Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:7]=1[CH2:8][NH:9][C:10]([C@:12]1([CH:24]([CH3:26])[CH3:25])[CH2:16][CH:15]([N:17]2C(C)=CC=C2C)[CH:14]=[CH:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].Cl.ON.[OH-].[Na+]>CO.O.CCOC(C)=O>[NH2:17][CH:15]1[CH2:16][C@@:12]([CH:24]([CH3:26])[CH3:25])([C:10]([NH:9][CH2:8][C:7]2[CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:6]=2[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:11])[CH:13]=[CH:14]1
Reactant: Cc1ccc(C)n1C1C=C[C@@](C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)(C(C)C)C1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(N)C1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
A mixture of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxamide (46 g, 97 mmol),hydroxyanime HCl (41 g, 580 mmol), and hydroxyamine (50% in H2O, 50 mL) in MeOH:H2O (2:1, 450 mL) was heated to 70° C. for 11 hr until no more starting material left as judged by HPLC. The reaction mixture was then cooled to r. t., the pH was adjusted to 11.0 with 1 N NaOH, and it was diluted with EtOAc. The aqueous phase was then extracted with EtOAc (5×). The organics were then combined, dried over sodium sulfate and evaporated to dryness to give 35 g of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropylcyclopent-2-ene-1-carboxamide as a yellow oil that crystallized upon standing.
Reaction SMILES: C(OC(C1N(CC2C3C=C(F)C=CC=3SC=2)C2C(C=1CN)=CC=CC=2)=O)C.Cl.C([O:31][C:32]([C:34]1[N:35]([CH2:49][C:50]2[C:51]3[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:52]=3[S:53][CH:54]=2)[C:36]2[C:41]([C:42]=1[CH2:43][NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])C>>[F:59][C:57]1[CH:56]=[CH:55][C:52]2[S:53][CH:54]=[C:50]([CH2:49][N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:42]([CH2:43][NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[C:34]3[C:32]([OH:33])=[O:31])[C:51]=2[CH:58]=1
Reactant: CCOC(=O)c1c(CNS(C)(=O)=O)c2ccccc2n1Cc1csc2ccc(F)cc12
Agent: CCOC(=O)c1c(CN)c2ccccc2n1Cc1csc2ccc(F)cc12
Agent: Cl
Product: CS(=O)(=O)NCc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12

Procedure:
3-Aminomethyl-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride was converted to 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid as a colorless solid. MS: 431.3 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.CCN(CC)CC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH2:17][CH2:16]3)[N:3]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccc3c(c2)CCC3)c2nc[nH]c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
2,6-Dichloro-9H-purine (1.89 g, 10 mmol), 5-aminoindan (1.33 g, 10 mmol) and Et3N (2.79 mL, 20 mmol) were dissolved in BunOH (15 mL). The solution was stirred for 2 h at 90° C. After cooling, PriOH (90 mL) was added slowly with stirring. After 1 h the precipitate was filtered, washed successively with small quantities of PriOH and Pri2O, and dried in vacuo to afford the title compound as a lemon-coloured powder (1.54 g, 54.1%). TLC (80:15:5 CHCl3/MeOH/AcOH): RF=0.61.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](O)[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 7.7 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (200 mg, 1.44 mmol) and 3-dimethylaminopropyl chloride hydrochloride (114 mg, 0.72 mmol) in order. The mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (14% methanol/chloroform) to give the subject compound (13 mg, yield 7%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:13][NH2:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH3:2][C:3]1([CH2:13][NH:14][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC1(CN)CCCc2ccccc21
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: CC1(CNc2cnccc2C(=O)O)CCCc2ccccc21
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from 1-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.24 (br s, 1H), 8.31 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.45 (br s, 1H), 7.42 (d, 1H, J=7.3 Hz), 7.05-7.15 (m, 3H), 3.44-3.57 (m, 2H), 2.72 (t, 2H, J=6.4 Hz), 1.59-1.92 (m, 4H), 1.32 (s, 3H). [M+H] calc'd for C18H20N2O2, 297; found 297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9](=[CH:15][N:16](C)C)[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[F:22].O.[CH2:24]([OH:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([CH:15]=[N:16][O:26][CH2:24][CH3:25])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[F:22]
Reactant: CSc1c(C(=O)C(=CN(C)C)C(=O)C2CC2)ccc(Cl)c1F
Reactant: CCO
Solvent: O
Product: CCON=CC(C(=O)c1ccc(Cl)c(F)c1SC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-chloro-3-fluoro-2-methylsulphenylphenyl)-3-cyclopropyl-2-(dimethylaminomethylene)-propan-1,3-dione (3 g) and O-ethylhydroxylaminehydrochloride (1 g) in ethanol (20 ml) was stirred at 25° C. for 2 hours. The mixture was poured into water and extracted with dichloromethane. The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated and the mixture purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and 1-(4-chloro-3-fluoro-2-methylsulphenylphenyl)-3-cyclopropyl-2-(ethoxyiminomethyl)-propan-1,3-dione (compound 5) was obtained as a reddish gum (2.4 -g), NMR (CDCl3) δ 1.1-1.4(m, 7H), 2.7(m, 1H), 2.4(s, 3H), 3.9(m, 2H), 7.0(m, 1H), 7.3(m, 1H), 7.6(s, 1H), 17.4(s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)CC1

