Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Yield: 48.8 %

Procedure:
2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmoles) is dissolved in methanol (100 ml), 0.6 g of palladium on carbon (10%) is added and the reaction medium is placed under a hydrogen atmosphere under 2 bars of pressure. The catalyst is filtered out and the solvent is evaporated off under reduced pressure. The residue is taken up in heptane and filtered: In this way 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained which will be used without further purification in the following stages. Pink powder. Meltine point: 123-124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 36.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.94 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16 g of 4-[4-(2,2,3,3,3pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.68 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].[F:8][C:9]([F:23])([F:22])[CH2:10][N:11]=[C:12]([NH2:21])[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>C(O)C>[F:8][C:9]([F:23])([F:22])[CH2:10][N:11]=[C:12]([NH2:21])[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([S:7][CH2:6][CH2:5][NH2:4])[N:15]=1
Reactant: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Reactant: NCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: NCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C

Procedure:
Sodium hydride (50% w/w dispersion in oil; 0.114 g.) was added portionwise to ethanol (2 ml.). To the resulting solution was added 2-aminoethanethiol hydrochloride (0.134 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]-6-chloropyrazine (0.1 g.) was added and the mixture heated under reflux on a steam bath for 22 hours. The mixture was cooled, evaporated, water added and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and the filtrate evaporated to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[(2-aminoethyl)-thio]pyrazine as a gum (0.16 g.) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:17]([CH:20]=1)[C:18]#[N:19]>CS(C)=O.[Pd]>[C:18]([C:17]1[CH:20]=[C:13]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])#[N:19]
Reactant: CCOC(=O)c1scnc1C
Reactant: CC(C)COc1ccc(Br)cc1C#N
Agent: [Pd]
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 120 °C

Procedure:
To a test tube-type reaction vessel (10 mL) were added ethyl 4-methylthiazole-5-carboxylate (85.5 mg, 0.5 mmol), 5-bromo-2-isobutoxybenzonitrile (127.1 mg, 0.5 mmol) obtained in Reference Example 3, a palladium species, a ligand, a base (1.0 mmol), an additive (0.15 mmol), and a solvent (1.7 mL). Thereafter, the reaction vessel was filled with nitrogen, heated to 120° C. under airtight seal, and the reaction mixture was stirred. After the reaction was complete, a portion of the reaction mixture was diluted with DMSO and the solution obtained was measured by HPLC. The total HPLC area % of the compounds A to D and TM was set as 100% and the calculated yield of the target material was computed from the HPLC area % of the target material. The results are shown in Table 10.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH3:23])[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:17]([CH3:23])[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: CCS(=O)(=O)N(C)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N(C)c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 101.9 %

Procedure:
A mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methyl)-ethanesulphonamide (150 mg, 0.39 mmol), 2M hydrochloric acid (4 ml) and dioxane (8 ml) was heated at reflux for 16 hours, cooled, and concentrated under reduced pressure. The solid residue was suspended in water, filtered off, and washed with water and ether to give the title compound (140 mg, 99%) as a white solid, m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>S(Cl)(Cl)=O.O.CN(C)C=O>[CH2:12]([N:14]([CH2:15][CH3:16])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:13]
Reactant: COc1ccccc1C(=O)O
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
N,N-dimethylformamide (0.52 ml, 6.70 mmol, 0.034 equiv) was added dropwise to a solution of 2-methoxy-benzoic acid (30.0 g, 197.2 mmol) in thionyl chloride (200 ml) at room temperature under an atmosphere of argon. The solution was stirred at room temperature for 45 minutes. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×100 ml). The acid chloride was dissolved in anhydrous THF (220 ml), cooled to 0° C., and diethylamine (105 ml, 1.01 mol, 5.1 equiv) was added dropwise. The suspension was stirred at 0° C. for 10 minutes, when TLC analysis indicated complete conversion. The reaction mixture was diluted with water (50 ml) and extracted three times with EtOAc. The combined organic layers were washed with water (100 ml) and concentrated aqueous NH4Cl solution (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 6:4 to 3:7) afforded the title compound (40.87 g, quant.). 1H NMR (400 MHz, CDCl3): δ=7.31 (ddd, J=9.0/7.3/1.7 Hz, 1H), 7.17 (dd, J=7.1 Hz/1.5 Hz, 1H), 6.95 (dt, J=7.5/1.0 Hz, 1H), 6.89 (br d, J=8.3 Hz, 1H), 3.80 (s, 3H), 3,62-3.48 (br m, 2H), 3.13 (q, J=7.4 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H). MS (ES+): 208 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:15]2[C:16]([CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:37])[CH3:36])=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[C:16]([CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:37])[CH3:36])=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:12][N:13]=1)[CH3:6]
Reactant: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(N)nc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.003 ml of ethyl chloroformate was added to a pyridine (1 ml) solution of 14.4 mg of 1-(2-(6-(6-amino-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 340 (step 1), and the reaction liquid was stirred at room temperature for 30 minutes. The reaction liquid was distilled under reduced pressure, and the resulting residue was dissolved in 1 ml of trifluoroacetic acid, and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was distilled under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] and through silica gel column chromatography (developing solvent: chloroform/methanol=9/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]2[N:26]=[C:25]3[N:17]([C:18](=[O:31])[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20]4[N:21]=[CH:22][NH:23][C:24]=43)[N:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]2[N:26]=[C:25]3[N:17]([C:18](=[O:31])[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20]4[N:21]=[C:22]([Br:32])[NH:23][C:24]=43)[N:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCn1c(=O)n2nc(CCc3nc(Cc4ccccc4)no3)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCn1c(=O)n2nc(CCc3nc(Cc4ccccc4)no3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-4-butyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (40 mg, 0.096 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature overnight, the reaction was quenched with phenol. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method A) to give desired product as white powder. LCMS calculated for C21H22BrN8O2 (M+H): 497.1. found: 497.0, 499.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2cc(Cl)ccc21
Yield: 91 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 5-chloroindole for the 3-methylindole, the title compound (2.0 g, 91%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[NH2:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2cc(C#N)ccn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(N)CCN(c2cc(C#N)ccn2)CC1
Temperature: 80 °C
Yield: 101.3 %

