Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]2[C:30]3[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=3[NH:24][C:23]([CH3:35])=[C:22]2[C:36]#[N:37])[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.N1C=CC=CC=1.[CH2:44]([S:47](Cl)(=[O:49])=[O:48])[CH2:45][CH3:46]>ClCCl>[C:36]([C:22]1[CH:21]([C:4]2[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[C:2]([NH:1][S:47]([CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])[CH:3]=2)[C:30]2[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=2[NH:24][C:23]=1[CH3:35])#[N:37]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc(OC)c2)c(OCC)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(NS(=O)(=O)CCC)c(OCc2cccc(OC)c2)c(OCC)c1
Reaction time: 17 h

Procedure:
To a solution of 4-[3-amino-5-ethoxy-4-(3-methoxy-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (220 mg) and pyridine (106 μl) in dichloromethane (5 ml) was added propane-1-sulfonyl chloride (94 mg). After stirring for 17 h, the mixture was diluted with dichloromethane and extracted with water and sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-:15].[K+]>C(O)CCC>[CH2:2]([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [K+]
Solvent: CCCCO
Product: CCCCOCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 14.9 %

Procedure:
11-bromoundecanoic acid (2 g, 17.5 mmol) was added to a solution of potassium hydroxide (1.7 g, 30.2 mmol) in 1-butanol (20 mL) and the solution was stirred at 40° C. for 5 hrs. After cooling, the reaction mixture was extracted with ethyl acetate and water at pH=2. The organic phase was then washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified over silica column chromatography in 2-10% ethyl acetate/hexane/0.2% formic acid to yield 11-(1-butoxy)undecanoic acid (336 mg, 17%). mp 29-30.5° C.; 1H NMR (300 MHz, CDCl3) δ0.84-0.96 (t, 3H, J=7.3, CH3), 1.18-1.46 (bm, 14H, methylene envelope), 1.47-1.68 (bm, 6H, CH2CH2OCH2CH2, CH2CH2COOH), 2.31 (t, 2H, CH2COOH), 3.32-3.46 (bm, 4H, CH2OCH2), 11.02 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3 δ14.02, 19.43, 24.74, 26.21, 29.11, 29.28, 29.35, 29.56, 29.64, 29.76, 31.85, 34.14, 70.63, 70.94, 179.82; m/z 259 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][C:8]([Cl:18])=[N:7][CH:6]=1)C.O1CCOCC1.[OH-].[Na+]>O>[Cl:18][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([C:4]([OH:19])=[O:3])=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
A mixture of 3.20 g (10.8 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid ethyl ester, 50 ml dioxane and 50 ml of a 2 M aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with two portions of tert-butyl methyl ether. The combined organic layers were extracted with 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2 with 2 M aqueous hydrochloric acid solution and extracted with four portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated to give 2.90 g (100%) of the title compound as an off-white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[CH:40][CH:39]=1>CCOC(C)=O.CCCCCC>[CH2:28]([C:26]1[N:25]([CH3:30])[N:24]=[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:38]4[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[CH:42][CH:43]=4)[C:4](=[O:31])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])[CH:27]=1)[CH3:29]
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 345, 60 mg, 0.1441 mmol) and THF (2.0 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (24.2 mg, 0.146 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. iPrOH (˜10 mL) affording the title compound in 41% yield (0.033 g, 0.059 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:43].C(Cl)CCl.C1[CH:49]=[CH:50][C:51]2N(O)N=[N:54][C:52]=2C=1.C1(CN)CC1>C(Cl)Cl>[CH:51]1([CH2:52][NH:54][C:22]([C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH2:12][NH:11][C:10](=[O:43])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])[CH2:33][CH2:34]4)[N:17]=3)[CH:20]=2)=[O:23])[CH2:49][CH2:50]1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: NCC1CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoic acid (250 mg) in methylenechloride (100 mL) were added EDC (100 mg), HOBt (70 mg) and cyclopropylmethylamine (110 uL). The reaction was stirred at r.t. overnight and evaporated in vacuo. Flash chromatography then provided the title compound as a white solid. LC-MS m/z 648 (M+H)+, 2.33 min (ret. time).
Reaction SMILES: [CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[I-].[Na+].[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:16]>CC(C)=O.C(C(C)=O)C>[I-:12].[CH2:1]([N+:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CCN(CC)CC
Agent: C=CCCCCCCCCCI
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: C=CCCCCCCCCC[N+](CC)(CC)CC

