Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([O:11][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: OC1CCCCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Brc1ccc2c(c1)C(OC1CCCCO1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.88 g (7.8 mmol) of (±)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol, 1.07 mL (11.7 mmol, 1.5 equiv) of 3,4-dihydro-2H-pyran, and 0.20 g (0.80 mmol, 0.1 equiv) of pyridinium p-toluenesulfonate in 38 mL of methylene chloride was stirred under nitrogen at ambient temperature overnight. The mixture was diluted with 115 mL of ether, washed with 45 mL of half-saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give 2.8 g of a cloudy oil. Purification by flash chromatography (5-30% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=327.0; 1H NMR (400 MHz, CDCl3) 7.68 (s, 0.5H), 7.39 (d, 0.5H, J 2 Hz), 7.25 (m, 1H), 6.95 (m, 1H), 4.90 (t, 0.5H, J 3 Hz), 4.80 (m, 1H), 4.48 (t, 0.5H, J 3 Hz), 3.95 (m, 0.5H), 3.67 (m, 0.5H), 3.52 (m, 0.5H), 3.42 (m, 0.5H), 2.85 (m, 1H), 2.67 (m, 1H), 2.10-1.83 (m, 3.5H), 1.82-1.52 (m, 8H), 1.43 (m, 0.5H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: COCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with 2,5,8,11,14,17-hexaoxanonadecan-19-ol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14,17-hexaoxanonadecan-19-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral-3-oxo-2,4,7,10,13-pentaoxatetradecyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C46H58Cl2F2N3O13: [(M+H)+]: 968, found: 968.
Reaction SMILES: [CH2:1]([CH:8]([C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>CC#N>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:10][C:9](=[O:11])[CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(NOCc1ccccc1)C(Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Intermediate (12a) (0.5 g, 1.7 mmol) was added to N-hydroxysuccinimide (290 mg, 2.6 mmol) and EDC (320 mg, 1.7 mmol) and dissolved in MeCN (6 mL). The mixture was stirred overnight at room temperature and then partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to provide intermediate (12b) as a foam (0.8 g, 2 mmol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1>C1CCCCC1>[CH:10]1([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1=CCCCCCC1
Reactant: OCCc1ccccc1
Solvent: C1CCCCC1
Product: c1ccc(CCOC2CCCCCCC2)cc1
Temperature: 83 °C

Procedure:
A mixture of 183 g phenylethyl alcohol, 980 g cyclohexane and 14 g AMBERLYST® 15 was heated to reflux (83° C.) with stirring. cyclooctene over a period of 3 hrs. After refluxing for 13 hrs at 83-89° C. the mixture was filtrated and concentrated on a rotatory evaporator at 45° C. and 25 mbar resulting in 233 g concentrate, containing 17% cyclooctene, 58% phenylethyl alcohol and 18% phenylethyl cyclooctyl ether and 2% diphenylethyl ether by GC analysis, which was vacuum distilled. The fraction with a boiling range of 89-103° C. at 0.7 mbar (13 g containing 7% phenylethyl alcohol, 80% phenylethyl cyclooctyl ether and 10% diphenylethyl ether by GC analysis) was subjected to flash column chromatography over silica with a 1:25 diethyl ether/pentane mixture, yielding 5 g phenylethyl cyclooctyl ether of 97.4% purity by GC analysis, nD20=1.5175.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)(=[O:26])[CH3:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.69 g), acetyl chloride (0.27 g) and pyridine (0.10 g) in dichloromethane (40 ml) was stirred at 0° C. for 4 hours. The mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with ether/petroleum ether to give 4-[acetoxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 297, 0.46 g) as a yellow solid: m.p. 82° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH:9]([F:21])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:22]([O:24][C:25](=[NH:29])[O:26][CH2:27][CH3:28])[CH3:23]>CC(C)=O>[CH2:22]([O:24][C:25](=[N:29][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:9]([F:21])[F:8])(=[O:19])=[O:18])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Reactant: CCOC(=N)OCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Temperature: 25 °C

Procedure:
11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:43][CH2:42][CH2:41][NH:40][CH:37]([CH3:39])[CH3:38])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CC(C)NCCN
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCNC(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and N-isopropylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 593.16 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([N:2]([CH3:3])[CH3:1])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 24a) from 1-(3-is dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), a 2M solution of dimethylamine in tetrahydrofuran (10 ml) and a solution of 3-bromophenylacetic acid (2.15 g) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as an oil (2.89 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1.N1CCCCC1>CCO>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]nnc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2
Temperature: 90 °C
Yield: 20.4 %

