Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.ClCCl>C(#N)C>[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: O=C(Cc1coc(-c2ccc(OCCCCl)cc2)n1)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CC(=O)N3CCCC3)co2)cc1
Yield: 50 %

Procedure:
To a solution of 2-[4-(3-chloropropoxy)phenyl]-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole ax64 (0.51 g, 1.46 mmol, 1 eq) in acetonitrile (10 ml) is added sodium iodide (0.022 g, 0.15 mmol, 0.1 eq) and 2-methylpyrrolidine (0.25 ml, 2.92 mmol, 2 eq). The mixture is stirred at reflux overnight. The mixture is poured into dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified by chromatography over silica gel (eluent: dichloromethane/methanol/ammonia 95:4.5:0.5) to give 0.29 g of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole 52 as a yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH2:28][CH2:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][N:6]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH2:28][CH2:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.4 %

Procedure:
A solution of methanesulfonyl chloride (0.029 mL, 0.38 mmol) in DCM (0.5 mL) was is added dropwise to 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 5.1, preparation of starting materials) (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(4-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (92 mg, 52.7%) as a solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH3:11][C:12](C=C)=[O:13].[C:16]1(C)C=CC=C[CH:17]=1.CCCCCC>[Pd]>[CH2:1]([C:3](=[C:4]1[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]([C:12](=[O:13])[CH3:11])[CH2:7]2)[CH2:9][CH3:10])[CH3:2]
Reactant: CCC(CC)=C1C=CC=C1
Reactant: Cc1ccccc1
Reactant: C=CC(C)=O
Agent: [Pd]
Solvent: CCCCCC
Product: CCC(CC)=C1C2CCC1C(C(C)=O)C2
Temperature: 50 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 6,6-diethyl-fulvene (prepared as described in J. Org. Chem., 1990, 55, 3395; 86.0 g, 0.64 mol) and methyl-vinyl-ketone (44.9 g, 0.64 mol) was stirred for 5 h at 50° C. The mixture was cooled to room temperature and diluted with toluene/hexane (1/9, 600 ml). The solution was hydrogenated at normal pressure using palladium on charcoal (10%) as a catalyst. After 5 h the mixture was filtered, concentrated in vacuo and the residue was distilled (bp. 70° C./0.01 Torr) to yield the title compound (65.5 g, 50%) as a mixture of 2 isomers in a ratio of 3:1. Odor description: Woody, floral, Vertofix, Lilial, ambery.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:31]([O:33]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:37][NH2:38]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:31](=[O:33])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by flash chromatography to give the title compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.18 (d, 3H), 1.19 (d, 3H), 2.26 (s, 6H), 2.79-2.83 (m, 1H), 3.51 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 2H), 7.05-7.07 (m, 2H), 7.18-7.22 (m, 3H), 7.25-7.27 (m, 2H), 7.54-7.56 (m, 1H), 7.56-7.59 (m, 1H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:8])[CH:7]=1.[CH3:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C.C(OCC)(=O)C>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][O:31][CH:26]([CH3:25])[CH2:27]3)[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=1
Reactant: CC1CNCCO1
Reactant: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn2c(O)cc(N3CCOC(C)C3)nc2c1Cc1cccc(C(F)(F)F)c1C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 0.17 mmol), prepared as described in Example 1, step d, in ethanol (1.5 mL) was added 2-methylmorpholine (85 mg, 0.84 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 145° C. for one hour. The reaction mixture was diluted with ethyl acetate (15 mL), washed with 5% HCl solution (3 mL). Organic layer was dried, filtered, and concentrated to dryness. The crude was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 39%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, MeOD) δ ppm 1.17 (br. s., 2H) 1.19 (d, J=1.26 Hz, 1H) 2.13 (br. s., 3H) 2.47 (br. s., 3H) 2.66 (t, J=11.62 Hz, 1H) 2.68 (br. s., 1H) 2.94-3.06 (m, 1H) 3.63 (br. s., 3H) 4.01 (br. s., 2H) 7.11 (br. s., 1H) 7.23 (br. s., 1H) 7.51 (br. s., 1H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([N:5]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(=O)NNC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-t-butyl-2-valerylhydrazine (4 g, 0.023M) in toluene (40 ml) at 5° C. was added benzoyl chloride (3.4 g, 0.024 M) and 50% aq. sodium hydroxide (0.98 g, 0.024M). After addition, the mixture was warmed to room temperature and stirred 2.5 hr. The mixture was diluted with ethyl acetate (50 ml) and washed with water (2×25 ml) and brine (1×25 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford N'-t-butyl-N-valeryl-N'-benzoylhydrazine as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([OH:19])([CH2:16][O:17][CH3:18])[CH2:13][C@H:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30]>>[OH:19][C@@:14]1([CH2:16][O:17][CH3:18])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:20](=[O:22])[NH:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[CH2:13]1
Reactant: COC[C@@]1(O)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: NOC1CCCCO1
Product: COC[C@@]1(O)C[C@@H](C(=O)NOC2CCCCO2)N(C(=O)OCc2ccccc2)C1
Yield: 59 %

