Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:28])[CH2:17][CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:15])=[C:11]([CH3:29])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:28])[CH2:17][CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:15])=[C:11]([CH3:29])[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(N)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
The compound (350 mg, 0.819 mmol) obtained in Example 89b was dissolved in methylene chloride (8 mL), trifluoroacetic acid (4 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and moisture was removed from the resulting residue azeotropically with toluene (×2). The resulting residue was dissolved in methylene chloride (8 mL), triethylamine (0.569 mL, 4.10 mmol) and di-tert-butyl dicarbonate (215 mg, 0.983 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2, v/v) to give the title compound (267 mg; yield, 100%) as a light yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][C:29]=3[F:42])=[C:23]([CH2:43][CH2:44][CH3:45])[N:22]3[N:46]=[C:47]([CH3:49])[N:48]=[C:21]23)[CH2:17][CH2:16][O:15]1>C(OCC)(=O)C>[CH3:50][C:14]1([CH3:13])[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][C:29]=3[F:42])=[C:23]([CH2:43][CH2:44][CH3:45])[N:22]3[N:46]=[C:47]([CH3:49])[N:48]=[C:21]23)[CH2:17][CH2:16][O:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.23 g, 62%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([N:17]1[C:21]([N:22]2[N:31]=[C:30]3[C:24]([CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][C:29]=43)=[CH:23]2)=[N:20][CH:19]=[N:18]1)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:36]([C:33]2[CH:34]=[CH:35][C:28]3[O:27][CH2:26][CH2:25][C:24]4[C:30](=[N:31][N:22]([C:21]5[N:17]([CH:14]([CH3:15])[CH3:16])[N:18]=[CH:19][N:20]=5)[CH:23]=4)[C:29]=3[CH:32]=2)=[O:37])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
A mixture of N-Boc piperazine (101 mg, 0.54 mmol), 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carboxylic acid (180 mg, 0.53 mmol), EDCI (151 mg, 0.79 mmol), HOBt (107 mg, 0.795 mmol) and triethylamine (216 L, 1.54 mmol) in DMF (2 mL) was stirred at RT for 20 h. The mixture was diluted with ethyl acetate and washed (water, saturated aqueous sodium hydrogen carbonate and then brine), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (258 mg, 96%). The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (20 mL) and treated with 4N HCl in dioxane (4 mL) and stirred for 3 h at RT before adding diethyl ether (20 mL). The resultant precipitate was collected by filtration and washed with diethyl ether to give 145 as a white solid (209 mg, 93%). 1H NMR (400 MHz, DMSO-d): δ 9.32 (s, 2H); 8.37 (s, 1H); 8.31 (d, J=2.20 Hz, 1H); 8.06 (s, 1H); 7.44 (dd, J=8.37, 2.21 Hz, 1H); 7.15 (d, J=8.37 Hz, 1H); 5.32-5.23 (m, 1H); 4.37 (t, J=4.98 Hz, 2H); 3.77 (s, 4H); 3.15 (t, J=6.94 Hz, 6H); 1.51 (d, J=6.59 Hz, 6H). LCMS: RT=6.02 min, M+H+=408
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH:16][C:17](=[O:19])[CH3:18])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58](ON2C3C=CC=CC=3N=N2)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH:16][C:17](=[O:19])[CH3:18])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
A mixture of 7β-amino-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.450 g, 1.21 mmol), triethylamine (0.245 mg, 2.42 mmol) and dichloromethane (10 ml) was stirred at room temperature for 10 minutes. To the mixture was added 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (0.678 g, 1.21 mmol) and allowed to react at 5° C. for 17 hours. The dichloromethane was removed by evaporation. Water (10 ml) and triethylamine (0.5 ml) were added to the residue. The aqueous layer was separated, washed with ethyl acetate (5 ml) and adjusted to pH 3.5 with citric acid. Precipitated substance was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was treated with ether and filtered to give pale yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem- 4-carboxylic acid (0.790 g, 92%), mp 167°-170° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11].Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 68.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.516 g, 1.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.540 g, 2.28 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient gave 0.509 g (68%) of the title compound as a brown solid, mp 72-82° C. 1H NMR (DMSO-d6) δ 1.25-1.34 (m, 2 H), 1.50-1.55 (m, 2 H), 1.62-1.74 (m, 4 H), 1.77 (s, 3 H), 2.15 (s, 3 H), 2.95 (quintet, 1 H), 3.88 (s, 2 H), 7.10-7.15 (m, 2 H), 7.20 (d, 1 H), 7.27 (t, 1 H), 7.35-7.37 (m, 2 H), 7.48-7.58 (m, 3 H), 7.96 (dd, 1 H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 651 (M-H). Anal. Calcd. for C32H29BrO8S.0.4H2O: C, 58.17; H, 4.55; N, 0.00. Found: C, 58.20; H, 4.55; N, 0.03.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[C:45](=[O:50])[CH2:46]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1=O
