Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][SH:18].[H-].[Na+]>C(N(CC)CC)C>[CH3:17][S:18][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: CS
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(SC)nc(C)c1[N+](=O)[O-]
Yield: 91.3 %

Procedure:
12.2 g of 2-chloro-4-sec. butylamino-5-nitro-6-methylpyrimidine (0.05 mole) are dissolved in 200 ml of alcohol and 10 ml of triethylamine are added to this solution. The reaction mixture is heated to reflux temperature and then 4.5 g of methylmercaptan (0.094 mole) are passed in. Subsequently 1.2 g of sodium hydride (0.05 mole) are added at 70° C and the mixture is refluxed for 1 hour. After the reaction mixture has cooled, the sodium chloride precipitate is filtered off with suction and the filtrate is evaporated to yield 11.7 g of 2-methylthio-4-sec.butylamino-5-nitro-6-methylpyrimidine of m.p. 37°-41° C (= 91.5% yield). On recrystallisation from petroleum ether, the melting point of the product rises to 48°-50° C.
Reaction SMILES: O1CCCCC1[S:7][CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11].Cl>CO>[SH:7][CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]
Reactant: CC(CSC1CCCCO1)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 1-[3-(tetrahydropyran-2-ylthio)-2-methylpropanoyl)-L-proline (1 g.) in a mixture of methanol (25 ml.) and concentrated hydrochloric acid (25 ml.) is stored at room temperature for 30 minutes. The solvents are removed in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (silica gel, Benzene/acetic acid, 3:1), Rf 0.5 (silica gel, Methyl-ethylketone/acetic acid/pyridine/water (14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=c1nc(-c2ccc(Cl)cc2Cl)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(2,4-dichloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (10.2 g, 0.033 mol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a light yellow solid (10.6 g, 98%). MS (ISP) 327.0 [(M+H)+]; mp 69.5° C.
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH3:13]O>>[O:1]([CH3:13])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CO
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Product: COC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 68 h
Yield: 56.3 %

Procedure:
α-D-glucose (500 g, 2.78 mol) and a strongly acidic cation exchange resin (100 g Amberlyst 15, BDH Chemicals) was suspended in methanol (1500 ml, 37.1 mol). The mixture was stirred at 65° C. for 68 hours. The progress of the reaction was followed by HPLC. 1H NMR analysis of the reaction mixture showed a 1:1 ratio of the α-and β-anomers. The ion exchange resin was removed by filtration and the solution was cooled to 4° C. The crystalline methyl α-D-glucopyranoside was removed by filtration (230 g, 43%) and the mother liquor was evaporated in vacuo to give a crude methyl D-glucopyranoside (304 g, 57%) as a thick syrup (1H NMR showed a ratio between α- and β-anomers of 2/3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[N:16]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:31]([OH:34])(=O)=[O:32].[NH3:35]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[N:16]([S:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:22])=[O:23])[C:17]([CH3:20])=[C:18]([S:31]([NH2:35])(=[O:34])=[O:32])[CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Reactant: N
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 8 %

