Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:41][C:38]5([C:35]6[N:36]=[CH:37][C:32]([F:31])=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform:Methanol 9.5:0.5 200 ml. Yield: 32 mg (55%). 1H NMR (400 MHz, CD3OD): δ 8.58 (d, J=0.5 Hz, 2H), 8.05-7.93 (m, 2H), 7.89-7.79 (m, 2H), 7.68 (s, 2H), 7.49-7.36 (m, 2H), 7.34-7.23 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.38 (m, 2H). LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([N:24]([CH3:25])[CH3:23])=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Yield: 46.3 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (100.0 mg, 0.31 mmol), dimethylamine (0.24 ml, 0.47 mmol, in 2.0 M tetrahydrofuran), EDC (90.1 mg, 0.47 mmol) and HOBt (63.5 mg, 0.47 mmol) in DMF 4 ml was added DIPEA (60.8 mg, 0.08 ml, 0.47 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC (n-Hexane:EtoAC:MeOH=6:3:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N,N-dimethyl-isonicotinamide as a yellow solid (52.9 mg, 46.5% yield).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[CH2:4][N:5]=[C:6]([NH2:23])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=O)[N:12]=1.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:16](=[O:18])[C:15]1[CH:20]=[CH:21][CH:22]=[C:13]([C:11]2[N:12]=[C:8]([NH:7][C:6]([NH2:23])=[N:5][CH2:4][C:3]([F:2])([F:25])[F:24])[S:9][CH:10]=2)[CH:14]=1
Reactant: COC(=O)c1cccc(-c2csc(NC(N)=NCC(F)(F)F)n2)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cccc(-c2csc(NC(N)=NCC(F)(F)F)n2)c1
Reaction time: 96 h
Yield: 20 %

Procedure:
A solution of crude methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzoate hydrochloride (1 g.) in ethanolic methylamine (33% w/v, 20 ml.) was allowed to stand at room temperature for 4 days. The mixture was then evaporated to dryness and the residue triturated with water to give 0.16 g. of N-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzamide (yield 20%). The n.m.r. spectrum in d6DMSO included the following resonances: 2.8 (d, 3H); 4.1 (m, 2H); 7.3 (s, 1H); 7.0-8.4 (complex, 7H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[NH:24]=[C:25]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[N:26]1C(C1C=CC=CC=1)=O.[CH3:40]C(C)([O-])C.[K+].[Cl-].[NH4+]>C(O)C>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:29]2\[C:25]([NH:24][CH3:40])=[N:26][C:27](=[O:31])[N:28]\2[CH3:30])[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN1CC(=N)N(C(=O)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: CNC1=NC(=O)N(C)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.6 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (26.0 g) in ethanol (100 mL) were added 4-imino-1-methyl-3-(phenylcarbonyl)imidazolidin-2-one (16.7 g) and potassium tert-butoxide (8.60 g) under ice-cooling. The reaction mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and ethanol was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was collected by filtration. The obtained solid was recrystallized from water/ethanol and further recrystallized from water/acetone for purification. To a solution of the obtained solid (2.03 g) in toluene (10 mL) was added a solution (4.8 mL) of methylamine in 40% methanol at room temperature. The reaction mixture was stirred at 70° C. overnight, a solution (4.8 mL) of methylamine in 40% methanol was added at room temperature, and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from heptane to give the title compound (223 mg).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:30])[C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)[C:17](=O)[CH3:18]>CO>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[NH:1][C:17]=1[CH3:18])=[O:30]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCl
Reactant: NC1=CC(=O)CCC1
Solvent: CO
Product: CC1=C(C(=O)CCCCCCl)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1

Procedure:
37 g (0.33 mol) 3-aminocyclohex-2-en-1-one and 42 g (0.13 mol) 1-chloro-7-(3-nitrophenyl-methylene)-nonane-6,8-dione are boiled under reflux in 400 ml methanol for 38 h. The mixture is concentrated and the residue is chromatographed with toluene/acetone=8/2. The title compound is obtained as a yellow oil. Yield: 18 g (34%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.[OH:23]C1C(OC)=CC=CC=1C(=O)C>>[OH:23][C:7]1[CH:2]=[CH:3][C:4]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]3([CH3:22])[C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1
Reactant: COc1cccc(C(C)=O)c1O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(O)ccc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate and as described in J. Med. Chem., 1989, 32, 2221-2226 starting from 1-(2-hydroxy-3-methoxyphenyl)-ethanone. MS m/z 250 [M-tBu+H]+
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20](=[O:22])[NH2:21])[CH:12]=1)=[O:10])C1C=CC=CC=1>CN(C=O)C.C1COCC1.CCOCC.[Pd]>[C:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([OH:10])=[O:8])=[CH:12]1)(=[O:22])[NH2:21]
Reactant: NC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)n1cc(C(=O)O)c2ccccc21
Reaction time: 8 h

