Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13](Cl)(=[O:15])=[O:14])(=[O:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[CH:17]1([NH:20][S:13]([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:15])=[O:14])[CH2:19][CH2:18]1
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(F)ccc1S(=O)(=O)NC1CC1

Procedure:
(Step 1) A solution of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (1.5 g), cyclopropylamine (0.43 ml) and triethylamine (0.87 ml) in tetrahydrofuran (15 ml) was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from methanol-water to give N-[2-(cyclopropylsulfamoyl)-5-fluorobenzyl]acetamide (1.06 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].C([O-])([O-])=O.[Na+].[Na+].[CH3:17][C:18](C)=O>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:17][CH3:18]
Reactant: CC(C)=O
Reactant: Oc1c(F)cc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOc1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of 30-2 (48.1 g, 214 mmol) and Na2CO3 (34 g, 321 mmol) in acetone (300 mL) was added a solution of Et2SO4 (39.6 g, 257 mmol) in acetone (100 mL) dropwise over 20 minutes and then the mixture was stirred at room temperature for one hour. The solid was filtered off and the filtrate was concentrated under vacuum to afford 30-3 (48.6 g, 90%) as a white solid. LRMS: calc 251.9 and found: 252.9 [M+1].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].CC(C)([O-])C.[K+].Cl>O.O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N+:23]#[C-:24])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: [C-]#[N+]C(C(=O)OCC)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Reaction time: 2 h
Yield: 28.5 %

Procedure:
2.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl isocyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added and the mixture is heated to reflux for 3 hours. 0.39 g of potassium tert-butoxide is then added once more and the mixture is once more boiled for 2 hours. It is then diluted using water, acidified using HCl and the solid is isolated. After separation on silica gel (eluant CH2Cl2 /MeOH 95/5), 1.0 g of the title compound is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[C:1]#[N:2])[C:7]1=[O:12]
Reactant: BrBr
Reactant: N#Cc1cccc2c1CCC2=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc2c1CC(Br)C2=O
Reaction time: 1 h
Yield: 33.1 %

Procedure:
2-Bromo-4-cyano-1-indanone can be obtained in the following way: a solution of 6.9 g of 4-cyano-1-indanone and 95 ml of chloroform is cooled to 5° C. A solution of 7.04 g of bromine and 20 ml of chloroform is then added dropwise over two hours at a temperature of between 0 and 5° C. After having left the reaction mixture stirring for one hour, the temperature of introduction being retained, the solution is allowed to return to room temperature and stirring is continued overnight. The reaction mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue thus obtained is purified by flash chromatography on a silica column, under a nitrogen stream at medium pressure (0.5 bar), with an ethyl ether/cyclohexane (20/80 by volume) mixture as eluent. 3.43 g of 2-bromo-4-cyano-1-indanone are thus obtained, which product melts at 124° C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
cis-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (22.3 g, 95.59 mmol) was dissolved in CH2Cl2 (240 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (25.42 g, 114.7 mmol) was added and the mixture was stirred for 30 minutes. NEt3 (19.99 mL, 143.4 mmol) was added and the mixture was slowly warmed to ambient temperature over 2 hours and stirred overnight. The mixture was diluted with CH2Cl2 and washed with 1N KHSO4 (2×100 mL) followed by washing with saturated aqueous NaHCO3 (100 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude orange solid was dissolved in minimal hot CH2Cl2 and hexanes were added with stirring until the solution became persistently cloudy. The warm mixture was cooled to ambient temperature and allowed to stand undisturbed for 1 hour. The solids were collected by filtration and the solid was successively washed with hexanes followed by 50% Et2O/hexanes and finally with hexanes again to provide the clean cis isomer of the product as a pale yellow solid (27.05 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:29]1([S:35]([N:38]=[C:39]=[O:40])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[O:28]=[C:3]1[C:2]([NH:1][C:39]([NH:38][S:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:37])=[O:36])=[O:40])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)NS(=O)(=O)c2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.5 g) in dichloromethane (40 mL) was added benzenesulfonyl isocyanate (0.23 g), and the resulting solution was allowed to stir for 1 h. The solvent was evaporated and the product was purified by chromatography to provide the title compound (0.7 g); chromatography solvent: methanol:dichloromethane (5:95); TLC: Rf =0.6, methanol:dichloromethane (10:90); MS: m/z=579(M+1), 577(M-1) by FAB.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]=3[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[CH2:17]([C:16]1[C:11]2[C:10]([OH:25])=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:39][CH:36]4[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(-c3ccc(NC4CCNCC4)cc3)cc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 97 reacting via Suzuki coupling of 6-(4-bromo-phenyl)-3-ethyl-1-phenyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-4-one and 4-amino-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[NH2:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1cc(C(C)(C)C)nn1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To 30 cm3 of concentrated sulphuric acid were added 8.5 g (0.044 mol) of 5-acetamido-1-methyl-3-tert-butylpyrazole, at 5° C. with vigorous stirring, followed by 2.5 cm3 (0.066 mol) of fuming nitric acid. After stirring for 2 hours, the reaction mixture was poured onto 100 g of ice and stirred for 30 minutes. The solid obtained was filtered off on a sinter funnel, washed with 20 cm3 of water and then dried under vacuum at 40° C. 8.5 g of the expected product were obtained in the form of a yellow solid, the melting point of which was 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)c(OC[C@@H](O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-CBS reagent (46.5 mL, 1M in toluene) was added to a THF solution (200 mL) of borane-diethylaniline complex (15.16 g) were stirred together 15 min at room temperature. 3-{2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (20 g) in 600 mL of dry THF was then added through an addition funnel at rt over 20 minutes. The mixture was stirred for 15 minutes and then was quenched by slow addition of 60 mL MeOH. After gas evolution ceased, the mixture was evaporated and water was added to the residue and extracted with ethyl acetate. Ethyl acetate layer separated and washed with water, brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by silicagel column (DCM; 10% EtOAc in DCM) to get pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.45 (d, 1H), 7.15-7.35 (m, 4H), 7.09 (t, 1H), 7.04 (d, 1H), 6.92 (m, 1H), 5.15 (m, 1H), 5.04 (s, 2H), 4.10 (m, 2H), 2.63 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: ClC(Cl)Cl
Product: CC1CCc2ncc([N+](=O)[O-])cc2C1
Yield: 72.7 %

