Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH:9]=[CH2:10])=[CH:3][O:4][Si](C)(C)C.[CH2:11]([O:13][CH:14](OCC)[CH3:15])[CH3:12].O>ClCCl.[Br-].[Zn+2].[Br-]>[Br:1][C:2](=[CH:3][CH2:4][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH:9]=[O:10]
Reactant: C=CC(Br)=CO[Si](C)(C)C
Reactant: CCOC(C)OCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: CCOC(C)CC=C(Br)C=O
Yield: 77.8 %

Procedure:
A solution of 2.21 g (10 mmoles) of 2-bromo-1-trimethylsiloxybut-1,3-diene in 30 ml of anhydrous dichloromethane are introduced into a 100 ml reactor traversed by a stream of nitrogen. 1.18 g (about 11 mmoles) of 1,1-diethoxyethane are slowly added and then 100 mg of anhydrous zinc bromide. After reaction for 10 minutes, 20 ml of water are added, the organic phase is collected, and the aqueous phase is extracted with 20 ml of dichloromethane. The dichloromethane fractions are combined and dried with 5 g of anhydrous magnesium sulfate. The solvent is eliminated by vacuum evaporation and the residue distilled, the boiling point of the product being 66° C. under 0.15 mm Hg. 1.72 g of product are obtained, representing a yield of 78%. The structure of the product obtained is confirmed by NMR analysis and mass spectrometry.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](OB(O)O)=[CH:8][CH:7]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[F-].[Cs+]>COCCOC.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: Brc1nccs1
Reactant: COCOCc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COCOCc1ccc(-c2nccs2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis(triphenylphosphine)palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:18]C)[N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:20])[N:3]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[NH2:20][C:4]1[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)CCN
Reactant: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Product: CC(C)CCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (45 mg) in 3-methyl-1-butylamine (0.234 mL) was heated in a microwave at 170° C. for 10 mins. The mixture was concentrated in vacuo to give a green oily residue. This was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound as a white solid (10 mg).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.C[C:10]1[N:11]2[CH2:18][CH2:17][N:16]=[C:12]2[CH2:13][S:14][CH:15]=1.C(O)(=O)/C=C/C(O)=O.N1CCN2CCCSC=12.C(O)(=O)/C=C/C(O)=O.N1CCN2C=CCSC=12>>[N:16]1[CH2:17][CH2:18][N:11]2[CH:10]=[CH:15][S:14][CH2:13][C:12]=12
Reactant: CC1=CSCC2=NCCN12
Agent: C1=CN2CCN=C2SC1
Agent: C1CSC2=NCCN2C1
Agent: O=C(O)/C=C/C(=O)O
Product: C1=CN2CCN=C2CS1

Procedure:
Employing the procedure of Example 1, Step D, but substituting for the 3-ethylthio-2H-[1,4]thiazine, used therein, an equimolar amount of 3-ethylthio-5-methyl-2H-[1,4]-thiazine, 2-methylthio-4,5-dihydro-6H-[1,3]thiazine, or 2-methylthio-6H-[1,3]thiazine, there is produced respectively, 2,3-dihydro-5-methyl-8H-imidazo[2,1-c][1,4]thiazine fumarate; 2,3,5,6-tetrahydro-7H-imidazo[2,1-b][1,3]thiazine fumarate; or 2,3-dihydro-7H-imidazo[2,1-b][1,3]thiazine fumarate.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1.[CH2:14]([N:21]([CH3:43])[C:22](=[O:42])[C@@H:23]([N:31]([CH2:39][CH:40]=O)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]([CH3:43])[C:22](=[O:42])[C@@H:23]([N:31]([CH2:39][CH2:40][NH:13][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][CH:3]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCNCCc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using 2-(1H-indol-3-yl)-ethylamine hydrochloride salt (tryptamine hydrochloride salt) (0.197 g, 1.0 mmol) and (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.41 g, 1.0 mmol) to give the title compound: TLC Rf =0.69 (silica gel, 85% chloroform/10% methanol/5% acetic acid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:43]([NH:50][CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][NH2:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][NH:53][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCC(NCc1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(NCc1ccccc1)c1ccccc1
Yield: 11.5 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (70 mg, 0.13 mmol) and N1-benzyl-1-phenyl-1,2-ethandiamine dihydrochloride (45 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (11 mg) as a diastereomeric mixture. 1H-NMR (400 MHz, CD3OD) d 7.50 (1H), 7.45-7.03 (17H), 4.40 (m, 1H), 4.25 (m, 1H), 4.06 (m, 1H), 3.80 (s, 2H), 3.03 (m, 1H), 1.33 (s, 9H); HRMS m/z 738.3281 (calc. of monoisotopic mass for C41H46N4O9 gives 738.3265).
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](O)(=O)C>O>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:11]
Reactant: COC(=O)c1cccnc1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)c1cccnc1

