Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][C:24]1[C:28]([S:29]([NH2:32])(=[O:31])=[O:30])=[C:27]([CH3:33])[O:26][N:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([C:28]2[C:24]([CH3:23])=[N:25][O:26][C:27]=2[CH3:33])(=[O:30])=[O:31])=[O:21])=[CH:19][CH:18]=1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1c(C)noc1C

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 3,5-dimethyl-isoxazole-4-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C17H19FN3O7S: 428.1; found: 428.0. 1H NMR (500 MHz, CDCl3) δ: 2.44 (s, 3), 2.75 (s, 3), 3.65 (s, 3), 4.77 (s, 2), 6.45 (s, 1), 7.01 (m, 2), 7.26 (m, 2). 13C NMR (125 MHz, CDCl3) δ:10.83, 13.24, 48.33, 63.23, 92.57, 114.23, 115.71, 115.89, 130.19, 130.29, 130.96, 157.85, 158.89, 159.44, 161.71, 163.68, 170.81, 177.09.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CN(C)C=O.Br[CH2:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[Cl:29].Cl.CO>CO>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:18][C:19]2[CH:24]=[C:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:22]=[CH:21][C:20]=2[Cl:29])[CH:9]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cl)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 2.8 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in 35 N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-1-chloro-4-(methylsulfonyl)benzene (0.30 g), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate100%→ethyl acetate:methanol=4:1) to give a yellow solid. The obtained solid was dissolved in methanol, and 2N hydrochloric acid-methanol solution (0.1 ml) was added. The solvent was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate to give the title compound (5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C@H:12]2[CH2:16][O:15][C:14]([NH2:17])=[N:13]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:16][O:15][C:14]([NH2:17])=[N:13]2)=[CH:6][CH:5]=1
Reactant: NC1=N[C@@H](/C=C/c2ccc([N+](=O)[O-])cc2)CO1
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(N)cc2)CO1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
(S)-4-[(E)-2-(4-Nitro-phenyl)-vinyl]-4,5-dihydro-oxazol-2-ylamine (0.95 g) was dissolved in methanol (40 ml) before addition of Pd/C 10% (95 mg). The reaction mixture was hydrogenated for 1 hour at room temperature and then the catalyst was filtered off and washed with methanol. The residue was concentrated in vacuo and purified by Isco chromatography (column: Silicycle Si-Amine, AcOEt) to afford (S)-4-[2-(4-amino-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine (800 mg) as an off-white solid. MS (ISP): 206.2 ([M+H]+).
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]#[N:16]>C(O)C.N>[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]([NH2:16])=[O:1]
Reactant: OO
Reactant: N#Cc1cnn(C2CCCCC2)c1N
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18 ml of 30% strength hydrogen peroxide solution are added to a solution of 5-amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile (1.86 g, 9.81 mmol) in a mixture of 73 ml of ethanol and 90 ml of concentrated aqueous ammonia solution at room temperature, and the mixture is stirred at room temperature for 1 h. The nonaqueous solvents are then stripped off in a rotary evaporator. The product precipitates as solid from the remaining mixture and is filtered off with suction, washed with a little water and dried under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([C:12]#[N:13])[CH2:11][CH2:10]1.[OH-:14].[Na+].OO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([C:12]([NH2:13])=[O:14])[CH2:10][CH2:11]1
Reactant: [OH-]
Reactant: N#CC1(c2c(F)cccc2F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)C1(c2c(F)cccc2F)CC1
Yield: 84 %

Procedure:
1-(2,6-Difluorophenyl)cyclopropanecarbonitrile (5.42 g) was hydrolyzed at ambient temperature with an aqueous solutions of 5N sodium hydroxide (20 mL), 55% tetrabutylammonium hydrogensulfate (0.5 mL) and 30% hydrogen peroxide (5 mL) in toluene (5 mL) for 39 hours. The prepared semi-solid reaction mixture was diluted with ethyl acetate and the phases were separated. The aqueous phase was neutralized with 5% hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were washed with 5% hydrochloric acid, then brine, and dried over anhydrous sodium sulfate. Filtration and evaporation gave 1-(2,6-difluorophenyl)cyclopropanecarboxylic acid amide as light-brown solid (4.98 g, 84% yield). M.p. 136.7-137.6° C. (from ethyl acetate). GC/MS: m/z 197 (purity 97.5%, RT 9.85 min.). 1H-NMR (DMSO-d6): δ 7.43-7.34 (m, 1H), 7.10-7.01 (m, 2H), 6.96 (br s, 1H), 6.64 (br s, 1H), 1.50-1.46 (m, 2H), 1.00-0.97 (m, 2H). 1H-NMR (CDCl3): δ 7.61-7.26 (m, 1H), 6.98-6.90 (m, 2H), 5.44 (br s, 2H), 1.79-1.74 (m, 2H), 1.17-1.12 (m, 2H). 13C-NMR (DMSO-d6): 173.4, 164.2, 160.9, 130.3, 116.5, 112.1, 19.05, 15.8.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=O.CO.Cl>O1CCCC1>[N+:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:3][OH:2])[NH:6][CH2:7]2)=[CH:12][CH:11]=1)([O-:17])=[O:16]
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CNC(CO)C2
Yield: 38.7 %