Procedure:
A mixture of (4′-cyano-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-carbamic acid benzyl ester (240 mg), ammonium formate (300 mg), and Pd/C (20 mg) in isopropyl alcohol (8 mL) was heated at 80° C. for 30 min. The reaction mixture was cooled and filtered through diatomaceous earth to provide 4-amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carbonitrile (150 mg) as a foam. MS (CI) m/z 217 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.54 (s, 1H), 8.06 (d, 1H), 6.89 (d, 1H), 4.02-3.85 (m, 2H), 3.40-3.32 (m, 2H), 1.81-1.78 (m, 4H), 1.35 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]=[C:6](Cl)[S:5][N:4]=1.[CH2:9]1[O:13][CH2:12][O:11][CH:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:13]1[CH2:9][CH:10]([CH2:14][O:15][C:6]2[S:5][N:4]=[C:3]([S:2][CH3:1])[N:7]=2)[O:11][CH2:12]1
Reactant: CSc1nsc(Cl)n1
Reactant: OCC1COCO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCC2COCO2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To 10 ml of N,N-dimethylformamide, 835 mg of 3-methylthio-5-chloro-1,2,4-thiadiazole and 520 mg of glycerol formal were dissolved, and added 204 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 20 minutes and at room temperature for 30 minutes. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. After the organic layer was dried by anhyrous sodium salfate, the organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography (hexane:ethyl acetate=20:1), followed preparative HPLC to obtain 250 mg of 5-(1,3-dioxolane-4-yl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17](=[O:20])[CH2:18]Cl)[CH2:15][CH2:14][NH:13][C:12]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17](=[O:20])[CH2:18][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:15][CH2:14][NH:13][C:12]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2C(=O)NCCN2C(=O)CCl)cc1OC
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(=O)NCCN2C(=O)CN2CCOCC2)cc1OC

Procedure:
7.8 g of the 3-(3,4-dimethoxyphenyl)-4-chloroacetylpiperazin-2-one prepared in accordance with Example 7, 50 ml of toluene and 4.5 g (0.05 mol) of morpholine are boiled under reflux for 3 hours. The reaction mixture is then concentrated in vacuo, an aqueous solution of potassium carbonate is added to the residue and the mixture is extracted by shaking with methylene chloride. The organic phase is separated off and the methylene chloride is removed by evaporation.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[OH:39][CH2:38][C:37]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][C:8]([NH:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16]([CH3:18])[N:17]=1)=[O:9])=[O:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([NH:6][CH2:7][C:8]([NH:10][NH:11][C:12]1[NH:13][N:14]=[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]([CH3:18])[N:17]=1)=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)NCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)NCC(=O)NNC1=NC(C)C(c2ccccc2)=NN1
Yield: 65.6 %

Procedure:
A solution of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.815 g) in ethanol (32 ml) containing anhydrous hydrogen chloride was shaken with 5% palladium on carbon (0.4 g) under atmosphere of hydrogen gas at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off, and the filtrate was evaporated. The residue was dissolved in water and made alkaline with an aqueous solution of sodium bicarbonate under ice cooling. The resulting precipitates were collected by filtration, washed with water, dried, and recrystallized from ethanol to give colorless crystals of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (1.198 g), m.p. 144.5°~145.5° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[CH2:4][NH:5][S:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7].C1(=O)C=CC(=O)C=C1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)C>[CH2:21]([C:20]1[N:5]([S:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:7])=[O:8])[CH2:4][C:3]2[C:15]([CH:19]=1)=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CCS(=O)(=O)NCc1c(F)cccc1CC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCS(=O)(=O)N1Cc2c(F)cccc2C=C1Cc1ccccc1
Yield: 50.3 %