Procedure:
4-Methylcyclohexanone (170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (300 mg, 1.51 mmol) in 1M methanolic ammonia (30 mL, 30 mmol). The solution was heated at gentle reflux for 3 h. Evaporation of the solvent gave an orange residue which was suspended in CHCl3 and flash chromatographed over silica gel (16 g) eluting with EtOAc/hexane (1:10) to afford a white solid (211 mg, 73% yield): mp 50°-52° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3cccc(C#N)c3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-isoquinolin-1-yl]-benzonitrile LC-MS m/e 356(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(O)(C(=O)OCC)CCC3(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=CCC(C)(C)c2ccc(C(=O)Oc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/-) ethyl 4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate (Compound E54, 35.0 mg, 0.077 mmol) in 10 mL benzene was added a catalytic amount (approximately 2 mg) of p-toluenesulfonic acid monohydrate. The solution was heated to reflux under a Dean-Stark trap for 3 h, and then cooled to room temperature and stirred overnight. The solvent was removed under reduced pressure and the title compound isolated from the residue by column chromatography (10% EtOAc-hexanes).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16]Br)(=O)C.[C:18](=O)(O)[O-:19].[Na+]>CO>[CH3:18][O:19][CH2:16][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH3:15])[C:5]=1[OH:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(C)c(OC(C)=O)c(CBr)c1
Agent: [Na+]
Solvent: CO
Product: COCc1cc(C(=O)OC)cc(C)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of crude methyl 4-acetoxy-3-bromomethyl-5-methylbenzoate (4.63 g, 0.00154 mol) in methanol (100 mL) was mixed with sodium bicarbonate (6.48 g, 5 equivalents). The mixture was refluxed under a nitrogen atmosphere. After 1.5 hours, TLC analysis showed complete conversion. The reaction was cooled to room temperature and evaporated to dryness. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer was separated and washed with water. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product (1.5 g) was purified by flash chromatography on silica using 10% ethyl acetate/hexanes as eluent. Purified Yield=0.833 g (40%), white waxy solid.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:47])([F:46])[F:45])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([NH2:43])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:44]([F:46])([F:45])[F:47])[O:30][N:29]=[C:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([C:41]([N:43]=[S:2]([CH3:4])[CH3:1])=[O:42])=[CH:33][CH:32]=3)[CH2:27]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(C)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of dimethylsulfoxide (38 mg) in dichloromethane (1 mL) at −60° C. was added trifluoroacetic anhydride (105 mg). After the reaction mixture was stirred for 10 minutes at −60° C., a solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxamide (75 mg, in 1.5 mL of dichloromethane and 0.4 mL of dimethylsulfoxide) was added. The reaction mixture was allowed to warm to −20° C. over 1 h, then quenched with water and extracted with dichloromethane. The combined organic extract was washed with aqueous 1.0 N of NaOH and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 95:5) as eluent to afford the title product, a compound of the present invention, as semi-solid (70 mg, 82% yield).
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])C.[OH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22]CC#N)[CH2:17]1>>[OH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:14][C:13]2[NH:3][C:4](=[O:12])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:17]1
Reactant: N#CCCCN1CCC(O)C1
Reactant: CCN(CC)C(=O)c1ccccc1C
Product: O=c1[nH]c(CCCN2CCC(O)C2)cc2ccccc12
Yield: 20.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2-methylbenzamide (3.45 g) and 4-(3-hydroxypyrrolidin-1-yl)butyronitrile (1.5 g), 3-[3-(3-hydroxypyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (536.3 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:17][CH2:24][CH3:25])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Reaction time: 7 h