Procedure:
(2S,4R)-Benzyl 4-hydroxy-4-(methoxymethyl)-2-(tetrahydro-2H-pyran-2-yloxycarbamoyl)pyrrolidine-1-carboxylate is prepared from (2S,4R)-1-(benzyloxycarbonyl)-4-hydroxy-4-(methoxymethyl)pyrrolidine-2-carboxylic acid and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine following Method G (yield=59%). 1H NMR (300 MHz, CHCl3) δ 7.57-7.18 (m, 5H), 5.33-5.07 (m, 2H), 4.64-4.45 (m, 1H), 4.09-3.21 (m, 7H), 2.44-1.98 (m, 3H); ESI(+) calcd. for C15H18NO6 (308.11). Found 308.0
Reaction SMILES: Br.[Br:2][CH:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[N:10][N:9]([CH3:12])[C:8]=2[CH:13]=1.[N:20]1[N:21]=[CH:22][N:23]([NH2:25])[CH:24]=1>C(#N)C>[Br-:2].[NH2:25][N:23]1[CH:24]=[N+:20]([CH:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=[CH:22]1
Reactant: Cn1nnc2ccc(C(Br)c3ccccc3)cc21
Reactant: Nn1cnnc1
Agent: Br
Solvent: CC#N
Product: Cn1nnc2ccc(C(c3ccccc3)[n+]3cn(N)cn3)cc21
Product: [Br-]
Reaction time: 2 h

Procedure:
A mixture of 8.2 parts of 6-(bromophenylmethyl)-1-methyl-1H-benzotriazole monohydrobromide, 3.45 parts of 4H-1,2,4-triazole-4-amine and 64 parts of acetonitrile was stirred first for 2 hours at reflux temperature and then overnight at room temperature. The precipitate was filtered off and the filtrate was concentrated, yielding 4-amino-1-[(1-methyl-1H-benzotriazol-6-yl)phenylmethyl]-4H-1,2,4-triazolium bromide. To a stirred solution of the latter, 7.3 parts of a phosphinic acid solution 50% and 7.3 parts of a hydrochloric acid solution 12N in 40 parts of methanol and 20 parts of water was added dropwise a solution of 3.45 parts of sodium nitrite in 20 parts of water. Upon complete addition, stirring was continued for 30 minutes at room temperature. The methanol layer was evaporated and the residue was treated with an ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 36 parts of tetrahydrofuran. The salt was filtered off and crystallized from 45 parts of ethyl acetate. The product was filtered off and dried, yielding 3.1 parts (40.7%) of 1-methyl-6-[phenyl-(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole ethanedioate(1:1); mp. 164.9° C. (compound 67).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](Cl)(=[O:18])[CH3:17].FC(F)(F)C(O)=O>O>[C:16]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: OC(c1ccccc1)c1cccnc1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(c1ccccc1)c1cccnc1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.39 g 2-chloro-α-phenyl-3-pyridinemetanol (see Ex. 20), 3.14 g acetyl chloride and 8 ml trifluoroacetic acid is stirred for 1 hr. at room temperature. The reaction liquid is added dropwise to water, and the solid formed is filtered, washed, dried and crystallised from cyclohexane. Yield: 4.46 g title product, m.p. 100°-2° C.; Cl 13.82 (13.55).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:15])([CH3:16])[C:12]([O:14][CH3:18])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2]
Reactant: CC(C)(Nc1ccc(C(N)=O)c(F)c1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Temperature: 57.5 °C

Procedure:
A solution of 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoic acid and K2CO3 (1.5 equivalents) in DMF (10 fold) was stirred at RT for 10 min. MeI (1.5 equivalents) was added and the reaction mixture was heated at 55-60° C. for 2 h. The solvent was removed under reduced pressure and the reaction mixture was poured in water, extracted with ethyl acetate (100 mL×2), dried over Na2SO4, concentrated and purified by column chromatography. 1H NMR (CDCl3, Freebase): δ (ppm) 7.9 (t, 1H), 6.5 (bs, 1H), 6.4 (d, 1H), 6.2 (d, 1H), 5.6 (bs, 1H), 4.6 (bs, 1H), 3.75 (s, 3H), 1.6 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].O>ClCCl>[CH3:31][O:30][C:28]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)=[O:29]
Reactant: COC(=O)Cl
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C1CCN(C(=O)OC)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (303 mg, 1.02 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.213 mL, 1.53 mmol) and methyl chloroformate (0.213 mL, 1.53 mmol) were added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3) to give 1-methoxycarbonyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (287 mg, yield: 79%).
Reaction SMILES: [CH3:1][C:2]1(C)NS(=O)(=O)[N:4]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:3]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=2)=[CH:33][CH:32]=1.[CH2:46]1[CH2:50]O[CH2:48][CH2:47]1>>[F:29][C:30]([F:44])([F:45])[C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH:46]3[CH2:50][CH:3]4[NH:4][CH:48]([CH2:1][CH2:2]4)[CH2:47]3)[CH:38]=2)=[CH:35][CH:36]=1
Reactant: CC1(C)CN([P+](c2ccccc2)(c2ccccc2)c2ccccc2)S(=O)(=O)N1
Reactant: Oc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cccc(OC3CC4CCC(C3)N4)c2)cc1
Temperature: 25 °C

