Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:48]=[CH:49][CH:50]=2)[CH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][Si](C(C)(C)C)(C)C)[N:34]=2)=[O:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:48]=[CH:49][CH:50]=2)[CH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][OH:40])[N:34]=2)=[O:30])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OCc2cccc(CNC(=O)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(OCc2cccc(CNC(=O)NCc3cccc(CO)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 97.6 %

Procedure:
To a suspension of N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-{[6-(tert-butyldimethylsilyloxy)methylpyridin-2-yl]methyl}urea (6) (410 mg, 0.57 mmol) in THF (2.2 mL), which was stirred, was added dropwise a solution of 1.0M TBAF in THF (0.64 mL), and stirred for 4 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=20:1) to give N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-[(6-hydroxymethylpyridin-2-yl)methyl]urea (7) (336 mg, 98%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH:9]=[CH:10][CH2:11]Cl)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:4]3[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Cc1cccnc1C=CCCl
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1C=CCN1CCc2nc(N)sc2CC1
Yield: 45 %

Procedure:
Prepared from 3-(3-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 45% of theory, Melting point: 188°-190° C. (ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([OH:15])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.CO.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:6]1[C:5]2[C:4]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:3][CH:2]=[CH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=S(=O)(O)c1cc(Br)cc2cnccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1cncc2cccc(S(=O)(=O)O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Treat a solution of 7-bromo-isoquinoline-5-sulfonic acid (150.00 g, 0.520 mol) and 4-methoxyphenylboronic acid (90.87 g, 0.598 mol) in DMF (1,400 mL) and MeOH (375 mL) with 2M aqueous Na2CO3 (652 mL). Deoxygenate the resulting slurry 3× with N2, then add Pd(OAc)2 (2.33 g, 0.0104 mol) and dppb (5.54 g, 0.0130 mol). Heat the resulting reaction mixture at ˜70° C. for 3 hr, then allow to cool to room temperature overnight. Dilute the reaction mixture with H2O (4,000 mL) and adjust the pH to ˜pH 2 with 5N aqueous HCl. Allow the resulting slurry to stir at room temperature for 30 min, then recover the brown solid by vacuum filtration, washing with H2O and drying under vacuum filtration. Dissolve the brown solid in DMF (1,000 mL) and 2M aqueous Na2CO3 (650 mL) and filter the resulting solution through a pad of Celite®, washing with DMF (400 mL)/H2O (400 mL). Treat the filtrate with 5N aqueous HCl to adjust the pH to ˜pH 2. Allow the resulting slurry to stir at room temperature for 30 min, then recover the solid by vacuum filtration, washing with H2O and drying under vacuum filtration overnight. Dissolve the solid in DMF (1,000 mL) and 2M aqueous Na2CO3 (1,000 mL) again and treat the resulting solution with Celite® to create a slurry. Stir the resulting slurry at room temperature for 30 min, then filter through a pad of Celite®, washing with H2O. Treat the filtrate with 5N aqueous HCl to adjust the pH to ˜pH 2. Stir the resulting slurry at room temperature for 30 min, then recover the solid by vacuum filtration, washing with H2O and drying under vacuum filtration overnight. Crush the solid, then wash with EtOAc, drying under vacuum filtration overnight, followed by drying in a drying oven under reduced pressure at ˜35° C. to afford the title compound (136.79 g, 83% yield) as a yellow solid: TOF-MS [ES+; m/z] 316.0624/316.0643. Anal. Calcd. For C16H13NO4S: C, 60.94; H, 4.15; N, 4.44; S, 10.16. Found C, 60.76; H, 4.13; N, 4.50; S, 9.90.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=12.[C:12]([O-])(=[O:14])C.[Na+].C=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[OH:14][CH2:12][C:3]1[N:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: N#Cc1ccc2nccn2c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2ncc(CO)n2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of imidazo[1,2-a]pyridine-6-carbonitrile (7-1) (1.43 g, 10 mmol) in 3 mL of acetic acid were added sodium acetate (3.03 g, 37 mmol) and then formaldehyde (6 mL, 37% in water). The reaction mixture was stirred at 100° C. overnight. After cooled to room temperature, the mixture was adjusted to pH>7 with aqueous Na2CO3. The precipitate was collected to afford the title compound (1.4 g). MS (m/z): 174.0 (M+H)+
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:17][NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[S:20]>C1C=CC=CC=1>[F:26][C:23]([F:24])([F:25])[CH2:22][N:21]=[C:19]1[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:14]([Cl:13])[CH:15]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][S:20]1
Reactant: O=C(Cl)N(CCl)c1ccccc1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C1N(Cc2ccc(Cl)c(Cl)c2)C(=NCC(F)(F)F)SCN1c1ccccc1
Yield: 40.2 %

