Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][NH2:28])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1cc(NC(=O)NN)cc(OC)c1
Agent: Cl
Product: COc1cc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc(OC)c1

Procedure:
ninhydrin, 4-(3,5-dimethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[CH2:25].C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([CH:24]=[CH2:25])=[CH:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: C=Cc1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C=Cc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-vinylbenzyl chloride (9.9mg, 0.065 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701) (19.6 mg, 88%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 547.2 (M++H, C23H25ClF3N4O2).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:28]1[O:31][C@H:29]1[CH3:30]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([CH2:28][C@@H:29]([OH:31])[CH3:30])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: C[C@H]1CO1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C[C@H](C)O)cc3)CC2)nc1

Procedure:
This compound was prepared from the product of example 54 (step A), and (S)-propylene oxide according to the procedure from example 58. MS (ESI) m/z 410 [M+H]+. GPR119 Human EC50: 1.6 nM
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1>ClCCl>[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NN=C(c2ccc(NC(=O)C(C)(C)C)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11.2 mmol) of pivaloyl chloride were added to a solution of 3 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25° C. for one hour. The precipitate formed Was filtered, washed with 3×5 ml of dichloromethane, then with 3×20 ml of water and dried to yield 1.59 g of pure product, m.p. 225°-227° C. (decomp.). The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3×20 ml of water, then with 3×15 ml of 4% aqueous sodium hydroxide solution, finally with 2×30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the former product of 1.59 g and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3×3 ml of ethanol and dried to yield 3.38 g (87.8%) of the pure product, m.p.: 225°-227° C. (decomp.).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)[CH3:25]
Reactant: CCOC(=O)CC(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.2 g (0.030 mol) of 60% sodium hydride in 100 mL of toluene was added 6.12 g (0.030 mol) of 4-(benzyloxy)phenol and the reaction was stirred at room temperature for 30 minutes followed by the addition of 5.85 g (0.030 mol) of ethyl 3-bromobutyrate. The resulting mixture was heated to reflux overnight and then filtered. The filtrate was washed with 0.5N sodium hydroxide solution, 3% sodium carbonate solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 5.45 g of the bis-ether as a white solid. Electrospray Mass Spec: 314.8 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)c(C)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4-dimethylaniline to yield 2-[(2,4-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:17]1[O:18][C:19]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH3:2])[CH2:11][CH2:10]3)[O:18][C:19]=2[CH:25]=1
Reactant: CC(=O)NC(C)CCC1CCNCC1
Reactant: Oc1ccc2nc(Cl)oc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Yield: 77 %