Procedure:
To a solution of compound 4e (195 mg, 0.46 mmol) in DCM (0.9 mL) was added ClSO3H (0.45 mL, 7.02 mmol) at −40° C. under Ar. The mixture was slowly warmed to rt and stirred for 48 h. To the mixture was added dropwise to NH3 (3N in THF, 20 mL) at −20° C. and the mixture was stirred for 2 h, evaporated, redissolved in water, extracted with EA, washed with brine, dried with Na2SO4, concentrated and purified by prep-HPLC to afford compound 4 (16 mg, 8%) as light yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 8.28 (s, 1H), 7.49 (t, J=1.8 Hz, 1H), 7.33 (d, J=1.6 Hz, 2H), 5.71 (s, 2H), 2.88 (m, 4H), 2.57 (s, 3H), 1.35-1.27 (m, 24H). LC-MS (ESI+) m/z: 496.6 [M+1]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH:14]C(OC(C)(C)C)=O)[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH2:14])[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous hydrogen chloride was bubbled into a solution of (3(S)-tert-butoxycarbonylamino-2oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)acetic acid methyl ester (103, 1 g, 2.86 mmol) in 25 ml of ethyl acetate for 2 minutes then stirred for 1 hour at room temperature. The reaction was evaporated to give 2-oxo-3(S)-amino-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl acetic acid methyl ester hydrochloride as a white solid. The hydrochloride salt was suspended into 20 ml of dichloromethane and cooled to 0° C. Triethylamine (1.6 ml, 11.5 mmol) was added to the suspension followed by the dropwise addition of dihydrocinnamoyl chloride (0.9 ml, 6 mmol). The mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with 25 ml of dichloromethane and washed twice with 50 ml of water and once with 50 ml of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous, yellow oil that was purified by flash chromatography eluting with 1:1 ethyl acetate/dichloromethane to afford 1.35 g (92%) of the title product as a white solid. 1H NMR (CDCl3) δ 7.45-7.02 (14 H, m), 6.37-6.32 (1H, d), 4.78-4.72 (1H, m), 4.52-4.3 (3H, m), 3.82-3.77 (1H,m), 3.74 (3H, s), 3.03-2.87 (4H, m), 2.58-2.45 (2H, m), 2.45-2.35 (1H, m), 2.25-2.16 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=O)[CH2:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([Mg]Br)[CH3:16].Cl.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1>O1CCCC1.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:15][CH3:16])([CH2:20][CH3:21])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC[Mg]Br
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCC1(CC)CC(C)(C)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-chroman-2-one (U.S. Pat. No. 6,252,090, 4 g, 15.7 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with a 3M solution of ethyl magnesium bromide (10.5 mL, 31.5 mmol) and stirred at ambient temperature for 2 h. The reaction mixture was poured into cold dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue which was dissolved in 50 mL of benzene, treated with p-toluene sulfonic acid (1 g, 3.92 mmol) and the resulting reaction mixture was refluxed overnight. The reaction mixture cooled to ambient temperature, filtered on silica gel and washed with 10% ethyl acetate in hexane. The filtrate and washings were evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow oil (3.9 g, 84%).
Reaction SMILES: S(OC1CCN2C3C=CC=CC=3CC3C=CC=CC=3C2C1)(C1C=CC(C)=CC=1)(=O)=O.[C:31]([CH:33]1[CH2:51][CH2:50][N:36]2[C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH:35]2[CH2:34]1)#[N:32].O>CCOCC.C1COCC1>[NH2:32][CH2:31][CH:33]1[CH2:51][CH2:50][N:36]2[C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH:35]2[CH2:34]1
Reactant: N#CC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
To a suspension of 10 g LiAlH 4 in 400 ml of dry ether a solution of 8 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino [1,2-a]-dibenzo[c,f]-azepine (axial) in 300 ml of THF is added. Then the mixture is refluxed for 30 minutes, whereupon it is cooled by means of ice. After that 40 ml of water are added to the mixture carefully so as to hydrolyse the excess of LiAlH 4. The resulting precipitate is filtered off after which the filtrate is evaporated.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](Cl)=[O:4].[CH3:7][C:8](=[C:10]([CH3:12])[CH3:11])[CH3:9]>C(C(CC(C)C)=O)C(C)C.[Zn]>[Cl:1][CH:2]1[C:10]([CH3:12])([CH3:11])[C:8]([CH3:9])([CH3:7])[C:3]1=[O:4]
Reactant: CC(C)=C(C)C
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Zn]
Solvent: CC(C)CC(=O)CC(C)C
Product: CC1(C)C(=O)C(Cl)C1(C)C

Procedure:
This process is described in U.S. Pat. No. 4,028,418 Gradual addition of dichloroacetyl chloride to a stirred solution of 2,3-dimethyl-2-butene in diisobutyl ketone containing suspended zinc particles resulted in a yield of 2-chloro-3,3,4,4- tetramethylcyclobutanone of 75%, calculated on starting dichloroacetyl chloride of 3.9, a molar ratio of dichloroacetyl chloride to 2,3-dimethyl-2-butene of 1.3, a temperature of 43° C, zinc in the form of turnings having a largest dimension of 0.841 mm and a starting concentration of 2,3-dimethyl-2-butene of 2.4 mol per liter of diisobutyl ketone. Modifying this experiment by reducing the molar ratio of zinc to dichloroacetyl chloride to 1.1 resulted in a decrease in yield to 51%, the theoretical yield still being 77.4% cf. Example VIII of U.S. Pat. No. 4,028,418.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][C:6]1[C:14]([CH2:20][C:21](OCC)=[O:22])([CH2:18][CH3:19])[O:15][CH2:16][CH2:17][C:5]2=1.[Li+].[BH4-].C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:12])[CH3:13])[CH:10]=1)[NH:7][C:6]1[C:14]([CH2:20][CH2:21][OH:22])([CH2:18][CH3:19])[O:15][CH2:16][CH2:17][C:5]2=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Yield: 78.3 %