Procedure:
1.00 g of N-chloromethyl-N-phenylcarbamoyl chloride and 1.55 g of 1-(3,4-dichlorobenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 m1 of benzene, and the solution was heated under reflux. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; eluent: hexane/ethyl acetate (10/1)] to give 0.88 g of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:21])([F:22])[F:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 54 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (23 mg, 0.0542 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 54% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.05 (br s, 1 H), 8.59 (s, 1 H), 7.38 (s, 1 H), 7.16-7.13 (m, 2 H), 7.05-7.01 (m, 2 H), 4.86 (br s, 2 H), 4.14 (s, 2 H), 3.49-3.37 (m, 6 H), 2.40 (m, 2 H), 2.04 (m, 2 H), 1.87 (m, 2 H); MS m/z 521 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Temperature: 30 °C
Reaction time: 0.4 h

Procedure:
p-Hydroxybenzoic acid (59.05 grams, 0.4275 mole), sodium ethoxide catalyst (0.133 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (404 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Nitrophenylisocyanate (73.85 grams, 0.450 mole) is initially added in an aliquot of 25.00 grams, followed by 25.00 and 23-85 gram aliquots eleven then nine minutes later, respectively, and so as to maintain a 80° to 82° C. reaction temperature. After the last aliquot of p-nitrophenylisocyanate is added, heating of the reactor commenced and a 160° C. reaction temperature is achieved 24 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into one gallon of deionized water. A precipitated yellow powder is recovered via filtration of the aqueous slurry then dissolved into 1900 milliliters of boiling methanol and refluxed therein (65° C.). After cooling the methanol solution to 5° C. and maintaining therein for twelve hours, a first crop of pale yellow colored crystalline product is filtered off and dried at 110° C. under vacuum to a constant weight of 92.5 grams (79.6% isolated yield). No attempt was made to recover a second crop of crystalline product from the mother liquor. Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate revealed the presence of the expected secondary amide N--H stretching (solid state) at 3385 cm-1 (sharp), the secondary amide carbonyl stretching (solid state) at 1655 cm-1 (sharp), the hydroxyl group O--H stretching centered at 3232 cm-1 (broad) and the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as -hydroxy-4'-nitrobenzanilide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH2:13])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:13][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27]
Reactant: COC(=O)CN1CC(CN)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Yield: 46 %

Procedure:
To a solution of {6-(aminomethyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 29, (0.14 g, 0.37 mmol) in THF(1 mL) is added benzoyl chloride (80 μl, 0.75 mmol) and triethyl amine (0.71 mL, 4.99 mmol). The reaction is complete with a few minutes. Methanol (5 mL) is added to the reaction mixture and then the solvents are removed in vacuo to provide a residue which is purified by HPLC to afford 84 mg (46% yield) of the desired product. 1H NMR (CDCl3) δ 9.37–9.33 (d, J=9.4 Hz, 1H), 9.06–9.03 (d, J=5.5 Hz, 1H), 7.73–7.64 (m, 4H), 7.59–7.48 (m, 2H), 7.41–7.48 (m, 4H), 5.68 (bs, 1H), 5.37–5.30 (m, 1H), 4.644.57 (d, d, J=17.5, 2.37 Hz, 1H), 4.4.6–4.40 (d, J=17.6 Hz, 1H), 4.15–4.08 (d, d, J=14.5, 6.9 Hz, 1H), 3.82–3.76 (d, J=17.6 Hz, 1H), 3.76–3.70 (d, d, J=14.7 Hz, 1H), 3.42 (s, 3H), 3.38–3.33 (d, J=17.6 Hz, 1H), 2.81–2.76 (m, 1H), 2.35–2.25 (d, d, J=16.3, 14.2 Hz, 1H); 13C (CDCl3) 172.6, 170.5, 168.0, 165.9, 148.2, 141.0, 137.7, 134.3, 133.8, 132.4, 132.3, 132.0, 130.7, 129.0, 128.9, 127.7, 127.6, 127.5, 127.2, 124.7, 52.6, 50.5, 49.3, 49.1, 46.7, 32.6; MS 487 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH2:27]1[O:35][C:34]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:28]1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:35][C:34]=2[CH:33]=1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc2c(c1)OCO2

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.894 g) in toluene (4 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.04 g) was added saturated aqueous sodium hydrogen carbonate solution (3 ml) and a solution of 3,4-methylenedioxyphenylboronic acid (0.600 g) in ethanol (2 ml). The mixture was heated under reflux for 4 hours, cooled and then poured into ether (40 ml) and water (40 ml). The organic layer was separated, washed with water (2×30 ml), brine (30 ml) and then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (30 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale brown crystalline solid, m.p. 222° C. with softening at 198° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:34]=2[Cl:33])[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 1.8 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2,3-dichloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.4 mg, 1.8%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH2:30])=[CH:18][CH:17]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:30][C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[S:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OC)cc3)ccnc2n1
Yield: 98.4 %