Procedure:
A mixture of 22 g/h of methyl nicotinate, 57 g/h of acetic acid and 20 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 400° C., over 100 ml of catalyst E, which contained 2% by weight of sodium oxide, the remainder being anatase. The catalyst was prepared similarly to Example 8, by impregnating 980 g of TiO2 carrier I with a solution which contained 20 g of Na2O (as aqueous NaOH). The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of nicotinic ester and of acetic acid was 100% in each case. The selectivity with respect to 3-acetylpyridine was 60%. In addition, pyridine was formed with a selectivity of 29%.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[C:9](=O)([O-])[O-:10].[Ca+2]>CO>[CH3:9][O:10][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)/C=C/CBr
Agent: [Ca+2]
Solvent: CO
Product: COC/C=C/C(=O)OC
Yield: 77.9 %

Procedure:
A mixture of 54 g of methyl 4-bromocrotonate and 30.2 g of calcium carbonate in 200 mL of methanol was refluxed for 5 days. The mixture was filtered and the solvent was removed from the filtrate. The residue was dissolved in ether and washed with water containing a trace of hydrochloric acid. The ether solution was dried over magnesium sulfate. The solvent was removed and the residue was distilled to give 30.6 g of methyl 4-methoxycrotonate. This material was stirred in 170 mL of 1N sodium hydroxide for 3 min. The solution was washed with ether and the aqueous layer was acidified with sulfuric acid. The mixture was extracted several times with ether. The combined extracts were washed with brine and dried over magnesium sulfate. The solvent was removed to give 4-methoxycrotonic acid as a crystalline solid. A 10 g portion of this acid was stirred in 50 mL of benzene at 0° C. and 8.3 mL of oxalyl chloride was added. The mixture was stirred at room temperature for 6 hr. The solvent was removed and the residue was distilled to give 4-methoxycrotonyl chloride as a colorless liquid.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][NH2:43]>>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][NH:43][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccc(Cl)cc2Cl)n1

Procedure:
Followed the same procedure in the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.11 g, 0.3 mmol) was displaced with 2-(2,4-dichlorophenyl)ethylamine (0.14 mL, 0.9 mmol) to give the title compound as a yellow solid. MS m/e 492 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>CO.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (5 mmol) in MeOH (30 mL) was added Pd/C (1 g), then the mixture was stirred for 18 hours at 20° C. under 1 atm. H2. The reaction was filtered and concentrated to give gray yellow oil. MS (m/z): 296 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Yield: 99 %

Procedure:
Prepared in analogy to Example 3(b) from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and methanesulfonyl chloride. The crude material was purified by partitioning between dichoromethane and water to yield the title compound as a yellow oil (yield 99%). MS (m/e): 406.4 (M+H+, 100%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:20][CH2:21][C:22](=[O:35])[N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:25][CH2:24]3)[C:8]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:20][CH2:21][C:22](=[O:35])[N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:27][CH2:28]3)[C:8]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Temperature: 70 °C

