Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][NH:13][C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].CS(O)(=O)=O.[OH-].[K+]>O1CCOCC1.C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:8]3[NH:13][CH:14]=[C:15]([CH3:16])[C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(Cl)c2[nH]cc(C)c12
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid ethyl ester (180 mg), 3-chloroaniline (160 μl), and methanesulfonic acid (98 μl) in 1,4-dioxane (5 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was suspended in ethanol (6 ml) and treated with a solution of potassium hydroxide (170 mg) in ethanol (2 ml) and then refluxed overnight. The ethanol was evaporated and replaced with methanol (8 ml) and potassium hydroxide (56 mg) added and then the mixture was refluxed overnight. The mixture was evaporated to dryness and the residue dissolved in water which washed twice with diethyl ether. The aqueous was then acidified with concentrated hydrochloric acid to afford a precipitate. The precipitate was filtered off and washed with water. The solid was then sucked dry and dried to afford the title compound (178 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.[OH-].[K+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:15]2[O:16][C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@H:14]2[F:13])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: CSc1nc(N)nc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CSc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
2-Amino-6-methylthiopurine (Sigma Chemical Company; 0.6 g, 3.3 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.3 g, 1.2 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 200 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (4,000 I.U.) and purine nucleoside phosphorylase (6,500 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 14, the reaction was diluted to 400 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide and 8,000 I.U. thymidine phosphorylase and 6,500 I.U. purine nucleoside phosphorylase were added. On day 25, the pH of the reaction was adjusted to 6.9 with KOH. On day 39, the reaction was filtered. The filtrate was applied to a 2.5×13 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form) and the product was eluted with methanol/water (3/7). After the solvent was removed under vacuum, the residue was suspended in water and lyophilized to obtain title compound that analyzed as a 0.5 hydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:41])=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[N+:36]=2[O-:37])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:35]5[N+:36]([O-:37])=[C:31]([C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)[C:32]([CH3:41])=[CH:33][CH:34]=5)=[O:39])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)[n+]([O-])c1-c1ccc(F)cc1
Yield: 72.8 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.649 mmol), 6-(4-fluorophenyl)-5-methylpyridine-2-carboxylic acid 1-oxide (192.5 mg, 0.779 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (224 μL, 1.30 mmol) and HATU (296 mg, 0.779 mmol) and in the same manner as in Example 58, the title compound (254 mg, 73%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])C1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:25][C:24]([F:26])([F:27])[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:32]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:33]=3)[CH:30]=[CH:31][C:9]=2[OH:8])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2cn3ccccc3n2)ccc1O
Yield: 56 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give the title compound (130.3 mg, 45.9%) as a white solid. Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C(11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give the title compound (18.3 mg, 20.2%) as a white solid.
Reaction SMILES: C(C1N([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)C2=NC(C)=CC(C)=C2N=1)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:35].C(O)(C)C.O>ClCCl>[CH:14]([C:15]1[CH:32]=[CH:31][C:18]2/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:35]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: N#C/C=C1\c2ccccc2CCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
[step 1] (E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (JP-B-2526005; 523 mg, 2.00 mmol) was dissolved in dichloromethane (5 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.10 g, 2.60 mmol) was added at 0° C., and the mixture was stirred at room temperature for 45 min. Isopropyl alcohol (0.5 mL) and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100) to give (E)-(2-formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (518 mg, 100%).
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:16]([Mg]Br)[CH3:17]>[Co](Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:2]([CH:2]([C:17]2[CH:16]=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCC(Cl)c1cccc(OC)c1
Reactant: CC[Mg]Br
Agent: Cl[Co]Cl
Product: CCCCCC(c1cccc(OC)c1)C(CCCCC)c1cccc(OC)c1

Procedure:
The preparation was effected in analogy to example 1(c) from 1-chlor-1-(3'-methoxyphenyl)-hexane and ethyl magnesium bromide activated with cobalt - (II) - chloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCc2ccccc2OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2OC2CCN(C)CC2)c1
Yield: 57.7 %

