Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C)C=O.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([I:22])=[CH:17][C:16]=1[OH:23].N1C=CN=C1>O>[C:2]([Si:5]([O:23][C:16]1[CH:17]=[C:18]([I:22])[C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(I)c(Cl)cc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(I)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
TBDMSCl (5.22 g) was added to an N,N-dimethylformamide (50 ml) solution of 2,4-dichloro-5-iodophenol (10 g) synthesized according to the production method described in WO 2001/027088 and imidazole (2.83 g), and the resulting mixture was stirred at room temperature for 4 hours. Water (150 ml) was added to the solution, and then extracted with n-hexane (200 ml). Then, the n-hexane solution was sequentially washed twice with water (100 ml) and once with a saturated aqueous sodium chloride solution (100 ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane) to yield pale yellow oily tert-butyl(2,4-dichloro-5-iodophenoxy)dimethylsilane (11.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12]Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20].ClC1C=CC=CC=1Cl.[Sn](Cl)(Cl)(Cl)Cl>O=[Pt]=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][CH:23]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH2:11][CH2:12][NH:24]1)=[O:20]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: COc1cc(C(=O)NCC#N)cc(OC)c1OC
Agent: O=[Pt]=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: COc1cc2c(cc1OC)C(CNC(=O)c1cc(OC)c(OC)c(OC)c1)NCC2
Reaction time: 8 h

Procedure:
A mixture of 2.0 g. of 1-(3,4-dimethoxyphenyl)-2-chloroethane and 2.5 g of 3,4,5-trimethoxybenzamidoacetonitrile (obtainable from aminoacetonitrile and 3,4,5-trimethoxybenzoyl chloride) is allowed to stand overnight at 20° in 100 ml. of o-dichlorobenzene and with 2.6 g. of tin tetrachloride; the mixture is thereafter heated for 3 hours to 110°. The solution is concentrated by evaporation, and the residue is shaken with chloroform and sodium hydroxide solution. The chloroform solution is evaporated, and the thus-obtained crude 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 30 ml. of methanol and hydrogenated with 200 mg. of PtO2 at 20° and under normal pressure. After filtration, evaporation, and purification by chromatography on silica gel, 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is obtained; hydrochloride, m.p. 234°-236°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[CH2:16][C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:15][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: CC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 457 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 277 mg of 3-pentyn-1-ol, to which 132 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 467 mg of 4-(2-fluorophenyl)-6-(3-pentynyloxy)pyrimidine (the present compound (153)).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chlofororm (100 ml×3). The chloroform layer was washed with water (150 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.36 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([O:36]C)=[O:35])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1.O>[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([OH:36])=[O:35])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of anhydrous K2CO3 (249 mg, 1.8 mmol) in tetrahydrofuran (8 ml) and water (12 ml) is degassed with argon and then methyl cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (150 mg, 0.35 mmol) is added. The reaction is stirred 1.5 hours at room temperature, the organic solvent is evaporated and the aqueous layer is acidified and extracted with methylene chloride. The dried extracts are evaporated to give a solid which is recrystallized from ethyl acetate-hexane to give pure cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylic acid, mp 169°-170°(d).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:19]=2[CH3:30])[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37](Cl)=[O:38]>>[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37]([N:16]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:11][CH2:12]1)=[O:38]
Reactant: Cc1ccc(-c2ccncc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: Cc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 232 (36 mg) is treated with acid chloride 8 (29 mg, 0.11 mmol) using Method D to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:29]=[C:30]=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:30](=[O:31])[NH:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCN=C=O
Reactant: Oc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) is added dropwise under a nitrogen atmosphere to a solution of 2-phenylphenol (5.0 g, 29.3 mmol) and octyl isocyanate (5.5 g, 35.5 mmol) in 75 mL of methylene chloride. After the addition, the solution is stirred overnight at room temperature. The solution is washed with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.09 g of a tan solid. Recrystallization from diisopropyl ether-hexane gives the title compound as a white crystalline solid (6.88 g, 72%), mp 59°-60° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH3:15])[C:13]#[N:14].[C:20](OC)(=[O:23])[CH2:21][SH:22].C(N(CC)CC)C>C(O)C>[CH3:15][N:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[CH3:1])[C:13]1[S:22][CH2:21][C:20](=[O:23])[N:14]=1