Procedure:
To a stirred solution of 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid, methyl ester (460 mg, 0.1 mmol), in THF (1 mL) and MeOH (1 mL) was added 1M NaOH (0.16 mL, 0.16 mmol). The reaction mixture was heated in a sealed tube at 70° C. for 4 h. 1M NaOH (0.2 mL, 0.2 mmol) was added and heated for 5 h more. 1N HCl (0.5 mL) was added and the volatiles were removed in vacuo. A precipitate formed and it was collected by filtration and dried at open air to afford 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid as a pale yellow solid. LCMS: m/e 552 (M+H)+, ret time 2.10 min, column A, 2 minute gradient.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:17])[C:10]1=[O:32])=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:8][C@H:9]1[CH:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:32]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1[C@H](N)C(=O)N1OCC(=O)O

Procedure:
(3S-trans)-[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. diphenylmethyl ester (4.4 g1 10.0 mmol) was dissolved in a solution of 33 ml of trifluoroacetic acid and anisole (3.3 ml; 30.0 mmol) at -10° C. The mixture was evaporated in vacuo 10 minutes later and the residue was stirred with ether, filtered off and dried over P2O5 to give colorless crystals of (3S)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid, trifluoroacetate salt (yield 2.87 g). The salt (2.87 g; 10.0 mmol) was suspended in dry acetonitrile. MSTFA (5.57 ml; 30.0 mmol) was added and stirring was continued for 30 minutes. After evaporating in vacuo the residue was dissolved in dry tetrahydrofuran and then added to a mixture of the [[[(4-methoxyphenyl)methoxy]-carbonyl]amino]benzeneacetic acid 1-hydroxybenzotriazole ester (4. g, 10.0 mmol) in 25 ml of dry tetrahydrofuran at 0° C., stirred overnight at room temperature and evaporated in vacuo. After adding ether the crude silylated product was decomposed with 1 ml methanol. After removing the solvents in vacuo the residue was stirred with ether/petroleum ether to give colorless crystals of the title compound.
Reaction SMILES: [CH2:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20]/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[CH2:37][C:38]([O:40]/[CH:41]=[CH:42]/[CH:43]=[CH:44]/[CH:45]=[CH:46]/[CH:47]=[CH:48]/[CH:49]=[CH:50]/[CH:51]=[CH:52]/[CH:53]=[CH:54]/[CH:55]=[CH:56]/[CH2:57][C:58]([OH:60])=[O:59])=[O:39])=[O:19].CN([CH2:64][CH2:65][CH2:66]N)C>C1(C)C(C)=CC=CC=1>[CH2:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20]/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[CH2:37][C:38]([O:40]/[CH:41]=[CH:42]/[CH:43]=[CH:44]/[CH:45]=[CH:46]/[CH:47]=[CH:48]/[CH:49]=[CH:50]/[CH:51]=[CH:52]/[CH:53]=[CH:54]/[CH:55]=[CH:56]/[CH2:57][C:58]([OH:60])=[O:59])=[O:39])=[O:19].[CH3:64][CH2:65][CH2:66][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH:50]([CH2:49][CH2:48]/[CH:47]=[CH:46]\[CH2:45][CH2:44][CH2:43][CH2:42][CH3:41])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CN(C)CCCN
Agent: C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/CC(=O)O/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/CC(=O)O/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/CC(=O)O
Solvent: Cc1ccccc1C
Product: CCCCC/C=C\CCC(CCCCCCCC(=O)O)C(CCCCCCCC)CCCCCCCCC(=O)O
Temperature: 200 °C
Yield: 20 %