Procedure:
A solution of 482 mg of 1-t-butoxycarbonyl-4-{2-[2-(3-methoxylphenyl)ethyl]phenoxy]piperidine (prepared in a similar manner to that described in Example 37) in 5 ml of tetrahydrofuran was added dropwise to a dispersion of 44.5 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran, whilst stirring. After the addition was complete, the reaction mixture was heated under reflux for 1 hour and then cooled. Sufficient sodium sulfate decahydrate was then added to the reaction mixture, in order to decompose any excess of the hydride, after which the mixture was stirred for about 30 minutes. Insoluble materials were filtered off, and then the filtrate was freed from the solvent by distillation under reduced pressure. The resulting oily residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 220 mg (yield 57%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][N:11]=1)([OH:3])=[O:2].N1C=CC=[CH:23][CH:22]=1.S(Cl)(Cl)=O>C(O)C>[C:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)([O:3][CH2:22][CH3:23])=[O:2]
Reactant: O=C(O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Reaction time: 2 h

Procedure:
A mixture of 3-(2-carboxy-1-cyclohexen-1-yl)-5-phenylpyrazole (15.0 g) and pyridine (125 ml) is treated at 25° C with thionyl chloride (13.5 g); after stirring for 2 hours, ethanol (40.0 g) is added, and the mixture is stirred for 3 hours. The reaction mixture is partitioned between water and methylene chloride; the organic layer is washed with water and evaporated to give 3-(2-carboethoxy-1-cyclohexen-1yl)-5-phenylpyrazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Fc1cnc(Nc2ccc(C(F)(F)F)cc2)nc1Nc1ccc(C(F)(F)F)cc1

Procedure:
In a manner similar to the preparation of N2-N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gave N2,N4-bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.06 (bs, 1H), 7.75 (d, 2H, J=9 Hz), 7.67 (d, 2H, J=9 Hz), 7.63 (d, 2H, J=9 Hz), 7.54 (d, 2H, J=9 Hz), 7.19 (bs, 1H), 6.96 (s, 1H); 19F NMR (CDCl3): δ −17598 (s, 3F), −17676 (s, 3F), −46549 (s, 1F); HPLC: 85% pure.
Reaction SMILES: [CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:11])[F:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][CH:8]=[C:9]([F:10])[F:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=C(F)F)C4CCCC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4-[1-(1-cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the desired product (39 mg, 98%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.Cl>ClC(Cl)C>[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[C:25]([C:7](=[O:8])[CH:6]([CH3:10])[CH3:5])[CH:24]=2)[CH2:29]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)C(=O)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To 8.00 g of anhydrous aluminum chloride suspended in 100 ml of dichloroethane was added dropwise 3.20 g of 2-methylpropanoyl chloride dissolved in 50 ml of dichloroethane under ice cooling. Then, to the mixture was added 5.27 g of 2-(1,3-isoindolinedion-2-yl)indane, and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water containing hydrochloric acid, the organic layer was collected by separation, washed with water and dried, and then the solvent was removed. The resulting crystals were recrystallized from ethyl acetate-n-hexane to obtain 4.92 g of 2-(1,3-isoindolinedion-2-yl )-5-(2-methylpropionyl)indane.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:6][CH2:5]1.[N:7]1([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:6]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH:8]1[CH2:9][NH:10][CH2:11][CH2:12][N:7]1[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: BrCCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(N3CCNCC3CCC3CO3)nsc2c1
Yield: 73.8 %

