Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)=[C:4]([C:44]([F:47])([F:46])[F:45])[CH:3]=1.[CH:48](=O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.N1CCCCC1.C([BH3-])#N.[Na+].C1COCC1>O.C(O)(C)C>[CH2:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)=[C:4]([C:44]([F:46])([F:45])[F:47])[CH:3]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1nn(-c2ccc(N)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNCC1
Product: CCCCc1nn(-c2ccc(NCc3ccccc3)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of 70 mg (0.093 mmole) of 2-[4-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 56), 33 mg (0.31 mmole) of benzaldehyde, 2.1 mL of piperidine, and 2.5 mL of isopropanol was stirred at 95° C. overnight. The crude material obtained after cooling and evaporation of volatiles was dissolved in 2.2 mL MeOH, charged with 1.3 mL of a 1M solution of sodium cyanoborohydride in THF (1.3 mmole), and stirred at room temperature for 2 hours. Water (160 mL) was added at 0° C., and the resulting mixture stirred at 0° C. for 2 hours. After evaporation of volatiles, the crude product was flash chromatographed over silica gel (gradient elution with 0.5-5.0% MeOH/CH2Cl2) to afford 27 mg (38%) of the desired product as a cream-colored solid, mp >107° C. (gradual), homogeneous by TLC (9:1MeOH/CH2Cl2), mass spectrum (FAB) m/e 774 (M+1)+.
Reaction SMILES: C(C1C=CC=CN=1)=C.C(OC(=O)C)(=O)C.[C-]#N.[K+].C([O-])([O-])=O.[Na+].[Na+].[C:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[N:26]>O.CCO.[Ni]>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][CH2:25][NH2:26]
Reactant: N#CCCc1ccccn1
Agent: [Ni]
Agent: C=Cc1ccccn1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: NCCCc1ccccn1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-Vinyl pyridine (105 g) and acetic anhydride (204 g) were combined at room temperature, and a solution of KCN (130 g) in 250 ml of water was added dropwise to the stirring solution. The rate of addition was adjusted to maintain a gentle reflux. After the addition was complete, the mixture was refluxed for 22 h, and the pH of the solution then adjusted to 8 with aqueous Na2CO3 solution. The mixture was extracted with DCM (600 ml), the extracts dried over MgSO4 and then evaporated to a brown oil. The oil was then vacuum distilled at approximately 0.6 mmHg pressure. The product distilled over as a clear oil at 100-107° C. in 56% yield. The oil of 2-(2-cyanoethyl)-pyridine (200 mg, 1.5 mmol) was taken up in 6 ml of EtOH and treated with 2 ml of 0.88NH3 solution and 50 mg of RaNi. The mixture was hydrogenated at 30 psi H2 pressure for 16 h, and was then filtered and evaporated to give the title product (ca. 200 mg) which was used with no further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22].O1CCOCC1>CO>[ClH:22].[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)[CH:16]=[CH:15][N:14]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1(c2ccnc(S(C)(=O)=O)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C2(N)CC2)ccn1
Reaction time: 8 h

Procedure:
To a solution of [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-carbamic acid tert-butyl ester (606 mg, 1.94 mmol) in methanol (10 mL) is added a solution of 4 N HCl in dioxane (2 mL, 8 mmol). The mixture stirred overnight and is then concentrated and the residue is triturated with ether-ethanol. The solid is collected by filtration to afford the title compound.