Procedure:
Example IX involves the procedures followed above to prepare undecylenyl chloride, undecylenyl iodide, and triethylammonium undecylenyl iodide. All reagents were obtained from Aldrich unless specified otherwise. Undecylenyl iodide was made stepwise from undecylenol (Aldrich). Undecylenol was allowed to react with thionyl chloride and pyridine to form undecylenyl chloride which was then converted to undecylenyl iodide by reaction with sodium iodide in acetone or methyl ethyl ketone. Undecylenyl triethylammonium iodide was formed by the reaction of undecylenyl iodide and triethylamine in alcohol. Polyalkylenes were then made by polymerization of the corresponding 1-olefins using the isotactic catalyst TiCl3AA (Alpha Products)/diethylaluminum chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=O)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.[OH2:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]=[C:22]([C:21](=[O:24])[NH2:20])[N:23]=[C:19]2[CH3:18])=[CH:6][CH:7]=1
Reactant: O
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Solvent: Cc1ccccc1
Product: Cc1nc(C(N)=O)cn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 15.3 g. (0.1 mol.) of 4-chlorophenyl-isocyanate in 120 ml. of toluene is added dropwise to the stirred solution of 8.61 g. (0.105 mol.) of 2-methyl-imidazole in 60 ml. of water at 10° to 12° C., under cooling. The reaction mixture is stirred at room temperature for one hour. The separated product is filtered off, washed with water and dried. 17.4 g. (74%) of 1-(4-chlorophenyl)-carbamoyl-2-methylimidazole are obtained; m.p.: 138°-140° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].O[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[C:16]=1[C:25]([OH:27])=O.C[OH:29]>>[N:1]([CH2:4][C@H:5]([NH:13][C:25]([C:16]1[N:17]([CH3:24])[C:18]2[C:23]([CH:15]=1)=[C:22]([OH:29])[CH:21]=[CH:20][CH:19]=2)=[O:27])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CO
Reactant: Cn1c(C(=O)O)c(O)c2ccccc21
Reactant: [N-]=[N+]=NC[C@H](N)Cc1ccccc1
Product: Cn1c(C(=O)N[C@@H](CN=[N+]=[N-])Cc2ccccc2)cc2c(O)cccc21

Procedure:
From (R)-2-azido-1-benzylethylamine (prepared as described by Horwell, et al., J. Med. Chem., 1991, 404-414) and 4 hydroxy-1-methyl-1H-indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES (M++H)=350; [α]D=+94.8° (MeOH, C=1).
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O-:38])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.[Na+]>CC(C)=O.CN(C=O)C>[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O:38][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: CC(C)(C)C(=O)OCBr
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1