Solvent: CCN(CC)CC
Solvent: COCCO
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 7 h
Yield: 50.3 %

Procedure:
A mixture of N-[5-chloro-7-(3-isopropoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.22 g, 0.43 mmol), triethylamine (0.29 ml, 2.13 mmol), 1-methylpiperazin-2-one (0.24 g, 2.13 mmol) in 2-methoxyethanol (3 ml) was heated to 80 C for 12 hours and then at 100 C for 7 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 2-8% methanol in dichloromethane to give the product as an light orange solid (0.129 g, 51%). NMR Spectrum: (DMSOd6) 1.18 (d, 6H), 1.98 (m, 2H), 2.52 (t, 2H under DMSO), 2.72 (t, 2H), 2.88 (s, 3H), 3.04 (s, 2H), 3.34 (t, 2H under H2O), 3.83 (m, 1H), 3.97 (s, 3H), 4.22 (t, 2H), 4.42 (s, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H), 7.83 (s, 1H), 8.34 (s, 1H), 9.52 (s, 1H). Mass Spectrum: M+H+ 596 and M+H− 594.
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[F:36][C:37]1[C:38]([NH:47][C@H:48]2[CH2:52][CH2:51][CH2:50][C@@H:49]2[NH2:53])=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1.[F:54][C:55]1[CH:56]=[CH:57][C:58]([C:64]2[N:69]=[CH:68][CH:67]=[CH:66][N:65]=2)=[C:59]([CH:63]=1)[C:60](O)=[O:61]>>[F:54][C:55]1[CH:56]=[CH:57][C:58]([C:64]2[N:65]=[CH:66][CH:67]=[CH:68][N:69]=2)=[C:59]([CH:63]=1)[C:60]([NH:53][C@H:49]1[CH2:50][CH2:51][CH2:52][C@@H:48]1[NH:47][C:38]1[C:37]([F:36])=[CH:42][C:41]([C:43]([F:46])([F:44])[F:45])=[CH:40][N:39]=1)=[O:61]
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34: 200 mg, 0.76 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 166 mg, 0.76 mmol) except after the reaction was complete it was concentrated in vacuo and the residue was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.05% ammonia)/methanol), then by column chromatography (silica, 0-50% ethyl acetate/petrol) and then triturated with DCM/petrol to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.Cl.[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH3:17]>ClCCl>[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1])=[O:24])[CH3:17]
Reactant: CC1=NCCN1
Reactant: CN(C)CCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NCCN1C(=O)CCCCCN(C)C
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Dichloromethane (400 mL), 2-methyl-2-imidazoline (56.38 g, 0.637 mol), and triethylamine (283.51 g, 2.802 mol) are placed in a 2000 mL three-necked round bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, addition funnel, and argon inlet. The solution is brought to reflux and 15 min later a solution of 6-(N,N-Dimethylamino)hexanoyl chloride.hydrochloride (150 g, 0.700 mol), prepared as described in example II, dissolved in dichloromethane (300 mL) is added dropwise over 45 min. The mixture is refluxed for an additional 2 h before being cooled to room temperature. The salts are filtered and washed with methylene chloride. The combined filtrates are washed with 5% NaHCO3 solution (3×300 mL) and water (300 mL). After drying over MgSO4 and filtration, the organic layer is concentrated first by rotary evaporation at 50° C. and then by Kugelrohr distillation at 60°-70° C. (0.2 mm Hg) to give 95.20 g (66%) of an oil which solidifies on standing.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.N[C:14]1C=CC(C)=CC=1.C(OC=C(C(OCC)=O)C(OCC)=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: Fc1ccc2nccc(Cl)c2c1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Product: Cc1ccc2nccc(Cl)c2c1

Procedure:
This compound was made in a manner analogous to that of the synthesis of 4-chloro-6-fluoroquinoline described in Example 12. Starting from p-toluidine and diethyl ethoxymethylenemalonate the compound was obtained as a solid of mp 47°-51°.