Procedure:
(4,4-Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)triphenylphosphonium (172 mg, 0.420 mmol) was added to a solution of 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (95 mg, 0.42 mmol), and 4′-trifluoromethylbiphenyl-3-ol (50 mg, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred for 18 hat ambient temperature. Volatiles were removed under reduced pressure. The resultant material was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at ambient temperature for 4 h. Volatiles were removed under reduced pressure, the crude product dissolved in methanol (2 mL) and the solution loaded onto a SCX cartridge (5 g). The cartridge was eluted with methanol (3×10 mL) to remove triphenylphosphine oxide. Elution with ammonia in methanol (2M, 10 mL) followed by evaporation in vacuo afforded crude 3-(4′-trifluoromethylbiphenyl-3-yloxy)-8-azabicyclo[3.2.1]octane as an oil. The crude material was then purified by preparative LCMS to afford 3-exo-(4′-trifluoromethylbiphenyl-3-yloxy)-8-azabicyclo[3.2.1]octane as the trifluoroacetic acid salt (36.9 mg, 0.080 mmol, 38%) M.S. (ESI) (m/z): 348 [M+H]+.
Reaction SMILES: COC1C=[N:10][C:9]([C:12]#[N:13])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15].[CH2:19]([O:21][C:22]([CH3:24])=O)C.O>>[CH3:19][O:21][C:22]1[CH:24]=[N:10][C:9]([C:12]2[NH:13][C:14]([CH3:15])=[N:17][N:18]=2)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: CCOC(C)=O
Reactant: CC(=O)NN
Reactant: COc1cnc(C#N)c2[nH]ccc12
Solvent: O
Product: COc1cnc(-c2nnc(C)[nH]2)c2[nH]ccc12
Temperature: 150 °C
Yield: 26 %

Procedure:
A mixture of 4-methoxy-7-cyano-6-azaindole (0.131 g, 0.757 mmol) and acetic hydrazide (0.270 g, 3.645 mmol) was heated in a sealed tube at 150° C. for 48 h. The reaction mixture was cooled and the solid residue was diluted with EtOAc-H2O. The aqueous phase was separated and re-extracted twice with EtOAc. The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc), affording the title compound (0.0455 g, 26%) as a colorless solid:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24](OC(C)=O)=[O:25].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([O:13][C:24](=[O:25])[CH3:23])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a stirred solution of benzyl-2-(tert-butoxycarbonylamino)-3-hydroxybutanoate (2.8 g, 9.06 mmol) in THF (80 mL) was added Ac2O (1.1 g, 10.87 mmol), Et3N (1.51 mL, 10.87 mmol) and DMAP (280 mg) and stirred at RT for 15 min. The volatiles were removed under reduced pressure. The residue obtained was diluted with EtOAc (150 mL) and washed with cold 0.5N HCl solution (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3-acetoxy-2-(tert-butoxycarbonylamino)-butanoate 11 (2.8 g, 88%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([N:25]=C=O)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)=O>C(#N)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([S:22]([N:25]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COC(=O)c1cc(O)c2ccccc2n1
Agent: O=C=O
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
According to the procedure of Wright, Synthesis, 1984, 1058, methyl 4-hydroxy-2-quinolinecarboxylate (2.03 g, 0.01 m) and p-toluenesulfonyl isocyanate (1.97 g, 0.01 m) were mixed in reagent grade acetonitrile at RT. The heterogeneous mixture was heated at reflux until the evolution of CO2 had ceased (ca 2-3 hours). During this time a yellow solid formed. After cooling to RT, the yellow solid was collected by filtration, washed with acetonitrile, and dried to give methyl 4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (2.93 g, 82%), melting point of 264°-265° C. (dec.), as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl.C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
53 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.8 ml of methanol/water (10/1), and 0.387 ml of a solution of 1N potassium hydroxide in methanol/water (10/1) was added thereto. The mixture was stirred at room temperature for 50 minutes. The mixture was neutralized with 1N hydrochloric acid under cooling with ice, and 20 ml of ethyl acetate was added thereto. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol/acetic acid=15/1/0.15). The fractions containing the desired product were collected, and the organic layer was washed with a 4% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 49 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11]/[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C(/CCc1ccc(Cl)cc1)c1ccccc1
Yield: 73.5 %

Procedure:
A solution of (Z)-ethyl 5-(4-chlorophenyl)-3-phenylpent-2-enoate (139 mg) and 4M NaOH (1.1 ml) in EtOH (10 ml) was stirred at rt for 4 h. The mixture was poured into water (30 ml), acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated to afford a crude, which was purified by crystallisation from hexane/ethylacetate to afford (Z)-5-(4-chlorophenyl)-3-phenylpent-2-enoic acid (93 mg) as colourless solid.