Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]2[CH:39]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]4[CH:39]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: CCOc1cccc2nc(CCl)cn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-5-ethoxyimidazo[1,2-a]pyridine (316 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (442 mg, yield: 60%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][N:9]=1.[Br:20]C1C=CC=CC=1C(C1C=CC=CC=1[N+]([O-])=O)=O.NC1C=CC=CC=1C(C1C=CC=CC=1Br)=O>>[Br:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][N:9]=1
Reactant: O=C(c1ccccc1Br)c1ccccc1[N+](=O)[O-]
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Agent: Nc1ccccc1C(=O)c1ccccc1Br
Product: O=C1CN=C(c2ccccc2Br)c2ccccc2N1

Procedure:
To make the 6-(o-bromophenyl) product one can follow the procedure shown by Sternbach et al., J. Med. Chem. 6, 263 (1963), for the preparation of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepin-2-one using the Sandmeyer reaction followed by catalytic hydrogenation of the resulting 2-bromo-2'-nitrobenzophenone. This product, 2-amino-2'-bromobenzophenone, can be substituted in the process described by Sternbach et al. to produce 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cu][C:43]#[N:44].N#N>CN(C)C=O>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:43]#[N:44])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: N#C[Cu]
Agent: N#N
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C#N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added copper(I) cyanide (17 mg, 0.19 mmol). The resulting reaction mixture was N2 purged and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 150° C. for 30 min. LC-MS indicated only the starting bromide was present. Added tetrakis(triphenylphosphine)palladium(0) (10 mg, 6 mol %) into the reaction mixture. Repeated microwave irradiation at 150° C. for 30 min. An aliquot indicated the desired product was formed and all starting bromide was consumed. Reaction crude was partitioned between water and hexanes. The aqueous phase was back extracted with diethyl ether. The combined extracts were dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates developed respectively by 20% EtOAc in hexanes and 4% EtOAc in dichloromethane. LC-MS: 595.03 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.86 (s, 1H), 7.61 (S, 0.5H), 7.67-7.71 (m, 2.5H), 7.64-7.68 (m, 1H), 7.32-7.36 (m, 1H), 6.98 (d, J=8.5 Hz, 0.5H), 6.95 (d, J=8.5 Hz, 0.5H), 6.68 (d, J=12 Hz, 1H), 5.62 (d, J=8.0 Hz, 0.5H), 5.46 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.80 (d, J=16.0 Hz, 0.5H), 4.06 (d, J=16 Hz, 0.5H), 3.79-3.86 (m, 1H), 3.70-3.78 (m, 3.5H), 3.16-3.24 (m, 1H), 3.75 (s, 1.5H), 3.16-3.25 (m, 1H), 3.14 (s, 1.5H), 3.13 (s, 1.5H), 1.15-1.27 (m, 6H), 0.54 (d, J=7.0 Hz, 1.5H), 0.37 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][CH:35]([CH2:34][CH2:33][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:40][CH2:39][O:38]1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-{[(1R)-1-Methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (100 mg, 0.274 mmol) was heated with potassium carbonate (37.8 mg, 0.274 mmol) in dry DMF (2 ml) at 60° C. under nitrogen for 1 hour and then cooled to room temperature. 4-(2-Bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (72.6 mg, 0.328 mmol) was added and the reaction mixture heated at 50° C., for 16 hours. LCMS indicated the reaction to be incomplete and more 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (35 mg) was added, and the reaction stirred at 50° C. for a further 5 hours and then partitioned between water (2 ml) and DCM (5 ml). The aqueous layer was further extracted with DCM (2×5 ml). The combined organic layers were combined and dried by passing through a hydrophobic frit and then evaporated to dryness using a nitrogen blowdown unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed autopreparation. Evaporation of the product containing fractions under a stream of nitrogen in a blowdown apparatus gave the title compound as a white solid (92 mg).
Reaction SMILES: [N:1]1([CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>CC(C)=O>[CH3:23][C@:20]12[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:25])([CH3:26])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:38][CH:39]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:41]([C:44]([CH3:46])=[CH2:45])[CH2:42][CH2:43][C@:5]1([CH2:4][NH:1][CH2:2][CH2:3][N:54]1[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]1)[CH2:22][CH2:21]2
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol) and 1-(methylsulfonyl)piperazine (78.7 mg, 0.48 mmol) in acetone (5 mL) was heated at reflux in a sealed tube for 18 h. The desired compound was detected by LCMS (M+1=790.7, 2.96 min, method 9).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH3:10])=[O:8])[CH:2]=1.[Br:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>>[Br-:11].[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH3:10])[CH:2]=1
Reactant: CC(C)CCBr
Reactant: CCC(=O)c1cccnc1
Product: CCC(=O)c1ccc[n+](CCC(C)C)c1
Product: [Br-]

