Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:29])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].Cl>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([CH3:29])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH3:18])[CH2:7][O:6]1)=[O:4]
Reactant: COCOc1ccc(C(C)=NOCCCCC2COC(C)(C(=O)OC)OC2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(O)cc2)CO1
Temperature: 50 °C
Reaction time: 20 h
Yield: 14.9 %

Procedure:
To a solution of Methyl-5-{4-[1-(4-methoxymethoxy-phenyl)-ethylideneaminooxy]-butyl}-2-methyl-[1,3]dioxane-2-carboxylate (prepared as per example 39) (1.5 g) in isopropyl alcohol was added concentrated hydrochloric acid and the reaction mixture was stirred at 50° C. for about 20 hours. Reaction mixture was cooled to ambient temperature and solvent was evaporated under reduced pressure on a rotavapor. Water was added to the residue and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure on a rotavapor. Crude product was flash chromatographed over silica gel using 15% ethyl acetate in petroleum ether as eluent to obtain 200 mg of pure product.
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.C(O)C.Cl>O.[Fe].C(O)C.O>[Br:1][C:2]([F:16])([F:17])[C:3]([F:14])([F:15])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
The product of the previous reaction, 4-(2bromotetrafluoroethoxy)nitrobenzene (20.0 g, 0.069 mole), is added to a 50 percent by volume solution of ethyl alcohol in water (30.0 g) and powdered iron filings (11.0 g, 0.20 mole) in a 250 ml 3-necked round bottomed flask fitted with a nitrogen padded reflux condenser and a dropping addition funnel. The mixture is purged thoroughly with nitrogen, and brought to reflux. A solution of concentrated HCl (1.3 ml, 0.0156 mole) in 8 ml ethanol/water (1:1 by volume) is added slowly drop wise over 30 minutes. The resulting reaction mixture is refluxed for 3 hours, then cooled to room temperature. The mixture is filtered and the solids are washed twice with dilute KOH (10 ml each, 0.01M), just enough to make the flitrate up to pH 7. The solids are then washed with acetone (25 ml) and the acetone wash is added to the flitrate. The flitrate phase-separates, and the lower phase is removed and distilled on a rotary evaporator (2.0 mm Hg (2.66 kPa), 100° C.) to recover the pure product (7.47 g, 0.026 mole, 37 percent yield) as a water white oil in greater than 99 percent purity.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][CH:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: CC1NCCNC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (3 mL) was added triethylamine (0.318 mL, 2.285 mmol) and 3-methyl-2-piperazinone (87 mg, 0.762 mmol, Sigma-Aldrich). The reaction mixture was heated to 120° C. for 20 min in a microwave reactor. The reaction mixture was concentrated in vacuo. The crude product was purified by silica chromatography (Biotage SP4), eluting with an increasing gradient of (2N NH3 in MeOH) in DCM. The relevant fractions were combined and concentrate to give the title compound as white crystals (151 mg)
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ncc(-c2ccc(Cl)cc2)o1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A suspension of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole and 1.94 g of potassium phthalimide in 15 ml of dimethylformamide was stirred at room temperature for 1 hour. The reaction mixture was poured into 300 ml of water, and the resultant precipitate was filtered and recrystallized from ethanol to give 2.4 g (71 percent) of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[OH-].[NH4+:34]>C(O)C>[NH2:34][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: O=S(=O)(c1cnccc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccncc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
To a 2-mL microwave vial was added 2-(4-(4-((4-chloro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (90 mg, 0.18 mmol), ethanol (1.5 mL) and aqueous ammonium hydroxide (1.5 mL, 39 mmol). The solution was then heated in the microwave at 110° C. for 2 h and then concentrated. The residue was diluted with saturated aqueous NaHCO3 and DCM. The solution was stirred for 5 min and then transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 5.0% MeOH/DCM) afforded 2-(4-(4-((4-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (63 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)c1
Yield: 46.5 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 47%). MS (ISP) 409.2 [(M+H)+]; mp 241° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>CCO>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH2:5][CH2:4][NH:3]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1cccc(C2NCCc3nc[nH]c32)c1
Temperature: 77 °C

