Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](B(O)O)[CH:49]=[CH:48]2>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([O:44][C:43]([F:42])([F:59])[F:58])[CH:46]=4)[CH:51]=3)[N:11]([C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:40][CH:41]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[C@@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc2cc(OC(F)(F)F)ccc2c1
Solvent: COCCOC
Product: C[C@@H](c1ccc(C(=O)NCCC(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2cc(OC(F)(F)F)ccc2c1
Temperature: 100 °C

Procedure:
tert-Butyl N-{4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate (10 mg, 0.016 mmol), 6-trifluoromethoxy-2-naphthylboronic acid (5.1 mg, 0.02 mmol), and TEA (14 ul, 0.1 mmol) were dissolved in dimethoxyethane (0.5 ml) and deoxygenated by vacuum-N2 fill cycles. The catalyst Pd(PPh3)4 (2 mg, 10% mol) was added and the mixture was deoxygenated again before heated in microwave reactor to 100° C. for 10 min. The mixture was quenched with 1.5 ml of CH3CN:H2O (3:1, with 5% TFA) and product separated through reverse phase preparative HPLC. The collected product was treated with 1 ml of TFA-DCM (1:2) for 30 min, and the residue lyophilized to give N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine as fine powder. NMR (500 MHz, DMSO-d6) δ: 1.91 (d, J=7.0 Hz, 3H); 2.46 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 5.78 (q, J=7.0 Hz, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (s, 1H); 7.57 (t, J=1.9 Hz, 1H); 7.58˜7.60 (m, 2H); 7.72 (d, J=8.4 Hz, 2 H); 7.94 (d, J=1.9 Hz, 2H); 8.04 (br s, 1H); 8.06 (br s, 1H); 8.09 (d, J=9.1 Hz, 1H); 8.13 (d, J=8.6 Hz, 1H); 8.44 (t, J=5.5 Hz, 1H). MS C32H24Cl2F3N3O4 Cald: 641.11; Obsd (M+1): 642.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Cl)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Cl)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one 170 (100 mg, 0.510 mmol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (98.4 mg, 0.561 mmol). PTSA (175.9 mg, 1.2 mmol) was added to the reaction mass, which was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude (E)-5-chloro-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one (171), which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 22% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:19])([F:18])[F:20])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=3)=[O:41])[CH:3]=[C:4]([F:30])[C:5]=2[F:29])[N:9]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: COc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3+MeOD) δ ppm 2.83 (dd, J=13.9, 3.8 Hz, 1H), 3.14 (dd, J=13.9, 3.0 Hz, 1H), 3.29-3.39 (m, 1H), 3.87 (d, J=8.3 Hz, 1H), 4.04 (s, 3H), 4.60 (d, J=8.3 Hz, 1H), 4.67 (quin, J=6.3 Hz, 1H), 7.11-7.21 (m, 1H), 8.03 (ddd, J=11.6, 6.9, 2.7 Hz, 1H), 8.15 (d, J=1.3 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H)
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](C)N.CCN(CC)CC.N(C)(C)C.BC(O)=O.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:33]1([NH:32][C:31]([NH:30][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:3])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)[C@H](C)N
Agent: BC(=O)O
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of L-alanine methyl ester hydrochloride (5.97 g, 42.8 mmol) in CH2Cl2 (100 ml) was added Et3N (4.33 g, 42.8 mmol), and the mixture was stirred for 20 minutes at room temperature. A solution of Me3N.BH2COOH (5.00 g, 42.8 mmol) in CH2Cl2 (50 ml) was then added to the reaction mixture, followed by N,N'-dicyclohexylcarbodiimide (DCC) (9.27 g, 49.1 mmol) in CH2Cl2 (50 ml). After 72 hours, the N,N'-dicyclohexylurea (DCU) precipitate which formed was filtered off, and the solvent was removed under reduced pressure. The solid residue was then washed with diethyl ether (3×300 ml), and the combined washes were filtered prior to removal of the ether under reduced pressure. This procedure was repeated with water (3×300 ml) as solvent, following which, evaporation of the water from the combined washes was aided by passage of a dry air stream over the solution. Further purification of the resulting yellow oil was performed by flash chromatography using ethyl acetate/acetone (95:5) as the mobile phase. After the peptide-containing fractions were combined and the solvent removed in vacuo, the peptide oil was distilled under vacuum at 50° C. Final purification of the distilled oil was performed by flash