Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[O:23])[CH:18]=[CH:17][C:15]=2[N:16]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22]([NH:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([NH:11][C:2]4[N:10]=[CH:9][N:8]=[C:7]5[C:3]=4[N:4]=[CH:5][NH:6]5)[S:13][C:14]=3[CH:20]=2)=[O:23])=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Reactant: Clc1ncnc2nc[nH]c12
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc2nc(Nc3ncnc4[nH]cnc34)sc2c1

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(9H-purin-6-ylamino)-benzothiazol-6-yl]urea was prepared from 6-chloropurine (17 mg, 0.11 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 42.5 mg, 0.11 mmol) according to GP 1. The reaction mixture was purified by pTLC (dichloromethane:methanol=9:1) to yield a yellow solid (35.4 mg, 70 μmol, 64%). LC/ESI-MS: m/z=505 [M(35Cl)+H]+; m/z=503 [M(35Cl)−H]−; Rt=3.87 min.
Reaction SMILES: [C:1]([NH:9][N:10]=[C:11](OCC)[CH2:12][CH2:13][CH2:14][CH3:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]1[CH:38]=[CH:37][C:24]([O:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:39][CH2:40][CH3:41])[CH:22]=1.C(Cl)(Cl)Cl>C(O)C>[CH2:12]([C:11]1[N:19]([CH2:20][C:21]2[CH:38]=[CH:37][C:24]([O:25][CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:39][CH2:40][CH3:41])[CH:22]=2)[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1cc(CN)ccc1OC(C(=O)OC)c1ccccc1
Reactant: CCCCC(=NNC(=O)c1ccccc1)OCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCc1nnc(-c2ccccc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 36.7 %

Procedure:
To a solution of 43.2 mg (0.175 mmol) of ethyl valerate benzoylhydrazone (from Step K) in 0.2 ml of ethanol was added a solution of 82 mg (0.262 mmol) of methyl 2-(4-aminomethyl-2-propylphenoxy)-2-phenylacetate (from Step J) in 0.2 ml of ethanol. The resulting solution was stirred under N2 at 50° C. for 5.5 hours. After dilution with 0.4 ml of ethanol, the solution was then stirred at 70° C. under a condenser for 13 hours. Next, the solution was co-evaporated with CHCl3. The residue was chromatographed twice in silica gel columns (gradient elution, first with 0.5-3% and then with 0.3-2% MeOH in CHCl2) to give 32 mg (37%) of the title compound as a white glass; homogeneous by TLC in 9:1 CH2Cl2 -MeOH.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:22])([CH3:21])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([OH:26])=[O:25].C([O-])(O)=O.[Na+:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:21])([CH3:22])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([O-:26])=[O:25].[Na+:31]
Reactant: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)[O-]

Procedure:
Prepared as in Example 128 from 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid (Example 134) and NaHCO3 as a white solid (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.23 (s, 6H), 2.56 (s, 3H), 3.86-3.94 (m, 1H), 4.07 (s, 2H), 6.66 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 360 (MH++H-Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1)=[CH2:11]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: OCc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc(CO)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (94 mg, 0.134 mmol) was added to a degassed solution of (4-bromo-pyridin-2-yl)-methanol (252 mg, 1.34 mmol) and tributyl(vinyl)tin (0.588 mL, 2.01 mmol) in toluene (10 mL) under nitrogen and the reaction mixture was stirred at 50° C. for 18 hours. Additional tributyl(vinyl)tin (0.176 mL, 0.67 mmol) and bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol) were added and stirring was continued for 18 hours at 80° C. under nitrogen. The reaction mixture was cooled to room temperature and silica gel was added. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:2 to 1:4 to afford the title compound (282 mg, 1.34 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ3.60-3.80 (br s, 1H), 4.78 (s, 2H), 5.52 (d, J=10.9 Hz, 1H), 6.01 (d, J=17.6 Hz, 1H), 6.69 (dd, J=17.6, 10.9 Hz, 1H), 7.22 (d, J=5.4 Hz, 1H), 7.27 (s, 1H), 8.52 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+].Cl>C(O)C.O>[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methoxybenzaldehyde (3.4 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam, bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is filtered and air-dried. Recrystallization from n-butyl chloride yields 3.2 g., m.p. 152°-157°C. An additional recrystallization from n-butyl chloride yields material with m.p. 159°-160.5°C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5](=[O:10])[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=1.Cl>>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[CH2:4][C:5](=[O:10])[N:6]([CH2:7][CH2:8][CH3:9])[C:2]2=[O:1])=[CH:16][CH:15]=1
Reactant: CCCN1C(=O)CN(c2ccc(NC(C)=O)cc2)C1=O
Agent: Cl
Product: CCCN1C(=O)CN(c2ccc(N)cc2)C1=O
Yield: 90 %