Procedure:
Histamine dihydrochloride (3.68 g, 0.02 mol), KOH (3.36 g, 0.06 mol), and 3-bromobenzaldehyde were dissolved in H2 0 (250 mL) and EtOH(100 mL). The reaction mixture was heated for 24 h at 77° C. open to the atmosphere. The resulting white precipitate was filtered and dried under vacuum at 40° C. to give the title compound.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:17]1[C:25]2[CH:24]=[CH:23][C:22]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[C:21]([OH:33])[C:20]=2[CH:19]=[N:18]1.O>CN(C)C=O>[CH2:1]([O:33][C:21]1[C:22]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[N:18][N:17]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: Oc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reaction time: 2 h
Yield: 107.5 %

Procedure:
Under a nitrogen atmosphere, n-propyl iodide (257 μl, 2.64 mmol) and cesium carbonate (860 mg, 2.64 mmol) were added to a solution of 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol (700 mg, 2.20 mmol) in N,N-dimethylformamide (7 ml) at room temperature. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (852.6 mg).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: C1=COCCC1
Reactant: O=C1CC[C@@H](CO)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC[C@@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.0 g, 8.6 mmol, Acros) in dichloromethane (10 mL) were added 3,4-dihydro-2H-pyran (0.94 mL, 10.3 mmol, Aldrich) and pyridinium p-toluenesulfonate (0.22 g, 0.86 mmol, Aldrich). After stirring at room temperature overnight, the reaction mixture was washed with water (5 mL) and brine (5 mL). The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to obtain 1.6 g (93%) of the title compound. MS (DCI/NH3) m/z 218 (M+NH4)+.
Reaction SMILES: [OH:1][CH:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.C[N+]1([O-])CCOCC1>C1COCC1.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g of tert-butyl 4-hydroxy-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate in 40 ml of THF-CH3CN (1:1) at r.t. were added 2.0 g of MS 4A, 435 mg of NMO, and 88 mg of TPAP, and the reaction mixture was stirred at r.t. overnight. The mixture was filtered through a Celite pad, washed with CHCl3 and CHCl3-MeOH (9:1), and the filtrate was concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane-AcOEt (100/0-0/100) as eluent to give the intended compound as a colorless solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:29][CH:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH:30]([S:32]([NH:35][C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])=[CH:28][CH:27]=1)=[O:26])(=[O:34])=[O:33])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg) was added to a stirred mixture of 4-(t-butoxycarbonyl)benzoic acid (195 mg), 2-propanesulfonamide (98 mg) and 4-dimethylaminopyridine (126 mg) in dichloromethane (3.7 ml). The mixture was stirred overnight, diluted with ethyl acetate, washed (1N HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography, eluting with acetone:hexanes (75:25), to afford the product (193 mg): TLC, Rf =0.64, acetone:hexanes (75:25): MS, m/e=356(M+29), 330(M+3), 329(M+2), 328(M+1), 272, 223, 222, 205, 204, 166.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]([N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])[CH3:28]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][O:32][CH3:33])[CH2:12][CH2:11]2)[CH3:24])=[CH:4][CH:3]=1
Reactant: CCNCCOC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: CO
Product: CCN(CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1)CCOC
Temperature: 25 °C

Procedure:
A solution of 200 mg (corresponds to 0.43 mmol) of trans-Methanesulfonic acid 3-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 4.3 ml of methanol was cooled to 0° C., treated with 0.44 ml (1 mmol) of Ethyl-(2-methoxy-ethyl)-amine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave 144 mg (83%) of pure trans-(4-{3-[Ethyl-(2-methoxy-ethyl)-amino]-prop-1-ynyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 407 (MH+, 1Cl). The following compounds were prepared from the corresponding mesylates and secondary amines:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[C:12]([C:9](=[O:11])[CH3:10])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: CC(=O)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled with 3-acetylphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 234.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=O)=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]([CH2:34][CH3:35])[CH2:32][CH3:33].CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:15][N:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNCC
Reactant: O=Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Reaction time: 0.5 h