Procedure:
To 7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (5.0 g, 21.2 mmol) in dry tetrahydrofuran (18.5 ml) was added 10M borane-methyl sulfide complex (2.4 ml). The mixture was heated at reflux for 1.5 h while distilling off the methyl sulfide formed. The reaction mixture was cooled and methanol (2.7 ml) was added cautiously followed by 6N hydrochloric acid (5.4 ml). The mixture was then refluxed for 2.5 h and concentrated to dryness under reduced pressure. The solid residue was dissolved in water, the solution basified with 2.5N sodium hydroxide solution and the product extracted into dichloromethane. The crude product was purified by chromatography using silica gel and 5% methanol saturated with ammonia in dichloromethane to yield 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-methanol (1.71 g).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:27]([OH:29])[CH3:28])[C:14]([NH:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[O:26][C:14]([C@H:13]([NH:12][C:6]3[C:7]4[CH:11]=[CH:10][S:9][C:8]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@@H:27]([OH:29])[CH3:28])=[N:16][N:17]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.53 g, 1.29 mmol) in THF (90 mL) was added PS-BEMP (1.76 g, 3.87 mmol, ˜2.2 mmol/g) and p-TsCl (265 mg, 1.39 mmol) at room temperature. The mixture was stirred at room temperature for 8 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (139 mg, 27%) and the dehydration product 4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (8 mg, 2%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.20 (dd, J=4.7, 8.4 Hz, 1H), 4.78 (b, 1H), 4.63 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.11 (dd, J=5.3, 8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.6 Hz, 2H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: [N+](C1C=CC=CC=1F)([O-])=O.NC1(SC2C=C(F)C=CC=2)C=CC=CC1.C1([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)C=CC=CC=1>>[F:48][C:45]1[CH:44]=[CH:43][C:42]2[S:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[NH:34][C:33](=[O:32])[C:47]=2[CH:46]=1
Reactant: O=C(Nc1ccccc1Sc1ccc(F)cc1)Oc1ccccc1
Agent: NC1(Sc2cccc(F)c2)C=CC=CC1
Agent: O=[N+]([O-])c1ccccc1F
Product: O=C1Nc2ccccc2Sc2ccc(F)cc21

Procedure:
Thus, 1-chloro-2-nitrobenzene may be reacted with 4-fluorobenzenethiol in the presence of a base to form 1-nitro-2-phenylsulfanyl-(4-fluorobenzene). The nitrofluorobenzene may be reduced to 1-amino-2-phenylsulfanyl-(4-fluorobenzene) which can converted (for example, as shown) to [2-(4-fluoro-phenylsulfanyl)-phenyl]-carbamic acid phenyl ester. Such an ester may be cyclized as shown to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, which can then be reacted with piperazine to form the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1

