Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.C(O[C:23]([N:25]1[CH2:30][CH2:29][O:28][C@@H:27]([C:31]([OH:33])=O)[CH2:26]1)=O)(C)(C)C.O.ON1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(N(CC)CC)C>[CH2:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([C:31]([N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:7]3[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:33])[CH2:26]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: CC(C)CNCc1ccc2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)CCO1
Reaction time: 8 h

Procedure:
A mixture of 5.6 g of N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine, 5.0 g of (−)-(2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid, 0.8 g of 1-hydroxybenzotriazole hydrate and 5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3 mL of triethylamine in 100 mL in dichloromethane was stirred overnight. The mixture was concentrated under reduced pressure and partitioned between 100 mL of ethyl acetate and 100 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography (20%-50% ethyl acetate/hexanes gradient elution) gave the product as a resin: MS (m+1)=449.3; H NMR (400 MHz, CDCl3) 7.3-6.7 (complex m, 5H), 4.6 (br d, 1H), 6.8-6.7 (m, 2H), 4.4 (d, 1H), 4.2 (m, 4H), 4.15 (q, 1H), 4.08 (br d, 1H), 3.95 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.0 (dd, 1H), 2.2 (m, 1H), 2.0 (m, 1H) 1.45 (2×s, 9H), 0.9 (dd, 6H).
Reaction SMILES: [NH2:1][C:2]([CH:20]([F:22])[F:21])([CH2:6][CH2:7][CH2:8][NH:9]C(OCC1C=CC=CC=1)=O)[C:3]([OH:5])=[O:4].C([O:27]C(N=[N+]=[N-])=O)(C)(C)C.C(OC(NN)=O)(C)(C)C.C(Br)C1C=CC=CC=1.[CH:50]1([NH:56]C2CCCCC2)[CH2:55]CCC[CH2:51]1>[Na].CN(C)C=O>[NH2:9][CH2:8][CH2:7][CH2:6][C:2]([NH:1][C:51](=[O:27])[CH:50]([NH2:56])[CH3:55])([CH:20]([F:21])[F:22])[C:3]([OH:5])=[O:4]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NC(CCCNC(=O)OCc1ccccc1)(C(=O)O)C(F)F
Agent: BrCc1ccccc1
Agent: CC(C)(C)OC(=O)NN
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(N)C(=O)NC(CCCN)(C(=O)O)C(F)F
Reaction time: 8 h

Procedure:
To a solution of 3.2 g of 2-amino-5-benzyloxycarbonylamino-2-difluoromethylpentanoic acid in 10 ml of 1 M aqueous sodium hdyroxide is added at 0° C. simultaneously a solution of tert-butoxycarbonylazide, prepared from 3 g of tert-butoxycarbonylhydrazine, and a solution of 5.5 ml of 2 M aqueous sodium hdyroxide. The reaction mixture is stirred overnight then extracted twice with 50 ml of ether. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. Usual work-up gives a solid residue which is dissolved in 15 ml of dry dimethylformamide and treated at room temperature with 1.6 g of benzylbromide in the presence of 2 ml of dicyclohexylamine. The reaction mixture is stirred for 14 hours and then the precipitate is filtered off. The filtrate is evaporated under reduced pressure. The resulting residue is partitioned between 100 ml of ethylacetate and water. The organic phase is washed successively with 20 ml of 1 normal aqueous hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate, 20 ml of water and 50 ml of brine then dried over magnesium sulfate. The solvent is evaporated and the residue taken up in 10 ml of trifluoroacetic acid. After 1 hour at room temperature the excess trifluoroacetic acid is stripped off under reduced pressure and the residue is taken up in a saturated solution of sodium bicarbonate and extraccted with 50 ml of ether. The ether phase is dried over magnesium sulfate and then added at 0° C. to a solution of N-benzyloxycarbonyl-O-ethoxycarbonylalanine (2 g) in 20 ml of ether. Stirring is continued overnight at room temperature. The solvent is evaporated and the resulting syrupy residue is taken up in glacial acetic acid (20 ml) and hydrogenated over Pd/C 10% (200 mg). After completion of the hydrogen uptake the catalyst is filtered off. The filtrate is concentrated under reduced pressure with toluene and the residue purified by ion exchange chromatography on an acidic resin to give 5-amino-2-(2-aminopropionylamino)-2-difluoromethylpentanoic acid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[Na].C(O)(=O)C.O>C(O)C>[C:12]1([C:9]2[N:10]=[CH:11][C:6]3[C:4](=[O:5])[NH:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:7]=3[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Nc1ccccc1N
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Nc2nc(-c3ccccc3)ncc21

