Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)=[C:2]=[O:3].[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:54][CH:55](Br)[CH3:56]>C(#N)C.CC(=O)CC.O>[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH:55]([CH3:56])[CH2:54][S:39]/[C:38]/1=[N:40]\[C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)=[O:3])[CH3:29]
Reactant: CC(Br)CBr
Reactant: CCc1ccc(C)cc1NC(N)=S
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCC(C)=O
Product: CCc1ccc(C)cc1N1/C(=N/C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1C
Temperature: 60 °C
Yield: 13.3 %

Procedure:
3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a)(0.16 g, 0.42 mmol), 1-(2-ethyl-5-methylphenyl)thiourea (CA41) (0.081 g, 0.42 mmol), and cesium carbonate (0.13 g, 0.39 mmol) in acetonitrile (1.9 mL) was stirred at room temperature for 3 hours. The reaction was diluted with butanone (2 mL) and potassium carbonate (0.12 g, 0.83 mmol) and 1,2-dibromopropane (0.090 mL, 0.83 mmol) were added. The reaction was heated to 60° C. for 6 hours. The reaction was diluted with water and extracted with dichloromethane (2×) and the organic layers were filtered through a phase separator and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.034 g, 13%).
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CN(Cc1ccccc1)C(=O)Cc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CN(Cc1ccccc1)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 60.6 %

Procedure:
A mixture of 10.0 g (0.031 mole) of N-benzyl-N-methyl-o-bromophenylacetamide having a boiling point of 202° to 203° C. under 0.5 mmHg, 6.1 g (0.037 mole) of 2,6-dichloroaniline, 5.2 g (0.037 mole) of anhydrous potassium carbonate, 2.6 g of cuprous bromide and 2.6 g of copper powder was reacted in 150 ml of xylene for 72 hours to obtain 7.5 g of a colorless needle having a melting point of 85° to 86° C. The yield was 56.0%.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CC(CS)C(=O)O
Reactant: C1=COCCC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(CSC1CCCCO1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-mercapto-2-methylpropanoic acid (2.4 g.) and freshly distillled 2,3-dihydro-4H-pyrane (1.9 g.) in benzene (60 ml.), boron trifluoride etherate (2.8 g.) is added. After two hours, potassium carbonate (4 g.) is added, the mixture is stirred and filtered. The filtrate is concentrated to dryness to yield 3-(tetrahydropyran-2-ylthio)-2-methylpropanoic acid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=2)[CH:16]=1.C(N(CC)CC)C.C(O)(C)C>C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:23]=2)[CH:16]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl piperazine-1-carboxylate (24.0 mg, 0.125 mmol) was added to a mixture of 4-chloro-2-(2-chloropyrimidin-4-yl)phenol (Preparation 874, 30.1 mg, 0.125 mmol), and triethylamine (61.2 uL, 0.437 mmol) in isopropyl alcohol (0.2 mL, 3 mmol). The reaction mixture was stirred at ambient temperature. After 18 hours, LC/MS analysis indicated the reaction was not complete. The reaction mixture was heated 30 minutes at 70° C. then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate, filtered, and concentrated to give the product as a light brown paste (50 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[CH:4]=[N:5]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>O1CCCC1>[OH:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=NO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1cc(Br)c(O)c(C#N)c1
Yield: 93.6 %

Procedure:
A mixture of 12.0 g (44.0 mmol) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde oxime and 18.9 g (90.0 mmol) of trifluoroacetic anhydride in 100 ml of tetrahydrofuran was cooled in an ice-water bath. A solution of 15.2 g (150.0 mmol) of triethylamine in 40 ml of tetrahydrofuran was added. After refluxing overnight, the solvent was stripped. The residue was partitioned between water and methylene chloride. The organic phase was washed with 1N hydrochloric acid followed by saturated sodium bicarbonate, then dried and evaporated. The residue was crystallized from hexane to provide 10.4 g (41.2 mmol, 94%) of 2-hydroxy-3-bromo-5-(1,1 dimethylethyl)benzonitrile; mp 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH:17](=[O:19])[CH3:18]>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:17]([OH:19])[CH3:18])[S:8][C:6]=2[N:7]=1
Reactant: CC=O
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Product: CC(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1

Procedure:
2-chloro-4-morpholinothieno[2,3-d]pyrimidine (300 mg) was reacted with acetaldehyde via General Procedure D to give 1-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)ethanol. This crude intermediate was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 via General Procedure A to yield 100.2 mg of 308 following reverse phase HPLC purification. MS (Q1) 382.1 (M)+
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([NH2:36])[N:30]=[CH:29][C:28]=2[CH2:27]1>>[NH2:36][C:31]1[N:30]=[CH:29][C:28]2[CH2:27][CH:26]([CH2:25][NH:24][C:20](=[O:22])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:9])=[O:10])[C:13]3=[O:23])[CH2:35][CH2:34][C:33]=2[N:32]=1
Reactant: NCC1CCc2nc(N)ncc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nc(N)ncc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 6-(aminomethyl)-5,6,7,8-tetrahydro-2-quinazolinamine using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C(P(=O)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]CO)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:1][Cl:4])=[CH:23][CH:22]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C(Cl)Cl
Agent: CCCCP(=O)(CCCC)CCCC
Product: COc1ccc(CCCl)cc1

