Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]1[NH:9][C:10]([CH3:30])=[C:11]([C:26]([O:28][CH3:29])=[O:27])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+]=[N-].[H][H].C([OH:35])C>[Pd]>[C:7]([OH:6])(=[O:35])/[CH:8]=[CH:13]\[C:14]([OH:16])=[O:15].[NH2:1][CH2:4][CH2:5][O:6][CH2:7][C:8]1[NH:9][C:10]([CH3:30])=[C:11]([C:26]([O:28][CH3:29])=[O:27])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (103 g) in ethanol (2.5 l) was stirred for 16 hours at room temperature under one atmosphere of hydrogen in the presence of 5% palladium on calcium carbonate (40 g). The reaction mixture was filtered and evaporated and the residue treated with a solution of maleic acid (22 g) in ethanol (100 ml). The reaction mixture was stirred at room temperature for 2 hours and then the resulting solid collected, washed with ethanol, and dried to give the title compound (100 g), m.p. 169°-170.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][N:36]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][N:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NN4CCCCCC4)cc3)c2cc1OC
Yield: 65.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminohomopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (48 mg, yield 65%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:22])([Cl:21])[Cl:20])[CH:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:21])([Cl:20])[Cl:22])[CH:16]=[CH:15][N:14]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1cc(C(Cl)(Cl)Cl)ccn1
Reaction time: 4 h
Yield: 81.2 %

Procedure:
17 ml (0.3 mol) of methyl isocyanate and 1 ml of triethylamine were added to 21.2 g (0.1 mol) of 2-amino-4-trichloromethylpyridine and 400 ml of toluene at 25° C. After 4 hours at 80° C., the resulting solid was isolated. 21.8 g (82%) of the desired product were obtained. Mp.: 192°-195° C.; Active Ingredient Example 2.001
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)\[CH2:5][CH3:6].[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1([CH2:5][CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
To a solution of 1-[(E)-3-chloro-1-ethyl-1-propenyl]-3-nitrobenzene (Preparation 15, 50 g, 0.22 mol) in dichloromethane (40 ml) was added rhodium (11) acetate dimer (2.0 g, 4.6 mmol). To the mixture was added dropwise at room temperature over 6 hours a solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture stirred at room temperature for 16 hours. To the mixture was added dropwise at room temperature over 7 hours a solution of ethyl diazoacetate (20 ml, 21.70 g, 0.190 mol) in dichloromethane (20 ml), then the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue purified by silica column (1 kg) chromatography, eluting with 1:1 hexane/dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale orange oil (10.5 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22](O)=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1.C(N1C=CN=C1)([N:38]1C=CN=C1)=O.C(=O)(O)[O-].[NH4+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([NH2:38])=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Trans-7-chloro-5-(1 -naphthyl)-1 -(2,2-dimethyl-3-dimethylamino-propyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.16 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (1.91 g, 11.8 mmol) were dissolved in dimethylformamide (75 ml). Stirring for 1 h at room temperature was followed by addition of ammonium bicarbonate (1.86 g, 23.5 mmol) in one portion to the reaction mixture, which was stirred for further 18 hours at room temperature. The solvent was concentrated under reduced pressure and the residue flash chromatographed directly (dichloromethane/methanol/aqueous ammonia 99:1:0.1 to 98:2:0.2). The solid was taken up in dichloromethane and a stoichiometric amount of 1N HCl in ether was added. Removal of the solvent provided a solid which was dissolved in ethanol and precipitated with ether to give the title compound (0.42 g, 36%) as a colorless solid.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1>O>[CH3:21][C:18]1[C:17]2[C:4]([OH:14])=[CH:5][C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:15][C:16]=2[O:20][N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Cc1cc(N)on1
Solvent: O
Product: Cc1noc2nc(-c3ccccc3)cc(O)c12
Temperature: 25 °C

