Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([NH:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:22]([OH:27])[OH:23])=[O:16]
Reactant: COc1ccc(Br)c(NC(=O)C(C)(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(NC(=O)C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of N-(2-bromo-5-methoxyphenyl)-2,2-dimethylpropanamide (2.82 g, 9.85 mmol) in tetrahydrofuran (20 mL) at −78° C. was added slowly a solution of n-butyllithium in hexanes (2.5 M, 8.30 mL, 20.7 mmol). The solution was stirred for 30 minutes in a −40° C. bath, then was cooled back to −78° C. Triisopropyl borate (6.82 mL, 29.6 mmol) was added slowly. The solution was stirred for 1 hour at −40° C., then was stirred at 0° C. for 30 minutes. Saturated aqueous ammonium chloride was added. The mixture was extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to afford a residue that was triturated with hexanes. The hexanes were decanted and the residue was stirred in methanol/water to precipitate a white solid that was isolated by filtration, washed with water, and dried to yield 1.36 g of 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid, m.p. 256-257° C. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18](O)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([F:17])[CH:8]=1.[O:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([C:18]([NH:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[C:9]([F:17])[CH:8]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1CCOCC1)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (45 mg, 0.145 mmol), tetrahydro-2H-pyran-4-amine (14.7 mg, 0.15 mmol) and triethylamine (61.3 μl, 0.44 mmol) in dichloromethane (2 mL) a 50 wt % solution of 1-propanephosphonic acid cyclic anhydride (64.9 μl, 0.22 mmol) in ethylacetate was added. After stirring for 1 hr, the reaction mixture was diluted with dichloromethane (10 mL) washed with NaHCO3 solution (10 mL) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with dichloromethane to 20% methanol in dichloromethane to afford the title compound: (18 mg, 0.046 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[F:10][C:11]([F:19])([F:18])[C:12](=O)[C:13](OC)=[O:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][C:13](=[O:14])[C:12]([C:11]([F:19])([F:18])[F:10])=[N:8]2
Reactant: Nc1cccc(Br)c1N
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: CCO
Product: O=c1[nH]c2c(Br)cccc2nc1C(F)(F)F
Yield: 29 %

Procedure:
A solution of 3-bromobenzene-1,2-diamine (1.00 g, 5.35 mmol, CombiBlocks, Inc., San Diego, Calif.) and methyl 3,3,3-trifluoro-2-oxopropanoate (0.655 mL, 6.42 mmol; Alfa Aesar, Ward Hill, Mass.) in EtOH (15 mL) was stirred at reflux under argon for 17 h. The mixture was concentrated in vacuo. Purification by silica gel (0-70% EtOAc/Hexanes) provided 8-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (224b, 29% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (1H, br. s.), 8.04 (1H, d, J=7.8 Hz), 7.95 (1H, d, J=8.2 Hz), 7.38 (1H, t, J=7.9 Hz). 19F NMR (377 MHz, DMSO-d6) δ ppm −68.44 (3F, br. s.). MS (ESI, pos. ion) m/z: 293.0 (M+1).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2].C(O)(C)(C)C.C(Cl)(Cl)(Cl)[Cl:23].ClOC(C)(C)C>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH3:16])[C:5]([O:4][CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(NS(C)(=O)=O)cccc1OCC#N
Agent: CC(C)(C)OCl
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: -4 °C
Yield: 49 %

Procedure:
N-(3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.87 g, 7.78 mmol) was suspended in a 1:1 mixture of t-butanol and carbon tetrachloride (80 ml) and cooled in an ice bath. t-Butyl hypochlorite (TCl, 0.85 g, 7.78 mmol) was added dropwise. The mixture was maintained at -4° C. overnight then warmed to room temperature. The volatiles were removed at reduced pressure. N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.05 g, 49% yield) was obtained by recrystallization from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](Cl)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([O:24][CH3:23])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CON1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F

Procedure:
6 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-chloropyrimidine, 60 ml of methanol and 3.3 g of methanolic sodium methanolate solution (30%) are boiled under reflux for 24 hours, concentrated by evaporation, and the residue taken up in ethyl acetate and the organic phase washed with water. After drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point of 104-106° C. (compound 3.350).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O1CCCC1>[CH2:1]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
First, 25.0 g of benzyl bromide, 36.42 g of 4′-bromo-4-hydroxybiphenyl, 36.4 g of potassium carbonate, and 300 ml of methyl ethyl ketone were put in a1 flask, and stirred under reflux for six hours. After the reaction, 300 ml of tetrahydrofuran was added to the reaction solution, and a mixture was cooled to ambient temperature. Insoluble material was filtered off, and toluene was added to the filtrate to separate an organic layer. The organic layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from acetone, to obtain 42.56 g (Y: 85.8%) of 4-benzyloxy-4′-bromobiphenyl. The purity of the resultant compound was 99.0% as measured by GC.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1(CCN2[C:34](=[O:35])[CH:33]=[CH:32][NH:31]C2=O)CCCCC=1>>[NH2:31][C:32]1[N:9]([CH2:8][CH2:7][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[C:34](=[O:35])[CH:33]=1
Reactant: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Reactant: O=c1cc[nH]c(=O)n1CCC1=CCCCC1
Product: Nc1cc(=O)n(CCC2=CCCCC2)c(=O)n1CCC1=CCCCC1
Yield: 85 %