Procedure:
A solution of 1,1-dimethylethyl 9-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 63) (9 g, 22.65 mmol), zinc cyanide (3.99 g, 34.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.62 g, 2.265 mmol) in DMF (90 ml) was heated at 80° C. for 24 hrs. The reaction was cooled, diluted with EtOAc (400 ml) and water (400 ml) and filtered to remove insoluble material. The filtrate was separated and the organic layer washed with water, dried over magnesium sulphate and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:9 then 1:3 to give the title compound (5.1 g) as a colourless oil. MS (ES): C15H18N2O3 requires 274; found 174 [M+H−100]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:20]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCCCC1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a 3-neck round-bottomed flask was added zinc powder (0.40 g, 6.12 mmoL) followed by anhydrous THF (15 mL). To the stirred suspension was slowly added TiCl4 (0.32 mL, 0.55 g, 2.9 mmoL) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2 h. To the reaction mixture was added a solution of methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.193 g, 0.75 mmoL) and cyclooctanone (0.31 g, 2.46 mmoL) in anhydrous THF (5 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere to 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (5 mL) followed by 10% K2CO3 (5 mL). The reaction mixture was filtered through a pad of Celite with the aid of H2O and EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was dried (MgSO4), filtered, and the filtrate was concentrated to give a yellow oil. The crude product was purified by flash chromatography on silica gel with a CH2Cl2:MeOH gradient (100:0 to 95:5) to give 0.159 g (60%) of compound 158 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 1.36-1.54 (m, 8 H), 1.59 (m, 2 H), 2.14 (m, 2 H), 2.20 (m, 2 H), 3.80 (s, 3 H), 6.67 (d, J=8.3 Hz, 2 H), 6.93 (d, J=8.3 Hz, 2 H), 7.26 (d, J=8.1 Hz, 2 H), 7.87 (d, J=8.1 Hz, 2 H), 9.30 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[N:34]=2)[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN1CCCC1=O>[C:36]([NH:35][C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]3[CH:23]=[C:22]([NH:21][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]5([C:1]#[N:2])[CH2:4][CH2:5]5)[CH:7]=4)[CH:41]=[CH:40][CH:39]=3)=[N:31][N:30]2[CH:32]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (1.50 g, 8.01 mmol) in tetrahydrofuran (30 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (1.16 mL, 13.3 mmol), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure, and the residue and N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (1.89 g, 6.67 mmol) were dissolved in N-methylpyrrolidone (30 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (2.25 g, 75%) as a pale-brown powder.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:24]2([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]2)[O:23][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH:14]=[CH:13][C:12](=[O:22])[CH2:11]2.[O:31]1CCCC1.[OH-].[Na+].OO>C(OCC)(=O)C.CO>[O:31]1[C@H:13]2[C:12](=[O:22])[CH2:11][C@H:10]3[C@:15]([CH3:16])([C@@H:14]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@H:3]1[C@@H:2]([C@:24]4([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]4)[O:23][C@H:4]1[CH2:5]2)[CH3:1])[CH2:8][CH2:9]3
Reactant: C1CCOC1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)C=C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@@H]6O[C@@H]6[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of (5α,25R)-spirost-1-en-3-one (2.87 g, 6.96 mmol), tetrahydrofuran (30 mL), methanol (50 mL) and 15% sodium hydroxide (1 mL) was stirred under nitrogen atmosphere. The mixture was cooled to 0° C. and 30% hydrogen peroxide (5 mL) was added. The reaction mixture was gradually warmed to room temperature and stirred for 4 hours. The reaction was diluted with ethyl acetate, cooled to 0° C., and then quenched with saturated sodium bisulfite solution. The mixture was washed with saturated sodium bisulfite (2×), brine (1×), dried (sodium sulfate), filtered and concentrated in vacuo to give 2.64 g, (88%) of the title compound.
Reaction SMILES: C1COCC1.[BH4-].[Na+].[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].N>O.C(O)(=O)C>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -7.5 °C
Reaction time: 2.5 h

Procedure:
In a 250 mL round bottom flask dry THF (35 mL) was taken. It was cooled to −10 to −5° C. and NaBH4 (2.0 g) was added. After that acetic acid (33.7 mL) was added dropwise at −5 to 0° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazol o[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added into the reaction mixture, keeping the temperature between −2 to 0° C. It was stirred for 2-3 h at −5 to 0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.2 g, % Y-83.6%, % Purity by HPLC-60.1%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[F:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(F)c1F
Yield: 72 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,3-difluorobenzoyl chloride (72 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 67 mg of 2,3-difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 206 %

Procedure:
To a solution of 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.51 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.96 ml) and water (0.96 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were recrystallized from ethanol to give 7-(2-chloro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 162) (1.5 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[C:7]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Clc1nccnc1Cl
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nccnc2-c2cc(C)cc(C)c2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
First, 5.00 g of 2,3-dichloropyrazine, 10.23 g of 3,5-dimethylphenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.55 g of 3,5-dimethylphenylboronic acid, 1.80 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1. The solvent was distilled off, and the obtained solid was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that Hdmdppr (abbreviation), which was the pyrazine derivative to be produced, was obtained as a white powder in a yield of 44%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (f-1).