Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:15]1=[O:23]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: ClCCCC#Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCC#Cc2ccccn2)c2ccccc21
Temperature: -50 °C
Yield: 45.8 %

Procedure:
2-(5-chloropent-1-ynyl)pyridine (59 mg, 0.33 mmol), 1-methyl-1H-benzo[d]imidazol-2(3H)-one (44 mg, 0.3 mmol) and K2CO3(70 mg, 0.511 mmol) were poured into DMF (0.45 mL) and the resulting mixture was heated at −50° C. overnight. The mixture was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 40 mg of 1-methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one as a yellow oil (Yield: 43%).
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].O1CCCC1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:13]1([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)#[CH:2]
Reactant: O=C1CCOCC1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of ethynylmagnesium chloride in tetrahydrofuran (0.5 M, 12 ML, 6.0 mmol) was added with cooling in an ice-water bath to a solution of tetrahydro-4H-pyran-4-one (0.496 g, 5.0 mmol) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred at room temperature for 1 h. Aqueous saturated ammonium chloride solution (10.0 mL) was then added and mixture extracted with ether (2×20 mL). The ether layers were washed with saturated aqueous sodium chloride solution (20 mL), then combined, dried over MgSO4, filtered and concentrated to give 4-ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (0.60 g, 96.2% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15](Cl)=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:22]
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)ccc2C1=O
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3c(c2)NC(=O)C(C)(c2ccc([N+](=O)[O-])cc2)C3=O)CC1
Yield: 31 %

Procedure:
A mixture of 3-(4-nitro-phenyl)-7-chloro-3-methyl-1H-quinoline-2,4-dione (0.3 g, 0.90 mmol) and 1-methylpiperazine (3.0 mL) was heated at reflux temperature overnight. Excessive 1-methylpiperazine was removed by evaporation in vacuo. The residue was diluted with water (50 mL), and the resulting suspension was extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 ml×2), dried over anhydrous MgSO4, and concentrated under reduced pressure. The pure objective compound (0.11 g, 31%) was obtained as yellow solid by a flash column chromatography (CH2Cl2: MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.90 (s, 3H, CH3), 2.35 (s, 3H, NCH3), 2.50-2.55 (m, 4H, NCH2), 3.35-3.44 (m, 4H, NCH2), 6.13 (d, J=2.4 Hz, 1H, ArH), 6.64 (dd, J=9.2, 2.4 Hz, 1H, ArH), 7.52 (d, J=9.0 Hz, 2H, ArH), 7.82 (d, J=8.8 Hz, 1H, ArH), 8.15 (d, J=9.2 Hz, 2H, ArH); m.p. 150-151° C.; MS(EI) m/e 394 [M+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[N:3]=1.[H][H].O>CO.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: Nc1nc(Cl)nc(Cl)c1N

Procedure:
To a solution of 4-amino-2,6-dichloro-5-nitropyrimidine, prepared as described in a), in methanol (30 ml), was added Raney nickel freshly prepared from 500 mg of alloy. The reaction mixture was stirred 20 hours in the hydrogen atmosphere. Then a new catalyst, prepared from 500 mg of alloy, was added and the reaction mixture was stirred next 24 hours in the hydrogen atmosphere. The catalyst was removed, the reaction mixture was concentrated in vacuo and the residue was extracted with hot water. Product, which was obtained after cooling of the water solution, was purified by chromatography (SiO2, VI—1:1)
Reaction SMILES: Cl[CH:2](Cl)[O:3]C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[C:8]=1[Cl:17].O>C(Cl)Cl.[Ti](Br)(Br)(Br)Br>[Cl:6][C:7]1[C:8]([Cl:17])=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[CH:11][C:12]=1[CH:2]=[O:3]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Cl)c(Cl)c1OC
Agent: Br[Ti](Br)(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
105.2 g of dichloromethoxymethane are added to a solution of 122.6 g of 1,2-dichloro-3,4-dimethoxybenzene in methylene chloride, and titanium tetrabromide is added dropwise to the mixture at -50° to -60° C. The mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into water and the organic layer is separated. The aqueous layer is extracted with chloroform, and the extract and the above-obtained organic layer are combined. The mixture is washed with water, dried and evaporated to remove solvent. The residue is washed with n-hexane to give 106 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][O:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCO)c3ccccc32)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Yield: 62.8 %