chromatography on a column packed with petroleum ether and eluted with ethyl acetate/n-butyl alcohol (95:5). The peptide-containing fractions were combined, and the solvent was removed by the passage of a dry air stream over the solution to give the desired crystalline dipeptide. (Due to the hygroscopic nature of (1), a clear oil may result, which may be crystallized by storage under high-vacuum for several weeks.) Yield: 0.452 g (5.23%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]12CCCN=C1C[CH2:16][CH2:15][CH2:14][CH2:13]2.BrCCCC#N.C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH2:15][CH2:14][C:13]#[N:12])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CCCCBr
Solvent: CC#N
Solvent: O
Product: N#CCCCOC(=O)c1cc(O)ccc1O
Yield: 78.4 %

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.6 g; 30 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 g; 33 mmol), 4-bromobutyronitrile (4.9 g; 33 mmol) and acetonitrile (70 ml) was heated under reflux overnight. The reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×150 ml), dried over magnesium sulphate and filtered. The organic solvent was then removed in vacuo. The residue (6.2 g) was recrystallised from ethyl acetate/hexane to yield 5.2 g (78%) of the desired 3-cyanopropyl 2,5-dihydroxybenzoate.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([CH2:23][O:24]C(=O)C)[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:23][OH:24])[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethy-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.19 g, 3.35 mmol) is dissolved in hot toluene (20 mL) and methanol (80 mL) is added, followed by a few drops of 1 M. methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as an amorphous solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3F)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1.[H-].[Na+].[ClH:33]>O1CCCC1.CO>[ClH:33].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reactant: OCc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2OCc2ccc(F)cc2)cc1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of 2-(morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.60 g, 2.07 mmol), and 4-fluorobenzyl alcohol (3.3 g, 26.2 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (1.03 g, 2.58 mmol) at 0° C. After stirring at 60° C. for 5 hours, the resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish colorless oil. The methanol (10 ml) solution of resulting oil was treated with 4N hydrochloric acid (5 ml). The residue obtained by evaporation was washed by ethyl acetate to furnish 6-(3-(4-fluorobenzyloxy)pyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one hydrochloride (0.23 g, 0.53 mmol, 31%) as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>[OH-].[Na+]>[CH2:18]([S:25][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C=CCn2c(=O)n(CCSCc3ccccc3)c(=O)n21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.2 g (0.005 mol) of 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid were dissolved in 10 ml (0.10 mol) of 1-M sodium hydroxide solution. The solution was treated with 1 ml (0.008 mol) of benzyl mercaptan and the mixture was stirred at 100° C. for 3 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with two 20 ml portions of ethyl acetate. The organic layer was extracted with 50 ml of saturated sodium bicarbonate solution. The aqueous extract was acidified with concentrated hydrochloric acid and re-extracted with two 25 ml portions of ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated to give 2-(2-benzylthioethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid in the form of a colourless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.C(N(CC)CC)C.[CH2:32](Br)[CH:33]=[CH2:34]>CN(C)C=O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH:33]=[CH2:32])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Reactant: C=CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