Reaction SMILES: C1C=C[C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2C=1.C([Li])CCC.CCCCCC.[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24]>>[O:25]1[C:26]2[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:5]=[CH:4][C:27]=2[CH2:24][CH2:23]1
Reactant: CCOCC
Reactant: O=C1CCc2ccccc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of dihydrocoumarin (0.338 mL, 3.00 mmol) in dry diethyl ether (10 mL) was cooled to -78° C. and a solution of n-butyllithium in hexane (2.38M, 1.30 mL, 3.00 mmol) was slowly added. The reaction was stirred at 20° C. overnight. The reaction was cooled to -78° C. and carbon dioxide was bubbled through for 10 min. The reaction was warmed to 20° C. and partitioned between water and ether. A solution of 10% aqueous HCl was added to the aqueous phase until the pH was less than 1. The aqueous phase was washed with ether, and the ether washed with saturated sodium chloride solution. The title compound was obtained as a white solid (0.175 g). NMR (CDCl3, 300 MHz) δ 7.83 (1H, d, J=8 Hz), 7.42 (1H, d, J=8 Hz), 6.96 (1H, t, J=8 Hz), 4.80 (2H, t, J=8 Hz), 3.30 (2H, t, J=8 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][C:10](=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([N:19]2[C:10]([CH2:9][OH:8])=[N:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC(c2ccccc2)=N1
Reactant: NNc1ccccc1
Solvent: CCO
Product: OCc1nc(-c2ccccc2)nn1-c1ccccc1
Yield: 60.9 %

Procedure:
A mixture of 2-phenyloxazol-4(5H)-one (600 mg, 3.35 mmol) and phenylhydrazine (420 mg, 382 μL, 3.69 mmol) in ethanol (10 mL) was refluxed for 2 h. The reaction mixture was concentrated in vacuo. The obtained suspension was filtered, washed with EtOH and dried in vacuo to give 513 mg of a light yellow solid which proofed to be product. The filtrate was evaporated to give 430 mg of a yellow solid which also contained a considerable amount of product. Thus, the product was obtained after purification of the evaporated filtrate by flash chromatography (using silica gel and an ethyl acetate/dichloromethane gradient) and combination with the precipitated product as light yellow solid (711 mg, 2.83 mmol, 84.4%). MS: M=252.2 (M+H)+
Reaction SMILES: [O:1]=[C:2]([N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH2:6][C:5]1=[O:22].Br[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:22]=[C:5]1[N:4]([CH2:3][C:2](=[O:1])[N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH:6]1[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)N1CCCCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)N3CCCCc4ccccc43)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of 1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)ethyl]-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.0 g, 2.28 mM) in 15 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (0.78 g, 2.5 mM) in 3 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 1/1 providing 1.4 g of white solid.
Reaction SMILES: [Cl-].[CH3:2][NH3+:3].C[Al](C)C.CO[C:10](=[O:26])[CH:11]=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl>C1(C)C=CC=CC=1>[CH3:2][NH:3][C:10](=[O:26])/[CH:11]=[C:12](\[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)/[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)C=C(c1ccc(C#N)cc1)n1ccnc1
Reactant: C[NH3+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)/C=C(\c1ccc(C#N)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.35 g of methylammonium chloride in 10 ml of toluene is mixed under argon with 7.5 ml of trimethylaluminum in 10 ml of toluene by instillation and stirred for 2 hours at room temperature. 50 mg of the E-methyl ester of example 1 is mixed in 2 ml of toluene with 2 ml of the above-produced reagent. It is stirred for 6 hours at 80° C., then mixed at room temperature with 1M hydrochloric acid and extracted with ether. The acid phase is alkalized with potassium carbonate and extracted with ethyl acetate. After washing with water and drying, the ethyl acetate phase is concentrated by evaporation. 30 mg of the title compound (50%) remains; melting range: 172°-180° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Oc1ccccc1F
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccccc2F)cc1[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 48 h
Yield: 383.5 %

Procedure:
To 4-fluoro-2-nitrotoluene (25 g, 0.016 mol), 2-fluorophenol (15.8 mL, 0.017 mol) in NMP (350 mL) was added potassium carbonate (22.27 g, 0.016 mol) and the mixture was stirred at 160° C. for 48 h. After cooling at room temperature, water (350 mL) was added and the solution was extracted into ethyl acetate (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 95:5 to yield 15.17 g of 4-(2-fluoro-phenoxy)-2-nitrotoluene: MS: 248 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([N:16]2[CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)(O)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.O>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([N:16]2[CH2:17][CH:18]=[C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(O)(c3cccnc3)CC2)c1F