Procedure:
A solution of 3-(2-Hydroxy-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester (0.41 g, 1.16 mmol), TsCl (0.23 g, 1.22 mmol), triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure and the residue dissolved in EtOAc. The organic solution was washed with 10% KHSO4, dried over Na2SO4, and purified by silica gel chromatography (hexanes/EtOAc, 1/2) to give 0.37 g of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester as a yellow oil (63% yield): 1H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H), 3.52 (t, J=7.24 Hz, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.34 (t, J=7.06, 2H), 7.00 (d, J=8.24 Hz, 1H), 7.17–7.31(m, 4H), 7.44 (d, J=8.02 Hz, 1H), 7.56–7.67(m, 4H), 7.93 (t, J=1.72 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]([CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[C:7](=[O:15])[C:6]=2[CH:16]=1.ClC([O:20][C:21](Cl)(Cl)Cl)=O.C([N:27](CC)CC)C.N>O1CCCC1>[C:21]([O:13][CH2:12][CH:11]([OH:14])[CH2:10][N:8]1[C:7](=[O:15])[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9]1)(=[O:20])[NH2:27]
Reactant: CCN(CC)CC
Reactant: O=c1c2cc(Cl)ccc2on1CC(O)CO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)OCC(O)Cn1oc2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.4 %

Procedure:
To a solution of 1.00 g of 5-chloro-2-(2,3-dihydroxypropyl)-1,2-benzoisoxazolin-3-one in tetrahydrofuran (20 ml) was added 0.40 g of trichloromethyl chloroformate and the mixture was stirred at room temperature. After 30 minutes, the reaction mixture was cooled to 5° C. followed by adding dropwise 0.42 g of triethylamine. After stirring at the same temperature for 30 minutes, 5.0 ml of a 28% ammonia solution was added. Furthermore, after stirring at room temperature for 2 hours, the reaction mixture was refluxed by heating for 3 hours followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with a 10% NaCl solution. The organic layer was dried over anhydrous magnesium sulfate and the drying agent was removed by filtration. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (developing solvent: ethyl acetate) through silica gel to afford 0.75 g (64.1%) of the title compound having melting point 161°-162° C. as a colorless powder.
Reaction SMILES: CO.[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.Cl.C(=O)([O-])O.[Na+]>O>[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: CC(C)CCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CCc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture composed of 10 ml of methanol, 1.3 g (6.4 mmol) of the above 2-(3-methylbutyl)nitrobenzene, and 6.4 ml of concentrated aqueous hydrochloric acid solution, 1.4 g (25.1 mmol) of reduced iron was added in portions and heated to 60° C. with stirring for 1 hour. The reaction mass was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and filtered to remove precipitated iron hydroxide. The filtrate was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.95 g of the desired product as oil. Yield was 85%.
Reaction SMILES: [CH3:1][I:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CC(C)=O>[I-:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc2[nH]cc(Cc3cccnc3)c2c1
Reactant: CI
Solvent: CC(C)=O
Product: COc1ccc2[nH]cc(Cc3ccc[n+](C)c3)c2c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (10.4 ml; 0.167 mol) was added to a stirring mixture of compound of Description 1 [5-methoxy-3-(pyridin-3-ylmethyl)-1H-indole] (5.3 g; 0.022 mol) in acetone (150 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum. The residual solid was washed with diethyl ether giving the desired compound (7.5 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C1N=[CH:22][N:21](C(N2C=NC=C2)=O)[CH:20]=1.C1COCC1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:21]([CH3:22])[CH3:20])=[O:15])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(C)C)O2
Yield: 73.9 %

Procedure:
Following the amide coupling procedure described in protocol A, 504 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 361 mg CDI (2.23 mmol) and 1.1 mL of a 2.0 M solution of NN-dimethylamine in THF (2.2 mmol) produced 412 mg of 6-hydroxy-N,N,2,5,7,8-hexamethylchroman-2-carboxamide as amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O.O1CCOCC1.C(OCC)C.[ClH:38]>>[ClH:38].[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[NH:11][NH2:12]
Reactant: COc1cc(F)c(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(F)c(NN)c(F)c1
Reaction time: 0.5 h