Procedure:
Ethyl 3-pyridyl ketone was reacted with 1-bromo-3-methylbutane according to the procedure of Parb a) of Example 6 to give 1-(3-methylbutyl)-3-propionyl pyridinium bromide as a pale brown crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH2:5].C(O[C:10](=O)[C:11]([F:14])([F:13])[F:12])C>C1(C)C(C)=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:10]1[NH:1][CH2:2][CH:3]([OH:6])[CH2:4][N:5]=1
Reactant: NCC(O)CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: OC1CN=C(C(F)(F)F)NC1
Yield: 112.5 %

Procedure:
1,3-Diamino-2-hydroxypropane (10 g, 111 mmol) and ethyltrifluoroacetate (13.5 ml, 114 mmol) were dissolved in xylene (85 ml) and refluxed overnight in a Dean-Stark apparatus. The solvents were evaporated in vacuo to give a dark viscous oil 21 g identified by 300 MHz nmr as product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])C.O.C(=O)(O)[O-].[Na+]>C(O)=O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:21]=[O:23])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc(N(C=O)Cc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 67 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (7.2 g; 0.025 mole) was dissolved in formic acid (80%; 70 ml) and the solution was heated to 55° C. with stirring. Acetic anhydride (25 ml) was added dropwise at this temperature, allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was added to iced water (100 ml) and the aqueous mixture was neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and evaporated. Pure N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-formamide (5.32 g; 67%) was obtained by chromatography on silica-gel in dichloromethane followed by crystallisation from ethanol. M.p. 72°-3° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=1.C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C.[CH3:36][CH:37]([CH3:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>CN(C)C=O>[CH3:14][C:10]([S:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:37]([CH3:36])[CH3:47])[N:5]=1)([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(Sc1nc(CCN)cs1)C(=O)O
Reactant: CC(C)CCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCCCCC(=O)NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (0.30 g) synthesized in Example 483-3 in dimethylformamide (4.0 mL) were added HOBT monohydrate (0.092 g), diisopropylcarbodiimide (0.10 mL) and 8-methylnonanoic acid (0.10 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed three times each with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried to give 2-methyl-2-[(4-{2-[(8-methylnonanoyl)amino]ethyl}-1,3-thiazol-2-yl)thio]propionic acid resin.
Reaction SMILES: [C:1](/[C:4](/[CH3:29])=[CH:5]/[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)([OH:3])=[O:2].[H][H]>[Pd].O1CCCC1>[C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cccc3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 10% (w/w) palladium on carbon (0.75 g) and methyl E-4-[7-(2-carboxyprop-1-enyl)naphth-1-ylmethyl]-3-methoxybenzoate (4.38 g), in tetrahydrofuran (100 ml) was hydrogenated under 3.7 bar of hydrogen for 2 h. To the reaction mixture was added a slurry of 10% (w/w) palladium on carbon (0.75 g) and tetrahydrofuran (20 ml). After hydrogenating for 2 h more, the reaction mixture was filtered through diatomaceous earth with tetrahydrofuran washes. The solvent was evaporated and the residue was dissolved in ether. Evaporation and vacuum drying overnight afforded methyl 4-[7-(2-carboxypropyl)naphth-1-ylmethyl]-3-methoxybenzoate (4.22 g, 96%) as a colorless glassy solid; mp 110.0°-129.0° C.; MS(CI), m/e=393(M+H).
Reaction SMILES: [CH3:1][S:2]([O:5]C)(=[O:4])=[O:3].[CH3:7][S:8]([CH3:10])=[O:9]>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:7][S+:8]([CH3:1])([CH3:10])=[O:9]
Reactant: CS(C)=O
Reactant: COS(C)(=O)=O
Product: CS(=O)(=O)[O-]
Product: C[S+](C)(C)=O
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A 50 g amount of dimethylsulfoxide and 10 g of methyl methanesulfonate were heated and stirred under reflux conditions at 100°C for 20 hours. The mixture was allowed to stand at room temperature and crystals of a product were collected by filtration. The crystals were then washed with acetone yielding 5.97 g of a white, crystalline product. When this product was recrystallized from alcohol, S,S,S-trimethylsulfoxonium methanesulfonate having a melting point of 222.0° to 222.5°C. (decomposition) was obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:33]1([C@H:39]([NH2:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([C@H:39]([NH:46][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:14]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=4)=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH:27]=3)=[O:29])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N[C@@H](c1ccccc1)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccccc1)c1ccccn1)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
7-{[2-(4-Trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (30 mg, 0.069 mmol), [S]-C-phenyl-C-pyridin-2-yl-methylamine (15 mg, 0.082 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.082 mmol), 1-hydroxybenzotriazole (10 mg, 0.075 mmol), and triethylamine (0.038 ml, 0.27 mmol) were combined in 1 ml of dichloromethane. After stirring overnight at room temperature, the mixture was diluted with 30 ml of dichloromethane and washed with 2×20 ml of water, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum to provide 39 mg of a yellow solid. Purification by preparative thin-layer-chromatography on silica gel eluting with 4% methanol in dichloromethane. The product-containing band was collected and eluted with 5% methanol in ethyl acetate to afford 22 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])O.[Na+].[Na+].[NH3:12].C(O)(=O)C(CC(O)=O)O>>[NH2:12][C@H:2]([C:1]([OH:9])=[O:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C([O-])CC(O)C(=O)[O-]
Reactant: N
Agent: O=C(O)CC(O)C(=O)O
Agent: [Na+]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0 h