Procedure:
(27.3 mg, 73%) from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 25 mg, 0.1 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol), HRMS-FAB+ for C20H21N2O2SF, calculated MH+ : 373.13861; found: 373.13569.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:18][NH2:19]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](=[N:18][NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: NN
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chlorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chlorobenzophenone hydrazone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([N:14](C(OC(C)(C)C)=O)[NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].CO>CO>[ClH:35].[ClH:35].[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([NH:14][NH2:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1(NN)CCN(Cc2ccccc2)CC1
Yield: 90 %

Procedure:
A solution of ethyl 1-benzyl-4-(N,N'-di-tert-butyloxycarbonylhydrazino)piperidin-4-yl-carboxylate (D26, 14.2 g, 0.030 mol) in methanol (50 ml) was treated with 10% HCl/methanol (100 ml) and heated under reflux for 2 h. The solution was concentrated in vacuo and the residue treated with dry toluene (80 ml) and again concentrated in vacuo to remove any traces of moisture. The residue was trituated with ether and the material filtered off and immediately placed in a vacuum dessicator to give the title compound (D27) (9.48 g, 90%) as a very hygroscopic orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=c1ccc(Br)c[nH]1
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCC2)nc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.4 %

Procedure:
A mixture of 5-bromo-1H-pyridin-2-one (4.0 g, 23 mmol), Ag2CO3 (3.77 g, 1.37 mmol), cyclopentyl bromide (7.4 mL, 29 mmol) and toluene (30 ml) was stirred at 60° C. for 2 days. The reaction was filtered through Celite® and the filter cake was washed with EtOAc. Concentration and vacuum distillation gave the sub-title compound (5.09 g, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:42][CH2:43][CH2:44][CH3:45])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:8]1[CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:4].N1C=CC=CC=1.[NH4+].[Cl-].[CH3:55][C:56](OC(C)=O)=[O:57]>>[C:56]([O:41][CH:26]([C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][C@H:8]1[C@H:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[O:11][C:10]([CH3:12])([CH3:13])[N:9]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])(=[O:57])[CH3:55]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (32 mg, 0.05 mmol) in Ac2O (6 mL) was added pyridine (0.5 mL) dropwise. The reaction mixture was stirred at rt overnight. Satd aq NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (4S,5S)-tert-butyl 4-((S)-2-(acetoxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (25 mg, 73%). MS: 687 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCNC3)c2c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-fluoro-2-((S)-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (110 mg) in dichloromethane (3 ml) at 0° C. was added DIPEA (55 μl) followed by methanesulfonyl chloride (25 μl) and the reaction was allowed to warm to room temperature and stirred for 2 h.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:19])=[C:6]([Br:18])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:18][C:6]1[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]2([CH3:2])[O:22][CH2:21][CH2:20][O:3]2)[C:5]=1[CH3:19]
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Br)c1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Yield: 89.4 %

Procedure:
A suspension of 6-acetyl-4-bromo-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (3.2 g), ethylene glycol (3.1 g) and p-toluenesulfonic acid (0.2 g) in toluene (35 ml) was heated under reflux for 10 hours with removing water formed. After cooling on standing, the reaction mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the resulting crude crystals were washed with hexane to obtain 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (3.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]I)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][O:30][CH3:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
According to Scheme 7 Step 7: To a cooled solution of 14(A) (220 mg, 0.43 mmol) in DMF (2 mL) under nitrogen atmosphere was added dropwise at 0° C. sodium methoxide 2M (in methanol, 215 μL, 0.43 mmol). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (100 mL) and the aqueous layer was extracted twice with DCM (100 mL). The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 25 g C18) using water/CH3CN 6/4 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(methoxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(B) (16 mg, 9%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].[OH-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Cl)c1
Yield: 91.3 %

