Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.[CH2:23](OC=C(C#N)C#N)C>C(O)(C)C>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)=[C:13]3[N:14]=[CH:23]2)=[CH:5][CH:6]=1
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(Nc2nccc(-c3ccc(C)cc3)c2N)cc1
Solvent: CC(C)O
Product: Cc1ccc(-c2ccnc3c2ncn3-c2ccc(C)cc2)cc1
Yield: 84 %

Procedure:
0.70 mol of N2,4-dip-tolylpyridine-2,3-diamine and 2.56 mol of 2-(ethoxymethylene)malonnitrile were added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 84%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=4)=[N:18][CH:19]=[C:14]3[CH2:13][N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Br:35])[C:11]2=[O:36])[CH:7]=[CH:8][CH:9]=1.Br>>[BrH:35].[NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[N:18][CH:19]=[C:14]3[CH2:13][N:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Br:35])[C:11]2=[O:36])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN)c2)C(=O)N(c2ccccc2Br)C3)cc1
Agent: Br
Product: NCCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccc(O)cc4)nc32)c1
Temperature: 150 °C
Yield: 142.5 %

Procedure:
25 mg of 1-[3-(2-aminoethyl)phenyl]-3-(2-bromophenyl)-7-(4-methoxyanilino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 59) was treated with 2 ml of 40% aqueous hydrobromic acid and the mixture heated at 150° C. for 2 hours. The mixture was cooled and evaporated. The residue was triturated with hexane to afford 20 mg (80%) of 1-[3-(2-aminoethyl)phenyl]-3-(2-bromophenyl)-7-(4-hydroxyanilino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrobromide as a white solid of melting point 210° C. (decomposition).
Reaction SMILES: [C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:25](N(CC)CC)C.CI>O1CCCC1>[C:1]([CH2:6][N:7]([CH3:25])[CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)CN(C)CCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10 mmol of 1-[2-[[(carbethoxy)-methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole and 10 mmol of triethylamine in 20 ml. of dry tetrahydrofuran is added 10 mmol of methyliodide. After stirring at room temperature for 24 hours, the mixture is filtered. The filtrate is stripped in vacuo to dryness, and the residue is dissolved in chloroform and chromatographed on silica gel eluting with a gradient of ethylacetate in chloroform. Evaporation of the product-containing fractions gives 1-[2-[[(carbethoxy)methyl]methylamino]ethyl]-5-[(4-methoxy-benzyl)thio]-1H-tetrazole. Deblocking with mercuric acetate as above gives 1-[2-[(carboxymethyl)methylamino]ethyl]-1,4-dihydro-5H-tetrazole-5-thione which when substituted in the reaction with 7-D-mandelamidocephalosporanic acid gives 7-D-mandelamido-3-[1-[2-[(carboxymethyl)methylamino]ethyl]tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 95.9 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.40 g, 1.6 mmol) and ammonium acetate (1.22 g, 15.8 mmol) in methanol (5.0 mL) and acetonitrile (5.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (0.20 g, 3.2 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give crude product (0.39 g, 97%), which was used directly in the next step. LCMS calculated for C16H13FN (M-NH2)+: m/z=238.1. Found: 238.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:14][OH:15])[CH3:13])=[N:9][N:8]=2)[CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:14][O:15][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:13])=[N:9][N:8]=2)[CH:2]=1
Reactant: Clc1ncccn1
Reactant: CC(=NO)c1nnc(-c2cccnc2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone oxime (0.1 g, 0.436 mmol) in acetonitrile (5 ml) was stirred at ambient temperature and treated with cesium carbonate (0.43 g, 1.31 mmol) and 2-chloropyrimidine (0.079 g, 0.654 mmol). The reaction mixture was allowed to stir at ambient temperature and monitored by TLC and LC/MS. After 2 days, the mixture was concentrated in vacuo. The residue was stirred with ethyl acetate, filtered and the ethyl acetate concentrated in vacuo. Purification by recrystallisation gave a single isomer of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]-N-pyrimidin-2-yloxy-ethanimine (70 mg, 23%) in form of beige crystals.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36](/B(O)O)=[CH:37]\[CH2:38][CH2:39][CH3:40]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CCC/C=C/B(O)O
Product: CCCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-1-penten-1-ylboronic acid (34 mg, 0.3 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4-pent-1-enyl-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](Br)([Br:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C)C.[Sn](Cl)Cl>O>[CH2:1]([O:3][P:4]([CH:9]([Br:17])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)C(Br)(Br)C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CC(C)O
Solvent: O
Product: CCOP(=O)(OCC)C(Br)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine t-butyl diethylphosphonodibromoacetate (75.6 g, 184 mmol) and isopropanol (190 mL). Cool to 0° C. Add a solution of tin (II) chloride (33.2 g, 175 mmol) in water (190 mL). After the addition is complete, warm to ambient temperature. After 1 hour, extract the reaction mixture three times with chloroform. Combine the organic layers and extract with water, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
Ethoxyacetyl chloride (1.78 g, 14.6 mmol) was added dropwise to a 0° C. solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part B of Example 57, 13.2 mmol) in dichloromethane (90 mL). After 1.5 h, more ethoxyacetyl chloride (0.3 mL) was added and stirring was continued for another 30 min. More ethoxyacetyl chloride (0.4 mL) was added and stirring was continued overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethanol (90 mL). Sodium hydroxide (1.06 g, 26.5 mmol) was added and the reaction was heated at reflux for about 1 d. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield a brown foam. The foam was triturated with ethyl acetate and sonicated briefly. A white solid was isolated by filtration. The filtrate was concentrated and the trituration process was repeated two more times. The off white solids were combined and dried to yield 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol (3.40 g, 76% over three steps).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[C:16]=[O:17]>>[CH3:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][NH:15][C:16]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:17]
Reactant: Cc1ccccc1CN=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: Cc1ccccc1CNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6j (56% yield) was synthesized from benzo[d]isothiazol-3-one and 2-methylbenzyl isocyanate as a white solid. mp 184-186° C.; IR(CHCl3) 3281, 1705, 1652, 1528 cm−1; 1H-NMR (DMSO-d6) δ2.32 (s, 3H), 4.52 (d, J=5.9 Hz, 2H), 7.15-7.19 (m, 3H), 7.27-7.30 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 9.18 (t, J=5.9 Hz, 1H); ESIMS m/e 299 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[N:30]1[C:39]2[C:34](=[CH:35][C:36]([F:41])=[C:37](F)[CH:38]=2)[C:33](=[O:42])[N:32]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]1=[O:51]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[N:30]1[C:39]2[C:34](=[CH:35][C:36]([F:41])=[C:37]([N:11]3[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)[CH:38]=2)[C:33](=[O:42])[N:32]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]1=[O:51]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cc(F)c(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cc(F)c(F)cc2F)C1
Yield: 52.8 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.231 g, 1.24 mmol), triethylamine (0.178 mL, 1.24 mmol), and 1-(2,4,5-trifluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example H-1, 0.18 g, 0.41 mmol) provided 0.13 g of the title compound as a solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH3:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:9](=[O:10])[CH2:8][CH2:7][C:6](=[O:5])[CH3:12])=[CH:17][CH:16]=1
Reactant: CC(=O)CCC(=O)Cl
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCC(=O)c1ccc(Cl)cc1
Reaction time: 0.54 h
Yield: 13.6 %

