Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6](=O)[C:5](=O)[C:4]([CH3:10])([CH3:9])[O:3]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][NH2:21])=[NH:19])([O-:14])=[O:13]>C(O)C>[CH3:1][C:2]1([CH3:11])[C:6]2[N:19]=[C:18]([C:17]3[CH:22]=[CH:23][CH:24]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=3)[N:20]=[N:21][C:5]=2[C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CC1(C)OC(C)(C)C(=O)C1=O
Reactant: N=C(NN)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC1(C)OC(C)(C)c2nc(-c3cccc([N+](=O)[O-])c3)nnc21

Procedure:
A mixture of 1.56 g. (0.01 mole) of 2,2,5,5-tetramethyl-3,4(2H,5H) furandione and 1.80 g. (0.01 mole) 3-nitro benzimidic acid hydrazide in 100 ml. absolute ethanol is refluxed under nitrogen for 18 hours at a bath temperature of 100°C. The excess water is removed from the condensate by using a Dean Stark trap filled with 3A molecular sieves. The resulting mixture is evaporated to dryness in vacuo at 40°C., and the resulting residue is recrystallized from hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-(m-nitrophenyl)furo[3,4-e]-as-triazine.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:44][CH:45]=1)[C:19]2=[O:70])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O>[NH2:46][C:43]1[S:44][CH:45]=[C:41]([C:40](=[N:66][O:67][CH3:68])[C:39]([NH:38][CH:20]2[C:19](=[O:70])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:29])=[O:30])=[C:17]3[C:15]([OH:16])=[O:14])=[O:69])[N:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Yield: 97.7 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (syn isomer, E-form) (5.93 g) in a mixture of pure formic acid (80 cc) and water (25 cc) is heated at 50° C. for 30 minutes. The mixture is then cooled to 20° C., filtered and concentrated to dryness at 30° C. under 20 mm Hg (2.7 kPa). The residue is taken up in acetone (150 cc), the mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), the operation is repeated twice more and the residue is then triturated in ether (75 cc) and filtered off. 7-[2-(2-Amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (3.4 g) is obtained in the form of a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 87 %

Procedure:
To the mixture of 6-chloro-5-fluoroindolin-2-one (Natrochem) (2.88 g, 15.5 mmol) and 3-chloro-2-fluorobenzaldehyde (3.69 g, 23.3 mmol) (Aldrich) in methanol (140 mL) was added piperidine (3.96 g, 46.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 4.4 g, 87%).
Reaction SMILES: [C:1]([O:4][C:5]([C:7]([F:21])([F:20])[C@@:8](C(=O)C)([C@@H:10]([CH:12]([C:14](=[O:16])[CH3:15])[OH:13])[OH:11])[OH:9])=[O:6])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([O:4][C:5]([C:7]([F:20])([F:21])[C@@H:8]([C@@H:10]([CH:12]([C:14](=[O:16])[CH3:15])[OH:13])[OH:11])[OH:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(=O)C(F)(F)[C@@](O)(C(C)=O)[C@H](O)C(O)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC(=O)C(F)(F)[C@H](O)[C@H](O)C(O)C(C)=O
Temperature: -65 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 0.995 g (2.6 mmol) of 1-(acetoxy)-3,5-bis(acetyl)-2-deoxy-2,2-difluororibose in tetrahydrofuran (10ml) at -65° C. were added 5.1 ml of a 1M solution of potassium t-butoxide in tetrahydrofuran (5.1 mmol) dropwise over 10 minutes. The reaction mixture was stirred 3 hours at -65° C. and then 0.58 ml of glacial acetic acid (10.2 mmol) were added to quench the reaction. The reaction mixture was then allowed to warm to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. Organics were dried with sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether (10 ml) and the resulting solid was dried under reduced pressure at 40° C. to give 0.63 g of 1-(acetoxy)-5-(acetyl)-2-deoxy-2,2-difluororibose.
Reaction SMILES: C1COCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][C:62]([F:65])([F:64])[F:63])=[CH:57][CH:56]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1>O>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH2:14][CH:41]1[CH2:42][CH2:43][CH:44]([CH:47]2[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([O:61][C:62]([F:63])([F:64])[F:65])=[CH:59][CH:60]=3)[CH2:51][CH2:52]2)[CH2:45][CH2:46]1
Reactant: c1ccc([PH](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)Oc1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
THF (100 ml) was added to 1,3-dioxan-2-ylethyltriphenylphosphinebromide (10.0 g, 21.9 mmol), followed by adding thereto potassium-t-butoxide (2.46 g, 21.9 mmol), stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 20 ml THF solution of the above 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (5.7 g, 15.6 mmol), stirring the mixture at the same temperature for one hour, stirring for 3 hours at room temperature, adding water (100 ml) to the reaction solution, extracting the product with ethyl acetate, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting residue according to column chromatography treatment using heptane/ethyl acetate (3/1) as a developing solvent, on silica gel, distilling off the solvent, hydrogenating the residue (5.1 g) in the presence of a catalyst of 5% Pd/C (0.30 g) in an ethanol solution, filtering off the catalyst, distilling off the solvent under reduced pressure, and recrystallizing the residue from heptane/ethanol (5/1), to obtain 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (3.25 g, 6.94 mmol). The yield of this product from 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane was 44.5%.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 28 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [CH:1]([OH:6])=[CH:2][C:3](=[CH2:5])[CH3:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CS(O)(=O)=O>[CH3:5][C:3](=[CH2:4])[CH2:2][CH2:1][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C=C(C)C=CO
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CCOC1CCCCO1
Yield: 100.5 %