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC=C(c3cccnc3)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(pyridin-3-yl)piperidin-4-ol (908 mg) was mixed with dichloromethane (15 ml), and TEA (1.1 g), DMAP (799 mg), and MsCl (749 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. Water and EtAOc were added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium carbonate. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 1′-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (477 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[F:27])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14](OC)=[O:15])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:28])[O:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[C:13]([CH2:14][OH:15])[CH:12]=[N:11][C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])[CH2:3]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2COC(C)(C)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(CO)cc2OCC2COC(C)(C)C2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 107.8 %

Procedure:
A solution of methyl 5-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)nicotinate (700 mg) in methanol (10 mL) was cooled to 0° C., and sodium tetrahydroborate (342 mg) was slowly added by small portions. The reaction mixture was stirred at 60° C. for 4 hr. The solvent was evaporated under reduced pressure, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (700 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]([O:17][C:18](=[O:21])[C:19]#[CH:20])[CH3:16]>[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.C1COCC1>[CH2:15]([O:17][C:18](=[O:21])[C:19]#[C:20][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: Clc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a four neck flask was charged with 1-chloro-4-iodo-benzene (130.0 g, 0.55 mol), bis(triphenylphosphine) palladium(II) chloride (7.57 g, 10.8 mmol, 2 mol %), copper(I) iodide (4.19 g, 22.0 mmol, 4 mol %) and dry THF (1.4 l). At r.t., cesium carbonate (355.3 g, 1.09 mol, 2 eq.) was added over 5 min. Afterwards propynoic acid ethyl ester (111.3 ml, 1.09 mol, 2 eq.) was added, and the reaction mixture was stirred overnight at 35° C. An additional portion of propynoic acid ethyl ester (11.1 ml, 0.11 mol, 0.2 eq.) was added, and the reaction was stirred for another 3 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (0.5 l) and heptane (1 l). The resulting suspension was stirred at 40° C. for 1 h and filtered over celite. The filtrate was concentrated, and the product purified by silica gel filtration (toluene/heptane 1:2) to yield 72.6 g (61%) of Va as a light yellow solid.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3[O:14][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[O-]S([O-])(=O)=O.[Mg+2].[F:111][C:112]1[CH:117]=[CH:116][C:115]([C:118](=[O:136])[CH2:119][CH2:120][CH2:121][C:122]([N:124]2[C@@H:128]([C:129]3[CH:134]=[CH:133][CH:132]=[CH:131][CH:130]=3)[CH2:127][O:126][C:125]2=O)=[O:123])=[CH:114][CH:113]=1>CC(OC)(C)C.C(#N)C.C(O)(C)C>[O:14]=[C:130]1[CH:131]=[CH:132][CH:133]=[CH:134][CH:129]1[C@H:128]1[CH2:127][O:126][CH2:125][N:124]1[C:122](=[O:123])[CH2:121][CH2:120][CH2:119][C:118]([C:115]1[CH:116]=[CH:117][C:112]([F:111])=[CH:113][CH:114]=1)=[O:136]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C(CCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: *CC(*)C
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: COC(C)(C)C
Solvent: CC(C)O
Solvent: CC#N
Product: O=C(CCCC(=O)N1COC[C@@H]1C1C=CC=CC1=O)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
KREDs described in Table 5 of Example 1 are screened using NADH and NADPH as co-factors and glucose dehydrogenase/glucose or isopropylalcohol (“IPA”) as co-factor regeneration system. 100 μl of cell lysate was added to a deep well plate (Costar #3960) containing 25 μl 5 mg/ml Na-NADP (Oriental Yeast) and 2 mM MgSO4 in 100 mM triethanolamine(chloride) (pH7.0), and 125 μl isopropyl alcohol containing 2 g/L (S)-1-(4-Fluoro-phenyl)-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentane-1,5-dione. After sealing the plates with aluminum/polypropylene laminate heat seal tape (Velocity 11 (Menlo Park, Calif.), Cat#06643-001), reactions were run for at least 16 hrs at ambient temperature. At the end of the reaction 1 ml acetonitrile (for reversed phase HPLC) or MTBE (for normal phase HPLC) was added per well. Plates were resealed, shaken for 20 minutes, and centrifuged (4000 rpm, 10 min, 4° C.). 200 ul of the organic layer was transferred into a new shallow-well microtiter plate for analysis.