Procedure:
11 g (0.11 mole) of phosgene were added to 4.4 g (0.02 mole) of tri-n-butylphosphine oxide during the course of 15 minutes at a temperature of 80° C. The temperature was then held at 90°-100° C. while 108 g (1.09 moles) of phosgene and 152 g (1.00 mole) of 2-(4-methoxyphenyl)ethanol were added over 1 hour. To complete the reaction, the mixture was kept at this temperature for another hour.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[C:38]1(C)C=CC=C[C:39]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:6][C:7]([CH3:9])([C:10]1[CH:15]=[CH:14][C:13]([CH:23]=[CH2:24])=[CH:12][CH:11]=1)[CH3:8])[CH3:2].[OH:21][C:5]([C:17]([F:19])([F:18])[F:20])([CH2:6][C:7]([CH3:8])([C:10]1[CH:11]=[CH:12][C:13]([CH:38]=[CH2:39])=[CH:14][CH:15]=1)[CH3:9])[C:4]([OH:3])=[O:22]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(C)(C)CC(O)(C(=O)O)C(F)(F)F)cc1
Product: C=Cc1ccc(C(C)(C)CC(O)(C(=O)OCC)C(F)(F)F)cc1

Procedure:
By heating 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributylvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120° C., 2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid ethyl ester, which provides the title compound, melting point 73-74° C., by alkaline saponification, is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C(Cl)Cl.[BH4-].C([O+](CC)CC)C.Cl.[CH3:34][O:35][NH2:36]>CO.C(N(CC)CC)C>[CH3:34][O:35][N:36]=[C:5]1[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:15])[C:2]([CH3:1])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1
Reactant: CON
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C1SC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
5-Methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (0.87 g) was mixed with a 1M methylene chloride solution of triethyloxonium tetrahydroborate (3 ml) at room temperature. The reaction mixture was stirred overnight at room temperature. Methoxyamine hydrochloride (0.25 g) and triethylamine (0.61 g) in methanol (10 ml) were then added at room temperature to the mixture. After 1 hr, the solvents were evaporated under reduced pressure. The residue was purified by column chromatography (chloroform) to yield 2-methoxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidin-4-one (0.38 g) having a melting point of 133-134° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[N:3]=1.[CH3:1][C:2]1[N:3]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(C)c2ccccc2)nc1C
Product: COC(=O)c1cnn(C(C)c2ccccc2)c1C
Temperature: 20 °C
Yield: 16 %
Yield: 19 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (280 mg, 2 mmol) in N, N-dimethylformamide (30 mL) was added (1-bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20° C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column: Dsisol, 10 μM, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid)-water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven: 20° C.; flow rate: 50 ml/minute, wavelength: 214 nm) to give methyl 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (90 mg, 19%) and methyl 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (80 mg, 16%). The product was used directly in the following reaction. LRMS (M+H+) m/z: calcd 244.12. found 244.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7](O)=[O:8].C(OC(=O)C)(=O)C>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:12](=[O:14])[O:13][C:7](=[O:8])[C:6]2=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Yield: 74.7 %