Procedure:
Di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (616 mg, 1.64 mmol) was heated in 4 M HCl in dioxane (5 mL, 20 mmol) at reflux. The solution over time became a suspension. At 30 min, the reaction was cooled, diethylether was added, and the solid was collected with a medium frit, washing with diethylether. This gave (2,6-difluoro-4-methoxy-phenyl)-hydrazine hydrochloride (0.246 g, 86%) as a tan solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.75 (br. s., 3H) 7.46 (s, 1H) 6.79-6.90 (m, 2H) 3.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([CH:6]=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][Mg]Br.BrC1C=C(C(O)C)C=C(F)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH:6]([OH:7])[CH3:12])=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1c(Cl)cc(Br)cc1Cl
Reactant: C[Mg]Br
Agent: CC(O)c1cc(F)cc(Br)c1
Product: CC(O)c1c(Cl)cc(Br)cc1Cl

Procedure:
The title compound was prepared from 4-bromo-2,6-dichlorobenzaldehyde (prepared according to WO 2008/021851) by reaction with methylmagnesium bromide following the procedure for 1-(3-bromo-5-fluorophenyl)ethanol as described.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)c(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(N(C)C3CCN(C)CC3)cc2)nc1-c1ccc(F)c(Cl)c1
Yield: 25 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-methylpyrimidine and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 25% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.69 (dd, 1H, J=7.2, 1.7 Hz), 7.49 (m, 1H), 7.41 (d, 2H, J=8.9 Hz), 7.20 (d, 1H, 8.5 Hz), 6.79 (d, 2H, J=8.5 Hz), 3.49 (m, 1H), 3.00 (d, 2H, J=10.6 Hz), 2.74 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 2.11 (m, 2H), 1.89 (m, 2H), 1.72 (d, 2H, J=11.6 Hz); MS (ESI): 440.3 [M+H]+, 220.8 [M+2H]2+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 0.87 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (181 mg, 1.0 equiv), K2CO3 (303 mg, 2.5 equiv.) and triphenylphosphine (45 mg. 0.2 equiv) were weighed in air and added in a flame-dried flask. Bis(dibenzylidenacetone)palladium (25 mg, 0.05 equiv) was added and the flask was closed by a septum. Dioxane (6 mL) was added and the mixture was stirred for 18 h (TLC control) at 90° C. The catalyst was filtered off and washed with EtOAc, the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 1/3 to 1/2) to give 2-amino-5-(1-methyl-1H-pyrazol-4yl)-4-trifluoromethyl-benzoic acid methyl ester (0.57 mmol, 66%) as a white solid. ESI-MS: m/z 300 [M+H]+, rt: 4.97 min.
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]3OP(O)(O)=O)C=2N=1.[OH:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56]C=NO)=[CH:52][CH:51]=1.N(C(CO)(CO)CO)CC(O)=O>>[OH:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]=[O:14])=[CH:52][CH:51]=1
Reactant: ON=CCc1ccc(O)cc1
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](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C(O)CNC(CO)(CO)CO
Product: O=Cc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
5 μl membranes isolated as described in Halkier et al, Archives of Biochemistry and Biophysics 322: 369-377, 1995, from E. coli expressing “12” was reconstituted with 0.225 units NADPH-cytochrome P450-reductase, 50 μg NADPH, 42 nCi p-hydroxyphenylacetaldehyde oxime, and 100 μg dilaurylphosphatidylcholine in a total volume of 100 μl of 30 mM Tricine pH 7.9. After incubation at 30° C. for 30 minutes the reaction mixture was applied to a TLC plate and analyzed as described above. Reconstitution of membranes from E. coli expressing “12” resulted in the accumulation of p-hydroxybenzaldehyde which is the stable dissociation product of p-hydroxymandelonitrile, the last intermediate in the biosynthesis of the cyanogenic glucoside dhurrin. This shows that demonstrates that “12” is the cytochrome P450 that catalyzes the conversion of p-hydroxyphenylacetaldehyde oxime to p-hydroxymandelonitrile. The cDNA is designated P450OX. A clone comprising the described cDNA of P450OX has been deposited on Jan. 10, 1997 with the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig, under the accession number DSM 11367.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:22])[CH2:14][CH:15]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=[CH:6]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2cc(C(=O)C=Cc3ccccc3)ccc2c1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2cc(OC)ccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(6-methoxy-2-naphthalenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(6-methoxy-2-naphthalenyl)-3-oxo-1-phenylpropyl]malonate was obtained as beige coloured solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCCO)C.CCOC(C)=O>[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: Clc1ccc(I)cn1
Solvent: CCOCCO
Solvent: CCOC(C)=O
Product: CN(C)CCNc1ccc(I)cn1
Yield: 34.7 %