Procedure:
19.2 g. of benzoylacetic acid ethyl ester (0.1 mol.) are added dropwise to a stirred mixture of 9.8 g. of 5-amino-3-methylisoxazole (0.1 mol.) and 50 g. of polyphosphorous acid heated to 120°-125°. After the reaction has occurred, which can be recognized by changing of the color to brown, the reaction mixture is heated for an additional half hour at 125°. After the mixture has cooled to room temperature, 250 ml. of water are added in portions and stirring is continued until the compound becomes crystalline. The collected 3-methyl-6-phenylisoxazolo[5,4-b]pyridin-4-ol is washed with water, dried and recrystallized from ethanol yielding 19.9 g. (88%), m.p. 281°-282°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: OB(O)c1ccccc1Cl
Reactant: COCc1cc(C(=O)OC)ccc1Br
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1Cl
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (15 g, 57.9 mmol) in toluene (120 mL) and water (30 mL) under nitrogen was added 2-chlorophenylboronic acid (19.9 g, 127.4 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (3.34 g, 2.8 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. LC/MS, M+(ESI): 291.0. 1H NMR (CDCl3, 400 MHz) δ 8.21 (1H, s), 8.01 (1H, d), 7.48 (1H, m), 7.34 (2H, m), 7.26 (2H, m), 4.33 (1H, dd), 4.20 (1H, dd), 3.94 (3H, s), 3.27 (3H, s).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19]>ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:2](=[O:8])[C:3](=[O:5])[N:20]([CH:21]([CH3:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:18]1=[S:19]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1ccc(F)cc1F)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(F)cc2F)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Ethyl chlorooxoacetate (0.53 mL, 4.77 mmol) was added to a stirring solution of the above thiourea (1.00 g, 3.67 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.75 g (62%) of 1-(2,4-difluoro-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 155.2–156.0° C.; 1H NMR (DMSO-d6): δ 7.55 (m, 2H), 7.30 (m, 1H), 4.80 (m, 1H), 1.51 (d, 3H), 0.99 (s, 9H); IR (KBr): 3550, 2970, 2230, 1770 cm1; MS (m/z) 326 (M+).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of ethyl 3-oxo-3-(4-pyridyl)propionate (13.9 g, 72.0 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 2.88 g, 72.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (17.2 g, 72.0 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml), and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10.9 g, 43%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (0.15 mL, 2.06 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in dichloromethane (15 mL) and stirred at 20° C., for 10 min. To this, pyridine (0.33 mL, 4.12 mmol) was added and the mixture was stirred further for 18 h. The solvent was removed from the mixture and water (15 mL) was added. The pH of the reaction mixture was adjusted to 3 using aqueous hydrochloric acid (10%). The solid obtained was filtered and the crude obtained was purified by column chromatography (silica gel, 2% methanol in chloroform) to obtain the title compound. Yield: 0.3 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.02 (s, 3H, CH3), 2.63 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.17 (s, 2H, CH2), 3.55 (s, 4H, 2CH2), 3.85, (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.09 (d, 1H, Ar), 7.15 (d, 1H, Ar), 8.08 (t, 1H, Ar), 8.15 (t, 1H, Ar); MS: m/e (ES+) 479 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[O:23].[OH-].[Na+]>C(#N)C.N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1ccc(CCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)N1CCC(C(=O)c2nccn2CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a cooled mixture of 54.2 g of 1-(2-phenylethyl)-1H-imidazole, 34.7 g of N,N-diethylethanamine and 50 ml of pyridine there were added dropwise 69.2 g of ethyl 4-chlorocarbonyl-1-piperidinecarboxylate(temp.≤0.20° C.) and then 30 ml of acetonitrile. The whole was stirred for 2 hours at room temperature and for 4 hours at reflux temperature. After cooling, there were added 30 ml NaOH 50% and refluxing was continued for 1/2 hour. The cooled reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was dried, yielding 38 g (33.9%) of ethyl 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)SC2CCCCC2)cc1OC
Yield: 66.3 %

Procedure:
The procedure of Example 3 is repeated using 2.7 g of α-(5-chloropentyl)-α-(cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile and 2.53 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.5 g of the desired product as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[C:32]2([CH2:37][CH2:36][N:35]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:31]1[C:32]2([CH2:33][CH2:34][N:35]([C:38]3[CH:45]=[CH:44][C:41]([C:42]4[NH:25][C:24]5[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]6[CH:14]=[CH:13][C:12]([N:15]7[CH2:20][CH2:19][O:18][CH2:17][CH2:16]7)=[CH:11][CH:10]=6)=[CH:5][C:4]=5[N:1]=4)=[CH:40][CH:39]=3)[CH2:36][CH2:37]2)[O:28][CH2:29][CH2:30]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC5(CC4)OCCO5)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 413 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 4-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)benzaldehyde. [M+H]+ calcd for C31H33N5O4: 540.25; found: 540.05.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([O:4][CH2:3][CH2:2][I:1])([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: OCCI
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 8 h