Procedure:
Employing the procedure of Example I, an amidoamine oxide was prepared from a polymeric fatty acid containing 87% C36 dimer acid and 13% trimer acid. For the reaction 352.2 gms of the polymeric fatty acid (Empol® 1016) was combined with 30 mls xylene, heated to 200° C. under a nitrogen atmosphere and 147.2 gms (20% equivalents excess) dimethylaminopropylamine added over a 2 hour period. Heating was continued at 200° C. while removing water until the acid value was 2.3. The reaction was terminated at that point and the xylene removed by vacuum distillation. One-hundred and seventy grams of the resulting amidoamine product was then dispersed in water (1000 mls) and reacted with 30% hydrogen peroxide (55.5 gms). The amber liquid product (14.5% solids) was slightly less viscous than the product obtained in Example I, possibly due to the lower solids content. Similar results are obtained when a polymeric fatty acid containing 80% C54 trimer acid and 20% C36 dimer acid is employed.
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2[CH:27]=N[C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.Cl.N[C:34]1(C)CCCC1NC(=O)C1C=CC=CC=1N1N=CC=N1.ClC1C=CC(C(F)(F)F)=CN=1>>[CH3:1][C:2]1([NH:21][C:22]2[CH:27]=[CH:34][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Agent: FC(F)(F)c1ccc(Cl)nc1
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 82) from N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 95 mg, 0.30 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 100 mg, 0.55 mmol) except this was heated at 140° C. for 17 hours and then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=2[C:17]([OH:19])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>N1C=CC=CC=1>[O:24]=[C:23]1[CH:22]([N:21]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]2=[O:13])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(Nc2ccccc2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccccc4)c3C2=O)C(=O)N1
Yield: 83 %

Procedure:
A mixture of 3-phenylaminophthalic acid (0.52 g, 2.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.60 g of the product at 4:6 hexanes-ethyl acetate, in 83% yield: mp 214-216° C.; 1H NMR (DMSO-d6) δ 1.99-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.84-2.97 (m, 1H), 5.13 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.11-7.16 (m, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.31-7.45 (m, 5H), 7.61 (t, J=7.8 Hz, 1H), 8.45 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 112.0, 113.4, 119.4, 121.9, 124.0, 129.4, 132.5, 136.2, 139.4, 142.8, 167.0, 168.3, 170.0, 172.8; Anal. calcd for C19H15N3O4: C, 65.32; H, 4.33; N, 12.03. Found: C, 64.93; H, 4.33; N, 11.79.
Reaction SMILES: Cl.Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[S:17]>C(#N)C>[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:16](=[S:17])[NH:15][C:10]=2[CH:9]=1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Solvent: CC#N
Product: S=c1[nH]c2ccc(-c3nn[nH]n3)cc2[nH]1
Reaction time: 5 h
Yield: 61.4 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (6.40 g, 25 mmol) in acetonitrile (100 ml) was added thiocarbonyl di-imidazole (4.86 g, 28 mmol). A further 100 ml of acetonitrile was added. The reaction was then stirred for 5 hours and the reaction analyzed by HPLC. The solvent was removed under reduced pressure and water added (100 ml). The pH of the reaction mixture was adjusted to pH 2.0 and the solid filtered and washed with water (50 ml). The material was dried to give 5-(2H-tetrazol-5-yl)-1,3-dihydrobenzimidazole-2-thione (3.35 g, 61% yield). The material was suspended in water (300 ml) and the pH adjusted to 11.0 with 40% (v/v) NaOH. Methanol (15 ml) was then added followed by Activated carbon (0.38 g) and the mixture stirred for 1 hour. The mixture was filtered and the solvent removed, under reduced pressure, to half its volume. The pH was adjusted to 2.0 with 50% (v/v) hydrochloric acid to yield an off white solid. The solid was filtered off and washed with water. The purity was >98% by hplc Rt=7.8 mins. The material was dried to yield 5-(2H-tetrazol-5-yl)-1,3-dihydrobenzimidazole-2-thione (2.37 g). 1H NMR (d6-DMSO, 400 MHz) 12.88 ppm (1H, s), 12.84 ppm (1H, s), 7.82 ppm (1H, dd, 8.4 Hz, 1.6 Hz), 7.78 ppm (1H, m), 7.30 ppm (1H, d, 8 Hz). MS (high resolution EI). Found 218.036514 m/z C8H6N6S to +4 ppm mass accuracy.