Procedure:
A scintillation vial was charged with 5-aminoindolin-2-one (37 mg, 0.247 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (40 mg, 0.272 mmol), piperidine (2.5 uL, 0.025 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed in vacuo and the residue loaded onto a silica gel column eluting with 92:8 CH2Cl2/MeOH to give 14 mg, 20% of a red solid. 1H NMR (400 MHz, d6-DMSO) δ 15.96 (bs, 1H), 10.15 (s, 1H), 8.21 (bs, 1H), 8.02 (bs, 1H), 7.73 (bs, 1H), 7.67 (s, 1H), 6.87 (s, 1H), 6.59-6.47 (m, 2H), 4.65 (bs, 2H); MS ESI 278.0 [M+H]+, calcd for [C15H11N5O+H]+ 278.10.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](Cl)=[O:11])=[CH:2]1.[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][OH:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:22][CH2:21][C:16]23[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14][CH2:15]3)=[O:11])=[CH:2]1
Reactant: OCC12CCN(CC1)CC2
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Solvent: ClCCl
Product: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 1H-indole-3-carbonyl chloride (45 mg, 0.25 mmol) in 3 mL of methylene chloride at 0° C. was added (quinuclidin-4-yl)methanol (36 mg, 0.25 mmol) in 2 mL of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was evaporated and water (10 mL) was added. The water layer was basified to pH 12 using 10% aqueous potassium hydroxide and extracted three times with 25 mL each of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield 8 mg of desired product. 1HNMR: 12.02 (bs, 1H); 8.13 (d, 1H); 7.9 (m, 1H); 7.42 (m, 1H); 7.18 (m, 2H); 4.3 (bs, 2H); 3.03 (m, 6H); 1.75 (m, 6H). MS (m/e): 285.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][C:3]=1[C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39].[CH:42]1[C:51]2[C:46](=[CH:47][C:48](B(O)O)=[CH:49][CH:50]=2)[CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[OH:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:3]1[N:4]=[C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[S:6][C:2]=1[C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[CH:42]=[N:43][CH:44]=[CH:45]2
Reactant: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Reactant: OB(O)c1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Temperature: 120 °C
Yield: 37 %

Procedure:
(S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.025 g, 0.038 mmol) was taken up in 1 mL of dioxane in a microwave safe tube. Isoquinolin-6-ylboronic acid (0.0098 g, 0.057 mmol), sodium carbonate, 2M in water (0.075 mL, 0.15 mmol), and tetrakistriphenylphosphine palladium (0) (0.0044 g, 0.0038 mmol) were added. The mixture was degassed with nitrogen and the tube was sealed. The tube was then heated to 120° C. in a Personal Chemistry microwave unit for 20 minutes. The mixture was diluted with 10 mL of EtOAc, washed with 5 mL of water and 5 mL of brine, and then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (pipette column, 25% to 70% EtOAc/hexanes), afforded (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)-5-(isoquinolin-6-yl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.010 g, 37% yield) as a white solid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[CH2:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH:1]=[CH2:2])[CH2:6][CH2:7]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: C=COCC1CCC(CO)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=COCC1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethanol (2.0 g, 0.010 mol) was dissolved in chloroform (20 mL), cooled to 0° C., and then methanesulfonyl chloride (0.85 mL, 0.011 mol) and triethylamine (1.5 mL, 0.011 mol) were added. The reaction was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate, and the extracts were washed with water, brine, and then dried over MgSO4 and concentrated. The product was purified via column chromatography on silica gel (40% ethyl acetate, 60% hexanes), to give 1.53 g of the desired product as a 3:1 mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.36-6.41 (m, 1H), 4.04-4.10 (m, 2H), 3.94-3.96 (m, 2H), 3.39-3.43 (m, 2H), 2.92 (s, 3H), 0.90-1.80 (m, 10 H) (major diastereomer).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:18][CH2:19][C:20](=O)[CH2:21][C:22](=O)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]3[N:15]=[C:20]([CH2:19][CH3:18])[CH:21]=[C:22]([CH2:23][CH3:24])[N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: CCC(=O)CC(=O)CC
Reactant: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Product: CCc1cc(CC)n2nc(CCCOc3ccc(Cl)cc3)nc2n1
Yield: 44 %

Procedure:
The title compound was prepared according to the experimentals described for Example 22 above from 3-[3-(4-chlorophenoxy)propyl]-1H-1,2,4-triazol-5-amine and 3,5-heptanedione in 44% yield; 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (dd, 1H), 7.29 (dd, 1H), 7.11 (s, 1H), 6.96 (dd, 1H), 6.94 (dd, 1H), 4.08 (t, 2H), 3.07 (q, 2H), 2.97 (t, 2H), 2.86 (q, 2H), 2.20 (m, 2H), 1.33 (t, 3H), 1.27 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[C:21]1([CH2:27][CH2:28][SH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:29][CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: SCCc1ccccc1
Product: Cc1c(SCCCSCCc2ccccc2)ccnc1CSc1ccncc1
Yield: 49 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-phenylethyl mercaptan gives, after silica gel chromatography and crystallization from diisopropyl ether, the title compound as a colorless powder; m.p. 48-50° C.; yield 49% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C@H:4]([OH:8])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1Cl
Yield: 94 %