Procedure:
To isoprenyl alcohol (80.0 g, 929 mmol) in CH2Cl2 (500 ml) at 0° C. was added one drop of methanesulfonic acid. To this solution was added 2,3-dihydropyran (100 ml, 1.10 mol) dropwise over 3 h. After the addition was complete triethylamine (5 ml) was added and the resulting mixture was filtered through a thin pad of SiO2 and concentrated to afford 159 g (100%) of 2-(3-methyl-3-butenyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:25]2[CH2:26][NH:27][CH2:28][CH2:29][N:24]2[CH2:23][CH2:22][OH:21])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Yield: 43.7 %

Procedure:
To a solution of 5-Bromo-5-decylbarbituric Acid (0.619 g) in 1.3 ml of dimethylsulfoxide, kept under stirring at 0° C., a solution of 0.93 g of N-(2-hydroxyethyl)piperazine in 0.7 ml of dimethylsulfoxide is added dropwise, then the reaction is stirred at room temperature for 1 hour. The mixture is then cooled to 0° C. and added with 30 ml of water. A white solid separates, which is kept under stirring for 1 hour, then is filtered and dried under vacuum at 50° C. 0.309 g of the product are obtained, m.p. 181-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[C:13]1([N:23]=[C:24]=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([NH:23][C:24]([NH:4][C:3]2[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:2]=2[OH:1])=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1cc(C(F)(F)F)ccc1O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-hydroxy-5-(trifluoromethyl)aniline (0.12 g, 0.7 mmol) in toluene (3 ml) was added to a solution of alpha-naphthyl isocyanate (0.11 g, 0.7 mmol) in toluene (3 ml). The reaction was stirred at RT overnight and the product filtered off. 0.17 g (72%) of the title compound was isolated. M.p. 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)c(Cl)c1Cl
Yield: 64.3 %

Procedure:
A solution of 2,3,4-trichlorobenzenesulfonyl chloride (15 mg, 0.055 mmol), 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) and dry pyridine (12 μL) in CH2Cl2 (200 μL) was stirred at room temperature over night. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 5 μm 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/CH3CN) to give 13 mg (65%) of the title compound. MS (ESI+) calcd for C13H8Cl3N5O2S 402.946428, found 402.946188.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[N:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:66]([F:69])([F:68])[F:67])=[C:56]([C:58]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:59])[CH:57]=1>CN(C=O)C.O>[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:66]([F:68])([F:67])[F:69])=[C:56]([CH:57]=1)[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:26](=[O:28])[CH2:25][NH:24][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:21][N:20]=2)=[O:23])[CH2:64][CH2:65]1)=[O:59]
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 38.9 %