Procedure:
78 g of 5-ethoxycarbonyl-4-(2-aminoanilino)-2-phenylpyrimidine are added to a freshly prepared boiling solution of 8 g (350 mmol) of sodium in 250 ml of absolute ethanol, while stirring. The suspension which has been formed thereby is heated under reflux for about 45 minutes until complete solution is effected. After cooling, the mixture is neutralized with 20 ml (350 mmol) of glacial acetic acid. 200 ml of ethanol and 200 ml of water are added, the precipitate is filtered off, washed with water and dried in vacuo; yield: 66 g (97%), with m.p. 260° to 261° C. (from dimethyl formamide/water).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:9]=1)=[O:7].Cl.O>CO>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22]([O:2][CH3:1])=[CH:23][CH:24]=2)[N:9]=1)=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1
Reaction time: 19 h

Procedure:
Sodium methoxide (1.530 g) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester (2.981 g) in methanol (190 mL) at room temperature, followed by stirring for 19 hours. Aqueous 1N hydrochloric acid (19 mL) was added to the reaction mixture. Water was added to the residue obtained by evaporation of methanol under reduced pressure. The insoluble product was recovered by filtration, and dried, to thereby give 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester as a solid (2.571 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:33])[C:21]([NH2:32])=[CH:22][C:23]=1[N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]1>CN(C=O)C>[F:17][C:18]1[C:23]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]2)=[CH:22][C:21]2[NH:32][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:33][C:20]=2[CH:19]=1
Reactant: CN1CCCN(c2cc(N)c(N)cc2F)CC1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
18 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde and 664 mg of ferric chloride are added to a solution of 19.1 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)benzene-1,2-diamine in 406 mL of DMF. The reaction medium is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified on a column 8 cm in diameter, with 3 kg of silica having a porosity of 0.063-0.2 mm. The elution is carried out with 2 L of pure dichloromethane and then 4 L of dichloromethane containing 10% of methanol, and then with dichloromethane containing 15% of methanol. 12 g of 5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole are isolated. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.41 to 2.31 (m, 8H); 2.91 (s, 3H); from 3.22 to 3.67 (m, 8H); 3.72 (m, 1H); 3.99 (m, 1H); 5.69 (dd, J=2.5 and 9.5 Hz, 1H); 7.32 (d, J=8.0 Hz, 1H); 7.75 (d, J=12.0 Hz, 1H); 9.40 (s, 1H). EI mass spectrum: m/z=443: M+. —m/z=373: (M−C4H8N)+—m/z=289: (m/z=373—C5H8O)+—m/z=84: C5H8O+. (base peak)—m/z=57: C3H7N+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=O)=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:26][CH:25]=1
Reactant: COc1ccc(CCC=O)cc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(CCC=C2SC(=O)N(CCCCSc3cccc4nccn34)C2=O)cc1

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(4-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.08 g (76.8%, yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14](OCC)=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:28]CC1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:28])[CH3:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1cn(Cc2ccccc2)cn1
Reaction time: 1 h