Procedure:
The concentrations of the substrates prior to entering the reactor were 0.168 M for sodium malate and 1.797 M for aqueous ammonia. The reaction time was 0.181 second, and the aqueous solution obtained after the reaction was examined with a high performance liquid chromatography/mass spectroscopy apparatus, which confirmed that an amino group had been introduced into the malic acid, and that aspartic acid had been produced. The aspartic acid concentration was 4.2 mM, and the reaction yield thereof was 2.5%.
Reaction SMILES: N1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[N+:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C([OH:27])C>>[N+:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[O:27])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Reactant: C1=C(N2CCCC2)CCCC1
Product: O=C(CC1CCCCC1=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(0.35 mole) of 1-pyrrolidino-1-cyclohexene and 85.0 g. (0.35 mole) of p-nitrophenacyl bromide by the method described in Example 39a gave 81.3 g. (89%) of crystals, m.p. 61°-63° (from ethanol).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2ccccc2o1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 45.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chlorobenzoxazole (71 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 65 mg (45%) of the title compound as an amorphous foam. FDMS: m/e=378.
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]1[N:24]([CH3:25])[C:23]([C:26]([CH3:38])([O:28][C:29]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:30]=2[F:37])[CH3:27])=[N:22][N:21]=1)[CH:15]=[O:16].[Cl-:39].[NH4+].Cl.O1CCOCC1.Cl>C1COCC1.C(OCC)(=O)C>[ClH:39].[F:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH3:4])[CH:17]=[CH:18][C:19]=1[C:20]1[N:24]([CH3:25])[C:23]([C:26]([CH3:38])([O:28][C:29]2[C:30]([F:37])=[CH:31][C:32]([F:36])=[CH:33][C:34]=2[F:35])[CH3:27])=[N:22][N:21]=1
Reactant: Cn1c(-c2ccc(C=O)cc2F)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: Cc1ccccc1
Reactant: [Cl-]
Agent: C[Mg]Br
Agent: Cl
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)c(F)c1
Reaction time: 1 h

Procedure:
A 1.4M methylmagnesium bromide/toluene solution (0.5 ml) was added to a solution of 3-fluoro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzaldehyde (90 mg) in THF (1 ml) under ice cooling, followed by stirring for one hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) to obtain 87 mg of a light yellow amorphous. The resulting amorphous was dissolved in ethyl acetate, a 4M hydrogen chloride/1,4-dioxane solution (0.2 ml) was added thereto so as to be hydrochloride. Ethyl acetate was added to the solid obtained by concentration and drying, followed by collecting by filtration, washing with ethyl acetate and drying under reduced pressure to obtain 1-(3-fluoro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenyl)ethanol monohydrochloride (83 mg) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:24]([CH3:28])([CH3:27])[CH3:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Iodo-phenyl)-carbamic acid tert-butyl ester (37a, 1.0 g, 3.13 g) was dissolved in THF (30 mL) and treated with Et3N (2.2 mL, 15.7 mmol), 3,3-dimethyl- 1-butyne (0.58 mL, 4.70 mmol), bis(triphenylphosphine) palladium (II) chloride (0.218 g, 0.31 mmol), and copper (I) iodide (0.03 g, 0.16 mmol). The reaction was stirred overnight at room temperature, then filtered and concentrated. The residue was chromatographed on silica gel eluting with 8:1 hexanes/EtOAc to give 0.7 g (82%) of the mostly clean desired product which was carried on without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:37])[NH:14][CH2:15][C:16]([N:18]2[CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[CH2:28][CH2:27][CH:19]2C(OC(C)(C)C)=O)=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-:38].[K+].[CH3:40][OH:41]>O>[C:6]([O:38][CH:19]1[C:27](=[C:40]=[O:41])[CH2:28][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:37])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:3])=[O:5])([CH3:7])([CH3:11])[CH3:4]
Reactant: CO
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC1C(=C=O)CC(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1

Procedure:
The operation is carried out in a fashion similar to that described in Example 9, but starting from 1.1 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-prolinate in solution in 30 cm3 of methanol and 0.12 g of potassium hydroxide dissolved in 15 cm3 of water. After treatment and recrystallization in diisopropyl ether, 0.4 g of (2RS,5SR)-3-{3-{2-[2-tert-butoxy-carbonyl-5-(2-fluorophenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at 180° C., is obtained.