Procedure:
DIPEA (151 mg, 0.2 mL, 1.17 mmol) was added to a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (100 mg, 0.39 mmol) in DMF (2 mL). HOBT (63 mg, 0.46 mmol) and EDCI (89 mg, 0.46 mmol) were then added at room temperature. After 2 minutes, (5-fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl-methanone hydrochloride salt (146 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 78 mg (39% yield) of 5-phenyl-pyridine-2-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.81%. 1H NMR (DMSO-d6): δ 9 (s, 1H), 8.8 (bt, 1H), 8.3 (d, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 5H), 4.4-4.2 (dd, 2H), 3.8-3.4 (m, 6H), 3.3-3.1 (m, 2H).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)=[CH:32][CH:31]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (80 mg, 0.41 mmol) and Et3N (58 μL, 0.41 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (70 mg, 0.29 mmol) and DMAP (5 mg, 0.04 mmol) and stir the resulting solution for 10 min. Add 4-Amino-benzoic acid methyl ester (77) (42 mg, 0.27 mmol) and stir the reaction solution 2d at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine, dry with Na2SO4 and filtrate it through a short pad of silica gel using EtOAc to obtain 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester (78) (91 mg, 88%) as a white solid. No further purification. 1H NMR (400 MHz, CDCl3): 2.60 (t, 2H, J=7.6 Hz); 2.91 (t, 2H, J=7.6 Hz); 3.70 (s, 6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.35 (s, 2H); 7.55 (d, 2H, J=8.3 Hz); 7.91 (d, 2H, J=8.6 Hz); 8.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[S:52]([C:55]1[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53]>C(Cl)Cl.CN(C=O)C>[CH:8]([OH:10])=[O:9].[CH3:45][C@@H:46]1[CH2:51][N:50]([C:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:10])[CH2:49][CH2:48][N:47]1[S:52]([C:55]1[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=1)(=[O:54])=[O:53]
Reactant: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@H](C)C2)cn1
Product: O=CO

Procedure:
To a solution of 6-methyl-3-pyridinecarboxylic acid (47.7 mg, 0.348 mmol) in DCM (2.00 ml) was added HATU (132 mg, 0.348 mmol) and DIPEA (0.152 ml, 0.870 mmol) and the mixture stirred for 15 min before addition of (2R)-2-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride (Description 6) (100 mg, 0.290 mmol) in DMF (2 ml). The resultant mixture was stirred for 16 h at room temperature then the reaction mixture was concentrated and the residue taken up in DMSO and purified by MDAP. The collected fractions were concentrated in vacuo and triturated with isohexane giving the title compound (77.7 mg) as a white solid.
Reaction SMILES: C(N(CC)C(C1CCCNC1)=O)C.C([O:16][C:17](=[O:55])[C:18]([NH:47]C(OC(C)(C)C)=O)([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40](=[O:46])[N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:35]1)[CH2:19][CH2:20][CH2:21][CH2:22][B:23]1[O:27]C(C)(C)C(C)(C)[O:24]1)C.[ClH:56]>O>[ClH:56].[ClH:56].[NH2:47][C:18]([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40](=[O:46])[N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:35]1)([CH2:19][CH2:20][CH2:21][CH2:22][B:23]([OH:24])[OH:27])[C:17]([OH:55])=[O:16]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCCC(C(=O)N(CC)CC)C1)NC(=O)OC(C)(C)C
Agent: CCN(CC)C(=O)C1CCCNC1
Agent: Cl
Solvent: O
Product: CCN(CC)C(=O)C1CCCN(CCC(N)(CCCCB(O)O)C(=O)O)C1
Temperature: 25 °C