Procedure:
To a well stirred suspension of anhydrous aluminium chloride (29.66 g, 0.223 mol) in 154.7 ml of chlorobenzene was added 4-oxopentanoylchloride (25.0 g, 0.187 mol) drop-wise, over a period of 30-35 minutes at room temperature (25-30° C.). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10 ml) the precipitated solid was filtered and filtrate was concentrated in a rotary evaporation to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2×100 ml), brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform-hexane (90:10) as eluent to give 5.3 g (13.60%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:18]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1nncs1
Solvent: c1ccncc1
Product: O=C(Nc1nncs1)c1ccc2ccccc2c1
Yield: 39.2 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazol (0.84 g, 8.0 mmol) in pyridine (5 ml) was added 2-naphthoyl chloride (1.9 g, 10 mmol). The resulting mixture was stirred at reflux temperature for 15 min. cooled and quenched with water (100 ml). The precipitate was filtered off, washed with water (2×10 ml) and heptane (2×10 ml) and dried in vacuo affording 0.80 g (38%) of the title compound as a solid.
Reaction SMILES: N[C:2]1[N:7]([CH2:8][C:9]2C=CC(Cl)=CC=2)[C:6](=[O:16])[NH:5][C:4](=O)[C:3]=1NC(=O)C(C)C.CC(C)([O-:27])C.[K+].C(Br)C.Cl>CN(C=O)C>[CH2:8]([N:7]1[C:2](=[O:27])[CH:3]=[CH:4][NH:5][C:6]1=[O:16])[CH3:9]
Reactant: CC(C)C(=O)Nc1c(N)n(Cc2ccc(Cl)cc2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCn1c(=O)cc[nH]c1=O
Reaction time: 1.5 h