Reaction SMILES: [C:1]([C:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]([CH3:16])([CH3:15])[C:4]=1O)#[N:2].O.[NH2:19][NH2:20].CC(O)=O>C(O)C>[NH2:2][C:1]1[NH:20][N:19]=[C:4]2[C:5]([CH3:16])([CH3:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][C:3]=12
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(C#N)=C(O)C1(C)C
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
32 g of tert-Butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate (0.134 mol) were added to 430 ml of absolute ethanol. To this solution, 9 ml (0.18 mol) of hydrazine hydrate were added, followed by 12 ml of glacial AcOH (1.5 eq); The mixture was stirred at 60° C. for 48 hours, the ethanol was removed, the residue was taken up with 400 ml of sodium hydrogencarbonate solution, and extracted several times with ethyl acetate up to total extraction of the desired product. The organic phases were dried and evaporated. After purification by flash chromatography (eluent: CHCl3/EtOH 97/3) and trituration with a mixture of hexane/ethyl acetate 9/1, 25 g of title compound were obtained. Total yield 30.5 g (yield: 88%)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:6])[CH2:3][CH2:2]1>C(O)C.C(O)(=O)C.[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C=Cc2cccc(F)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2cccc(F)c2)cc1
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a mixed solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[2-(3-fluorophenyl)vinyl]-1H-1,2,3-triazole-4-carboxamide (140 mg) obtained in Example 419 in ethanol/acetic acid (1/3, 8 ml) was added Pd/C (80 mg), and the mixture was stirred under a hydrogen stream for 15 hr. The catalyst was removed by filtration through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (110 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH3:26]>>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(C(F)(F)F)N2

Procedure:
Prepared according to the coupling procedure for Example 13 from 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophene-carbonitrile. A yellowish solid: mp 97-98° C.; 1H-NMR (DMSO-d6) δ 7.82 (s, 1H), 7.26 (d, 1H, J=1.7 Hz), 7.21 (dd, 1H, J=8.1, 2.1 Hz), 7.16 (s, 1H), 6.88 (d, 1H, J=8.1 Hz), 5.40 (m, 1H), 2.27 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H); MS (ESI) m/z 351 [M−H]−.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C@H:5]([CH3:22])[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH:9]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:24].CCOCC>C(O)(=O)C>[BrH:24].[CH2:1]([NH:3][C:4](=[O:23])[C@H:5]([CH3:22])[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH2:9])[CH3:2]
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)N

Procedure:
7.5 g (0.023 mol) of N-benzyloxycarbonyl-L-alanyl-L-alanine ethylamide were stirred for 1 hour in 50 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 300 ml of dry ether and, after stirring for a few minutes, the oil was allowed to settle and the ether decanted from the oil and discarded. The oil was then dissolved in methanol, the desired L-alanyl-L-alanine ethylamide hydrobromide crystallising out on the addition of ethyl acetate. The yield was 6.0 g (83%) and the melting point was 229°-231° C.; [α]D20 =-28.0° (c=1% in water).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=O.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21]P(=O)(OCC)OCC)=[CH:19][CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([CH:21]=[CH:3][C:5]2[S:9][C:8]([C:10]3[S:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2ccc(C=O)s2)s1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C=Cc3ccc(Cl)cc3)s2)s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 0.12 gram (0.0050 mole) of sodium hydride was added to a stirred solution of 1.2 gram (0.0057 mole) of 5-formyl-5'-methyl[2,2'-bithienyl] and 1.7 gram (0.0064 mole) of diethyl 4-chlorobenzylposphonate in 20 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for about three huurs. Analysis of the reaction mixture by thin layer chromatography indicated starting materials remained. Additional sodium hydride was added, and the mixture was stirred at room temperature for several hours. The reaction mixture was quenched with an aqueous solution saturated with ammonium chloride. This mixture was extracted several times with diethyl ether. The extracts were combined and washed with an aqueous solution saturated with sodium chloride. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel to yield 2-(4-chlorophenyl)-1-(5'-methyl[2,2'-bithienyl]-5-yl)ethene as a solid, m.p. 157°-162° C.