Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].CC([Si](C)(C)[O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=1)[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14])(C)C>C1COCC1>[CH3:32][C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][C@@H:25]([O:24][C:22]1[CH:21]=[C:12]([CH:11]=[C:10]([OH:9])[CH:23]=1)[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14])[CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O[Si](C)(C)C(C)(C)C)cc(C(=O)Nc2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
An aqueous solution of lithium hydroxide monohydrate (0.304 g, 7.25 mmol) was added to a solution of 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide (1.552 g, 2.90 mmol) in THF (40 mL) and stirred at RT overnight. The THF was removed in vacuo and the residual solution adjusted to pH 7 by addition of 1N hydrochloric acid (7.25 mL). A gum formed, and the solution was filtered and the gum dissolved in methanol. The filtrate was partitioned with ethyl acetate (75 mL) and the organics washed with brine, dried (MgSO4), combined with the methanol solution and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give the required product (0.865 g)
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[NH:15][CH:14]=[N:13][CH:12]=1.[H-].[Na+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: c1ncc(-c2ccc3c(c2)CCCC3)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Yield: 50.1 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1H-imidazole(387 mg, 1.95 mmol), NaH (60%, 76 mg, 1.89 mmol), and SEMCl (474 uL, 2.28 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (321 mg, 52%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.92 (t, 2H, J=9.0 Hz), 1.80-1.83 (m, 4H), 2.77-2.81 (m, 4H), 3.51 (t, 2H, J=9.0 Hz), 5.28 (s, 2H), 7.08 (d, 1H, J=9.0 Hz), 7.29 (s, 1H), 7.48 (d, 1H, J=6.0 H z), 7.54 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:40]I)(=[O:33])=[O:32])=[CH:27][CH:26]=1>O1CCCC1.CCCCCC.CN(C)P(=O)(N(C)C)N(C)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:40][CH2:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=S(=O)(NCCCCC(CI)CCCOC1CCCCO1)c1ccc(Cl)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCOC1CCCCO1
Reaction time: 0.25 h

Procedure:
To a solution of 0.11 ml cyclohexyl-isopropylamine (0.68 mmol) in 1 ml dry tetrahydrofuran at 0° is added dropwise 0.23 ml (0.57 mmol) of a 2.5M solution of n-butyllithium in hexane. The mixture is allowed to stir for 15 min at 0°. The reaction mixture is then cooled to -78° and 0.077 ml (0.57 mmol) t-butyl acetate is added and the mixture is stirred at -78° for 0.5 h. Then a solution of 0.12 g (0.22 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(tetrahydropyranyloxy)propyl]-1-iodo-hexane in 0.5 ml hexamethylphosphoric triamide is added followed by 1 ml dry tetrahydrofuran. The reaction temperature is raised to -23° and allowed to warm to 0° over a period of 1 h. The reaction is then quenched by the addition of 5 ml saturated aqueous ammonium chloride solution and extracted with ether. The organic layer is washed with water (3×25 ml) and brine, dried, filtered and concentrated to give a yellow oil which is chromatographed using 3:7 ethyl acetate/hexane to yield t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(tetrahydropyranyloxy)propyl]-octanoate; NMR (CDCl3): delta 2.2 (t,2H), 1.6 (s,9H); IR (neat): 1721 cm-1.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH:35]2[CH2:37][CH2:36]2)[N:17]2[CH2:22][CH2:21][C:20]([CH2:29][C:30]3([CH3:33])[CH2:32][O:31]3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])=[CH:12][CH:11]=1>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH:35]2[CH2:37][CH2:36]2)[N:17]2[CH2:22][CH2:21][C:20]([CH2:29][C:30]([OH:31])([CH3:33])[CH3:32])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])=[CH:12][CH:11]=1
Reactant: CC1(CC2(c3ccccc3)CCN(C(c3ccc(Br)cc3)C3CC3)C(=O)O2)CO1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(c2ccc(Br)cc2)C2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium triethylborohydride (1 mol/L in tetrahydrofuran, 4.9 mL) was added to an ice-cold solution of 3-[(4-bromo-phenyl)-cyclopropyl-methyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one (compound processed from diastereomer 2 obtained in Step 3; 1.86 g, ca. 85-90% pure) in tetrahydrofuran (15 mL) at such a rate that the solution temperature remained below 10° C. The resulting solution was stirred in the cooling bath for one more hour and at room temperature for another 3 h. Then, the solution was cooled in an ice bath and the reaction was quenched by the careful addition of water (7 mL). After the addition of hydrochloric acid and ethyl acetate, the organic phase was separated, washed with brine, and dried (MgSO4). The solvent was evaporated to afford the title compound. Yield: 1.45 g (88% of theory); Mass spectrum (ESI+): m/z=458/460 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)F