Procedure:
In a solution of 259 g. 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.1 mol.) in 1700 ml. dimethylformamide, 400 g. of well pulverized potassium carbonate and 300 g. of ethyl iodide are introduced. The reaction mixture is stirred for 7 hours at 65° and filtered under suction, while hot, to remove excess potassium carbonate. Upon standing over night, 165 g. of 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester crystallize out of the solution, m.p. 112°-115°. After evaporation of the mother liquor, an additional 80 g. are obtained. The total yield amounts to 85% of theory. The compound is recrystallized from ligroin (90°-100°), m.p. 113°-115°.
Reaction SMILES: [Br:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=1.[CH3:14][Mg]Cl>C1COCC1>[Br:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]([OH:11])[CH3:14])[CH:9]=[C:4]2[CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1cc2cc(Br)sc2nc1Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2cc(Br)sc2nc1Cl
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-6-chlorothieno[2,3-b]pyridine-5-carbaldehyde (2.4 g, 8.7 mmol) (Meth-Cohn, O. Narine B. Tetrahedron Lett., 1978, 2045) in THF (50 mL) at −20° C. was added methylmagnesiumchloride (3.04 mL of 3N in THF, 9.1 mmol) dropwise. The reaction was stirred at −20° C. for 45 minutes and then quenched with 25 mL NH4Cl (sat) and 25 mL of water. The reaction was diluted with ether and the layers were separated. The organic layer was washed with brine and concentrated. Purification by column chromatography afforded 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanol. LC/MS (M+1, found=293.8). 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.30 (s, 1H), 5.32 (qd, J=6.3, 2.7 Hz, 1H), 2.19 (br s, 1H), 1.55 (d, J=6.3 Hz, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:14]3[CH2:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[C:23]1([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:15][C:14]4[CH2:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCc2oc3ccc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 22 %

Procedure:
The product of step E was coupled with sodium benzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 70:30 hexanes/ethyl acetate) provided tert-butyl 9-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (22 mg, 22%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.09 (br s, 1H), 8.00-7.91 (m, 2H), 7.86-7.77 (m, 1H), 7.58-7.37 (m, 4H), 4.68-4.38 (m, 2H), 3.70 (br s, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.09-1.92 (m, 2H), 1.53-1.20 (m, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].O.[CH:10]1C=CC=CC=1>>[C:3]1([CH:1]([CH3:10])[CH3:2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccccc1
Reactant: CCc1ccccc1
Solvent: O
Product: CC(C)c1ccccc1

Procedure:
The benzene column 140 produces a benzene column overhead stream comprising benzene in a line 142 and a benzene column bottom stream comprising ethylbenzene and PEBs in the line 144. The overhead benzene stream in the line 142 may be provided with a water concentration of up to about 500 wppm and a temperature of at least about 120° C. and preferably greater than 125° and no more than about 170° C. A portion of the overhead benzene stream in the line 142 is diverted to the transalkylation reactor 150 by a line 166. DIB in the heavies column intermediate stream transported by the line 168 mixes with the benzene in the line 166 to provide the transalkylation feed stream in a line 154. The DIB transalkylates with benzene over the transalkylation catalyst bed 156 in the transalkylation reactor 150 to produce cumene. Transalkylation effluent in the line 152 has a greater concentration of cumene and a smaller concentration of benzene and DIB than in the line 154. The benzene column overhead stream remaining in a line 102 is reacted with propylene over alkylation catalyst in the alkylation reactor 120 as described with respect to FIG. 4. Alkylation effluent in a line 126 is mixed with transalkylation effluent in the line 152 to provide combined effluent streams in the line 136.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1([C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:30][CH2:31]2)=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOc1cc2ccnc(Cl)c2cc1OCC
Reactant: O=C(N1CCCCC1)N1CCNCC1
Product: CCOc1cc2ccnc(N3CCN(C(=O)N4CCCCC4)CC3)c2cc1OCC

Procedure:
In like manner, 1-chloro-6,7-diethoxyisoquinoline and 1-(piperidinocarbonyl)piperazine react to afford 1-(4-piperidinocarbonyl-1-piperazinyl)-6,7-diethoxyisoquinoline, while 4-chloro-6,7-dimethoxyquinazoline and 1-(piperidinocarbonyl)piperazine react to afford 4-(4-piperidinocarbonyl-1-piperazinyl)-6,7-dimethoxyquinazoline respectively. The latter compound is, of course, identical in every respect with the product of Example V.