Procedure:
1-Carbamoyl-1H-indole-3-carboxylic acid benzyl ester (1.33 g, 4.52 mmol) was dissolved in a mixture of DMF/THF 1:1 (28 mL), Pd/C (10%, 250 mg) was added and the solution was degassed 3 times replacing air with nitrogen then nitrogen with hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight and the catalyst was removed through a pad of Celite and washed with THF. The solvents were concentrated under high vacuum to give a yellow solid which was taken up in Et2O and filtered-off to afford the title compound. 1H-NMR (400 MHz, DMSO): δ (ppm) 12.6 (m, 1H), 8.54 (bs, 1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.85 (m, 2H), 7.34-7.27 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1c(Cl)cccc1Cl
Reaction time: 1.7 h
Yield: 21 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,6-dichlorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.7 hours and poured into 1.5 l of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving %) 48 g (79(of a light yellow viscous oil. The crude product was crystallized using 125 ml of ether, filtered, air dried and dried to a constant weight at 60° to give 13 g (21%) of a white solid m.p. 156°-158°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:14][NH2:15])=[O:13].[C:16](OCC)(OCC)(OCC)[CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[O:13][C:16]([CH3:17])=[N:15][N:14]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1cccc2c(Br)cccc12
Product: Cc1nnc(-c2cccc3c(Br)cccc23)o1
Yield: 88 %

Procedure:
5-Bromo-1-napthoic hydrazide (D2) (2.00 g, 7.5 mmol) was stirred at reflux under Ar in triethyl orthoacetate (20 ml) for 20 h. The mixture was cooled in ice, and the solid was filtered off, washed with petroleum ether (b.p. 60-80° C.), and dried in vacuo at 60° C., giving the title compound (1.92 g, 88%) as a light brown powder.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=C=O)=CC=1.[C:14]([O:18][CH2:19][CH2:20]O)(=[O:17])C=C.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH2:8][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCCO
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C=Cc1ccccc1
Product: CCOC(N)=O
Reaction time: 2 h

Procedure:
A hydroxyl polyester having an acid number of 0.3 and a hydroxy number of 48.1 was prepared from 714 g (11.5 moles) of ethylene glycol and 1460 g (10 moles) of adipic acid in the conventional manner. 400 ppm of hydroquinone were added to this polyester to obtain a 50% styrene solution of the polyester. 4676 g (2 equivalents) of this solution were allowed to react with 248 g (2.85 equivalents) of tolylene diisocyanate and 116 g (1 mole) of hydroxylethyl acrylate at 65° C. or less for two hours. To the resulting reaction product were added dropwise over 1.5 hours 364 g of styrene and 2.7 g of dibutyltin dilaurate. The reaction was allowed to continue at 70° C. for further two hours until no NCO remained in the reaction system, thereby to obtain a 50% styrene solution of an unsaturated acrylic urethane (hereinafter called Acrylic Urethane I). The urethane was found to have a weight-average extension of molecular chain of 600 A.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(CCl)cn1
Product: Cl

Procedure:
The title compound was prepared in accordance with the general method of example E from 5-(hydroxymethyl)-2-methylpyridine and thionylchloride.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1)[CH3:8]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Product: CCOC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Yield: 109.7 %

Procedure:
Ethyl 2-chloro-nicotinate (1.86 g, 10.0 mmol)was dissolved in 10 ml of dimethoxyethane. Tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) was added and the reaction vessel purged by alternating vacuum and nitrogen gas three times. A solution of 4-trifluoromethylphenylboronic acid (2.09 g, 11.0 mmol) in 20 ml of dimethoxyethane was added to the reaction mixture followed by 10 ml of a 2M sodium carbonate solution. The reaction mixture was heated at 90 C. for 1.5 h before being cooled and extracted with 150 ml of ether. The organic layer was washed with 50 ml of 2N NaOH, 2×50 ml water, and brine before being dried (magnesium sulfate), filtered and concentrated under vacuum to afford 3.24 g of a brown oil. This material was purified by silica gel chromatography eluting with 5 to 10% ethyl acetate in hexanes to afford 2.34 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:12]([O:10][CH2:9][C:3]1([CH:2]=[O:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=CC1(CO)CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [H-].[Na+].C[N:4]([CH3:7])[CH:5]=[O:6].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([F:15])[CH:9]=1.Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1C(N)=O>C(OCC)C.O>[F:15][C:10]1[CH:11]=[CH:12][C:13]([CH2:7][NH:4][C:5](=[O:6])[C:23]2[CH:22]=[CH:18][CH:17]=[N:25][C:24]=2[O:14][C:13]2[CH:12]=[CH:11][C:10]([F:15])=[CH:9][CH:8]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cccnc1Cl
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.95 %