Procedure:
To a solution of ethyl 3-chloro-4-(3-indolylcarbonylamino)phenylacetate (1.25 g, 3.50 mmol) in THF (35 mL) was added 0.25N NaOH (21 mL, 5.23 mmol) under stirring. The reaction mixture was then stirred at room temperature for 24 hours. The reaction mixture was poured in 1N HCl (30 ml) under stirring at 0° C. The crystals thus precipitated were collected by filtration, whereby 3-chloro-4-(N-(3-indolylcarbonyl)amino)phenylacetic acid (1.05 g, 91%) was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl[CH:11]([CH:17]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:1]=2)[CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(C#N)cn12

Procedure:
2-Amino-5-cyanopyridine (15.5 g, 152 mmol) was dissolved in ethanol (500 mL) in 2 L round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 730 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture was heated at reflux for 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel chromatography to give ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (13.9 g).
Reaction SMILES: N1C=CC=CC=1C1NC2C=CC=CC=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:22]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[N:23]1.[Br:29][C:30]1[CH:35]=[C:34](I)[CH:33]=[CH:32][C:31]=1[O:37][CH3:38]>CCOC(C)=O.[Cu]I.CN(C=O)C>[Br:29][C:30]1[CH:35]=[C:34]([N:22]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[N:23]2)[CH:33]=[CH:32][C:31]=1[O:37][CH3:38]
Reactant: OCc1cc[nH]n1
Reactant: COc1ccc(I)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2ccc(CO)n2)cc1Br
Temperature: 60 °C
Yield: 77.9 %

Procedure:
To a 100 mL round bottom flask was added copper (I) iodide (30.4 mg, 0.16 mmol), 2-(2-pyridyl)benzimidazole (31.2 mg, 0.16 mmol), cesium carbonate (625 mg, 1.92 mmol) and DMF (5.3 mL). The reaction mixture was heated to 60° C. for 1 h then (1H-pyrazol-3-yl)methanol (235 mg, 2.40 mmol) and 2-bromo-4-iodo-1-methoxybenzene (500 mg, 1.60 mmol) were added and the mixture was heated at 100° C. for 18 hours. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc in Hepane) to afford (1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg) MS [M+2H+]=285.0.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1C=CC=C2C=1N=CC=C2.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:25])[CH3:24]>CO.[Cu]>[C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:4][CH3:5])(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccccc1Br
Reactant: Oc1cccc2cccnc12
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1NC(C)=O
Yield: 866.6 %

Procedure:
2.3 ml of a 28% solution of sodium methoxide in methanol and 63 mg of copper powder were added to 40 ml of methanol, and the mixture was heated under reflux for 1 hour. Then, 145 mg of 8-hydroxyquinoline and 2.14 g of 2-bromo-1-acetylaminobenzene were added thereto, and the mixture was heated under reflux for 3 hours. The reaction mixture was treated in a usual manner, to obtain 1.43 g (yield: 87%) of the desired compound.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3](OC(C)(C)C)=[O:4].[CH3:45][N:46](C)[C:47](Cl)=O>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([N:46]([CH3:47])[CH3:45])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:13]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCBr)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added to tetrahydrofuran (10 ml). Under ice cooling, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5 was added. After stirring the reaction mixture at room temperature for 30 minutes, 1,5-dibromopentane (0.10 ml, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 3 days, followed by the addition of sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 15 minutes and then added with 1,5-dibromopentane (0.10 ml, 0.74 mmol). The mixture was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (51 mg, 30%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:3]=1[C:10](=[O:12])[CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1c(O)cc(C)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
1.62 g (9.75 mmol) of 1-(2,6-dihydroxy-4-methylphenyl)ethanone (35) are dissolved in 30 ml of dimethylformamide, and 4.0 ml (33.7 mmol) of benzyl bromide and 13.8 g (100 mmol) of potassium carbonate are added. The reaction mixture is stirred at room temperature for 3 hours. This is followed by addition of water and extraction twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator. 1.35 g (40%) of compound 36 are obtained as a colorless crystalline product. C23H22O3 (346.2) MS (ESI+): 347.15 (M+H+).