Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)C)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[F:42][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=1[CH2:34][N:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:13]1[S:14][C:15]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[C:11]([CH2:10][NH:8][CH3:1])[C:12]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc(NC(=O)NOC)cc2)c1CN(C)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc(NC(=O)NOC)cc2)c1CNC
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of ethyl 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylate (3.64 g, 5.47 mmol) in ethanol (100 ml) were added 1N hydrochloric acid (8 ml) and 10% palladium-carbon (50% wet, 1.82 g). The mixture was stirred vigorously under hydrogen atmosphere for 6 hours. The catalyst was removed, and the filtrate was neutralized with 1N sodium hydroxide solution. The solvent was distilled off, and the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to an NH-silica gel (Fuji Silysia Chemical) chromatography to give the title compound (2.43 g, 77%) as yellow powders.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:9]=[O:10].[OH-].[K+].Cl>O>[OH:10][CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: C=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A mixture of uracil (3.6 g, 32.1 mmol), formaldehyde (37% in water) (3.25 ml), KOH (1.4 g, 25 mmol) in water (45 ml) was stirred at 50° C. for 20 h. The reaction was acidified with 1 N HCl to give a white precipitate. The solids were collected dried under vacuum to give the 5-(hydroxymethyl)-2,4(1H,3H)-pyrimidinedione (2.01 g, 44%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1Cl.[N-:30]=[N+:31]=[N-:32].[Na+]>C(#N)C>[N:30]([C:7]1[CH:6]=[N:5][N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[C:3](=[O:29])[C:2]=1[Cl:1])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=Nc1cnn(-c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)c(=O)c1Cl
Yield: 92 %

Procedure:
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in acetonitrile (10 mL) was added of 0.09 g of sodium azide. The mixture was heated to reflux for 4 h. The suspension was filtered to give the title compound as a solid (0.280 g, 95%). Mp 184–186° C., 1H NMR (DMSO-d6) 10.1 (1H, s, NH), 8.75 (1H, d, 6 Hz), 8.67 (1H, d, 3 Hz), 8.28 (1H, s), 8.27 (1H, s), 8.18(1H, dd, 1 Hz, 3 Hz), 7.97 (1H, m), 7.65 (1H, dd), 7.57(1H, d, 6 Hz), 7.25 (1H, t, 9 Hz), 6.94 (1H, dd).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:19])(=O)=O>ClC(Cl)(Cl)Cl>[Cl:19][CH:3]([C:2](=[O:1])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Cl)C(=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
131 g of the methyl 3-oxo-3-(p-methoxyphenyl)propionate obtained in the above (1) was dissolved in 1.3 l of tetrachloromethane, and to the solution was added dropwise 85 g of sulfuryl chloride at 45° to 50° C. over 1 hour. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, cooled, washed with water and dried. Subsequently, the oily product of the residue obtained by evaporation of the solvent was distilled under reduced pressure to obtain 140 g of methyl 2-chloro-3-oxo-3-(p-methoxyphenyl)propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.[F:14][C:15]1[C:20](Br)=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:15]1[C:20]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: Cc1cnc(F)c(Br)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cc(C)cnc2F)c(OC)n1
Yield: 33.4 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (842 mg, 4.60 mmol) was dissolved in degassed n-PrOH (55 ml) and then 2-fluoro-3-bromo-5-methylpyridine (800 mg, 4.21 mmol), Na2CO3 (1.46 g, 13.77 mmol), PPh3 (348 mg, 1.33 mmol) and Pd(OAc)2 (101 mg, 0.45 mmol) were added. The suspension was stirred at reflux for 2 hours. After cooling, the solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was triturated with Et2O to give 350 mg of the title compound as a gray powder (31% yield).