Procedure:
13.47 g (40 mM) of 6amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracil were dissolved in 130 ml of DMF, treated at 5° C. with 4.57 g (40.8 mM) potassium t-butoxide and after dissolution, 3.28 ml (44 mM) of ethylbromide added. After 3 hr another 1.14 g of t-BuOK and 1.64 ml of ethylbromide were added. After a further 1.5 hr, 1.64 ml of ethylbromide were supplemented. After a total of 22 hr the solution was neutralized with 1N HCl to pH 7 and the solvents evaporated in vacuo. The residue was taken up in dichloromethane-water and the organic phase collected giving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of 1N NaOH and heated under reflux for 1 hr. The solution was treated twice with 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The solid was diluted with water, collected, and dried. The crude material was recrystallized from methanol to give 7.42 g (49.2%) of 3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-xanthine, mp 221-2° C.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]=[C:30](Cl)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:18])[C:15](=[C:30]([NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:16]#[N:17])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reactant: C=C(C)C(=O)Oc1cccc(NC(=O)CC#N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1cccc(NC(=O)C(C#N)=C(NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a mixture of 4.89 g (20 mmol) of 3-(2-cyanoacetamido)phenyl methacrylate, 5.88 g (20 mmol) of N-(4-methylphenylsulfonyl)benzenecarboximidoyl chloride and 200 ml of methylene chloride was added dropwise 4.05 g (40 mmol) of triethylamine with 10 ml of methylene chloride rinse. The resultant solution was stirred for 1 hr and washed twice with 10% HCl and once with water. The solution was dried over magnesium sulfate and concentrated after adding t-butylpyrocatechol inhibitor. The solid residue was treated with ligroine, collected and recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].N1C=CC=CC=1.[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>O1CCCC1>[CH3:16][S:13]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOCCOS(C)(=O)=O

Procedure:
To 30g of 2-ethoxyethanol in 300ml of tetrahydrofuran 27.4ml of pyridine were added and 26.4ml of mesyl chloride added dropwise at room temperature over 15 minutes. The mixture was refluxed overnight, the solid that formed filtered off and the solvent evaporated off from the residue. The residue was distilled under 20m Hg to give 2-ethoxyethyl methanesulphonate.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH:17]([OH:50])[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]([OH:49])[CH2:33][N:34]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]1)=[O:29])=[O:21])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:51]1([N:57]=[C:58]=[O:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1C=CC=CC=1>[CH2:1]([N:5]([CH2:16][CH:17]([O:50][C:58](=[O:59])[NH:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]([O:49][C:58](=[O:59])[NH:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:33][N:34]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]1)=[O:29])=[O:21])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:14])([CH3:15])[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCN(CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Solvent: c1ccccc1
Product: CCCCN(CC(COC(=O)C1CCCCC1C(=O)OCC(CN(CCCC)C1CC(C)(C)NC(C)(C)C1)OC(=O)Nc1ccccc1)OC(=O)Nc1ccccc1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.4 g of bis{3-[N-butyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-2-hydroxypropyl}1,2-cyclohexanedicarboxylate, obtained as described in Example 18, and 2.4 g of phenylisocyanate in 30 ml of benzene was refluxed, with stirring, for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a vitreous mass having an Rf value of 0.58 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11](OC)OC>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[O:9][CH:10]=[CH:11][C:4]=2[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COC(COc1cc(C)ccc1Br)OC
Solvent: Clc1ccccc1
Product: Cc1ccc(Br)c2occc12
Temperature: 25 °C
Yield: 75 %

Procedure:
To a 500 ml round bottom flask was added 15.6 g polyphosphoric acid (PPA) and anhydrous chlorobenzene (260 ml). The mixture was brought to reflux and 1-bromo-2-(2,2-dimethoxy-ethoxy)-4-methyl benzene (8.11 g, 29.5 mmol) in chlorobenzene (60 ml) was added dropwise over 2 h. The reaction was heated to reflux for 3 h, cooled to room temperature, passed through a silica plug and concentrated. Column chromatography (100% hexane) afforded 4.67 g (75%) of product as a white waxy solid: mp 32–33° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.46 (3H, s), 7.02 (1H, d, J=7.9 Hz), 7.16 (1H, d, J=2.2 Hz), 7.43 (1H, d, J=7.9 Hz), 8.10 (1H, d, J=2.2 Hz); MS (EI) m/z 210 ([M+]).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH2:13]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1)[CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:19][C:18]1[CH:22]=[CH:23][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=1)[CH3:12]
Reactant: CCc1ccc(C[Mg]Cl)cc1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc(CC)cc1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution (42) of (4-ethylbenzyl)magnesium chloride prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL), and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═9/1) to give 1,1-diethoxy-3-(4-ethylphenyl)propan-2-one (43) as a colorless oily substance (1.29 g, 5.04 mmol, 50.6%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Product: C=CC(=O)NC1=C(C#N)C(c2cc(Br)c(OC)c(OC)c2)c2ccc(N(C)C)cc2O1

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and acryloyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 6.96-6.23 (m, 7H), 5.92 (d, J=10.2, 1H), 4.73 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.96 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]CC1C=CC=CC=1)[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2.CCOCC>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OCc4ccccc4)c(OC)cc3cc2c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1nc2nc3cc(O)c(OC)cc3cc2c(=O)[nH]1
Yield: 6 %

Procedure:
A solution of ethyl 7-methoxy-8-benzyloxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (198 mg., 0.488 mmole) in trifluoroacetic acid (4 ml.) is stirred at room temperature for 8 days. Ether (15 ml.) is added and the yellow precipitate which forms separated by filtration. It is taken up in chloroform and the solution filtered through diatomaceous earth to remove a small amount of insoluble material. The filtrate is decolorized with charcoal and concentrated under reduced pressure to small volume. The solid which forms is filtered and dried; 9 mg., 6% yield; m.p. 265°-266°C. (dec.).