Procedure:
4-Trifluoromethylphthalic acid (106.6 g.) and acetic anhydride (215 cc.) are heated at the reflux temperature for 30 minutes. After concentrating the mixture under reduced pressure (30 mm.Hg), the residue is stirred with cyclohexane (420 cc.). After filtration and drying, 4-trifluoromethylphthalic anhydride (73.5 g.), melting at 54° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To the stirred solution of 125 mg of tert-butyl trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate in 4 mL of N,N-dimethylformamide was added 133 mg of potassium carbonate, followed by 68 mg of iodomethane. The suspension was stirred at room temperature over night. After removal of the volatile material in vacuo, 80 ml of ethyl acetate was added. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was to provide 121 mg (97% yield) of tert-butyl trans-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate after flash column chromatography eluting with ethyl acetate/hexane (3:7). MS: 525.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].IC.[C:11](=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccccc1S
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirred at room temperature for 1 hour. A thin layer chromotography (100% hexanes) sample indicated that the reaction had not gone to completion, so an additional equivalent of base and iodomethane were added and the reaction mixture was stirred overnight at room temperature. The reaction was acidified with 10% aqueous citric acid and extracted with hexanes (2×125 mL). The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound as a pale yellow oil (yield: 6.68 g; 60%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([N:12]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13]CO)CCC.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[C:33]1([NH:39]C2C3C(=CC=CC=3)C=CC=2)C=C[CH:36]=[CH:35][CH:34]=1>>[C:1]([O:6][CH2:7][CH:13]([NH:12][CH2:16][CH2:17][CH2:18][CH3:19])[NH:39][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCN(CCO)CCCC
Reactant: C=C(C)C(=O)OC
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: CC(C)[O-]
Agent: [Al+3]
Product: C=C(C)C(=O)OCC(NCCCC)NCCCC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottomed flask fitted with a magnetic stirrer, heating mantle, and distillation head was charged with a mixture of methyl methacrylate (100 g, 1.0 mol, available from TCI), 2-dibutylaminoethanol (43.3 g, 0.25 mol, available from Matheson, Coleman and Bell, Norwood, Ohio), aluminum isopropoxide (5.0 g, 24 mmol, available form Alfa Aesar), and N-phenyl-1-naphthylamine (2.5 g, 11 mmol, available from Aldrich). The mixture was stirred and heated at 80° C. for one hour. The temperature of the reaction mixture was increased 10° C. per hour until a temperature of 110° C. was reached. By this time about 20 mL of material (methanol and methyl methacrylate) had distilled over from the reaction flask. The reaction mixture was left at room temperature overnight. The next day, the reaction mixture was heated at 115° C. for 2 hours and then heated at 135° C. as material distilled from the reaction flask. After 1 hour at 135° C., the desired product, di(butylamino)ethyl methacrylate, was distilled from the reaction flask at reduced pressure and collected at a temperature of 113-118° C. at 2.5 mm pressure. NMR spectral analyses confirmed the structure of the product. The boiling point reported previously for this methacrylate (U.S. Pat. No. 2,138,763 (DuPont)) is 108-109° C. at 2 mm pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14]Cl)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH:28][CH2:27][CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: Fc1cc2c(c(OCCCl)c1)OCCC2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1cc2c(c(OCCNCCc3c[nH]c4ccc(F)cc34)c1)OCCC2
Temperature: 90 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (0.26 g, 1.1 mmol), 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.45 g, 2.1 mmol) and triethylamine (0.30 ml, 2.1 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.19 g (48%) of product as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:18])=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[K+]>OCC(CO)O>[CH3:18][C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: CC(=CCCCCCCC(=O)O)CCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: CC1=CCCCCCCC(=O)OCCCCC1
Temperature: 152 °C
Yield: 0.1 %

Procedure:
24.5 g (95.5 mol) of 14-hydroxy-9-methyltetradec-8-enoic acid, (Z/E=80/20) were placed in 50 ml of glycerol and treated with 0.54 g of potassium hydroxide (50 percent). The resulting water was distilled off. Thereupon, the distillation headpiece was removed and the special headpiece (see FIG. 1) was fitted and filled with glycerol. After the addition of 1 g of sodium methylate the mixture was heated to 152° C., 6 mbar. After 24 hours the addition of 1 g of MeONa was again effected. After 48 hours extraction of the content of the special headpiece yielded 19 g of crude product. By chromatography 19 g (82%) of 10-methyloxacyclopentadec-9-en-2-one were obtained having the following characteristics: Z/E=80/20;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCCc1ccccc1

Procedure:
Batch size: 5.1 g (33.9 mmol) 3-(3-pyridyl)-acrylic acid, 6.6 ml (76.4 mmol) oxalyl chloride and 5.9 g (30.8 mmol) 7-phenyl-heptylamine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C(OC1C=CC2C(=C(OCC(=O)C)C=CC=2)N=1)(=O)C>>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:17][C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Product: CC(=O)Oc1ccc2cccc(OCC(=O)c3ccccc3)c2n1
Yield: 74 %

Procedure:
2-Acetoxy-8-(2-oxo-2-phenylethoxy)quinoline (6a) was prepared from 2-acetoxy-8-hydroxyquinoline (5b) and 2-bromoacetophenone by the same procedure as 5c in 74% yield. mp: 141°-142° C.; 1H-NMR (CDCl3): δ1.92 (s, 3H, CH3), 5.66 (s, 2H, OCH2), 7.11 (d, 3-H), 7.25-8.04 (m, 8H, Ar--H), 8.05 (d, 4-H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Cl:12])[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2[C:25]([CH:31]([CH3:33])[CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[S:20]1(=[O:35])=[O:34].[F-].[K+].CN(C=[O:42])C>O>[CH:31]([C:25]1[C:22]2[C:23](=[O:24])[N:19]([CH2:18][O:42][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=3[Cl:12])[S:20](=[O:35])(=[O:34])[C:21]=2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1)([CH3:33])[CH3:32]
Reactant: CN(C)C=O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: FC(F)(F)c1nn(-c2ccccc2)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1c(Cl)c(C(F)(F)F)nn1-c1ccccc1)C2=O
Yield: 69 %

Procedure:
A mixture 1-phenyl-3-trifluoromethyl-4-chloropyrazole (524 mg; 2 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (696 mg, 2 mmol), and KF (232 mg; 4 mmol) in DMF (8 ml) was stirred at 20° C. for 16 hours and the mixture was diluted with water. The above mixture was extracted with methylene chloride (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The white residue was recrystallized from methylene chloride/hexane and purified by column chromatography (silica gel; 20% ethyl acetate/hexane; methylene chloride) to afford 730 mg (69%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-trifluoromethyl-4-chloropyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =Cl; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 185°-1870° C.