Procedure:
A solution of 25-2 (4.6 g, 18.8 mmol) in THF (50 mL) at ambient temperature was treated dropwise with LiAlH4 (9.4 mL, 9.4 mmol, 1M in THF). After stirring for 1 hour the reaction was quenched with a saturated sodium potassium tartrate solution. The mixture was then poured into EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated to yield 25-3 as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)[CH:27]=[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.15 g, 0.062 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.63 g, 0.282 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with 4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (2.0 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification using flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.40 g, 17%) as a yellow oil.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C[O-].[Na+]>CCOCC>[O:9]=[C:1]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:22])[F:21])=[CH:14][CH:15]=2)[N:20]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH2:2]1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with dimethyl but-2-ynedioate 70 (6.0 g, 42 mmol) and 50 mL of ether. To this solution was added a solution of 1-(4-(trifluoromethyl)phenyl)hydrazine 69 (7.6 g, 43 mmol) in 100 mL of ether over 30 min. After stirring at room temperature for 30 min, the reaction was concentrated and redissolved in MeOH (200 mL). The solution was added dropwise over 1 h to a NaOMe solution (made from sodium metal (3.9 g, 169 mmol) in 200 mL of MeOH). This mixture was stirred at room temperature for 1.5 h, the MeOH was removed, 100 mL of 5 N HCl was added, and the precipitate was collected by filtration. The solid was triturated with CH2Cl2 to give methyl 5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate 71.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc([N+](=O)[O-])cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, yellow solid (69 mg, 80%), MS (ISP) m/z=347.5 [(M+H)+], mp 193.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:18](=[O:19])[N:17]([CH2:21][CH3:22])[CH2:15][CH3:16])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(N2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N1CCN(c2ccc(OC)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
In 75 ml of chloroform was dissolved 10.4 g (0.054 mole) of 1-(4-methoxyphenyl)piperazine at room temperature, and a solution of 7.4 g (0.054 mole) of diethylcarbamoyl chloride in 50 ml of chloroform was dropped to the above solution over a period of 30 minutes. The mixture was stirred at 50° C. for 2 hours, and the insoluble substance was removed, and the filtrate was concentrated under reduced pressure and 100 ml of a 35% aqueous solution of sodium hydroxide and 300 ml of ether were added to the concentrate. The mixture was stirred for a certain time, and the ether layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography and distillation under reduced pressure to obtain 7.4 of purified 1-(4-methoxyphenyl)-4-diethylcarbamoylpiperazine having a boiling point 195° C. at 0.5 mm Hg. The yield was 47.0%. Elementary analysis values are as follows.
Reaction SMILES: CC([O:4]C(/N=N/C(OC(C)C)=O)=O)C.CC1N=CSC=1CCO.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:37]1([P:30](=[O:4])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cc1ncsc1CCO
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
DIAD (3.16 ml, 16.1 mM) was added to a stirred solution of methyl 3-nitro-5-hydroxy benzoate (2.11 g, 10.7 mM), 2-(4-methylthiazol-5-yl) ethanol (1.55 ml, 12.8 mM) and triphenylphosphine (4.21 g, 16.1 mM) in THF (50 ml) under an argon atmosphere at room temperature. After 1 hr reaction mixture concentrated in vacuo, and the residue triturated with diethyl ether to give a colourless solid (triphenylphosphine oxide). Diethyl ether conc. to give a dark brown gum, purification on silica gel (50% to 75% EtOAc/iso-hexane) gave the product contaminated with reduced DIAD and triphenylphosphine oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 ml), 2M NaOH (20 ml, 40 mM) added, heated at 65° C. for 4 hrs then cooled and concentrated. The residue was diluted with water (140 ml)/2M NaOH (40 ml), the precipitated triphenylphosphine oxide filtered, then acidified with c. HCl to pH=1–2. The precipitate was filtered, washed with water, dried under high-vacuum to give 3-nitro-5-(4-methyl-thiazol-5-yl) ethoxy] benzoic acid as a colourless solid (3.12 g, 79% over 2 steps); 1H NMR δ (d6-DMSO): 2.39 (s, 3H), 3.23 (t, 2H), 4.35 (t, 2H), 7.78 (s. 1H), 7.90 (m, 1H), 8.22 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4].O1CCC[CH2:17]1>>[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)Cc1cccc(C#N)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To the cooled solution of sodium hydride (91 mg, 2.285 mmol, 60% suspension in oil) in anhydrous tetrahydrofuran was added a solution of methyl 2-(3-cyanophenyl)acetate (400 mg, 2.285 mmol) dropwise at 0° C. Reaction mixture was stirred at room temperature for 1 h. TLC showed complete consumption of starting material. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic part was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography to afford methyl 2-(3-cyanophenyl)propanoate (180 mg, 48%).
Reaction SMILES: [C:1]([C:3]1([OH:18])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:20][CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:18][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH:6]([CH:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]3)[CH2:5][CH2:4]2)=[O:29])[CH2:24][CH2:23]1)[CH2:20][CH3:21]
Reactant: C#CC1(O)CCC(C2CCC(CCC)CC2)CC1
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC1(OC(=O)C2CCC(CCC)CC2)CCC(C2CCC(CCC)CC2)CC1
Reaction time: 8 h