Procedure:
A solution of N-[1-methyl-3-(piperidin-4-yl)propyl]acetamide hydrochloride (500 mg), 2-chloro-1,3-benzoxazol-6-ol (361 mg) and N,N-diisopropylethylamine (826 mg) in DMF (15 mL) was stirred at 100° C. for 10 hr. The reaction mixture was allowed to cool, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate/THF mixed solvent (10/1), and the solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (543 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(O)cc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)c(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-4-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.6 Hz), 8.07 (1H, d, J=7.3 Hz), 8.01 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.20 (1H, d, J=2.5 Hz), 6.97 (1H, dd, J=8.4, 2.5 Hz), 5.37 (1H, dq, J=7.3, 7.1 Hz), 3.91 (3H, s), 2.41 (3H, s), 1.59 (3H, d, J=7.1 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Sc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Sc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of methyl 3-[4-[2-(phenothiazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoate (7.5 g, 16.70 mmol) obtained in example 4 in methanol (50 mL) was added aqueous 10% sodium hydroxide (20 mL). The reaction mixture was stirred at ca. 25° C. for 3 h. The solvent was removed under reduced pressure and the residue was acidified with 2 N hydrochloric acid, extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of dichloromethane and methanol (9:1) as an eluent to afford the title compound (6.0 g, 83%) as a white solid. mp: 79-82° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 48.8 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.163 mmol, 44.4 mg) synthesized in Synthetic Example 3 and 4-hydrazinocarbonothioylaminobenzoic acid (0.163 mmol, 34.4 mg) were stirred with dimethylformamide (3 mL) and two drops of concentrated hydrochloric acid at room temperature for 20 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (37 mg, yield 48%).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:23])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g) was dissolved in 20 ml toluene. 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-thiophenecarbonylchloride (0.76 g). The mixture was stirred at room temperature for 14 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2thiophenecarbonyl)hydrazine, was removed by filtration and washed with water. m.p. >200° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].CO[SiH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][C:23]=3[F:32])=[C:18]([F:33])[CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[CH2:1]([Si@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][C:23]=3[F:32])=[C:18]([F:33])[CH:17]=2)[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCOc1ccc(-c2ccc(C3CC[SiH](OC)CC3)cc2F)c(F)c1
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCCC)cc3F)c(F)c2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.5 g (20 mmol) of 4'-(4-methoxy-4-silacyclohexyl)-2,2'-difluoro-4-propoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2, 2'-difluoro-4-propoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 7.1 g of the trans isomer (yield 86%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)=O.II.O.[Cl-].[Na+]>C(O)(=O)C.II>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: II
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(S)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
3-Chlorosulfonylbenzoic acid (156.0 g, 0.707 mol), acetic acid (240 mL), and red phosphorus (78.5 g, 2.53 mol) were placed in a 2-L three-neck flask. The mixture was heated to 110° C. and stirred while a solution of iodine (2.82 g, 0.011 mol) in acetic acid (66 mL) was added dropwise over about 30 min, so as to maintain the color of iodine vapor. The stirred mixture was cooled to 100° C. and treated dropwise with 41 mL (2.3 mol) of water over a 10-min period, then heated at reflux temperature for 1.5 h and subsequently cooled to 90° C. Following the addition of saturated sodium chloride solution (250 mL) and water (500 mL), the mixture was kept at 0-5° C. for 1 h and filtered. The damp filter cake was slurried with 450 mL of acetone, and the excess red phosphorus was removed by filtration; then the acetone was evaporated from the filtrate while adding 500 mL of water. The resultant solid was filtered off and dried under vacuum to give 100.1 g (92%) of 3-mercaptobenzoic acid, mp 138-141° C. (lit. mp 138-141° C.); 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 3.59 (s, SH), 7.36 (t, J=7.8 Hz, H-5), 7.51 and 7.90 (2d, J=7.8 Hz, H-4 and H-6), 8.03 (s, H-2); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 171.77 (C═O), 134.49 (C-4), 132.24 (C-1), 130.86 (C-2), 130.34 (C-3), 129.42 (C-5), 127.59 (C-6). Preparation of 2-Ethylhexyl 3-Mercaptobenzoate
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=2[I:16])=[O:8])[CH2:4][O:3]1.[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>>[C:30]([O:33][CH2:34][CH2:35][N:9]([C:10]1[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=1[I:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:29])([CH3:1])[O:6]1)=[O:8])(=[O:32])[CH3:31]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C2COC(C)(C)O2)c1I
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carbamido)-2,4,6-triiodo-1,3-di-(acetoxymethyl) benzene was alkylated with 2-bromoethyl acetate according to Example 30a. The crude product, containing some O-alkylated material was used directly in next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:5]2.[NH2:36][NH2:37]>O1CCOCC1>[NH:36]([C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:5]2)[NH2:37]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nc4cc3-c3ccccc3)cc2)CCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(NN)nc4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To a microwave vial was added tert-butyl {1-[4-(6-chloro-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) (4.05 g, 8.34 mmol), anhydrous hydrazine (5.24 mL, 167 mmol), and 1,4-dioxane (15 mL). The reaction mixture was then heated under microwave irradiation for 5 minutes at 100° C. (high absorption). The reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl {1-[4-(6-hydrazino-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) as an orange solid/foam. MS (M+H)+: observed=482.3, calculated=482.59.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])=[O:8].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 94.9 %

Procedure:
Using 5-bromo-2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1F
Product: CN(CC(=O)Nc1ncn(Cc2ccccc2F)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.54 mmol) of 4-amino-1-(2-fluorobenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 113 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.35 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(2-fluorobenzyl)-5-imidazolecarboxamide (yield 97%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[C:15]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[CH:26]=3)=[CH:14]2)[N:7]=1)=O.C(NCC)C>CO>[NH2:5][C:6]1[N:7]=[C:8]([CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[C:15]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[CH:26]=3)=[CH:14]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2cn(Cc3cccc(NC(=O)C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Solvent: CO
Solvent: CCNCC
Product: COc1ccc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)cc1C
Yield: 18.9 %

Procedure:
A solution of 212 mg (0.43 mmol) 2,2,2-Trifluoro-N-{6-[3-(4-methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridin-2-yl}-acetamide, excess diethylamine and 5 mL of methanol were heated at 45° C. overnight. The solid was collected by filtration and purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 32.4 mg of 1-(6-Amino-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-1H-quinolin-4-one. LC-MSD, m/z for C24H21N3O3 [M+H]: 400.16 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.5 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.[C:49](O)(=[O:52])[CH:50]=[CH2:51]>ClCCl.CN(C)C1C=CN=CC=1>[C:49]([O:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:32]2[CH:33]=[CH:34][C:29]([C@H:26]3[CH2:25][CH2:24][C@H:23]([CH2:22][CH2:21][CH:17]4[O:18][CH2:19][CH2:20][O:16]4)[CH2:28][CH2:27]3)=[CH:30][CH:31]=2)=[CH:36][CH:37]=1)(=[O:52])[CH:50]=[CH2:51]
Reactant: C=CC(=O)O
Reactant: OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC4OCCO4)CC3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC4OCCO4)CC3)cc2)cc1
Reaction time: 8 h

Procedure:
3.38 g of dicyclohexylcarbodiimide in 5 ml of dichloromethane was added dropwise while stirring at 0°-5° C. within 5 minutes to a solution of 6.2 g of 6-[4'-[trans-4-(2-[1,3]dioxolan-2-yl ethyl)cyclohexyl]-biphenyl-4-yloxy]-hexan-1-ol, 1.48 g of acrylic acid and 1.67 g of 4-dimethylamino-pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 5.14 g of 6-[4'-[trans-4-(2-[1,3]dioxolan-2-yl-ethyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.