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.Cl[Si:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:8][Si:7]([CH3:10])([CH3:9])[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: C[Si](C)(C)Cl
Reactant: c1cn[nH]n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)n1nccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A 1000-mL 4-necked round-bottomed flask was charged with a solution of 2H-1,2,3-triazole (30 g, 434.78 mmol, 1.00 equiv) in benzene (500 mL). To this solution was added chlorotrimethylsilane (49.3 g, 456.48 mmol, 1.05 equiv) drop wise 0° C. followed by addition of triethylamine (48.3 g, 478.22 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140-150° C. affording 2-(trimethylsilyl)-2H-1,2,3-triazole as colorless oil (11 g, 18%). To a solution of 2-(trimethylsilyl)-2H-1,2,3-triazole (6.2 g, 43.97 mmol, 2.74 equiv) in DMF (100 mL) was added tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate (6.2 g, 16.06 mmol, 1.00 equiv). The resulting solution was refluxed for 3 hours. Upon completion, the mixture was cooled down to room temperature and concentrated on a rotary evaporator affording tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as brown solid (2.3 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:29](=[O:30])[CH:28]=[C:27]([CH3:32])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Product: CC(C)=CC(=O)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 77.9 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (300 mg, 0.84 mmol) and 3,3 dimethyl acryloyl chloride (98 μL, 0.88 mmol) and following the procedure as outlined in Example 1, 287 mg of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-amide was isolated as a white powder in 100% purity @ 254 nm; LCMS (APCI): 439 [M+H]+; mp 175° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:15](Cl)([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:18][S:15]([O:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: CC(C)Oc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Oc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-isopropoxyphenoxy)ethanol (3.50 g), mesyl chloride (2.20 g) and triethylamine (2.0 g) in 20 ml of methylene chloride is stirred at RT for 3 hours. It is then poured into water and extracted with methylene chloride. The solvent is removed from the combined organic layers by rotoevaporation, and the residue is purified by column chromatography to give 2-(4-isopropoxyphenoxy)ethyl methanesulfonate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:27][CH3:28])=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([C:15](=O)[C@H:16]([NH:24][CH3:25])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH:14]=2)[CH:8]=1.C(N(CC)CC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:17]([C@@H:16]([NH:24][CH3:25])[CH2:15][N:12]1[CH2:13][CH2:14][C:9]([C:7]2[CH:8]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=2[O:27][CH3:28])=[CH:10][CH2:11]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N1CC=C(c2cc(F)ccc2OC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a mixture of (2R)-1-[4-(5-fluoro-2-methoxy-phenyl)-1,2,3,6-tetrahydropyridin-1-yl]-2-methylamino-3-phenyl-propan-1-one hydrochloride (0.41 g, 1.0 mmole) in 20 mL of tetrahydrofuran at 0° C. under N2 was added of triethylamine (0.14 mL, 1.0 mmol), followed by slow addition of 1.9 mL (1.9 mmole) lithium aluminum hydride (1 M solution in THF). After addition, the cooling bath was removed and the mixture was stirred at room temperature for 2.5 hours. The reaction was quenched by the slow addition of saturated NH4Cl solution and the mixture was filtered through a celite pad. The solution was concentrated to afford 0.36 g (100% {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine as a yellow oil which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3CCCC[C:8]3=2)[C:3](=O)[C:2]1=[O:15].NC1C=CC=C2C=1CCC2.ClC(Cl)(Cl)C(O)O.Cl.[NH2:34][OH:35].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:6]1[CH:5]=[CH:4][C:9]([NH:1][C:2](/[CH:3]=[N:34]/[OH:35])=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1Nc2c(ccc3c2CCCC3)C1=O
Reactant: NO
Agent: Cl
Agent: Nc1cccc2c1CCC2
Agent: O=S(=O)([O-])[O-]
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