Procedure:
A mixture of 4-bromo-1,2-epoxybutane (1.06 g; 7.02 mmol), 3-(1-piperazinyl)-1,2-benzisothiazole (1.65 g; 7.52 mmol), potassium carbonate (1.6 g; 11.3 mmol) and acetone (20 ml) was stirred under reflux for 19 hours. Confirming complete consumption of the starting materials, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the objective compound (1.5 g). Yield, 73.8%. IR νmaxfilm (cm-1): 1590, 1560, 1490, 1460.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>>[C:6]1([C:8]#[C:9][CH:24]([C:23]2[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:22]=2[O:21][CH3:20])[OH:25])[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)c1OC
Yield: 99 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3,4-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) was reacted to give the title compound (1.50 g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 7.45-7.28 (m, 6H), 6.88-6.83 (m, 1H), 5.97-5.92 (d, 1H), 5.73-5.68 (d, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29]C)=O)(C)(C)C.C[Si](C)(C)Cl.Cl.CN(C)C=O>C(#N)C.O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:29])[NH:19][N:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:22]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
25 mg of 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester, 7.4 mg trimethylchlorosilane and 11.3 mg KI dissolved in 1 ml of acetonitril are stirred for 2 h at 60° C. Subsequently 0.5 ml of a 4N solution of hydrochloric acid in dioxane is added and stirred for 2 h at room temperature. The solution is diluted into DMF (dimethylformamide)/water and directly purified by HPLC (high performance liquid chromatography) on a RP18 (reversed phase 18) column giving 4.5 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
7.44 grams of 2-benzyl-2-ethoxycarbonyl-cyclopentanol obtained in Example 14 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued under reflux condition for 12 hours. Then the procedure as described in Example 23 was followed, to give 12.53 g of yellow liquid. MS: m/e 367(M++1), 366(M+), 364(M+−2), 293(M+—CO2CH2CH3), 247(M+—CH3C6H4CO), 231(M+—CH3C6H4CO2), 201, 184, 156, 139, 119 (base), 91, 77.
Reaction SMILES: [O:1]=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C1N(CCO)CCN(CCS(O)(=O)=O)C1.[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[C@H:40]([CH2:42][CH3:43])[CH3:41].N[C@H](C(O)=O)C(C)C.N[C@H](C(O)=O)CCC(O)=O.N[C@H](C(O)=O)CCCCN>>[OH:1][CH:42]([CH3:43])[C@H:40]([CH3:41])[C@@H:39]([C:44]([OH:46])=[O:45])[NH2:38]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: CC(O)[C@H](C)[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
By using a cell lysate prepared from 2-e-2 cells at OD660 of 7 according to the method described in <5>, the reaction characteristics for various amino acids were evaluated. The cell lysate and a substrate solution were mixed, then the reaction proceeded at 30° C. for 1 hour, and the production of new substances was evaluated by TLC or amino acid analysis. The substrate reaction mixture contained 5 mM amino acid, 5 mM Fe2+, 5 mM 2-oxoglutaric acid, 5 mM ascorbic acid, and 100 mM HEPES (pH 7). In addition to L-isoleucine, the amino acids L-leucine, L-valine, L-glutamic acid, and L-lysine were each individually evaluated. The 4-hydroxyisoleucine which was produced was analyzed by the method described in Example 1. The results are shown in Table 6. Production of amino acids other than L-isoleucine was not observed. Therefore, it was suggested that this enzyme was an isoleucine-specific dioxygenase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]([CH2:17][C:18]1[N:22]([CH2:23][C:24](O)=[O:25])[N:21]=[C:20]([C:27]([F:30])([F:29])[F:28])[C:19]=1[Cl:31])=[N+:15]=[N-:16].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[N:14]([CH2:17][C:18]1[N:22]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:25])[N:21]=[C:20]([C:27]([F:30])([F:28])[F:29])[C:19]=1[Cl:31])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To 2.71 g (13.7 mmol) of 1-(4-Chlorophenyl)piperazine and 3.58 g (12.5 mmol) of (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 40 mL of anhydrous dimethylformamide was added 4.36 mL (31.2 mmol) of triethylamine. The solution was cooled to 0° C., and 5.21 g (13.7 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) was added. After 2 hours the reaction was diluted with two volumes of water, and the solvent was decanted away from the resulting oil. The oil was crystallized by dissolving in methanol and adding water in small portions. The product was isolated as a white solid by filtration: 1H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.97 (d, 2H), 5.48 (s, 2H), 4.62 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H) ppm; MS (ES) M+H expected=462.1, found=462.0.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CC(C)C.N[C@@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)C(C)C.N[C@@H](C(O)=O)C(C)C>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@@H](N)C(=O)O
Agent: CC(C)C[C@@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@@H](N)C(=O)O
Product: CSCC[C@H](N)C(=O)O

Procedure:
D-Met, S-Me-Cys, He, D-Ile, Leu, D-Leu, Val, D-Val
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:12]#[N:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(CC#N)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a stirred solution of 100 g of 4-isopropylbenzyl chloride in 1500 mL of N,N-dimethylformamide was added 32.0 g of sodium cyanide under ice-cooling. The mixture was stirred at 70° C. for 4 hours, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 96.5 g of (4-isopropylphenyl)acetonitrile.