Procedure:
2-Amino-6-borono-2-[2-(3-diethylcarbamoyl-piperidin-1-yl)-ethyl]-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except N,N-diethylpiperidine-3-carboxamide is used as the amine in step 6. The final step is as follows: a solution of (2R/S, 3″R/S)-2-tert-butoxycarbonylamino-2-[2-(3-diethylcarbamoyl-piperidin-1-yl)-ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (128 mg) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give a diastereomeric mixture of the title compounds as a colorless foam (54 mg); 1H NMR (D2O, 300 MHz) δ 3.46 (m, 2H), 3.26 (m, 4H), 3.10 (m, 2H), 2.94 (m, 4H), 2.20 (m, 2H), 1.62-1.92 (6H, m), 1.28 (m, 2H), 1.10 (t, J=7.0 Hz, 3H), 1.06 (m, 1H), 0.93 (t, J=7.0 Hz, 3H) and 0.64 (t, J=7.5 Hz, 2H); MS (+CI): m/z for C18H36BN3O5: expected 385.3. found 386.2 (M+H)+, 368.2 (M+H−H2O)+.
Reaction SMILES: [O:1]1[CH:12]([C:13]([O:15]C2CCCCC2)=[O:14])[CH:2]1[C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[OH-].[K+:23].C(OCC)C>C1(O)CCCCC1.CO>[O:1]1[CH:12]([C:13]([OH:15])=[O:14])[CH:2]1[C:3]([OH:5])=[O:4].[CH:6]1([K:23])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(OC1CCCCC1)C1OC1C(=O)OC1CCCCC1
Reactant: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OC1CCCCC1
Product: O=C(O)C1OC1C(=O)O
Product: [K]C1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of 2.5 g (0.0085 mole) of dicyclohexyl epoxysuccinate dissolved in 40 ml of cyclohexanol, a solution of 0.4 g of potassium hydroxide dissolved in 3 ml of methanol was added dropwise at room temperature. After the mixture had been stirred for 2 hours, to this, 300 ml of ethyl ether was added. Then, the mixture was allowed to stand overnight at about 5° C. The precipitate thus formed was filtered and recrystallized from ethanol-ether mixture to give cyclohexyl potassium epoxysuccinate (EP-2) as colorless needles. Yield 1.2 g (48%), m.p. 187°-189° C.
Reaction SMILES: C([Sn](=O)CCCC)CCC.C[Si]([N:15]=[N+:16]=[N-:17])(C)C.FC(F)(F)C(C1C=CC(C#N)=CC=1)=CC1C=CC2C(C)(C)CCC(C)(C)C=2C=1.[F:46][C:47]([F:74])([F:73])[C:48]([C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1)=[CH:49][C:50]1[C:59]([CH3:60])=[CH:58][C:57]2[C:56]([CH3:62])([CH3:61])[CH2:55][CH2:54][C:53]([CH3:64])([CH3:63])[C:52]=2[CH:51]=1>C1(C)C=CC=CC=1>[F:46][C:47]([F:73])([F:74])[C:48]([C:65]1[CH:66]=[CH:67][C:68]([C:69]2[NH:70][N:17]=[N:16][N:15]=2)=[CH:71][CH:72]=1)=[CH:49][CH:50]1[C:59]([CH3:60])=[CH:58][C:57]2[C:56]([CH3:62])([CH3:61])[CH2:55][CH2:54][C:53]([CH3:64])([CH3:63])[C:52]=2[CH2:51]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1cc2c(cc1C=C(c1ccc(C#N)cc1)C(F)(F)F)C(C)(C)CCC2(C)C
Agent: CC1(C)CCC(C)(C)c2cc(C=C(c3ccc(C#N)cc3)C(F)(F)F)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC1=CC2=C(CC1C=C(c1ccc(-c3nnn[nH]3)cc1)C(F)(F)F)C(C)(C)CCC2(C)C
Temperature: 110 °C
Yield: 49 %

Procedure:
Dibutyl tin oxide (15.1 mg, 10% mol) and trimethylsilyl azide (0.16 ml, 1.22 mmol), are added successively to a solution of the (E) compound 4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]benzonitrile (0.24 g, 0.60 mmol) in anhydrous toluene (1.25 ml). The reaction medium is heated for 16 hours at reflux (110° C.) under an atmosphere of argon and with magnetic stirring. The mixture is purified by flash chromatography on silica (eluent CH2Cl2 then MeOH:CH2Cl2=5:95) to obtain, after evaporation and washing with pentane and drying, 0.13 g of a white solid, compound (E) 5-[4-[1-trifluoromethyl-2-(5,6,1,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]phenyl]-1H-tetrazole (compound CB63237) (yield=49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:44]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[CH:49]=1)[CH2:45][CH2:46][NH2:47])[CH3:43]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:47][CH2:46][CH2:45][N:44]([CH2:42][CH3:43])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[CH:49]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (91 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (177 mg, yield 100%).