Procedure:
A mixture of Compound 150 (0.2 g, 0.4675 mmol), Et2NH (0.037 mL, 0.360 mmol), and NaOAc (46 mg, 0.561 mmol) was dissolved in DCM:MeOH (20:1, 1 mL) and stirred for 30 min. To this solution was added NaBH3CN (0.056 mg, 0.891 mmol) and the mixture was stirred at RT overnight. The reaction was quenched with aqueous NaHCO3 and extracted into DCM. The organic layer was washed with water and dried over MgSO4. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, MeOD) δ ppm 0.99-1.27 (m, 6H) 1.35 (s, 6H) 1.59-1.89 (m, 5H) 2.06-2.16 (m, 1H) 2.17-2.28 (m, 1H) 3.21 (q, J=7.07 Hz, 4H) 4.59 (s, 2 H) 5.91 (dd, J=11.12, 5.56 Hz, 1H) 7.62-7.70 (m, 2H) 7.80 (dd, J=9.09, 4.80 Hz, 1H) 7.88 (dd, J=8.46, 2.91 Hz, 1H) 8.46 (s, 1H). [M+H] calc'd for C25H32FN5O2S, 486; found, 486.
Reaction SMILES: C(OC([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12])=O)C=C.C([SnH](CCCC)CCCC)CCC.CCCCCC>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12]
Reactant: C=CCOC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCCO)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 4-(allyloxycarbonyloxy)butyrate (352 mg, 4.94×10−4 mol) obtained from Example 11-(3) and bis(triphenylphosphine)dichloropalladium (2 mg) were dissolved in dichloromethane (3 ml). Tributyltin hydride (215 mg, 7.39×10−4 mol) was slowly added to the mixture at room temperature over a period of 5 minutes. After stirring at room temperature for 15 minutes further, hexane was added to the reaction mixture. The insoluble liberated oily material was separated by removing the supernatant liquid slowly. The insoluble residue was further washed twice with hexane. The oily residue was subjected to chromatography on a silica gel (15 g) column (eluent; ethyl acetate:hexane=3:1˜1:0) to afford the title compound (289 mg, 93% yield) as a colorless amorphous solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Br/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8]/[C:13](=[CH:12]\[CH3:18])/[C:14]([O:16][CH3:17])=[O:15]
Reactant: Oc1cccc(I)c1
Reactant: COC(=O)/C=C(/C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C/C=C(\Oc1cccc(I)c1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 11 g (0.05 mol) of 3-iodophenol is added dropwise at 0 to 5° C. to a solution of 3 g (0.055 mol) of KOH in 30 ml of dimethylformamide. 9 g (0.05 mol) of methyl 3-bromocrotonate are added at this temperature, and stirring of the solution is continued for one hour at room temperature. The mixture is treated with ice-water and extracted using methyl tert-butyl ether, and the methyl tert-butyl ether phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 99/1). This gives 9.7 g (61% of theory) of the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1.CN(C)C=O>C(O)C>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:20]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)co2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of methyl 4-carbamoylbenzoate (4.67 g), 4-chlorophenacyl bromide (6.50 g) and N,N-dimethylformamide (5 ml) was stirred at 130° C. for 2 hours. Hot ethanol was added to the reaction mixture, which was filtered. The filtrate was cooled to obtain crystals of methyl 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoate (1.45 g, Yield: 18%). The product was recrystallized from ethanol. Pale yellow prisms. Melting Point: 183 to 184° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].COC(OC)OC>ClCCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[N:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: COc1ccc(C=NCC(OC)OC)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (2.42 g, 10 mmol), aminoacetaldehyde dimethylacetal (1.08 g, 10 mmol), and trimethylorthoformate (2.5 mL) were mixed in 1,2-dichloroethane (10 mL) at room temperature and stirred×2 hours. The solvent was removed in vacuo to give (3-benzyloxy-4-methoxy-benzylidene)-(2,2-dimethoxy-ethyl)-amine as a viscous oil, which was dissolved in diethyl ether (10 mL).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1c(N)cccc1C(=O)OC
Reaction time: 7 h
Yield: 99.1 %

Procedure:
A solution of 20.7 g (98 mmol) of methyl 2-methylamino-3-nitrobenzoate in 1200 mL of methanol was inerted with nitrogen. To this solution was added 5 g (2.3 mmol) 10% palladium on carbon (50% wet). The reaction was purged with hydrogen and stirred under balloon pressure hydrogen for 7 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 17.5 g (99%) of the title compound.