Procedure:
Under an argon atmosphere, 20 mg of N-(2-fluoro-6-cinnamylbenzyl)-2-methoxycarbonylethanesulfonamide, 3 mg of PdCl2(CH3CN)2, 6 mg of benzoquinone, 21 mg of lithium chloride, and 12 mg of sodium carbonate were dissolved in 1 mL of THF, followed by stirring under reflux for 36 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and to the filtrate was added water, followed by extraction with diethyl ether. Then, the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PTLC (n-hexane:ethyl acetate=1:1) to obtain 10 mg (yield 46%) of a title compound as a yellow solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O[CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2.C(O)(=O)C.C(O)(=O)C.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(CC(=O)C[C@@H]1C)=C[C@H]3C>>[C:1]([O:4][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([OH:25])[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(=O)O
Agent: C[C@@H]1C=C2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: CC(=O)OC[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
Substituting 19-hydroxy-5-androsten-17-one acetate for the 17β,19-dihydroxy-1α,7α-dimethyl-5-androsten-3-one diacetate above, results in the formation of 5-androstene-17β,19-diol 19-acetate.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](Cl)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][C@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>O1CCOCC1>[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N:30]2[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:25])[CH2:31]2)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
Solid Na2CO3 (400 mg, 3.8 mmol, 3.8 eq) is added to a solution of 1-benzyl-4-chlorophthalazine (250 mg, 0.98 mmol, 1 eq) and (5)-2-methyl-piperazine (400 mg, 4.0 mmol, 4.0 eq) in dioxane (5 mL). The resulting suspension is heated at 100° C. for 48 h. The reaction mixture is concentrated, EtOAc (50 mL) and water (15 mL) are added. The organic fraction washed with water and then brine, then is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the title compound as a white solid (200 mg, 64% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.C(N(C(C)C)CC)(C)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>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH3:16])[N:21]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformamide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[C@H:11]1[O:16][CH2:15][C@@H:14]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]2[CH2:12]1.[CH:28]1([B-](F)(F)F)[CH2:30][CH2:29]1.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].COC1CCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:8]([C:7]1[C:2]([CH:28]2[CH2:30][CH2:29]2)=[C:3]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:4]=[CH:5][C:6]=1[F:10])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](c3ccc(F)c(C#N)c3Cl)OC[C@@H]2C1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: COC1CCCC1
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](c3ccc(F)c(C#N)c3C3CC3)OC[C@@H]2C1
Temperature: 100 °C

Procedure:
To a microwave vial was charged with (3R,9aS)-tert-butyl 3-(2-chloro-3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (30 mg, 0.076 mmol), potassium cyclopropyltrifluoroborate (16.8 mg, 0.114 mmol), Pd(OAc)2 (1.7 mg, 7.58 μmol), X-Phos (7.2 mg, 0.015 mmol), and potassium carbonate (31.4 mg, 0.227 mmol). CPME (0.4 mL) and Water (40 μL) were added, and the reaction mixture was degassed with N2 and heated at 100° C. for 24 h. The reaction mixture was filtered to give the crude product, which was purified by prep-TLC (1000 μm, 5% MeOH/DCM) to give the title compound: LC/MS: [(M+1-56)]+=346.3.
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[C:2]#[CH:3].C(N(CC)CC)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].CCOCC>C1COCC1>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15]
Reactant: C#CC(=O)OCC
Reactant: Oc1ccccc1Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C=COc1ccccc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a stirring solution of 972 mg (11.56 mmol) of ethyl propiolate in 20 mL of THF at 0° C. is added a solution of 1.61 mL (11.56 mmol) of triethylamine in 5 mL of THF, followed by a solution of 2.0 g (11.56 mmol) of 2-Bromophenol in 5 mL of THF. The resulting clear orange-brown solution is stirred 5 h at 0° C., then poured into 100 mL of Et2O and extracted with H2O (1×100 mL). The organic layer is separated and washed with sat. Na2CO3 (1×100 mL), dried (MgSO4), and the solvent removed in vacuo to provide 2.97 g of the title compound as an orange oil which is used without any further purification: 1H NMR (CDCl3, 300 MHz) δ7.71 (d, 1H, J=12.3), 7.61 (d, 1H, J=7.4), 7.37-7.08 (m, 3H), 5.47 (d, 1H, J=12.3), 3.72 (s, 3H); Rf =0.40 in hexane/EtOAc 5/1.