Procedure:
A mixture of 19.5 parts of N-[4-(2,4-dioxo-3-propyl-1-imidazolidinyl)phenyl]acetamide and 480 parts of concentrate hydrochloric acid was stirred and refluxed for 5 hours. The reaction mixture was cooled, and precipitated product was filtered off and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 15 parts (90%) of 1-(4-aminophenyl)-3-propyl-2,4-imidazolidinedione; mp. 133.2° C. (23).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(N(CC)CC)C>ClCCl>[N:13]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[O:4])[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Cn2cccn2)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To a solution of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol) in 5 ml dichloromethane was added pyrazole (304 mg, 4.46 mmol) and triethylamine (0.31 ml, 2.23 mmol). Reaction was stirred at room temperature over night. Reaction was then diluted with 20 ml dichloromethane, washed with 2×25 ml water, 2×25 ml 1N HCl, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane to give 3-[2-(1H-1-pyrazolyl)acetyl]benzonitrile (330 mg, 70%) as a clear oil after drying. ES-MS (M+H+): 212.05
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>ClCCl>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:21])[CH2:13][CH2:12][N:11]([C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: C=C1CCN(C(=O)Nc2cccc(C)c2)CC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A solution of 1-benzyl-7-methylene-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (94 mg, 0.32 mmol) and 3-methylphenylisocyanate (42 μl, 0.33 mmol) was stirred in dichloromethane (2 ml) at room temperature for 3 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane as eluant (1:1) gave the product. (131 mg, 96%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][O:10][NH:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[CH3:28])(C)(C)C.OS(O)(=O)=O.C([O-])(O)=O.[Na+].O>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][O:10][CH2:9][CH2:8][CH2:7][OH:6])=[O:29])=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])[CH:15]=1
Reactant: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)NOCCCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)NOCCCO
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of N-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide (4.0 g, 7.27 mmol) in methanol (5 mL) at ambient temperature was added 5 M H2SO4 in methanol (0.073 mL, 0.364 mmol). After 1 h of stirring, to the reaction was added additional 5 M H2SO4 in methanol (0.035 mL, 0.182 mmol). After 2 h of stirring, the reaction was adjusted to pH 7 using saturated NaHCO3 (aq) (c.a. 1.5 mL), followed by addition of water (35 mL). The aqueous layer was extracted with ethyl acetate (1×20 mL, 2×10 mL). The extracts were combined, washed with brine, and dried over magnesium sulfate. The resultant mixture was filtered, and the filtrate solvent was removed in vacuo to obtain an oil that was dried on a vacuum pump over the weekend. The oil was purified by flash chromatography, eluted with a gradient of 100% hexanes to 100% ethyl acetate in 50 min. The solvent was removed in vacuo of combined fractions to obtain a solid which was dried on a vacuum pump for c.a. 6 h. Recrystalized solid in a mixture of hexanes and ethyl acetate to afford 4-fluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl-phenylamino)-benzamide as a solid (2.4 g, 74% yield): m.p. 120.8-122.4 C; 1H-NMR (400 MHz, (CD3)2CO) δ 10.91 (br s, 1H), 9.59 (br. S, 1H), 9.68 (m, 2H), 7.57 (d, 1H, J=8.54 Hz), 7.18 (d, 1H, J=8.34 Hz), 6.72 (m, 1H); 6.53 (m, 1H); 4.12 (t, 2H, J=6.11 Hz), 3.71 (t, 2H, J=5.86 Hz), 2.26 (s, 3H), 1.86 (m, 2H); 19F-NMR (376 MHz, (CD3)2CO) δ −108.14; MS 445.1 m/z (AP+), 443.1 m/z (AP−). Anal. Calcd. for C17H18FIN2O3: C, 45.96; H, 4.08; N, 6.31; F, 4.28; I, 28.57. Found: C, 45.78; H, 3.88; N, 6.14; F, 4.30; I, 28.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([OH:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CC(C)([O-])C.[K+].Br[CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[N:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1

Procedure:
Crude (S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester (44 g) was dissolved in DMF and treated with 12.2 g potassium tert-butoxide and 14.7 ml 1-bromopinacolone. After 2 h the solvent was removed in vacuo, the residue taken up in DCM and extracted with water. The crude product obtained after evaporation of the solvent was purified by flash column chromatography on silica eluting with heptane/ethyl acetate giving the title compound as colorless oil (45 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17]C)[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:2].CCO.Cl.[OH-].[Na+]>CCOC(C)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([OH:17])[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(O)n1
Temperature: 90 °C