This was synthesized according to the procedure described above for intermediate 6. The isonitrosoacetanilide was prepared by reacting 4-aminoindane 8, (7.04 g, 52.9 mmol) with chloral hydrate (10.5 g, 63.4 mmol) and hydroxylamine hydrochloride (13.2 g, 0.190 mol) in the presence of sodium sulfate (75 g, 0.53 mol). Pure product 9 was obtained as a brown solid (7.18 g, 66% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.00 (m, 2H) 2.80 (t, J=7.3 Hz, 2H) 2.88 (t, J=7.6 Hz, 2H) 7.05 (d, J=6.8 Hz, 1H) 7.12 (t, J=7.6 Hz, 1H) 7.45 (d, J=7.8 Hz, 1H) 7.71 (s, 1H) 9.49 (s, 1H) 12.19 (s, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([CH2:22][CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:11]([F:21])[CH:10]=1)=[O:7])[CH3:4].[CH3:24][O:25][C:26](=[O:37])[CH:27](Br)[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:37])[CH:27]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:22][CH3:23])=[CH:10][C:11]=2[F:21])[CH2:20][CH2:19]1
Reactant: COC(=O)C(Br)c1ccc(C#N)cc1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3ccc(C#N)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.4 %

Procedure:
A mixture of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide dihydrochloride (0.06 g, 0.16 mmol), bromo-(4-cyano-phenyl)-acetic acid methyl ester (0.05 g, 0.20 mmol), and anhydrous K2CO3 (0.08 g, 0.55 mmol) in DMF (5 mL) was stirred at rt for 20 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×30 mL). The combined organic phases were washed with water, dried (Na2SO4), and concentrated. The residue was purified (SiO2; acetone/DCM) to give the title compound (0.06 g, 79%). MS: mass calcd. for C26H31FN4O3, 466.24. m/z found, 467.4 [M+H]+. 1H NMR (CDCl3): 7.68-7.60 (m, 4H), 7.45 (dd, J=14.0, 2.4, 1H), 7.27 (br s, 1H), 7.13-7.08 (m, 1H), 6.85 (t, J=9.0, 1H), 4.14 (s, 1H), 3.72 (s, 3H), 3.10-3.03 (m, 4H), 2.69-2.56 (m, 4H), 2.04-1.95 (m, 1H), 1.74-1.62 (m, 2H), 1.59-1.48 (m, 2H), 0.92 (t, J=7.4, 6H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].OS(O)(=O)=O.[CH2:16](O)[C:17]([F:20])([F:19])[F:18]>>[C:6]([C@H:4]([C@@H:2]([C:1]([O:10][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:9])[OH:3])[OH:5])([O:8][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: OCC(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(OCC(F)(F)F)[C@@H](O)[C@H](O)C(=O)OCC(F)(F)F
Temperature: 25 °C
Yield: 33 %

Procedure:
d-Tartaric acid (23; 25 g, 0.17 mol), trifluoroethanol (200 ml) and H2SO4 (59 mL) were magnetically stirred and heated under reflux for 22 h. The solution was cooled to room temperature, partitioned between H2O and CH2C2. The H2O layer was extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with saturated aqueous NaHCO3, and brine, then filtered through a bed of Celite and evaporated in vacuo. The residue was dissolved in ethyl ether and filtered through a plug of silica. The silica was rinsed with ca. 600 mL. The ether was removed in vacuo and the residue was recrystallized from ether/hexane to yield 34 (17.3; 33%) as white crystals: mp 77-79° C.; 1H NMR (300 MHz, CDCl3) δ3.13 (two singlets, 2H), 4.6 (m, 6H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:28])[S:20][N:19]=2)=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O1CCCC1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:28])[S:20][N:19]=3)=[CH:14][CH:13]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)NCCCN4CCCC4)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Para-Tolyl isocyanate (4.5 g 0.0339 mol) was added to a solution of 3-(4-aminophenyl)-5-({[(3-pyrrolidin-1-ylpropyl)amino]carbonyl}amino)isothiazole-4-carboxamide (12.0 g, 0.0308 mol), diisopropylethylamine (6.0 g, 0.046 mol) in mixture of tetrahydrofuran (300 mL) and dimethylformamide (50 ml) at ambient temperature over 20 min. The resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was concentrated in vacuo to give off white solid, which was stirred in 20% tetrahydrofuran and ethyl acetate (200 mL) mixture, filtered the solid and washed with ethyl acetate the title compound as a white solid (15.8 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C:6]([C:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])[N:9]=1)=[O:7].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C:6]([C:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])[N:9]=1)=[O:7]
Reactant: CCC(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)O)c3)c3ccccn23)cc1OC

Procedure:
The compound is obtained by operating according to the preparation described in example 195 by saponification of methyl 3-{3-[3-methoxy-4-[propionylamino]benzoyl]-imidazo[1,5-a]pyridin-1-yl}benzoate obtained in example 191 with 1N sodium hydroxide solution. A yellow solid is collected, which solid is salified in the sodium salt.2.4H2O form. Melting point: 145° C.; 1H NMR (d6-DMSO): 1.08-1.24 (3H, t), 2.46-2.51 (2H, m), 4.03 (3H, s), 7.30-7.55 (3H, m), 7.88-8.38 (6H, m), 8.43 (1H, m), 8.60 (1H, m), 9.40 (1H, m), 9.45 (1H, m), 9.95 (1H, m)
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]1([CH2:26][C:27](Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(CCc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 5 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol of triethylamine, and 10 mL of THF, followed by 10 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.0 mmol of the intermediate acyl compound. Reduction of this intermediate was effected with 2 mmol of sodium cyanoborohydride. The product was obtained as a solid (m.p. 125°-126° C.). 1H NMR (DMSO-d6) δ0.76 (m, 7H), 1.12 (m, 1H), 1.38 (m, 1H), 1.87 (m, 2H), 2.27-2.46 (m, 4H), 2.97 (q, 2H), 6.98-7.38 (m, 10H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][C@H:59]([C:64](O)=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][C@H:59]([C:64]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-L-leucine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[N:3]=[C:2]([C:30]5[N:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Reactant: O=C(CN1CCc2nc(Cl)ccc2C1)N1CCN(C2CCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCc2nc(-c3cccnn3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-6-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (349 mg, 1 mmol), 3-(tributylstannyl)pyridazine (461 mg, 1.25 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol) in toluene (15 mL) is degassed by argon and heated at 110° C. in a sealed tube overnight. The mixture is cooled and saturated KF solution (10 mL) is added. The mixture is stirred at rt for 30 min, and then the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a white solid. MS (M+1): 393.2; 1H NMR (δ, CDCl3): 9.77 (m, 1H), 9.26 (dd, 1H), 8.05 (dd, 1H), 7.64 (d, 1H), 7.48 (d, 1H), 3.79 (s, 2H), 3.65 (q, 4H), 3.43 (s, 2H), 3.13 (t, 2H), 2.96 (t, 2H), 2.64-2.74 (m, 1H), 2.30 (q, 4H), 1.64-2.06 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([C:23]([O:25]C4C=CC=CC=4)=O)[C:15]=3[CH2:14]2)=[CH:10][C:9]=1[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:37])[CH3:36]>>[CH2:35]([NH:37][C:23]([C:16]1[C:15]2[CH2:14][N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:9]([CH3:34])[CH:10]=3)[C:21](=[O:22])[C:20]=2[CH:19]=[CH:18][N:17]=1)=[O:25])[CH3:36]
Reactant: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1C(=O)OC(C)(C)C
Reactant: CCN
Product: CCNC(=O)c1nccc2c1CN(Cc1ccc(C(=O)OC(C)(C)C)c(C)c1)C2=O
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (260 mg, pale brown solid) from phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 0.59 mmol, Step-2) and ethylamine (0.14 mL, 1.8 mmol, 70% aqueous solution) in a similar manner to Example-435 (Method-G).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[N+:12]([O-])=O)#[N:2].[N:15]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[NH2:2][C:1]1[C:3]2[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=2[NH:12][N:15]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C#N)s1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc2[nH]nc(N)c2s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To an ice-cooled suspension of methyl 5-cyano-4-nitro-thiophene-2-carboxylate (0.10 mol, 21.0 g) in 120 mL of hydrochloric acid 37% was added, dropwise, a solution of sodium nitrite (0.12 mol, 8.3 g) in 12 mL of water. After 1.5 hours, the cold suspension was added dropwise to a preformed solution of tin chloride (0.80 mol, 151.7 g) in 120 mL of hydrochloric acid 37%, at 5° C. After 3 hours, the cold suspension was filtered and the moist solid was treated with 350 mL of boiling water, for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were ice-cooled and treated, dropwise, with 180 mL of sodium hydroxide 17%. The obtained solid was filtered off and dried, under vacuum, at 50° C., to give 7.3 g of the title compound as a yellow solid (37% yield).