Procedure:
4.00 g of 4-(dimethylamino)pyridine are added to a solution of 16.00 g of 4-ethynyl-4′-propylbicyclohexyl-4-ol and 11.51 g of 4-propylcyclohexanecarboxylic acid in 120 ml of dichloromethane. 9.66 g of N,N-dicyclohexylcarbodiimide in 30 ml of methylene chloride are subsequently added dropwise at RT, and the mixture is stirred overnight. Conventional work-up gives 4-ethynyl-4′-propylbicyclohexyl-4-yl 4-propylcyclohexane-carboxylate (C 59 N 120 I, Δε−1.57, Δn 0.04).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 45 °C

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.70 g), 10% palladium on carbon (200 mg), ethanol (100 mL), and ethyl acetate (50 mL) is shaken under hydrogen atmosphere (5 bar) at 45° C. until the starting material is completely consumed. The catalyst is filtered off, the filtrate is concentrated in vacuo, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 70:30:0→50:40:10) to give the title compound. LC (method 1): tR=1.75 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4C=CC=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.OC[C:31]1N=C[N:33](C)[N:32]=1>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[N:24]=[CH:25][N:32]([CH3:31])[N:33]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: Cn1cnc(CO)n1
Reactant: FCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Product: Cn1cnc(COc2nn3c(-c4cc(CF)on4)nnc3c3ccccc23)n1
Yield: 52 %

Procedure:
Prepared from the product of Example 66 part c (85 mg, 0.28 mmol) and 3-hydroxymethyl-1-methyl-1,2,4-triazole using the method of Example 1 to yield a pale yellow solid (56 mg, 52%), 1H NMR (360 MHz, CDCl3) 67 3.96 (3H, s), 5.58 (2H, d, J=44 Hz), 5.73 (2H, s), 7.51 (1H, s), 7.81 (1H, t, J=7 Hz), 7.96 (1H, t, J=7 Hz), 8.08 (1H, s), 8.30 (1H, d, J=7 Hz), 8.72 (1H, d, J=7 Hz); MS (ES30) m/e 381 [MH]+.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C@H:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[Br:31])[NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(Cl)=[O:44]>C(Cl)Cl>[Br:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:21]=1[C@H:17]1[N:16]2[C:43](=[O:44])[O:14][C@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([CH3:2])[CH:4]=3)[C@@H:15]2[CH2:20][CH2:19][CH2:18]1
Reactant: O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCC[C@@H](c2cc(C(F)(F)F)ccc2Br)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H]2OC(=O)N3[C@H](c4cc(C(F)(F)F)ccc4Br)CCC[C@@H]23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol) in DCM (5 mL) was added DIPEA (0.9 mL, 0.509 mmol) and phosgene (252 mg, 0.509 mmol). The reaction mixture was stirred at room temperature for 30 minutes before the solvent was removed and the reaction was diluted with ethyl acetate (15 mL) and aqueous KOH (15 mL). The organic was dried over sodium sulfate, filtered, and concentrated before purification by preparative TLC to yield (1R,5S,8aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (200 mg, 0.347 mmol). MS ESI calc'd. for C22H16BrF9NO2 [M+H]+ 576.0 and 578.0. found 576.1 and 578.1.