Procedure:
The title compound was prepared as described in Example 3, using pivaloyloxymethyl bromide (0.051 g) in acetone (1ml), sodium iodide (0.039 g) and sodium 7β-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-[(5RS)-2,5-dihydro-2-oxofuran-5-ylmethyl]ceph-3-em-4-carboxylate (0.13 g) in DMF (2 mls).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[N:14]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 4-acetylbenzene-1-sulfonyl chloride (2 g, 9.2 mmol), piperidine (0.85 g, 10.0 mmol) and triethylamine (1.9 g, 18.4 mmol) in tetrahydrofuran (60 mL) was stirred at rt overnight. Brine (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. Removal of solvent in vacuo gave the title compound as a white solid (2.3 g, 94%). MS (M+H)+ 268.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=O.O>C1COCC1.CCOCC>[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=[CH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC=Cc2ccccc2Br)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 4-carboxyphenethyl triphenylphosphonium bromide (11.2 g, 22.8 mmol) in THF (200 ml) under argon, was added a 1M solution of lithium hexamethyldisilazide (50 ml) in THF at 20° C., giving a deep red colour. After stirring for 30 minutes, the reaction was treated with a solution of 2-bromobenzaldehyde (4.0 g, 21.6 mmol) in THF (15 ml) and stirred for a further 30 minutes at 20° C. The solution was poured onto a stirred mixture of water (100 ml) and ether (100 ml). The layers were separated and the aqueous portion washed again with ether (100 ml), acidified with 1N HCl and extracted with ether (100 ml). The ether extracts were dried over anhydrous magnesium sulphate and "flashed" through a pad of silica to remove impurities, rinsing with further portions of ether. The filtrates were evaporated to give 4-[3-(2-bromophenyl)prop-2-en-1-yl]benzoic acid (6.1 g) as a yellow gum, which slowly solidified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:16][CH:17]=O>CCO>[N:1]1[CH:16]=[CH:17][N:3]2[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1cc(CO)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1ccn2ccnc2c1
Yield: 81.8 %

Procedure:
To a solution of a (2-Amino-pyridin-4-yl)-methanol (0.40 g, 3.3 mmol) in EtOH was added NaHCO3 (0.56 g, 6.67 mmol) followed by chloroacetaldehyde (0.81 ml, 5.0 mmol). The mixture was refluxed for 2 h. Solvents were removed in vacuo and the crude mixture was partitioned between water and EtOAc. The aqueous was further extracted with EtOAc, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified using silica column chromatography (0-50% MeOH/Et2O) to afford 0.40 g of product MS: [M+H]+=149.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.O[N:14]1C(=O)CCC1=O.C(Cl)CCl>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH2:14])=[O:12])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)CCCC[C@@H]1CCSS1

Procedure:
A solution of lipoic acid (25.6 g, 124 mmol), N-hydroxysuccinimide (15.6 g, 136 mmol), and EDC (26.1 g, 136 mmol) in anhydrous CH2Cl2 (300 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with H2O (500 mL), saturated aqueous NaHCO3 (500 mL), saturated aqueous NaCl (500 mL) and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated to dryness giving the product as a yellow sold (35.4 g, 94%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[C:7]1([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl.O>[CH:3]1([CH2:2][N:14]2[C:15]3[C@:16]4([CH3:26])[C:23]([CH3:25])([CH3:24])[C@@H:19]([CH2:18][CH2:17]4)[C:20]=3[C:21](=[O:22])[N:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCC1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of (bromomethyl)cyclobutane (1.7 mL, 15.1 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 393 mg, 1.46 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) in N,N-dimethylformamide (7 mL) was heated in an oil-bath at 100° C. for 16 h. Additional quantities of (bromomethyl)cyclobutane (1.7 mL, 8.9 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) were added and the mixture was heated in an oil-bath at 135° C. for 6 days. The reaction mixture was allowed to cool and it was then diluted with dichloromethane (75 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with water (5×30 mL), sodium thiosulfate solution (30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 15-75% ethyl acetate/hexanes and then held under high vacuum to give (4R,7S)-1-(cyclobutyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (52 mg, 11%) as a yellow gum. ES(+)-MS (M+H) 337.
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:15]=[C:14]([C:16]([O:18]C)=O)[CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]#[N:22]>>[O:18]=[C:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([O:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:15]=1)[CH2:20][C:21]#[N:22]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCCc2ccccc2)n1
Product: N#CCC(=O)c1cccc(OCCc2ccccc2)n1

Procedure:
CH3CN addition to methyl 6-phenethoxypicolinate following the method described in Example 6 gave 3-oxo-3-(6-phenethoxypyridin-2-yl)propanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.33 g, quant.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[CH2:1]([N:3]([CH2:8][CH2:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH3:5])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCNCC
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCOC(=O)CCN(CC)CC
Temperature: 58 °C
Yield: 96 %