Procedure:
To a stirred solution of ethyl 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate (6.0 g, 0.015 mol) in THF (120 ml), was added 2.0 M solution of LiBH4/THF (20 ml, 0.30 mol) via syringe during 30min under a nitrogen atmosphere at room temperature. The mixture was refluxed for 10 hr, cooled, quenched with water and 5% HCl, and extracted with EtOAc. The organic phases were combined and washed with brine, dried over MgSO4, and evaporated to give a residue, which was chromatographed on silica gel. Elution with hexane-EtOAc (7:3) gave the product (4.3 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.18 (b, NH), 0.92 (t, 3H), 1.35 (d, 6H), 1.98 (m, 3H), 2.19 (m, 1H), 2.54 (t, 1H), 2.75 (m, 2H), 3.17 (m, 1H), 3.71 (t, 1H), 4.03(m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI (+) MS m/e=367 (MH+), ESI (−) MS m/e=365 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>CC#N>[C:28]([CH2:27][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:23])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1)#[N:29]
Reactant: Cc1ccc(F)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(F)cc1[C@H](OCC#N)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.2 g, 0.0037 mol) in MeCN (20 mL), NaH (0.27 g, 0.011 mol) was added at 0° C. The mixture was stirred for 1 hr followed by cooling to −40° C. and adding bromoacetonitrile (1.3 g, 0.011 mol) in portions. The mixture was stirred for 0.5 hour at −20° C. The reaction was quenched with H2O. The mixture was extracted with CH2Cl2. The organic layer was dried by Na2SO4, concentrate to get the target molecule (R)-tert-butyl 3-((R)-(cyanomethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.2 g, 90%).
Reaction SMILES: [O:1]([CH2:9][C@@:10]12[C@@H:27]3[C@H:18]([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C:22](=[O:28])[CH2:21][CH2:20]4)[CH2:17][CH:16]=[C:15]1[CH2:14][C:13](=[O:29])[CH2:12][CH2:11]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(CC(=O)CC1)=CC3>>[O:1]([CH2:9][C@@:10]12[C@@H:27]3[C@H:18]([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[CH:22]([OH:28])[CH2:21][CH2:20]4)[CH2:17][CH:16]=[C:15]1[CH2:14][C@H:13]([OH:29])[CH2:12][CH2:11]2)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Product: CC(C)(C)[Si](C)(C)OC[C@]12CC[C@@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(O)CC[C@@H]12

Procedure:
Substituting 19-t-butyldimethylsiloxy-5-androstene-3,17-dione, 4α-methyl-17β,19-di(4'-tetrahydropyranyloxy)-5-androsten-3-one and 1β-methyl-19-(4'-tetrahydropyranyloxy)-5-androstene-3,17-dione for the 17β,19-dihydroxy-5-androsten-3-one above results in the preparation of 19-t-butyldimethylsiloxy-5-androstene-3α,17-diol, 4α-methyl-17β,19-di(4'-tetrahydropyranyloxy)-5-androsten-3α-ol and 1β-methyl-19-(4'-tetrahydropyranyloxy)-5-androstene-3α,17β-diol, respectively.
Reaction SMILES: B.[CH2:2]1COCC1.C[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1>[CH3:2][CH:14]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[OH:16]
Reactant: CC1(C(=O)O)CCCCC1
Reactant: C1CCOC1
Agent: B
Product: CC(O)C1CCCCC1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
A three liter, three necked round bottom flask was equipped with a thermometer, magnetic stirrer, argon inlet and outlet adapters and a one liter addition funnel containing 922 ml of 1.0 molar BH3.THF. 1-Methyl cyclohexanecarboxylic acid (119.2 g; 0.84 m) was added to the reaction vessel and dissolved in 100 ml of THF. The reaction mixture was cooled with an ice bath to 5° C. and the BH3.THF was added dropwise over 25 min maintaining the temperature between 5°-15° C. After the addition was complete, the ice bath was removed. After about five min, the reaction exothermed and foamed violently. A much slower addition rate and constant cooling should help to avoid this exotherm. The reaction was allowed to stir for two hr at RT under nitrogen, then 150 ml of methanol was added cautiously. When the foaming ceased, the reaction was concertrated in vacuo using low heat and the residue was treated with 100 ml of 5% acetic acid. After stirring for thirty min, the reaction was transferred to a one liter separatory funnel, diluted with water (slurry dissolved) and extracted three times with ether. The combined ether extracts were washed twice with saturated sodium bicarbonate, twice with brine, dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo (low heat) to give 79.09 g of a clear water-white oil. The oil was distilled on a Kugelrohr apparatus at 75°-130° C. (25 mm of Hg). Most distilled at 90° C. to give 72.11 g of 1-methyl-1-cyclohexylmethanol.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC(c3ccccn3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: c1ccc(C2CCNC2)nc1
Yield: 74.9 %