Reaction SMILES: ClC(C1C(C)CC(C)(C)C(=[O:18])C1)C1C=CC=CC=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][C:25]2[CH:30]([CH3:31])[CH2:29][C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[CH:26]=2)=[CH:22][CH:21]=1.[OH-].[Na+].OO>CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]23[O:18][CH:26]2[C:27](=[O:34])[C:28]([CH3:33])([CH3:32])[CH2:29][CH:30]3[CH3:31])=[CH:35][CH:36]=1
Reactant: CC1CC(C)(C)C(=O)CC1C(Cl)c1ccccc1
Reactant: CC1CC(C)(C)C(=O)C=C1Cc1ccc(Cl)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CC(C)(C)C(=O)C2OC12Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The 1-(chlorobenzyl)-4,4,6-trimethylcyclohexan-3-one (315 g, 1.2 mol) obtained in (b) above was added to methanol (1500 ml) and the mixture warmed to 40° C. to give a clear yellow solution. The solution was then cooled to 10° C. and aqueous sodium hydroxide (25 g in 112 ml water) was added over a period of 10 minutes. Whilst maintaining the temperature of the reaction mixture between 15° and 20° C., 30% (w/v) aqueous hydrogen peroxide (138 ml, 1.2 mol) was added over a period of 30 minutes and the mixture was then stirred overnight. A further 30 ml was then added and the mixture stirred for 21/2 hours. The reaction mixture was then concentrated under reduced pressure and diluted with water (2 liters) and diethyl ether (1.5 liters). The aqueous layer was then extracted with diethyl ether (2×0.5 liters), dried and the solvent flashed off to give 1-(4 -chlorobenzyl)-1,2-epoxy-4,4,6-trimethylcyclohexan-3-one as a crystalline white solid (271 g), m.pt. 58°-59° C.
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH3:28])[N:10]=[C:9]1[S:29]CC1C=CC(OC)=CC=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].F[C:40](F)(F)[C:41]([OH:43])=O.[CH2:46](S)C>ClCCl>[CH:2]([O:43][CH:41]([CH3:40])[CH3:46])([CH3:3])[CH3:1].[CH2:1]([S:5]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH3:28])[NH:10][C:9]1=[S:29])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS
Reactant: CCCCS(=O)(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CCCCS(=O)(=O)N1C(=S)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 106.8 %

Procedure:
A solution of 0.80 g (0.0014 mole) of 1-(Butylsulfonyl)-1, 6-dihydro-2-[[(4-methoxyphenyl) methyl]thio]-4-methyl-6-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester, 0.52 ml (0.0057 mole) of trifluoroacetic acid and 0.21 g (0.0032 mole) of ethanethiol in 15 ml of dichloromethane was stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was flash chromatographed using ethyl acetate/ hexane (1:4) to give an oil which solidified very slowly. Trituration with isopropyl ether gave 0.33 g of the title compound as a colorless solid, melting point 118°-120° C. Analysis Calc'd. for C18H23N3O6S2 : C, 48.96; H, 5.25; N, 9.51; S, 14.52. Found: C, 48.99; H, 5.42; N, 9.32; S, 14.48.