Procedure:
2.68 ml of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole and 1.8 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was successively washed with diluted hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether as a developer. The crystals thus obtained were recrystallized from petroleum ether/diethyl ether to give 0.47 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-fluorophenyl)thiazole. The melting point of this product was from 193° to 195° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
In a similar manner as described above in Paragraph A, a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1 g, 4.5 mmol) and 4-(4-chlorophenoxy)aniline (1 g, 5 mmol) in dichloromethane was stirred as acetic acid (0.39 g, 6.5 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (2 g, 9.4 mmol) was added and the reaction was stirred for 3 days. The reaction was treated with aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 1.3 g of 1,1-dimethylethyl 4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinecarboxylate.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=O)[CH:2]=1.C[Li].[CH3:21]COCC.[Cl-].[NH4+]>C1COCC1>[C:16]([C:3]1[CH:2]=[CH:1][C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=1)(=[O:18])[CH3:21]
Reactant: CCOCC
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of dibenzo[b,f]thiepin-3-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) (415 mg, 1.63 mmole) in THF (20 mL) at 0° C. there was added methyl lithium in ether 1.4M (2.56 mL, 3.59 mmol); the mixture was stirred at 0° C. for 1 hour, then poured onto a well-stirred saturated aqueous ammonium chloride solution (100 mL). The organic phase was collected, washed twice with brine, dried and evaporated. Column chromatography on silica gel, eluting with a 1:2 mixture of ethyl acetate-hexane, afforded the title compound as a yellow solid (320 mg), m.p.: 82°-84° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1[C:7]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ncc(N)nc1C
Reactant: OCc1ccccc1
Product: Cc1nc(N)c(OCc2ccccc2)nc1C

Procedure:
The known 2-amino-5,6-dimethylpyrazine can be brominated by Preparation 72, Step A method, and then reacted with benzyl alcohol by Preparation 45 method to provide 2-amino-3-benzyloxy-5,6-dimethylpyrazine. The 2-amino group is converted to the 2-hydroxy by the method described by Sharp et al, ibid., (see Route III) which when treated with phosphorus oxychloride by Preparation 13, Step B method, there is obtained 2-chloro-3-benzyloxy-5,6-dimethylpyrazine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:15][C:16]1[CH:21]=[C:20]([CH2:22][S:23][C:24]2[C:29]([C:30]([NH:32][C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=3)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:19]=[CH:18][N:17]=1)(=[O:14])[CH3:13]>C(Cl)Cl.C(OCC)(=O)C>[C:12]([NH:15][C:16]1[CH:21]=[C:20]([CH2:22][S:23]([C:24]2[C:29]([C:30]([NH:32][C:33]3[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=3)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:9])[CH:19]=[CH:18][N:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(CS(=O)c2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Reaction time: 1 h
Yield: 48 %

Procedure:
m-Chloroperbenzoic acid(75%, 60 mg, 0.26 mmol) was added to a solution of 2-(2-acetylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound No. 4-1, 60 mg, 0.15 mmol) in methylene chloride (3 mL) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), the whole was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) twice and brine (10 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was filtered off with ethyl acetate to give 30 mg of the target compound as a colorless solid. (Yield 48%)
Reaction SMILES: C([S:4][CH:5]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>CO>[SH:4][CH:5]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(=O)O)SC(C)=O
Agent: N
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)NCC(=O)O

