Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([C:23]2([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:25][CH2:24]2)[CH:13]=1
Reactant: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2(c3ccccc3)CC2)cc1O
Yield: 27 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine (Intermediate 26) except that the reaction was carried out in ethyl acetate. The crude material was recrystallised from ethyl acetate to give a pink solid (yield=27%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]([Cl:19])=[CH:6][CH:5]=2.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C[Sn](C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCCc1c(Br)[nH]c2ccc(Cl)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCc1c(-c2ccc([N+](=O)[O-])cc2)[nH]c2ccc(Cl)cc12
Temperature: 50 °C
Yield: 31 %

Procedure:
A mixture of 200 mg (0.58.10−3 mol) of ethyl 2-bromo-5-chloro-1H-indole-3-butanoate, 498 mg (1.74.10−3 mol) of trimethyl(4-nitrophenyl)tin, 140 mg (0.46.10−3 mol) of triphenylarsine, 108 mg (0.12.10−3 mol) of tris(dibenzylideneacetone)dipalladium and 12 ml of dioxane is prepared and this reaction medium is heated at 50° C. for 6 days, with stirring. After cooling, 12 ml of water are added and the mixture is then extracted with ethyl ether. The organic phase is subsequently washed with water and then dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (85/15; v/v) as the eluent. The fractions containing the expected compound are purified again by reversed phase chromatography on C18-grafted silica using an acetonitrile/water mixture (7/3; v/v) as the eluent to give 70 mg of the expected compound in the form of a yellow paste (yield=31%).
Reaction SMILES: C([N:4]1[C:8]([C:9]2[CH:10]=[C:11](C=CC=2)C=O)=NC(C2C=CC(OC)=CC=2)=N1)C=C.[CH2:25]([N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:31][C:30]([C:41]2[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=2)[CH:44]=O)=[N:29]1)[CH:26]=[CH2:27].N1CCCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:72].CCO>C1COCC1.C(O)C>[ClH:72].[CH2:25]([N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:31][C:30]([C:41]2[CH:48]=[CH:47][CH:46]=[C:43]([CH2:44][N:4]3[CH2:8][CH2:9][CH2:10][CH2:11]3)[CH:42]=2)=[N:29]1)[CH:26]=[CH2:27]
Reactant: C=CCn1nc(-c2ccc(OC)cc2)nc1-c1cccc(C=O)c1
Reactant: C=CCn1nc(-c2cccc(C=O)c2)nc1-c1ccc(OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCn1nc(-c2cccc(CN3CCCC3)c2)nc1-c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A solution of mixture of 3-[2-allyl-5-(4-methoxy-phenyl)-2H-[1,2,4]triazol-3-yl]-benzaldehyde and 3-[-allyl-5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (1:1) (60 mg, 0.19 mmol), pyrrolidine (19 μl, 5 0.23 mmol) and acetic acid (13 μl, 0.023 mmol) in THF (5 ml) was stirred for 15 min at r.t then sodium triacetoxyborohydride (59 mg, 0.28 mmol) was added in a single portion. This mixture was allowed to react at r.t. under argon until all the aldehyde had been consumed (ca. 1.5 hr). Saturated aqueous Na2CO3 solution was then added, stirred for 15 min and extracted twice with EtOAc (20 ml). The combined organic phase was dried with Na2SO4 filtered and the solvent evaporated under reduced pressure. The resulting isomeric mixture, obtained as an oil, was chromatographed over SiO2 (Merck 230-400 mesh) using CH2Cl2/(2M NH3 in MeOH) 97:3, to provide the separate regioisomers. The isolated regioisomer was taken up in ethanol and was directly converted to its hydrochloride salt with 1.45N HCl/EtOH at 4° C. Following solvent evaporation the resulting pale yellow foam was dried under high vacuum (0.05 mmHg) at 50° C. for 3 h to afford the title compound (30 mg, 0.07 mmol, 38.8%), MS: m/e=375.5 (M+H+). The regiochemistry of alkylation was established by 1H-NMR, nOe spectroscopy.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[N:2]=1.[ClH:18]>C1COCC1.O1CCOCC1>[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([NH2:10])[CH2:9][CH2:8]2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2cccnn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-(pyridazin-3-yl)cyclopropylcarbamate (0.3 g) in THF (3 ml) at 0° C. was added HCl in dioxane (5 ml) and the mixture stirred at r.t. for 3 hr. The reaction mixture was concentrated, and the crude product was taken for the next coupling reaction. Yield: 0.21 g
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][C:8]=1[F:24])[CH3:2].C(O[CH2:32][N:33]([CH2:41][Si](C)(C)C)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)CCCC.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:9][C:8]=2[F:24])[CH2:41][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32]1)=[O:25])[CH3:2]
Reactant: CCCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of 4.5 g of 3-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-acrylic acid ethyl ester (13.1 mmol) and 7.68 g N-[(pentyloxy)methyl]-N-[(trimethylsilyl)-methyl]-benzenemethanamine (26.2 mmol) in 50 ml dichloromethane was added 10 μL. trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 min. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate solution and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica column, using a 7/3 hexane/ethyl acetate mixture as eluent.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.C([O-])(=O)C.[Na+].C(O)C.Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>O>[C:21]([N:25]1[CH:4]=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:26]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)n1ccc(C(F)(F)F)n1
Yield: 52.5 %