Procedure:
The product from Example 3f (79 mg, 0.41 mmol) was reacted with the product from Example 50b (88 mg, 0.41 mmol) for 23 h giving following the procedure from Example 1g providing the crude title compound that was triturated with 3:1 ether/THF to give the title compound (162 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.35 Hz, 3 H) 2.34 (s, 3 H) 3.05 (q, J=7.35 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d, J=6.98 Hz, 1 H) 6.85 (m, J=8.82 Hz, J=2.20 Hz, 2 H) 7.10 (d, J=8.09 Hz, 1 H) 7.23-7.32 (m, 4 H) 7.83 (d, J=8.83 Hz, 1 H) 8.41 (d, J=6.98 Hz, 1 H) 9.11 (d, J=8.83 Hz, 1 H) 11.16 (br s, 1 H) 14.39 (br s, 1 H); MS (ESI+) m/z 402 (M−Cl)+; (ESI−) m/z 400 (M−HCl)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH:10]=1)=[O:5])[CH3:2].[NH4+].O[N:22]1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([C:15]1[N:16]=[C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[S:13][CH:14]=1)(=[O:19])[NH2:22]
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(C(N)=O)cs2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution (7 mL) of the compound (1.0 g, 3.56 mmol) obtained in Example 33a in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carboditmide hydrochloride (WSC, 820 mg, 4.27 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt (704 mg, 4.63 mmol), and the mixture was stirred at room temperature for 4 hr. After confirmation of the termination of the reaction by TLC, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-ethyl acetate) and recrystallization (ethyl acetate-hexane) to give the title compound (524 mg, 52%) as colorless crystals.
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(N1CCCC1=[O:21])=C.C(O)(=O)C=C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:21])[CH2:12][CH3:13]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: C=CN1CCCC1=O
Agent: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCCCC(CC)C(=O)O

Procedure:
Under an inert gas atmosphere, 72 parts by weight of 2-ethylhexyl acrylate, 25 parts by weight of N-vinyl-2-pyrrolidone, 3 parts by weight of acrylic acid, and 0.2 part by weight of azobisisobutyronitrile were added to ethyl acetate, and then the contents were mixed. The mixture was subjected to solution polymerization at 60° C. Thus, a solution (solid content: 28 w t %) of an acrylic copolymer (2-EHA/AA/N-VP=72/3/25) was obtained.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:7]=1[CH2:8][C@H:9]1[CH2:11][O:10]1.Cl>C1COCC1>[F:5][C:6]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:7]=1[CH2:8][C@H:9]([OH:10])[CH2:11][CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: Fc1cc(F)c(C[C@H]2CO2)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: C=CC[C@@H](O)Cc1cc(F)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
CuBr(CH3)2 (3.3 g) was added to a reactor under the nitrogen atmosphere and cooled to −78° C. Vinylmagnesium bromide (240 ml) was added slowly to the reactor and stirred for 20 min. (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (30 g) dissolved in THF (90 ml) was added dropwise slowly over 30 min, stirred at −78° C. for 30 min, and heated to 0° C. 2N aqueous HCl (300 ml) was added slowly to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (34.5 g; yield: 100%).
Reaction SMILES: C([Li])CCC.CCCCCC.[Si:12]([O:19][C@H:20]([CH3:23])[C:21]#[CH:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[F:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])[CH:28]=[CH:29][C:30]=1[C:31](N(OC)C)=[O:32]>O.O1CCCC1>[Si:12]([O:19][C@H:20]([CH3:23])[C:21]#[C:22][C:31]([C:30]1[CH:29]=[CH:28][C:27]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])=[CH:26][C:25]=1[F:24])=[O:32])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CON(C)C(=O)c1ccc(NC(=O)c2cnccn2)cc1F
Reactant: C#C[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C[C@H](C#CC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.8 ml of n-butyllithium (2.46 M hexane solution was added to a tetrahydrofuran (80 ml) solution of 4.92 g of (3R)-3-(tert-butyl(dimethyl)silyl)oxy-1-butyne at −78° C., and the reaction liquid was stirred at the same temperature for 1 hour. A tetrahydrofuran (60 ml) solution of 2.7 g of N-(3-fluoro-4-((N-methoxy-N-methylamino)carbonyl)phenyl)pyrazine-2-carboxamide was added to it at −78° C., and the reaction liquid was heated up to room temperature and stirred for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][CH:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][CH:29]([CH3:33])[CH3:28])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: CC(C)CCN
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NCCC(C)C)nc2n1
Yield: 80.6 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (65 cc), N,'-carbonyldiimidazole (1.3 g) and 3-methylbutylamine (0.61 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(3-methylbutyl)acetamide (2.45 g), m.p. 136° C., is obtained.