Procedure:
In the manner of step (b) of Example 1, 1,3-bis[2-(1-cyclohexen-1-yl)ethyl]urea (from step (a), 55.00 g, 0.199 mol) was converted to 6-amino-1,3-bis[(2-(cyclohexen-1-yl)ethyl]uracil, isolated as a white powder (58.03 g, 85%), m.p. 172°-174° C.;
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.[CH2:12]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:11][C:18]([NH:17][C:15]([O:14][CH2:12][CH3:13])=[O:16])=[S:19])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:7]=1
Reactant: Nc1ncc(C2CC2)cc1Br
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncc(C2CC2)cc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-bromo-5-cyclopropyl-pyridin-2-ylamine (1.0 g, 4.69 mmol) in dry 1,4-dioxane (20 mL) was added ethoxy carbonyl isothiocyanate (0.55 mL, 5.16 mmol) under an argon atmosphere and stirred at room temperature for 6 hours. The solvent was evaporated and the title compound was obtained as light yellow oil (1.5 g, 98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[CH3:18][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
A methanol (200 ml) solution of indole-5-carboxylic acid (5.15 g) was refluxed in the presence of concentrated sulfuric acid (3 ml) at 85° C. for 4.5 hours. After the reaction, saturated aqueous sodium hydrogencarbonate solution was added at 0° C. and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain indole-5-carboxylic acid methyl ester (4.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:7]=3[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>CO.CN(C)C=O.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150 mL)-N,N-dimethylformamide (600 mL), 10% palladium on charcoal (5.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature overnight. After the unsoluble materials were filtered out, the methanol was removed under reduced pressure. Water (2 L) was added to the residue. The precipitated solid was filtered off and dried at 90° C. under reduced pressure to give the titled reference compound (44.02 g) as a pale yellow solid. (Yield 96%)
Reaction SMILES: ClS(O)(=O)=O.C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C\C(O)=O.[N+:22]([C:25]1[CH:41]=[CH:40][CH:39]=[CH:38][C:26]=1[O:27]/[C:28](=[CH:33]\[C:34]([O:36]C)=O)/[C:29]([O:31][CH3:32])=[O:30])([O-:24])=[O:23].[N+](C1C=CC=CC=1O/C(=C/C(OC)=O)/C(OC)=O)([O-])=O>>[N+:22]([C:25]1[C:26]2[O:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][C:34](=[O:36])[C:38]=2[CH:39]=[CH:40][CH:41]=1)([O-:24])=[O:23]
Reactant: COC(=O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: COC(=O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Product: COC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 300 parts by weight of chlorosulfonic acid. Thereto, 60 parts by weight of a mixture (content: 81.1% by weight, fumaric acid/maleic acid ratio=57/43) containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate was added dropwise at an inner temperature of 50° C. or below. After completion of addition, the inner temperature was raised to 60° C. and the mixture was stirred and kept at the same temperature for 5 hours and at an inner temperature of 70° C. for 3 hours to obtain a reaction solution containing 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield: 86%). After cooled to room temperature, the reaction solution was poured gradually into 360 parts by weight of water. The mixture was kept at an inner temperature of 60° C. for 8 hours and then cooled to an inner temperature of 0° C. gradually. Precipitated crystals were filtered and dried to obtain 30 parts by weight of a crystalline mixture of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 2.5% by weight; the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 96.7% by weight). The yield of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 2% and the yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 73%.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C([O:69][C:70](=[O:74])[CH2:71][NH:72][CH3:73])C.[OH-].[Na+]>>[CH2:1]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[C:28]([C:30]([N:72]([CH2:71][C:70]([OH:69])=[O:74])[CH3:73])=[O:31])[CH:27]=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)CC(=O)O)cc2o1

Procedure:
2-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzofuran-6-carboxylic acid (115 mg, 0.262 mmol), HATU (142 mg, 0.376 mmol), DIEA (0.3 ml, 1.02 mmol), and sarcosine ethyl ester hydrochloride (48 mg, 0.314 mmol) are reacted followed by base hydrolysis with 2N NaOH in an analogous manner to example 59 from to yield (66 mg, 25%) MS (ES) m/e: 508.2 (M−1)
Reaction SMILES: C(O)C.[CH2:4]([NH2:6])[CH3:5].[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>O>[CH2:4]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:5]
Reactant: COC(=O)c1ccncc1
Reactant: CCN
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccncc1
Reaction time: 8 h