Procedure:
The following materials were charged to the reaction vessel: anhydrous diethylamine (292 grams); ethyl acrylate (200 grams); phenothiazine (1.0 gram); and p-methoxyphenol (1.0 gram). This mixture was heated at reflux (about 56-60° C.) for 24 hours. At the end of this period, unreacted amine was removed by distillation. The product was recovered at 80°-81° C. and 10 mm. mercury pressure in a yield of 96 percent. The product is designated herein as Amine Catalyst IX and has the formula, (C2H5)2N--CH2CH2 -C(O)OC2H5, as verified analytically by infrared spectroscopy.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([NH:9][CH3:10])=[O:8])=O.[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[S:21])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[S:21][CH:1]([C:3]3[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=3[O:5][CH2:6][C:7]([NH:9][CH3:10])=[O:8])[N:23]([C:38](=[O:39])[C:37]3[C:41]([F:46])=[CH:42][C:43]([F:45])=[CH:44][C:36]=3[F:35])[N:22]=2)=[CH:18][CH:17]=1
Reactant: NNC(=S)c1ccc(Cl)cc1
Reactant: CNC(=O)COc1ccccc1C=O
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COc1ccccc1C1SC(c2ccc(Cl)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 0.17 h

Procedure:
The 2-(2-formyl-phenoxy)-N-methyl-acetamide (0.0311 mmol) is added to 4-chloro-thiobenzoic acid hydrazide (0.0342 mmol) in 0.1 mL of CH2Cl2. After 10 minutes, DIEA (0.05 mL) and 2,4,6-trifluoro-benzoyl chloride (0.0467 mmol) are added. The mixture is kept at room temperature overnight. After removal of solvent, the residue is purified by preparative HPLC (20-100% MeCN/H2O gradient) to give the product 2-{2-[5-(4-chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-methyl-acetamide as an off white solid: LC/MS (ES+): 520.1 (M+1)+.
Reaction SMILES: ClCCl.[F:4][C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][C:6]=1[OH:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CS(O[CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]=[CH2:44])[CH2:39][CH2:38]1)(=O)=O>C1(C)C=CC=CC=1.O>[F:4][C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH2:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][C:6]=1[O:22][CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH2:43][CH3:44])[CH2:39][CH2:38]1
Reactant: CC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Reactant: C=C[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@H]1CC[C@H](COc2ccc(OC[C@H]3CC[C@H](CC)CC3)c(F)c2F)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In the dichloromethane (50 mL) solution containing 10 g of 2,3-difluoro-4-(trans-4-ethylcyclohexyl)methoxyphenol, 12 g of tripotassium phosphate and 8.1 g of (trans-4-vinylcyclohexyl)methyl methanesulfonate were dissolved, and the solution was stirred at 80 to 100° C. for 2 hours. Water and toluene were added to the solution, and the organic layer was fractioned, washed with water and saturated saline, and then dried over silicagel. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization and column chromatography, to thereby obtain 7.9 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxy-4-(trans-4-vinylcyclohexyl)methoxybenzene (1b) in the form of colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C@@H:15]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28].[C:34](Cl)(=[O:36])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:27](=[O:29])[CH3:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[O:25][C:34](=[O:36])[CH3:35])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(=O)C=C[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCC(=CC=C1CC[C@@H](OC(C)=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 0.5 g. 9β-hydroxy-15-oxo-13-prostenoic acid ethyl ester, 5 ml. acetic anhydride, 2 ml. acetyl chloride and 0.52 g. p-toluenesulfonic acid is heated for 3 hours, with the exclusion of moisture, at 100°; poured, after cooling, into 100 ml. ice water containing 15 g. NaHCO3 ; and extracted twice with 50 ml. amounts of diethyl ether. The organic extract is washed until neutral with water, and dried over Na2SO4. After removal of the solvent and chromatographic purification (silica gel/petroleum ether/diisopropyl ether:triethylamine = 100:100:1), 9β,15-diacetoxy-12,14-prostadienoic acid ethyl ester is obtained. UV; 243-244 nm (ε = 19800).