foam (0.460, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH:20]([F:19])[F:29])=[CH:23][CH:24]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine prepared as described in Example 1.B. (1.09 g, 4.21 mmol) and 4-(difluoromethoxy)benzenamine (1.34 g, 8.42 mmol) in 1,4-dioxane (15 mL) was heated in a sealed tube at 100° C. for 16 h. The dark slurry was cooled to r.t. and diluted with diethyl ether. The solid was collected by flitration and triturated with ethyl acetate:hexane (1:9) and dried to give a tan solid (1.3 g, 81%) which was used directly.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:10]=[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([N:9]2[C:8]([NH2:7])=[CH:12][C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:10]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-n2nc([Si](C)(C)C)cc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc([Si](C)(C)C)cc2N)cc1
Temperature: 60 °C
Yield: 48.8 %

Procedure:
Place (2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester (504 mg, 1.46 mmol) in THF (10 mL). Add 4 M HCl in dioxane (4 mL, 16 mmol) and heat to 60° C. for 3 hours. Cool the reaction to room temperature and load onto a Varian™ SCX column. Wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH. Collect filtrate and concentrate under reduced pressure to yield 175 mg (49%) of 2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-ylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Si:33]([O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[N:7][CH:6]=1)[CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1-(6-bromopyridin-3-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethanol (1.58 g) and 2,6-lutidine (0.83 mL) in dichloromethane (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.31 mL) was added dropwise, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.79 g, yield 84%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:19, volume ratio).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:23]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
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: COCCOC
Product: Clc1ccnc(-c2cccc3c2oc2ccccc23)c1
Yield: 81.8 %

Procedure:
Dibenzo[b,d]furan-4-ylboronic acid (25 g, 118 mmol), 2,4-dichloropyridine (19.2 g, 130 mmol), Pd(PPh3)4 (4.1 g, 3.5 mmol) and potassium carbonate (48.9 g, 354 mmol) were added to dimethoxyethane (200 mL) and water (200 mL). The reaction mixture was degassed with nitrogen before being heated to reflux overnight. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane to yield 33.4 g of crude product. The product was crystallized from hexane to give 27.0 g (82%) of 4-chloro-2-(dibenzo[b,d]furan-4-yl)pyridine as white needles. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [CH3:1][N:2](C)[OH:3].[O:5]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:22].[CH3:23]COCC.CO>C(Cl)Cl>[CH3:23][O:3][N:2]([CH3:1])[C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:5]
Reactant: CCOCC
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: CN(C)O
Solvent: ClCCl
Solvent: CO
Product: CON(C)C(=O)CCCCCCCCCCCCCCCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
1.78 g of dimethylhydroxylamine (17.687 mmol; 3 eq.; MW=97.55) were dissolved in 10 mL of CH2Cl2 that had been distilled under argon and cooled to −78° C. 8.8 mL of AlMe3, 2M in hexane, (17.687 mmol; 3 eq.; MW=72.09) were added drop by drop at −78° C. and the reaction mixture was stirred at room temperature for half an hour. The solution was then cooled down to 0° C. and 1.55 g of oxacycloheptadecan-2-one (5.895 mmol; 1 eq.; MW=254.42), dissolved in 5 mL of distilled CH2Cl2, were added drop by drop. The reaction mixture was left at room temperature under stirring. Thin layer chromatographical analysis showed that the reaction was completed after one hour and a half. The solution was added dropwise into a mixture of 60 mL of Et2O/MeOH 2:1 cooled to −78° C. and then filtered over celite. 100 mL of a saturated, aqueous solution of NaHCO3 were added and the aqueous phase was extracted with ether. The organic phases were combined, dried over magnesium sulfate and then evaporated under reduced pressure to afford 1.66 g of N-methoxy-N-methyl-16-hydroxyhexadecanamide, corresponding to 5.262 mmol and a yield of 89%. The amide obtained in this way was subsequently used without any additional purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.Cl.[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][Cl:22])[CH3:17]>>[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][N:7]1[C:8]2[C:4]3[C:3](=[CH:14][CH:13]=[CH:12][C:5]=3[C:6]1=[O:11])[CH:2]=[CH:10][CH:9]=2)[CH3:17].[ClH:22]
Reactant: CCN(CC)CCCCl
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Agent: Cl
Product: CCN(CC)CCCN1C(=O)c2cccc3cccc1c23