Procedure:
In a four necked round bottomed flask, 500 gm of (R)-2-chloromandelic acid was taken in 2600 ml methanol. Then 18.8 gm of sulfuric acid was added and heated to reflux, till completion of reaction. Then excess of methanol was distilled off under reduced pressure. Residue was taken in dichloromethane and washed with aqueous sodium bicarbonate solution. Dichloromethane was distilled under reduced pressure to obtain 522 gm of Methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate as an oil. Yield: 94%. Purity: 98.5%
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:29]4[CH2:30][CH2:31][CH:27]([NH:26][CH3:25])[CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CNC1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CNC1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and methyl-pyrrolidin-3-yl-amine. 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.76 (m, 1H), 7.70-7.73 (m, 1H), 7.48-7.54 (m, 2H), 6.94-6.96 (m, 1H), 3.53-3.56 (m, 3H), 3.22-3.29 (m, 4H), 2.31-2.34 (m, 5H), 2.01-2.13 (m, 3H), 1.73-1.86 (m, 6H), 1.23-1.32 (m, 2H). m/z: 458.2 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH2:17]CCCCCCCCCCCCCC)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](C1OCC(CO)CO1)(C)C.C(Br)C1C=CC=CC=1>>[CH:16]([CH:15]1[O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:14]1)([CH3:17])[CH3:32]
Reactant: CC(C)C1OCC(CO)CO1
Reactant: CCCCCCCCCCCCCCCCCOCC(CO)COCc1ccccc1
Agent: BrCc1ccccc1
Product: CC(C)C1OCC(COCc2ccccc2)CO1

Procedure:
The 2-benzyloxymethyl-3-heptadecyloxy-1-propanol used as starting material is obtained by reacting 2-isopropyl-5-hydroxymethyl-1,3-dioxan with benzyl bromide to give 2-isopropyl-5-benzyloxymethyl-1,3-dioxan (oil), subsequent splitting with sulfuric acid and reaction with an equimolar amount of heptadecyl bromide.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O-2].[Mg+2].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:13].S(=O)(=O)(O)O>O.CCOCC>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(OC(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
In this example, 11.5 g L-proline and 8.0 g magnesium oxide are dissolved in 100 ml water, and then admixed with 60 ml ether. A solution of p-methylphenyl chloroformate [8.5 g; boiling point: 109°-110° C. (28-30 mmHg)] dissolved in 50 ml ether is added thereto, while cooling the mixture in an ice bath (5°-10° C.). After stirring for 30 minutes, the reaction solution is acidified by adding 60 ml concentrated sulfuric acid, and extracted three times with 60 ml ethyl acetate. The extract is washed three times with 40 ml 2N HCl and four times with 50 ml water, and then dried overnight over anhydrous sodium sulfate (30 g). After drying, the extract is filtered, and the filtrate is concentrated under reduced pressure. The resulting oily materials are admixed with 100 ml n-hexane, and left standing in a refrigerator (about -15° C.). The deposited crystals are filtered, and recrystallized from ethyl acetate-n-hexane (1:1 by volume), whereby p-methylphenyloxycarbonyl-L-proline (compound number 8; 9.25 g; mp: 76°-77° C.) is obtained. Yield: 74.3%.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9](=[O:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29]C(=O)C)=[CH:28][C:23]=2[O:22][CH:21]=1>CC#N>[OH:29][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([CH2:19][N:6]3[CH2:7][C@@H:2]4[CH2:8][C@H:5]3[CH2:4][N:3]4[C:9](=[O:11])[CH3:10])=[CH:21][O:22][C:23]=2[CH:28]=1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(=O)Oc1ccc2c(CCl)coc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1coc2cc(O)ccc12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of (1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone hydrochloride (330 mg, 2.35 mmol) and K2CO3 (0.831 g, 6.01 mmol) in MeCN (20 mL) was added acetic acid 3-chloromethyl-benzofuran-6-yl ester (450 mg, 2.00 mmol) and the reaction mixture was heated (50° C., 20 h). The solvent was removed in vacuo and the remaining residue was dissolved in water (10 mL) and 2-3 mL of 4 M KOH was slowly added to reach pH 13-14. The dark green solution was stirred (10 min) and treated with concentrated acetic acid until the solution reached pH 10. The aqueous mixture was extracted with 20% IPA/DCM (4×30 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a gummy yellow solid (540 mg, 94%). MS (ESI): mass calcd. for C16H18N2O3, 286.1; m/z found, 287.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 1H), 7.48 (dd, J=8.4, 2.5, 1H), 6.84 (t, J=1.8, 1H), 6.75 (ddd, J=8.4, 2.9, 2.2, 1H), 4.66 (s, 0.5H), 4.44 (s, 0.5H), 3.89-3.75 (m, 2H), 3.69-3.58 (m, 2H), 3.40 (dd, J=9.8, 2.3, 0.5H), 3.23 (dd, J=11.4, 2.0, 0.5H), 2.96 (dd, J=10.0, 2.2, 0.5H), 2.88 (dd, J=9.9, 2.2, 0.5H), 2.73 (dd, J=9.4, 7.0, 1H), 2.09 (s, 1.5H), 2.03-1.92 (m, 2.5H), 1.80 (d, J=10.1, 0.5H), 1.71 (d, J=10.1, 0.5H).