Procedure:
Sodium hydride dispersion, 60% by weight (167 mg, 4.2 mmol) and 25 ml dimethylformamide (DMF) is placed in a 65 ml round bottom flask equipped with a stir bar and a reflux condenser under nitrogen. P-fluorophenol (430 mg, 3.8 mmol) is added to the reaction mixture and stirred for one hour. The chloronicotinamide (850 mg, 3.2 mmol) is then added and the reaction heated to reflux for 16 hours. The mixture is then cooled to room temperature and poured into 50 ml of water. This is extracted with ethyl acetate (2×50 ml), and the combined organics washed with 1M NaOH (2×50 ml), water (2×50 ml) and brine (1×50 ml). The ethyl acetate is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a green oil. This is digested in diethyl ether, and the resulting green crystals filtered off. The solids are recrystallized in ethanol to yield 283 mg (25.95%) of the title product as a white solid.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1(=[O:26])[N:15]([CH2:16][CH2:17][C:18](O)=O)[C:14](=[O:21])[C:13]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:12]12.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=1>N1C=CC=CC=1>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([N:57]2[C:1](=[O:10])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=[C:18]2[CH2:17][CH2:16][N:15]2[C:14](=[O:21])[C:13]3[C:12](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]2=[O:26])=[CH:53][CH:52]=1
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(N)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(-n2c(CCN3C(=O)c4ccccc4C3=O)nc3ccccc3c2=O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Anthranilic acid (2.0 g, 14.6 mmol), 3-phthalimidopropionic acid (3.2 g, 14.6 mmol), and triphenylphosphite (4.0 mL, 15.3 mmol) were dissolved in pyridine (20 mL) and heated in a sealed tube at 100° C. for 2 hours. After cooling to room temperature, the tube was opened, p-anisidine (2.7 g, 21.9 mmol) was added and heating at 100° C. was resumed for 4 hours. The pyridine was removed by azeotroping with toluene, and the residue was suspended in CHCl3 and toluene. The solids that crashed out were removed, and the residue was purified by silica gel chromatography with gradient elution (0 to 100% EtOAc in hexanes). A white solid precipitated from several of the fractions which was isolated by filtration to provide A-1 (2.23 g, 36%). Data for A-1: LRMS: calculated M+H for C25H19N3O4: 426.14. Found: 426.16.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].[Na].CO>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:22][OH:23])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
178.7 g (628 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carbonitrile and 65.5 g (941 mmol) of hydroxylamine hydrochloride were added to a solution prepared from 17.3 g (753 mmol) of sodium and 1.5 l of methanol. The reaction mixture was stirred at room temperature overnight and subsequently diluted with 1 l of water. The suspension obtained was suction filtered and the crystals were dried. There were obtained 169.7 g (85%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime of decomposition point 269°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH2:9][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[CH3:8])[NH2:6]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Product: COC(=O)[C@@H](N)C(C)CCc1ccc(-c2ccccc2C#N)cc1

Procedure:
L-valine methyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester thus formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester is treated with tributyltin azide to give valsartan methyl ester, which is then hydrolyzed under alkaline condition to give finally valsartan.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9](=[O:20])[C:10]([NH:12][CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=O)[CH3:7].O>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:10]1[O:19][C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][N:12]=1)=[O:20])[CH3:7]
Reactant: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(C(C)(C)C)o1
Yield: 57.6 %

Procedure:
Phosphorus oxychloride (16.3 ml, 0.178 mol) is added to a stirred solution of N-(3.3-dimethyl-2-oxo-butyl) oxalamic acid ethyl ester (38.4 g, 0.178 mol) in toluene (p150 ml). The mixture is heated gradually to reflux, and then refluxed for 16 h. After cooling, the mixture is added portionwise to water (500 ml) and stirred vigorously. The organic phase is separated and washed thoroughly with saturated sodium hydrogen carbonate solution (500 ml) and then twice with water (500 ml). The organic phase is then dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 7:3 v/v) to give 5-tert-butyl-oxazole-2-carboxylic acid ethyl ester (20.23 g, 58%) as an oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:50](=O)(O)[O-].[Na+].Cl[CH2:56][CH2:57]Cl>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:50][CH2:56][CH3:57])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3)cc1
Reactant: O=C([O-])O
Reactant: ClCCCl
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and propionyl aldehyde (0.27 ml) were dissolved in 1,2-dichloroethane (25 ml), and to the solution, triacetoxy sodium borohydride (0.78 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 22) (0.49 g) as pale yellow amorphous.