Procedure:
To a mixture of 5 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one, 3 g of sodium acetate and 15 ml of ethanol was added 4.6 g of tert-butylhydrazine hydrochloride, and the mixture was heated to reflux for 2 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.0 g of 1-tert-butyl-3-trifluoromethyl-1H-pyrazole of the formula:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C(Cl)(Cl)Cl.[BrH:13]>C(OCC)(=O)C>[Br:13][CH:3]1[CH:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Br
Reactant: CC1CCCC(=O)C1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CCCC(=O)C1Br

Procedure:
3-Methylcyclohexanone, 22.4 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate, is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is added and heated to maintain elimination of hydrogen bromide. When all of the hydrogen bromide is evolved, the mixture is heated to its reflux temperature for 15 minutes, filtered and the filtrate evaporated to a small volume. The residue is placed upon an alumina column and eluted with methylene chloride. Evaporation of the eluate yields 35.5 grams of crude 2-bromo-3-methylcyclohexanone suitable for condensation with the triazoles of Examples 1 or 2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:30][CH2:29][CH:28]([C:25]3[S:26][CH:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:33][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCC(c3nc(-c4ccccc4)cs3)CC2)c1C

Procedure:
A solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (200 mg, 1.02 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (250 mg, 1.02 mmol) and diisopropylethylamine (0.357 ml, 2.05 mmol) in dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (201 mg, 51.5%) as a solid. mp 156-157° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chroman-2-carboxylic acid (4.3 g, 24 mmol) in THF (70 mL) was combined with 1M LAH in THF (30 mL, 30 mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water and then stirred for 2 hours. The THF solution was decanted from the solid, which was washed with fresh THF. The combined THF solution was dried (Na2SO4) and evaporated in vacuo to yield chroman-2-yl-methanol as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9]/[C:10](=[C:15](\[C@H:20]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]2)/[C:16]([O:18]C)=[O:17])/[C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+:30]>O1CCOCC1>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9]/[C:10](=[C:15](\[C@H:20]2[CH2:21][CH2:22][C@@H:23]([OH:26])[CH2:24][CH2:25]2)/[C:16]([O-:18])=[O:17])/[C:11]([O-:13])=[O:12])=[CH:27][CH:28]=1.[Na+:30].[Na+:30]
Reactant: COC(=O)/C(Cc1ccc(OCCN)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NCCOc1ccc(C/C(C(=O)[O-])=C(/C(=O)[O-])[C@H]2CC[C@@H](O)CC2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of dimethyl 2-(4-(2-aminoethoxy)benzyl)-3-(cis-4-hydroxycyclohexyl)maleate 12 mg, 0.03 mmol) in 1,4-dioxane (0.5 ml) was added 1 M NaOH (0.06 ml, 0.06 mmol) at room temperature, and the mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated, and the residue was dried in vacuo to give the title compound as a colorless solid (12 mg, quantitative).
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Oc1ccc(F)cc1)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of 7.2 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-fluorophenoxy)-3-trimethylacetylthio-propenate (prepared as described in Example 25) in dichloromethane at -20°, was added a solution of 25 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 4.6 g of the title compound as a pale yellow foam (67% of the theoretical yield).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>O1CCCC1>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCCCCCBr
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCC/C=C\CCCCCCCCBr
Yield: 78 %