Procedure:
To 2-iodoethanol (20 gm, 116 mmol) suspended in methylene chloride (500 mL) was added dimethylaminopyridine (100 mg) followed by diisopropylethylamine (30 mL, 174 mmol) and tert-butyldimethylsilyl chloride (19 gm, 128 mmol). The reaction was stirred overnight and the solvent was removed in vacuo and the residue was passed through a short column of silica gel and eluted with 95:5 methylene chloride: methanol. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[C:7]([O:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[O:21]1CC[CH2:23][CH2:22]1>C(OCC)(=O)C.Cl>[C:7]([O:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[CH2:16]/[CH:17]=[CH:23]/[C:22]([O:4][CH2:2][CH3:5])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethylphoshonoacetate (1.96 mL, 9.8 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium tert-butoxide (1.10 g, 9.8 mmol) was added. The solution was stirred for 40 min at room temperature. A solution of 3-(tert-butoxycarbonylamino)-3-methylbutanal (1.10 g, 5.5 mmol) in Tetrahydrofuran (6 mL) was added. The solution was stirred at room temperature. for 75 min. It was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (100 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (60 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (90 g) with ethyl acetate/hepatane (1:4) to give 1.27 g of ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[Br:12]Br.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>C(Cl)Cl>[BrH:12].[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]2[N:20]=[C:18]([NH:17][C:14]([NH2:16])=[NH:15])[S:19][CH:2]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: N=C(N)NC(N)=S
Reactant: BrBr
Solvent: ClCCl
Product: Br
Product: N#Cc1ccc(-c2csc(NC(=N)N)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 14.5 g. (0.1 mole) of p-acetylbenzonitrile in 250 ml. of methylene chloride is added 16.0 g. (0.1 mole) of bromine. After a few minutes of stirring at room temperature, the solution turns colorless. Stirring is continued an additional 15 minutes. The methylene chloride is removed on a rotary evaporator and 350 ml. of ethanol is added to the residue. To the suspension is added 11.8 g. (0.1 mole) of amidinothiourea. The reaction mixture is heated under reflux for 1 hour, then cooled in ice. The precipitate which forms amounts to 26.9 g. Recrystallization from DMF-EtOH gives 22.4 g. of product with m.p. 293°-295°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:24])=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[C:22]=2[NH2:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O1CCOCC1>[Cl:25][CH2:26][C:27]([NH:23][C:22]1[C:16]2[NH:17][C:18](=[O:21])[CH2:19][O:20][C:15]=2[CH:14]=[C:13]([F:24])[C:12]=1[C:3]1[C:2]([Cl:1])=[C:6]([C:7]([F:9])([F:8])[F:10])[N:5]([CH3:11])[N:4]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Cn1nc(-c2c(F)cc3c(c2N)NC(=O)CO3)c(Cl)c1C(F)(F)F
Solvent: C1COCCO1
Product: Cn1nc(-c2c(F)cc3c(c2NC(=O)CCl)NC(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 84.5 %

Procedure:
4-Chloro-3-[7-fluoro-5-amino-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-5-trifluoromethyl-1H-pyrazole (400 mg, 1.10 mmol) was dissolved in anhydrous dioxane and chloroacetyl chloride (139.5 mg, 1.20 mmol) was added. Solution was heated to reflux for 2 hr and solvent removed in vacuo. The residue was washed with ether to afford the title compound (410 mg, 0.93 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16](I)=[CH:15][N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>ClCCl.[Cu](I)I.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>[Cl:10][C:11]1[C:16]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: Clc1ncncc1I
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(C#Cc2cncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of 0.6 g of 1-chloro-4-ethynylbenzene, 1.44 g of 4-chloro-5-iodopyrimidine (J. Chem. Soc. Perkins Trans. I, 1977,621, Allen et al), 7.0 cc of triethylamine, 58 mg of copper iodide and 108 mg of dichlorobis(triphenylphosphine)palladium II was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was evaporated in vacuo. The resulting tan solid was partitioned between water and dichloromethane and the organic extracts washed twice with water, dried over sodium sulfate and evaporated to give a dark brown solid, 1.57 g. The solid was redissolved in dichloromethane and hexanes added to give 120 mg of a beige powder after filtration. The filtrate was purified by column chromatography on silica gel using 1:1 ethyl acetate/dichloromethane as the eluant. The middle rf spot fractions (silica gel TLC in 1:1) were pooled and evaporated to give 0.8 g of a yellow solid, 4-chloro-5-(4-chlorophenylethynyl)-pyrimidine