Reactant: Cc1ccccc1OCc1ccccc1N(C)C#N
Reactant: COC(=O)CS
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1OCc1ccccc1N(C)C1=NC(=O)CS1
Yield: 42.9 %

Procedure:
A solution of 6.3 g (0.01 mol) of 40% pure N-[2-(2-methylphenoxymethyl)-phenyl]-N-methyl-cyanamide, 1.1 g (0.01 mol) of methyl thioglycolate and 0.15 g of triethylamine in 100 ml of ethanol is heated under reflux for 18 hours. The mixture is concentrated and the residue is chromatographed over silica gel using cyclohexane/ethyl acetate (1:3). 1.4 g (43% of theory) of 2-{methyl-[2-(2-methylphenoxymethyl)-phenyl]-amino}-thiazol-4-one are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:49]=[C:48]([CH2:50][C:51](O)=[O:52])[O:47][N:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:51](=[O:52])[CH2:50][C:48]3[O:47][N:46]=[C:45]([CH3:44])[CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)on1
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-methyl-5-isoxazoleacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-methyl-isoxazol-5-yl)-acetamide (0.8 g, 84%) as a white solid: mp 179-181° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.71 min. (97%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.20 (s, 3H), 2.53-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.77 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.21 (s, 1H), 7.69-7.87 (m, 3H), 8.80 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 10.91, 21.95, 30.90, 33.46, 38.00, 48.85, 103.79, 121.99, 127.18, 131.54, 133.27, 134.75, 138.66, 159.51, 166.85, 166.90, 167.41, 169.77, 172.72; Anal. Calcd. for C20H18N4O6: C, 58.54; H, 4.42; N, 13.65. Found: C, 58.18; H, 4.19; N, 13.52.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5]Br.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5][O:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: CC(CF)(CF)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
171.2 g (0.79 mol) of 3,3-bisfluoromethyl-1-bromo-butan-2-one were added dropwise to a stirred mixture of 102 g (0.79 mol) of p-chlorophenol and 110 g (0.79 mol) of powdered potassium carbonate in 500 ml of acetone at 20° to 30° C. The mixture was subsequently stirred at 40° C. for 4 hours, the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 190.5 g (90% of theory) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-butan-2-one of boiling point 113°-117° C./0.1 mm Hg were obtained. ##STR74##
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([S:24][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:25])[CH3:23]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (335 mg, 1.01 mmol) (obtained as described in Reference Example 26(3)) in dimethylformamide (15 ml) was added potassium thioacetate (1.10 g, 8.80 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (235 mg, yield 75%) as a pale brown solid.
Reaction SMILES: [CH:1]1[CH:14]=[C:13]([NH2:15])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([S:9]([OH:12])(=[O:11])=[O:10])[C:3]=2[CH:2]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:23]([NH:15][C:13]1[CH:14]=[CH:1][CH:2]=[C:3]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:9]([OH:12])(=[O:10])=[O:11])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc2c(S(=O)(=O)O)cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2c(S(=O)(=O)O)cccc12)c1ccccc1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 1-naphthylamine-5-sulfonic acid (2 g, 8.9 mmol) in dichloromethane (5 mL), was added triethylamine (1.87 mL, 13.4 mmol). Benzoyl chloride (1.14 ml, 9.85 mmol) was added and the resultant solution was stirred at room temperature overnight. The reaction mixture was quenched by pouring into ice water, and the product was extracted into ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide crude intermediate 43 as a white solid that was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][NH:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: NC1CCCC1
Agent: ClCl
Solvent: ClCCl
Product: O=C(CNC1CCCC1)OCc1ccccc1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
A solution of Benzyl-2-bromoacetate (3.30 ml, 20.0 mmol) in 20 mL CH2 Cl2 was added drop-wise to a solution of cyclopentylamine (8.60 g, 100 mmol) in 20 mL of CH2Cl2, with stirring at 0° C. On completion of the addition of benzyl-2-bromoacetate, the reaction was stirred at room temperature 17 hours. The organic solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated Na2CO3 solution. The solution was extracted with 1N HCl . The aqueous layer was made basic with Na2CO3 and extracted with chloroform. The organic layer was dried (MgSO4) and evaporated. The residue was purified by silica gel flash column chromatography, eluting sequentially with hexane and hexane/ethyl acetate (1:1, v/v) to yield 2.3 g (50.0%) of the title compound as an oil. 1 H NMR (CDCl3) δ 6 1.25-1.85 (m, 9H); 3.0-3.12 (m, 1H); 3.43 (s, 2H); 5.15 (s, 2H); 7.27-7.42 (m, 5H); 13C NMR (CDCl3) δ 23.72, 32.71, 49.53, 59.03, 66.24, 128.1, 128.32, 135.42, 172.29.