Procedure:
A stirred solution of 2-chloro-5-iodopyridine (0.50 g, 2.18 mmol) and N,N-dimethylethylenediamine (0.81 g, 1.00 mL, 9.20 mmol) in 2-ethoxyethanol (5 mL) was heated in a sealed tube under microwave irradiation at 125° C. for 1 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual oil was purified by column chromatography (SiO2, 3:1 EtOAc/MeOH) to give the title compound (0.22 g, 36%) as a viscous oil which solidified on standing. δH (CDCl3) 8.19 (1H, br. s), 7.53 (1H, m), 6.23 (1H, m), 3.29 (2H, m), 2.52 (2H, m), 2.24 (6H, s). Exchangeable proton not observed. LCMS (ES+) 292.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.C[N:25](C)C=O>[Ni]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH2:25])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccc([N+](=O)[O-])c1)CC2
Reactant: CN(C)C=O
Agent: [Ni]
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1N)CC2

Procedure:
Prepared by catalytic hydrogenation of 2-amino-6-(3-(3-nitro-phenyl)allyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine using Raney nickel in anhydrous dimethylformamide (4.5 hours at ambient temperature). After purification by column chromatography the base is dissolved in isopropanol. By the addition of ethereal hydrochloric acid, cooling, filtering and drying at 100° C./0.1 torr over phosphorus pentoxide the title compound is obtained. Yield: 37% of theory, Melting point: 160° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31]OC(OC)N(C)C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[C:14]([CH3:31])[N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: COC(OC)N(C)C
Product: Cc1nc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c(=O)n1[C@H]1CCCC[C@@H]1O

Procedure:
Using the procedures described in Example 2 for the preparation of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one, substituting N, N-dimethylacetamide dimethylacetal for N,N-dimethylformamide dimethylacetal, the title compound was obtained that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 433.9 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.05-9.03 (m, 1H), 8.28 (s, 1H), 8.06 (d, J=7.7, 1H), 7.92 (s, 1H), 7.75-7.63 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 4.80-4.74 (m, 1H), 4.53 (s, 2H), 4.15-4.09 (m, 1H), 2.87 (s, 3H), 2.81-2.70 (m, 1H), 2.19-2.12 (m, 1H), 1.90-1.80 (m, 3H), 1.53-1.35 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.ClCCCl.C(N(CC)CC)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COCCOCCl
Reactant: Oc1cc(Br)cnc1Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCOCOc1cc(Br)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A dry 100 mL one neck round bottom flask was charged with 5-bromo-2-chloropyridin-3-ol (2.1454 g, 10.3 mmol), 40 mL dry DCE, and a stirbar. The slurry was fitted with an inert atmosphere inlet and cooled with an ice-water bath. To the stirring solution was added triethylamine (4.29 ml, 30.9 mmol) followed by 2-methoxyethoxymethyl chloride (1.17 ml, 10.3 mmol). The reaction was stirred at ice bath temperature for 1 h, and then at room temperature for 2 h. The reaction was cooled to 0° C. and treated with 2 mL MeOH. The slurry was filtered cold, and the solids were washed with DCE (2×50 mL). The filtrate was concentrated in vacuo and purified using 200 g SiO2 wet packed with DCE. A fraction that eluted from 500- to 1500 mL was isolated. The solvent was removed in vacuo to afford 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine (1.28 g, 41.9% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.38 (s, 3H) 3.55-3.59 (m, 2H) 3.86-3.89 (m, 2H) 5.36 (s, 2H) 7.71 (d, J=2.05 Hz, 1H) 8.12 (d, J=2.05 Hz, 1H). HPLC-MS: 2.04 min (>99%@215 nm; >99% @254 nm; m/z=295.9, calculated for C9H1179BrClNO3+H+=296.0; m/z=297.9, calculated for C9H1179BrClNO3+H+=298.0).