Procedure:
94 g (0.2 mol) of (6-carboxyhexyl)triphenylphosphonium bromide were suspended in 500 ml of tetrahydrofuran. 47 g (0.42 mol) of potassium t-butylate in 200 ml of tetrahydrofuran were added, followed by 50 g (0.22 mol) of 9-bromononanal. After work up and chromatography 52 g (78%) of 7Z-16-bromohexadec-7-enoic acid were obtained having the following characteristics: Z/E=90/10;
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][OH:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][O:5][C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]1[CH2:32][CH3:33])=[O:30]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: COCCOc1cc(F)c(CO)c(Cl)c1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCCOC)cc1Cl
Yield: 89 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (370 mg; 89%); MS (ISP): 492.3 (M+NH4)+.
Reaction SMILES: C([SiH](CC)CC)C.O[C:9]1([C:25]2[C:35]([OH:36])=[CH:34][C:28]3[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[C:10]1=[O:24].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[OH:36][C:35]1[C:25]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[C:10]2=[O:24])=[CH:26][C:27]2[O:32][CH2:31][CH2:30][N:29]([CH3:33])[C:28]=2[CH:34]=1
Reactant: CN1CCOc2cc(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCOc2cc(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of triethylsilane (1.3 mL, 8.2 mmol) in trifluoroacetic acid (8 mL) was added dropwise a solution of 3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one (1.04 g, 2.62 mmol) in dichloromethane (3 mL). The resulting solution was warmed to reflux and stirred under nitrogen for 90 min. Once cooled, the solvent was removed under reduced pressure to afford 3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate as a light brown foam: MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:51]2[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][OH:45])[CH2:49][CH2:50]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCN(CCO)CC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78 mg, 0.125 mmol; Example 6A) was reacted with N-(2-hydroxyethyl)piperazine (48.7 mg, 0.374 mmol) in acetonitrile (1.0 ml) to give the target compound (68 mg, 85% of theory).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][C@H:18]([S:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][N:16]2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][C@H:18]([S:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][N:16]2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: N[C@H]1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of (2S,4S)-2-[(3S)-3-t-butoxycarbonylaminopyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (2.14 g) in a mixture of trifluoroacetic acid (10 ml) and anisole (1 ml) was stirred on ice-bath for 1 hour. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give a residue of (2S,4S)-2-[(3S)-3-aminopyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine. To a solution of the residue in a mixture of ethyl acetate (40 ml) and water (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (1.06 g) in tetrahydrofuran (10 ml) under ice-cooling, keeping the pH between 8 and 9 with 1N aqueous sodium hydroxide solution. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ethyl acetate (50 ml). The solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (1.89 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH2:31])[CH2:26]1>CN1C(=O)CCC1>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([NH2:12])=[O:11])[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)=[N:3][C:2]=1[NH:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[CH2:26]1)[CH3:9]
Reactant: CN1CCCC(N)C1
Reactant: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1NC1CCCN(C)C1
Temperature: 190 °C
Yield: 22.4 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (8.8 mg), 1-methyl-piperidin-3-ylamine (8.0 mg) and NMP (0.5 mL) was heated at 190° C. for 30 minutes using a microwave reaction system. After the reaction liquid was cooled, the organic layer was distilled off under reduced pressure, and the residue was separated and purified by HPLC (column: SunFire® C18, 5 μm, 19 mm×100 mm, solvent: MeOH/0.1% HCOOH—H2O=10/90 (0 min)-10/90 (1 min)-95/5 (9 min)-95/5 (12 min), flow rate: 25 mL/min) to give (6-ethyl-5-[(1-methylpiperidin-3-yl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (2.4 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](B(O)O)[CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:22]=2)[CH:17]=[CH:16]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc3cc[nH]c3c2)c(-c2ccccc2)n1
Yield: 23.4 %

Procedure:
6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine (107 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and indol-6-boronic acid (0.256 g, 1.59 mmol) according to the general procedure of Example 1.