Procedure:
To a suspension of 2-[1-(phenylmethyl)-3pyrrolidinyl]pyridine (7.15 g, 30.0mmol) and 10% palladium on charcoal catalyst (1.90 g) in methanol (120 mL) was added dropwise a solution of ammonium formate (7.57 g, 120 retool) in water (30 mL). The mixture was heated at reflux for 30 minutes, allowed tocool to room temperature, and filtered. The filtrate was concentrated underreduced pressure, the residue was taken up in water (10 mL), and the solution was made basic with concentrated ammonia and extracted with dichloromethane (4×15 mL). The organic extracts were combined, driedover anhydrous potassium carbonate, and concentrated to a yellow oil. This crude product was chromatographed (silica gel, chloroform-methanol-ammonia75:25:5) to give the title compound (3.33 g, 75%) as a faint yellow liquid.
Reaction SMILES: C([CH:3]([NH:17]C(OC(C)(C)C)=O)[C:4](=[O:16])[CH2:5][P:6]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:8])[O-:7])C.C[Si](C)(C)[Br:27]>ClCCl.CO.O>[BrH:27].[NH2:17][CH2:3][C:4](=[O:16])[CH2:5][P:6]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:7])[OH:8]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)CP(=O)([O-])CC1CCCCC1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Br
Product: NCC(=O)CP(=O)(O)CC1CCCCC1
Reaction time: 7 h

Procedure:
A solution of 1.0 g of ethyl-3-(N-tert.-butoxycarbonylamino)-2-oxopropyl(cyclohexylmethyl)phosphinate in 15 ml of anhydrous dichloromethane under an inert atmosphere at room temperature is treated with 2.1 g of trimethylbromosilane. After stirring for 7 hours the volatile components are removed under reduced pressure to give a pale yellow oil. This oil is dissolved in methanol containing 1% of water and the clear pale yellow solution is stirred overnight at room temperature. The solvent is removed under reduced pressure to afford 3-amino-2-oxo-propyl(cyclohexylmethyl)phosphinic acid hydrobromide, m.p. 180°-182° C. Suspension in ethanol and treatment with propylene oxide affords 3-amino-2-oxo-propyl(cyclohexylmethyl)phosphinic acid, 1H-NMR (D2O): δ (ppm)=4.15 (2H, s, CH2N), 3.10 (2H, d, J=15 Hz, CH2 --P), 1.80 (2H, m, P--CH2), 1.73-1.52 (5H, m, 2×CH2 +CH), 1.34-0.95 (6H, m, 3×CH2).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[CH2:27]O.C(Cl)(Cl)(Cl)[Cl:30]>>[Cl:30][CH2:27][CH:21]1[CH2:22][CH:23]2[CH2:26][CH:20]1[CH:25]=[CH:24]2
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCC1CC2C=CC1C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCC1CC2C=CC1C2

Procedure:
A mixture of triphenylphosphine (20.98 g, 0.08 mol) and bicyclo[2.2.1]hept-5-ene-2-methanol (5.0 g, 0.0403 mol) in dry carbon tetrachloride (31.5 ml) was stirred and heated at 60° for 6 h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to afford a semi-crystalline mass, which was triturated with n-pentane (100 ml). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a yellow oil. Distillation of the oil afforded 5-chloromethylbicyclo[2.2.1]hept-2-ene as a colourless oil, b.p. 70°-72°/24 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16](Cl)=[O:17].[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:16](=[O:17])[CH2:15][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCNCC1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.5 g, 8.1 mmol) in THF (150 ml) is added TEA (2.3 ml, 16.1 mmol) followed by dropwise addition of chloroacetyl chloride (0.67 ml, 8.5 mmol). The reaction mixture is allowed to stir at room temperature for 2 hours and then treated TEA (2.3 ml, 16.1 mmol) followed by 4-piperidinol (4.07 g, 40.3 mmol). After stirring at 50° C. for 18 hours, the solvent is removed in vacuo and purification of the crude residue by reverse phase column chromatography (Isolute™ C18, 0-100% MeOH in water—0.1% TFA) to yield the title product. [MH+ 328.19].
Reaction SMILES: C(O[CH:4](SCC)[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:43])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]=1[NH2:42])C.C([O-])([O-])=O.[Ca+2].CCOC(C)=O>CC#N.O.Cl[Hg]Cl>[CH3:18][O:17][C:15]1[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]2[N:42]=[CH:4][C@@H:5]3[CH2:9][CH2:8][CH2:7][N:6]3[C:10](=[O:43])[C:11]=2[CH:16]=1
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCCCCOc1cc3c(cc1OC)C(=O)N1CCC[C@H]1CN3)N=C[C@@H]1CCCN1C2=O

Procedure:
A solution of the (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-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula IV. (672 mg, 1 mmol), HgCl2 (794 mg, 2.93 mmol) and CaCO3 (300 mg, 3 mmol) in CH3CN/H2O (4:1, 15 mL) was stirred at room temperature for 12 h until TLC (EtOAc), indicates complete loss of starting material. Then organic layer is evaporated in vacuum and the residue is diluted with EtOAc. To this saturated NaHCO3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate. The filterate is evaporated in vacuum to get crude 7-Methoxy-8-{4-[7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy]butoxy}-(11aS)-1,2,3,11a-tetrahy-dro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one of formula V, which was further purified by column chromatography on silica gel eluting with methanol:EtOAc (2:8).