Reaction SMILES: O[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]Br>CN(C)C=O>[Br:32][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
To 1-Hydroxymethyladamantane (366 gm.) and triphenylphosphine (598 gm.) in 1600 ml. dimethylformamide was added a solution of 366 gm. bromine in 800 ml. dimethylformamide over a 5 hour period. The mixtue was left overnight at room temperature and then distilled (under aspirator) to remove solvent and product. The distillate was poured into 8 liters of water and filtered. The solid was dissolved in petroleum ether (30°-60°), washed with K2CO3 solution, then with water, dried, and concentrated to dryness. The residue recrystallized from 2.5 liters methanol gave 426.6 gm., m.p. 43°-4°. (1st crop plus additional crops obtained on concentration of the mother liquors.)
Reaction SMILES: [OH:1]C1C2C(=CN=C(Cl)C=2)N=CC=1.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1)[CH:20]=[O:1]
Reactant: Oc1ccnc2cnc(Cl)cc12
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Product: O=Cc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A route to prepare 4-hydroxy 6-chloro 1,7 napthyridine is depicted in Scheme III. Starting with 2-chloro-4-methyl-5-nitropyridine, condensation with dimethylformamidedimethylacetal and subsequent oxidative cleavage yields 2-chloro-5-nitroisonicotinaldehyde. Chemoselective methyl addition to the aldehyde with methyllithium and titaniumtetrachloride at −50° C. followed by oxidation yields 1-(2-chloro-5-nitropyridin-4-yl)ethanone. Nitro reduction with iron in acetic acid, followed by a two step monotosylation yields N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide. Upon heating with dimethylformamidedimethylacetal and diisopropylethylamine in DMF at 105° C. and subsequent treatment with thiophenol at room temperature, 6-chloro-1,7-naphthyridin-4-ol is obtained IV. Conversion of IV to the corresponding triflate or benzyl ether using standard conditions yields bifunctional intermediates which can be taken through the chemical transformation depicted in Schemes 1 and 2 to yield 4,6 disubstituted 1,7 naphthyridines V.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([NH2:14])[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1>>[C:2]([CH2:3][C:4]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[O:5])(=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(N)c1
Product: CC(=O)CC(=O)Nc1cccc(NC(=O)CC(C)=O)c1

Procedure:
The process of the invention for the preparation of compounds of formula I wherein R' is ##STR11## comprises reacting diketene with m-phenylenediamine to obtain m-(acetylacetamido)-acetylacetanilide which is reacted with methyl orthoformate and then heated to obtain m-(3'-methoxycrotonylamino)-3 -methoxy-crotonanilide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzoyl chloride in substantially the same manner as described in Example 61 with one change: pyridine was used as a base instead of triethylamine; off-white solid: MS (EI) m/z 497.2 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.50-7.95 (m, 10H), 8.05 (d, J=7.7 Hz, 1H), 8.36 (d, J=7.0 Hz, 1H), 9.16 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](O)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]([NH2:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)CCCC2
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)c2c(n1)CCCC2
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (20.0 g, 121 mmol) in toluene (150 ml) was dropped phosphorus oxychloride (55.7 g, 363 mmol) at 90° C. The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was poured into 28% aqueous ammonia solution at 0° C. The solid was filtered and purified by silica gel column chromatography (3%MeOH/CHCl3) to give the object compound (13.5 g, 60%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:31])=[C:26]([Cl:39])[CH:25]=2)(=O)=O)=CC=1.[Na+].[I-:41]>CC(C)=O.O>[Br:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:31])=[C:26]([Cl:39])[CH:25]=2)=[C:16]([CH2:15][O:14][CH2:13][CH2:12][I:41])[CH:21]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2cc(Br)ccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCI)cc1Cl

Procedure:
Compound 164 (1.72 g, 2.73 mmol) was dissolved in dry acetone (2.7 mL) and dry NaI (0.82 g, 5.47 mmol) was added. The suspension was stirred in a light protected flask at room temperature for 20 h after which the reaction mixture was diluted with water and the water phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. This afforded the title compound as a yellow oil.