Procedure:
By the procedure described for Compound I, 6-bromobenz[cd]indol-2(1H)-one and 3-diethylaminopropyl chloride hydrochloride yield 6-bromo-1-(3-diethylaminopropylbenz[cd]-indol-2 (1H)-one (Ie), HCl salt, mp. 183°-185° C., while 3-dimethylaminopropyl chloride hydrochloride yields 6bromo-1-(3-dimethylaminopropyl) benz[cd]-2(1H)-one (If), HCl salt, mp. 264°-267° C. Similarly, 6-chlorobenz[cd]indol-2(1H)-one and methyl iodide yield 6-chloro-1-methylbenz[cd]-2(1H)-one (Ig), while benz[cd]indol-2(1H)-one and 4-chlorobenzyl chloride yield 1-(4-chlorobenzyl)benz[cd]indol-2(1H)-one (Ih), mp. 128°-129.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][O:11][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[O:7]2)[O:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N,N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3×50 mL of CH2Cl2. The combined organic extracts were washed with 3×50 mL of a 10% aqueous solution of CuSO4, 2×50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rƒ0.54 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[ClH:10].[N:11]([O-])=O.[Na+]>O>[ClH:10].[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][NH2:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSc1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(methylthio)aniline (6.3 g) and conc.HCl (45 ml) was added dropwise NaNO2 (3.6 g) in water (18 ml) under ice-cooling. After stirring for 30 min., SnC1H2O (28.6 g) in conc.HCl (24 ml) was added under ice cooling over 1 hour. After stirring for 1 hour, filtrate, washed with conc.HCl and water, and dried to give 14.1 g of [4-(methylthio)phenyl]hydrazine hydrochloride as a solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7](=[O:24])[C@@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[Li+].[OH-].C(O)(=O)C>C1COCC1.CO>[C:10]1([CH2:9][C@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7](=[O:24])[CH2:6][CH2:5][C:4]([OH:25])=[O:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a stirred solution of the intermediate ethyl-(5S)-6-phenyl-5-[(tert-butyloxy-carbonyl)-amino]4-oxo-hexanoate (0.250 g, 0.716 mmol) in THF-MeOH (8:2 ratio)(10 mL) was added 0.5N LiOH (10 mL) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then neutralized with glacial acetic acid and then extracted with EtOAc (3×25 mL). The organic extract was dried over anhydrous MgSO4 and evaporation of the solvent afforded a crude yellow residue. Column chromatography on silica gel elution with 50% EtOAc-hexane afforded (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoic acid 9 as a cream yellow solid (0.225 g, 98%); mp 108-110° C.; Rf 0.41 (50% EtOAc-hexane); IR (KBr) ν 1730 (CO), 3200 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.62-2.73 (4H, m, —COCH2CH2CO), 2.94 (1H, dd, J=6.9 and 13.8 Hz, —CHαPh), 3.10 (1H, dd, J=6.0 and 13.8 Hz, —CHβPh), 4.54 (1H, m, —CH—), 5.08 (1H, d, J=8.1 Hz, —NH—) and 7.13-7.35 (5H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 27.5, 28.3, 35.0, 37.5, 60.1, 80.1, 127.0 (2C), 128.7 (2C), 129.2 (2C), 129.3, 136.2, 155.4, 177.4 and 207.4; HRMS m/z calcd for C17H23NO5 (M+) 321.15831, found 321.15762. Anal. Calcd. for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.55; H, 7.34; N, 4.30.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:16])[CH:13]=[CH:14][C:8]=2[NH:7][CH:6]([CH2:28][C:29]([O:31]C)=[O:30])[C:5]1=[O:33])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1.CC#N.O>O>[CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:16])[CH:13]=[CH:14][C:8]=2[NH:7][CH:6]([CH2:28][C:29]([OH:31])=[O:30])[C:5]1=[O:33])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C(C)C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)N1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 110.5 %

Procedure:
A mixture of methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (275.1 mg, 0.61 mmol), 1.0 N LiOH (0.73 mL, 0.73 mmol), THF (3 mL), and H2O (2.3 mL) was stirred at 35° C. for 45 min, and the resulting solution was stirred at RT. After 17.5 h, the solution was filtered, and the filtrate was neutralized with 1.0 N HCl (0.73 mL). Since the product did not precipitate, the solution was acidified with TFA (0.2 mL) and concentrated. The resulting solid was triturated with H2O to leave a nearly colorless solid, which was dissolved with warming in 1:1 CH3CN/H2O. The solution was cooled to RT and diluted with several volumes of H2O/0.1% TFA. ODS chromatography (20% CH3CN/H2O-0.1% TFA), concentration, and lyophilization gave the title compound (293.4 mg, 80%) as a colorless powder: HPLC (PRP-1®, 20% CH3CN/H2O-0.1% TFA) K'=2.5; 1H NMR (400 MHz, CD3OD) δ 7.70-7.76 (m, 2H), 7.65 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.5, 2.2 Hz, 1H), 7.53-7.60 (m, 2H), 6.62 (d, J=8.5 Hz, 1H), 5.33 (d, J=16.9 Hz, 1H), 5.21 (dd, J=8.9, 5.2 Hz, 1H), 4.97 (d, J=1.9 Hz, 2H), 4.72-4.85 (m, 1H), 4.10 (d, J=16.9 Hz, 1H), 2.96 (dd, J=16.8, 8.9 Hz, 1H), 2.65 (dd, J=16.8, 5.2 Hz, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); MS (ES) m/e 436.2 (M+H)+. Anal. Calcd for C23H25N5O4.1.25 CF3CO2H.1.25 H2O: C, 51.00; H, 4.83; N, 11.66. Found: C, 51.12; H, 4.91; N, 11.37.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[C:19]([F:26])[C:18]=4[F:27])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH2:15][CH2:16][CH:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:1][CH2:2][CH2:3][O:4]4)[CH2:6][CH2:7]3)[CH2:12][CH:13]=2)=[C:18]([F:27])[C:19]=1[F:26])[CH3:25]
Reactant: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F

Procedure:
250 g of crude 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexan in 1000 ml of toluene are heated on a water separator for 3 h together with 80.0 ml (1.43 mol) of ethylene glycol with addition of 12.0 g (0.06 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is crystallised from acetonitrile, giving 8-[4-(4-ethoxy-2,3-difluorophenyl)cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane as colourless solid.