To a stirred solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.5 g; 1.37 mmol), prepared as in Example 10, and triethylamine (0.3 g; 3.0 mmol) in N,N-dimethylformamide (10 mL), was added allyl bromide (0.17 g; 1.4 mmol) in N,N-dimethylformamide (approximately 2 mL). The reaction mixture was stirred for 1.5 hours and the solvent removed. The residue was stirred with ammonium hydroxide and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2×50 mL) and purification of the combined methylene chloride layers by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2,3-dihydro-2-(1-prop-2-enylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.1 g; 0.27 mmol), m.p. 279°-281° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCN(C(C)=O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a suspension of 1-(4-hydroxyphenyl)piperazine (50 g) and potassium carbonate (46.5 g) in N,N-dimethylformamide (100 ml) was added dropwise benzyl chloroformate (47.86 g) at 0 to 10° C., and stirred for 4 hours at ambient temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (30:1) to give 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (60.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1.O.NN>CO.O.[Ni]>[Br:1][C:2]1[CH:16]=[C:6]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1cncc(F)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(Br)cc1NCc1cncc(F)c1
Temperature: 50 °C

Procedure:
To a solution of Example 12A (1.777 g, 5.45 mmol) in methanol (30 mL) was added hydrazine hydrate (0.74 g, 15.26 mmol), followed by 50% Raney® nickel in water (200 mg) and the mixture was heated at 50° C. for 60 minutes. After cooling, diatomaceous earth was added and the slurry was filtered through diatomaceous earth with dichloromethane. Concentration provided the crude title compound which was used without further purification. MS (ESI) m/z 295.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:33]=[C:32]([C:34]([NH:36][OH:37])=[NH:35])[CH:31]=[CH:30][N:29]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:37][N:36]=[C:34]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([NH2:27])[CH:33]=4)[N:35]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1cc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)ccn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (162 mg, 66%). MS (ISP) 492.1 [(M+H)+]; mp 277° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].Cl.[N:15](OC(C)(C)C)=[O:16]>C(Cl)Cl.O1CCOCC1>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[N:15]/[OH:16])=[CH:9]1)([CH3:11])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1ccc(=O)n(C(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1cc(C(=O)/C=N/O)ccc1=O
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
5-Acetyl-1-isopropyl-2(1H)-pyridone was dissolved in CH2Cl2 (300 ml). The solution was cooled to −30˜−25° C. To the cooled solution were added 4N hydrogen chloride in dioxane (55.3 ml) and t-butyl nitrite (10.4 g) at −30˜−25° C. The temperature of the reaction mixture was raised to 20-25° C. The mixture was stirred at the same temperature for 3 hours. The precipitated crystal was collected by filtration, and dried in the air at ambient temperature, to give (1E)-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)(oxo)acetaldehyde oxime (14.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].CN([CH:24]=[O:25])C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:6]([C:7]([CH3:15])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[CH:24]([OH:25])[C:16]=2[CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Cc1ccc(C(=O)NC(C)(C)c2ccccc2)c(Cl)n1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(c(Cl)n1)C(=O)N(C(C)(C)c1ccccc1)C2O
Yield: 59.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 2-chloro-6-methyl-N-(1-methyl-1-phenylethyl)nicotinamide (500 mg, 1.73 mmol) was dissolved in THF (20 mL), and the solution was treated with n-butyllithium-hexane solution (2.71 mol/L, 4.33 mL, 3.23 mmol) and DMF (0.335 mL, 4.33 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=80/20 to 75/25) to obtain 4-chloro-1-hydroxy-6-methyl-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (326 mg, yield 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OC(C1C(=O)N(CC2C=CC(F)=CC=2)C2C=CSC=2C=1N1CCN(C(C2OC=CC=2)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Reactant: O=C(CCl)c1ccccc1
Agent: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (10) and 2-chloroacetophenone by applying similar method as described for 4-(4-fluoro-benzyl)-7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (11). MP 246° C. 1H-NMR (DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.85 (m, 4H), 4.23 (q, J=6.8 Hz, 2H), 5.75 (s, 2H), 6.66 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 7.34 (d, J=5.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.73 (t, J=7.6 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 2H); EIMS m/z 520 (M+1).