Procedure:
To a flask containing (1S)—N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (3.5 g, 8.15 mmol) is added EtOH (50 mL) and HCl (12 N, 50 mL) and the solution is heated at 90° C. for 16 h. The solution is cooled to 0° C. and basified using 5N NaOH slowly, followed by addition of EtOAc (100 mL). The organic layer is washed with sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a white gummy foam. [mass expected (415.57); mass found (415.33)]
Reaction SMILES: [ClH:1].C(N(CC(O)CNC([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)CC)C.C(N(CC)CC)C.[Cl-].[CH3:38][O:39][C:40](=[O:46])[CH2:41][CH2:42][C:43](O)=[O:44]>C(Cl)Cl>[ClH:1].[CH3:38][O:39][C:40]([CH2:41][CH2:42][C:43]([O:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:13]=1)=[O:44])=[O:46]
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.005 mole) are mixed in 25 ml of methylene chloride with 0.7 ml triethylamine (0.005 mole) and 0.6 ml of succinic acid methylester chloride and the reaction mixture agitated for 1 h at room temperature. The solution is then washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. The residue is purified by low pressure chromatography using methylene chloride as the elution agent, as described in Example 3. 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxycarbonylethylcarbonyloxy-1-phenylindole hydrochloride is obtained as an oily product.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1>>[CH3:19][C:5]1[N:4]([CH2:3][CH:2]([O:1][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH3:20])[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Reactant: Oc1cccnc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1cccnc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 3-pyridinol; MS (ES) m/z 360 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:18].N.Cl>C(O)(C)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][SH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(C)O
Product: SCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 30.8 g of m-phenoxybenzyl bromide in 70 ml of isopropanol is reacted with 9.5 g of thiourea in 30 ml of water and the reaction mixture is refluxed briefly. After cooling, 25 ml of a 25% ammonia solution are added and the mixture is heated briefly to reflux and then allowed to cool, whereupon it is acidified with 18% hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated, affording the compound of the formula ##STR7## with a boiling point of 114°-116° C.'0.05 mm Hg.
Reaction SMILES: [ClH:1].Cl.[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>>[ClH:1].[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCC(=O)O)c3ccccc3)ccc21
Yield: 73.5 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)amide dihydrochloride and sodium hydroxide solution. Yield: 73.5% of theory, C27H28N6O3 (484.6); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
N-[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-acrylamide (2.80 g, 8.3 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (1.20 g, 21.0 mmol) followed by saturated ammonium chloride solution (3 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and EtOAc (50 ml) and the solution was concentrated under vacuum. The resulting residue was suspended in water (10 ml) and the solid precipitate collected by filtration and dried under vacuum to give the title compound (1.3 g, 51% yield) as a white solid. Tr=1.30 min, m/z (ES+) (M+H)+ 310.
Reaction SMILES: Cl[C:2]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3].N1C=CC=CC=1.[CH3:15][OH:16]>C(Cl)Cl>[NH:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:2]([O:16][CH3:15])=[O:3]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc[nH]1

Procedure:
40 ml of a solution of 45 (mmoles) of 2-chlorocarbonyl-1H-pyrrole in methylene chloride were added dropwise to a cold mixture of 4.3 ml of pyridine and 3.5 ml of methanol and the mixture was washed with water, then with 6 ml of N sodium hydroxide, and was extracted with methylene chloride. The organic phases were dried and concentrated to dryness and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 4.014 g of methyl 1H-pyrrole-2-carboxylate melting at ≈74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[C:14]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])(=[O:16])[CH3:15].N1C=CC=CC=1>O>[CH3:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][C:14](=[O:16])[CH3:15])[CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3cccc(OC(C)=O)c3)nc2n1
Yield: 78.6 %

Procedure:
The procedure is similar to that described in Example 3, but starting with 2-amino-7-methoxynaphthyridine (3.5 g), 3-acetoxybenzoyl chloride (4.4 g) and anhydrous pyridine (40 cc). The reaction mixture is poured into water (400 cc) and the precipitate obtained is separated by filtration and then washed with water (6×100 cc) and dried in the air. On recrystallization from ethanol (140 cc) of the product thereby obtained, N-(7-methoxy-1,8-naphthyridin2-yl)-3-acetoxybenzamide (5.3 g), m.p. 172° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[Br:11]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:5]#[N:6]
Reactant: NC(=O)CCC(=O)NBr
Reactant: N#CCc1ccccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccc1Cl
Yield: 65.7 %

Procedure:
To a solution of 2-chlorobenzylcyanide (1.0 g, 6.60 mmol) in CCl4 (25 mL) was added N-bromosuccinamide (1.29 g, 7.26 mmol) and 2,2′-azobis-(2-methylpropionitrile) (0.05 g, 0.33 mmol). The reaction mixture was allowed to reflux for 48 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with 0.1 M NaOH (50 mL). The organic phase was concentrated to dryness yielding 1.0 g (66%) product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CCOC(=O)CBr
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Product: CCOC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Yield: 100 %

Procedure:
6-Bromoquinolin-2(1H)-one (5.03 g, 22.5 mmol) was subjected to protocol K with ethyl bromoacetate instead of methyl bromoacetate to afford 6.96 g (100% yield) of ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate as a white solid. Method [7] Retention time 4.79 min by HPLC (M+=310 and 312) and (M+Na=332 and 334). The acetate (318 mg, 1.03 mmol) was subjected to the protocol in Example 1.53.4 to afford 228 mg (83% yield) of 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid as a white solid. Method [8] Retention time 4.79 min by HPLC (M+=282 and 282) and (M+Na=304 and 306).