Procedure:
A solution of 2-[3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid (E14, Isomer A; 15 mg, 0.029 mmol) in nitrogen-purged methanol (5 ml) was cooled in ice and treated with 35% aqueous ammonia (0.3 ml). After 2 h the solvents were evaporated in vacuo and the residue was triturated with ethyl acetate to give the title compound as a single isomer (Isomer A), 11 mg (80%), mp 228°-231° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].Cl[C:17](=[CH2:20])[C:18]#[N:19]>O>[C:18]([C:17]1[N:3]=[N:2][N:1]([CH:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][C:5]2=[O:15])[CH:20]=1)#[N:19]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1cn(C2CCc3ccccc3NC2=O)nn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 3-azido-2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine (1.01 g) and 2-chloro-acrylonitrile (0.95 g) in water (5 ml) is stirred at about 80° C. for 18 hours. Excess 2-chloro-acrylonitrile is distilled off in vacuo, and the precipitated product is filtered off, washed with water and dried (yield 1.1 g; 87% of theory), m.p. 214-216° C. (recrystallization from ethyl acetate/toluene).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=O.[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:17]([O:24][CH2:25][CH2:26][N:27]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[C:3]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COCCNc2ccccc2)cc1
Reactant: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: O=C(C1CCCc2c1c1ccccc1n2CCOCc1ccccc1)N1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) (1.5 g, 5.2 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21) (3.2 g, 10.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (5 mL) and dry zinc chloride (2.13 g, 15.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude material was purified by SCX cartridge and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (30-100% B, 12 g, 41 CV, 30 mL/min) to afford 600 mg (27%) of [9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (22) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.5, 21.7, 24.5, 25.7, 26.3, 273, 37.7, 42.8, 43.1, 46.7, 60.2, 68.7, 73.1, 108.2, 108.7, 117.8, 118.9, 120.5, 126.4, 127.3, 127.4, 128.1, 136.2, 137.8, 172.9.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 113 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:51][CH2:50][CH:49]([CH2:52]O)[CH2:48][O:47]1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:52][CH:49]([CH2:50][OH:51])[CH2:48][OH:47])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (85 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (134 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (45 mg), and diethylazodicarboxylic acid (0.1 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (41 mg, yield 39%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH2:29]>ClCCl.C1COCC1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:28][NH:29][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][CH:11]=1)[CH3:35]
Reactant: CCOC(=O)CNN
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CNNC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
At 0° C., to a solution of 4-isopropylbenzoic acid (3.28 g, 20.0 mmol), triethylamine (2.12 g, 2.93 mL, 21.0 mmol) in dichloromethane/THF (15 mL/5 mL), is added isobutylchloroformate (2.87 g, 2.72 mL, 21.0 mmol). The mixture is stirred at 0° C. for 20 min. with warming to room temperature over 2 hr., and then treated with ethyl hydrazinoacetate (2.18 g, 21.0 mmol) and stirred overnight. The mixture is then washed with water, brine and dried over Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, 5:1 dichloromethane-ethyl acetate) to provide ethyl[2-(4-isopropylbenzoyl)hydrazino]acetate (4.85 g, 97%). MS (ES+): m/e 251.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[N:9][N:10]=2)[CH:7]=1.[O:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)=[N:9][N:10]=3)[CH:7]=2)[CH2:23][CH2:22]1
Reactant: FC(F)(F)c1cccc(-c2nnc3ccc(I)cn23)c1
Reactant: NC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(-c2nnc3ccc(NC4CCOCC4)cn23)c1
Temperature: 110 °C

Procedure:
To a suspension of 6-iodo-3-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine (0.101 g, 0.26 mmol) and tetrahydro-2H-pyran-4-amine (0.131 g, 1.30 mmol) in toluene (1 mL) was added rac-Binap (0.049 g, 0.078 mmol), Pd(OAc)2 (0.012 g, 0.052 mmol) and Cs2CO3 (0.169 g, 0.52 mmol). It was flushed with argon then heated at 110° C. overnight. It was absorbed on SiO2 and purified on column chromatography on SiO2 with 60% 15% MeOH/EA in hexane. This product was further purified on C18 column chromatography using 20-40% ACN in water.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][O:25]2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCCO3)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(tetrahydrofuran-2-yl)methanone, the title compound was obtained as a white solid (47% yield). 1H NMR (400 MHz, CDCl3) δ 8.12-7.88, 6.97, 4.64-4.60, 3.93-3.42, 2.56-2.35, 2.10-1.93, 1.52-1.38, 0.84-0.62, 0.50-0.38, 0.17-0.05. MS (ES+) m/z 374.3 (M+1).