Procedure:
A mixture of 200 ml of ethanol and 20 ml water was cooled in an ice bath and saturated with ethylamine for 0.5 hr. then 80 g of crude methyl isonicotinate was added with cooling. Ethylamine was again bubbled onto the reaction mixture for 10 min and then it was allowed to stand overnight at room temperature. It was then concentrated in vacuo to leave 82.82 g of a pale oil which became semisolid on cooling.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](O)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:22])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccc(OCc3ccccc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
8-(benzyloxy)quinolin-2-ol (6.6 g, 26.3 mmol) was dissolved in POCl3 (50 mL). The mixture was stirred at 90° C. for 16 h. The POCl3 was evaporated and to the residue was added EtOAc (100 mL) and the solution was washed with a.q. NaHCO3 (80 mL) and H2O (80 mL). The EtOAc was removed under vacuum to give the desired compound (6.0 g, yield 85%). LCMS (m/z): 270.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=O)[CH:7]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[O:11][CH2:10]2)[CH:7]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Oc1ccc(Cl)cc1CN1COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (740 mg, 2 mmol), p-nitrophenyl chloroformate (407 mg, 2.02 mmol), and pyridine (330 mg, 4.17 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature for three hours. The corresponding aminoacid tert-butyl ester (2 mmol) and anhydrous triethylamine (405 mg, 4 mmol) were added and the resulting reaction mixture was stirred at room temperature overnight. After evaporation, the residue was partitioned between diethylether and dilute NaOH. The organic layer was washed with water, dilute HCl, and brine, and then dried over magnesium sulfate. The crude product was purified by either trituration or recrystallization. The tert-butyl ester was stirred in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at room temperature overnight. After evaporation of CH2Cl2 and excess TFA, the residue was recrystallized from benzene-acetone to afford pure desired product.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13]C1C=CC(C(OC)=O)=CC=1>>[CH3:13][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(C)(C)N)cc1
Yield: 34 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 4-methylbenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 34%.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH2:10][C:8](=[O:9])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=1.CC1[CH2:15][CH:16]([OH:22])CC(C)(C)C=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>CO>[C:16]([O:9][CH:8]1[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=[C:4]([CH3:3])[CH2:10]1)(=[O:22])[CH3:15]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: CC1=CC(C)(C)CC(O)C1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OC1CC(C)=CC(C)(C)C1

Procedure:
Prepared by reduction by means of sodium borohydride in methanol of β-isophorone [obtained according to J. Am. Chem. Soc., 63, 2308 (1941)]and subsequent acetylation of the obtained 3,5,5-trimethyl-cyclohex-3-en-1-ol by means of acetic anhydride in the presence of sodium acetate at 50°C during 20 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[N:27]=[CH:26][NH:25][N:24]=1>>[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Cl)n2)cc1
Reactant: Clc1nc[nH]n1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(Cl)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example A.17) (1.628 g, 5.0 mmol) and commercially available 3-chloro-1H-(1,2,4)triazole (0.776 g, 7 mmol) according to the general procedure IVa. Obtained as a white solid (1.651 g, 84%). MS (ISP) 393.1 [(M+H)+] and 395 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9]N1C(=O)CCC1=O.O>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a solution of 96 ml of 3-fluoroaniline in 1000 ml of dichloromethane, 147 g of N-chlorosuccinimide was added at 0° C., and stirred for 12 hours at room temperature. After addition of water to the reaction solution, the system was extracted with chloroform. The chloroform layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 21 g of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)[N:21]=2)=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: NC(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (0.10 g, 0.48 mmol), 4-(amidinoamino)benzamide nitrate (0.116 g, 0.48 mmol), and potassium carbonate (0.132 g, 0.96 mmol) in ethanol (10 ml) with was heated to 120° C. overnight in a sealed vessel. The reaction mixture was cooled to room temperature and the resulting solid was collected then washed with ethanol, water, and diethyl ether to provide the title compound as a beige solid, identical in all respects with the compound prepared in Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C:18]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1(CO)CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCC1(Nc2nc(Cl)ncc2Br)CCCC1
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.38 g (12.0 mmol) (1-amino-cyclopentyl)-methanol. After 16 hours at room temperature the batch is filtrated to remove the solid precipitate. The precipitate is dried. 1.48 g (4.8 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Solvent: ClCCl
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 48 h
Yield: 98 %

Procedure:
According to the general procedure, a solution of trans-stilbene (50 mg, 0.28 mmol) and rac-32 (8.8 mg, 0.0056 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave 39 (50 mg, 97%). mp 48-50° C. (lit.1 47-49° C.) 1H NMR (300 MHz, CDCl3): δ 7.39-7.25 (m, 10H), 3.01 (s, 4H); 13C NMR (75.5 MHz, CDCl3): δ 141.9, 128.6, 128.5, 126.0, 38.1.