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C:17]([O-:19])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[Na+].O>CS(C)=O>[CH3:4][CH2:5][C@H:6]([C:17]([O:19][CH2:1][CH3:2])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1
Reactant: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Reactant: CCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H](CC)[C@H](CO)Cc1cncn1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
9.80 mmoles of ethylbromide (1068 mg) were added dropwise within about an hour to a solution containing 9.80 mmoles (2432 mg) of pilocarpic acid sodium salt in 60 ml of dimethyl sulfoxide. The solution was stirred at room temperature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two portions of each 150 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 150 ml of distilled water, with 150 ml of 2% sodium bicarbonate solution and with 150 ml of distilled water. The ethyl acetate extracts were dried on calcium sulfate (30 min) and the ethyl acetate evaporated under reduced pressure, and the pilocarpic acid ethyl ester obtained was crystallized from a chloroform/ petroleum ether-mixture, whereby 448 mg (1.76 mmoles) of the ester were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][N:9]1[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:11]=[CH:10]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 25.6 %

Procedure:
A solution of 6-nitrobenzimidazole (2.0 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (3.5 g.) in methyl ethyl ketone (61 ml.) was treated with potassium carbonate (1.9 g.) and then heated under reflux for 24 hours. The solvent was then evaporated. The residue was extracted with ethyl acetate and inorganic material removed by filtration. The filtrate was evaporated. The resultant residue was purified by flash chromatography on a 6×30 cm. silica gel column using 1:1 v/v hexane:ethyl acetate as the eluent to give methyl 3-methoxy-4-(6-nitrobenzimidazol-1-ylmethyl)benzoate (K) (1.07 g., 26%); NMR: 3.9 (s,3H, OCH3), 4.0(s,3H, OCH3), 5.7(s, 2H, NCH2), 7.4(d, 1H, Ar), 7.8(d,1H, H4 -benzimidazole), 8.1(dd, 1H, H5 -benzimidazole), 8.6(br s,2H, H2,7 -benzimidazole).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2Cl)([O-:3])=[O:2].CN1C(=O)CCC1.[N-:29]=[N+:30]=[N-:31].[Na+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:29]=[N+:30]=[N-:31])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Temperature: 60 °C

Procedure:
6-Nitro-4-chloro-2-(3-fluorophenyl)-quinoline 3.2 g (9.50 mmoles) was placed in a 250 mL three neck round bottom flask equipped with a condenser, magnetic stirrer, silicone oil heating bath, nitrogen inlet and gas outlet. To this was added 75 mL of N-methyl pyrrolidinone then 6.0 g (95 mmoles, 10 equiv.) of sodium azide. The mixture was stirred and warmed to 60° C. for 18 hr. After this time the mixture was cooled, poured into a 1 L separatory funnel containing 500 mL water and 250 mL of ethyl acetate. The pH was adjusted to 9.0 and the layers separated. The aqueous layer was extracted twice with 100 mL of ethyl acetate, the organic layers combined, dried over Na2SO4, filtered and concentrated to yield a product, which was carried to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6]CN.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].C[CH2:22][N:23](CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][N:23]([CH3:22])[C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: CCCOc1c(CCN)cccc1OC
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(OC)c1OCCC
Reaction time: 1.5 h
Yield: 88.2 %

Procedure:
A solution of (3-methoxy-2-propoxybenzyl)methylamine (1.00 g, 4.78 mmol) in CH2Cl2 (40 mL) was treated with acryloyl chloride (0.42 mL, 5.2 mmol) followed by Et3N (0.74 mL, 5.3 mmol). After stirring for 1.5 h, the solution was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (1.11 g, 88%) as a tan oil and as a mixture of amide rotamers: 1H NMR (300 MHz, CDCl3) δ 7.06-6.94 (m, 2H), 6.85-6.70 (m, 1H), 6.65-6.58 (m, 1H), 6.18-6.13 (m, 1H), 5.73-5.63 (m, 1H), 4.64-4.58 (m, 2H), 3.89-3.84 (m, 2H), 3.79-3.78 (m, 3H), 2.99-2.86 (m, 3H), 1.73-1.66 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).