Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.N1C=CC=CC=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])[N:6]=1
Reactant: CCOC(=O)c1c[nH]nc1OCOC
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2C)nc1OCOC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A mixture of ethyl 3-(methoxymethoxy)-1H-pyrazole-4-carboxylate (1.80 g), 2-methylphenylboronic acid (2.45 g), pyridine (1.46 mL), copper(II) acetate (2.45 g) and dichloromethane (50 mL) was stirred at room temperature for 16 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give ethyl 3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carboxylate as a pale-yellow oil (2.39 g, yield 92%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2].[N:20]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CC[C@H]1C[C@@H](NC=O)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
((cis)-1-acetyl-6-bromo-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see Intermediate 44) (1 g, 3.08 mmol) and [4-(1-piperidinylmethyl)phenyl]boronic acid (1.572 g, 6.15 mmol, Intermediate 1) were mixed with Ethanol (8 mL), Toluene (8.00 mL). potassium carbonate (1.402 g, 10.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) were added and the mixture was stirred under nitrogen, at reflux at 110° C. After 3 hours, another sample of tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) was added and the reaction was left to stir overnight. The reaction was evaporated to dryness. The residue was diluted with DCM (150 mL), washed (water (150 mL), sat. sodium bicarbonate (200 mL), brine (200 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a black solid which was loaded onto an 20 g SCX-column, eluting with MeOH (120 mL) followed by MeOH/NH3 (300 mL). Product-containing fractions were evaporated to dryness to give a dark red solid which was purified on a 40+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 19:1). Product-containing fractions were evaporated to dryness to give a yellow/orange solid (1.00 g).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:10]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[N:9]=[CH:8]2>CCOC(C)=O.[Pd]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:13]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:9]=[CH:8]3)=[C:2]([F:1])[CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc2c(cnn2C2CCCCO2)cc1Oc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of tert-butyl 5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylcarbamate (400 mg, 0.85 mmol) in EtOAc (50 mL) is added Pd/C (10%, 50 mg). The resulting mixture is degassed by evacuation and backfilled with H2 three times. The mixture is stirred under an atmosphere of H2 at RT overnight. The solid is removed by filtration and the filtrate is concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (10:1) to give the desired product (300 mg, 80% yield). MS (m/z): 443.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
4-(4-Methoxyphenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(4-methoxyphenoxy)phenyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:24].ClCCl.CO.N>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)[CH3:24]
Reactant: COCCN(C)Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COCCN(C)Cc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-{[(2-methoxyethyl)methylamino]methyl}phenylamine. Yield: 150 mg (35% of theory); melting point: 130° C.-133° C.; C26H25ClN2O2 (M=432.94); calc.: molecular ion peak (M+H)+: 433/435 (Cl); found: molecular ion peak (M+H)+: 433/435 (Cl); Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21](=O)[C@@H:22]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[N:20]=[C:21]2[C@@H:22]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(F)cc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 44.4 %

Procedure:
A mixture of 3-[2-((S)-2-benzyloxycarbonylaminopropionylamino)-5-fluoro-phenylamino]azetidine-1-carboxylic acid tert-butyl ester (15.52 mmol) in AcOH (110 mL) was heated at 60° C. for 18 h, at 70° C. for 24 h and then at 80° C. for 6 h. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford the title compound as a yellow oil (3.23 g, 44%). LCMS (Method J): RT 3.60 min [M+H]+ 469.1.
Reaction SMILES: [CH2:1](N(CCCC)CCCC)CCC.CS(C)=O.O.[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21]=1[Cl:32].BrC>O>[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([O:31][CH3:1])=[O:30])[C:21]=1[Cl:32]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: CCCCN(CCCC)CCCC
Agent: CBr
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C
Yield: 80.8 %

Procedure:
A 200-mL reactor equipped with a 10-mL jacketed addition funnel below a cold-finger condenser at −10° C., a nitrogen inlet and overhead stirring was charged with tributylamine (20.4 g, 0.11 mol) and DMSO (45 mL). The mixture was stirred at 25° C., and 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (23.1 g, 0.1 mol) was added in portions. The reaction mixture was stirred at 30° C. while bromomethane (13.3 g, 8 mL, 0.14 mol) was condensed into the jacketed addition funnel and then added to the reaction mixture over 30 minutes. The mixture was stirred for an additional 3 h and then added over about 30 minutes to a reactor charged with water (200 mL) at 25° C. The resulting slurry was cooled to 5° C. and filtered. The filtered cake was washed with water (2×30 mL) and dried at 60° C. in a vacuum-oven for 16 h to give 18.4 g (81% yield) of the title compound as an off-white solid melting at 147-148° C.
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])C.[Si:10]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:41])=[CH:33][CH2:34]C1SCCCS1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Ca+2].[BH4-].[Na+].[Na]>C(Cl)Cl.C(O)C.C(O)(=O)C.CC(C)=O.O>[Si:10]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:41])=[CH:33][CH2:34][CH2:9][OH:7])([C:23]([CH3:25])([CH3:26])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](OCCCCC(F)=CCC1SCCCS1)(c1ccccc1)c1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)(C)[Si](OCCCCC(F)=CCCO)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a suspension of trimethyloxonium tetrafluoroborate (0.44 g, 2.97 mmoles) in dry methylene chloride (15 ml) was added at room temperature the dithialane prepared in 1I (1.45 g, 2.97 mmoles) and the mixture was stirred for 1 hr. Then a 9:1 mixture of acetone and water (5 ml) containing calcium carbonate (0.6 g, 5.94 mmoles) was added and the mixture was stirred overnight at room temperature. The precipitate was filtered off and after dilution with saturated brine the mixture was extacted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was dissolved in ethanol (10 ml) and sodium borohydride (56 mg, 1.48 mmoles) was added. The mixture was stirred 30 min at 0° C. The excess of sodium boronhydride was reacted with acetone, the mixture was acidified with acetic acid and concentrated under reduced pressure. The residue was taken with water and extracted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silicagel and elution with a 28:72 mixture of ethyl acetate and hexane afforded the title alcohol as an oil (0.813 g, 74%). NMR (H1, CDCl3, 60 MHz) characteristic peaks: 1.06 (s, 9), 3.4 to 3.8 (m, 4), 5.0 (dt, JHF =21 Hz, JHH =8 Hz, 7.2 to 7.76 (m, 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:29][O:28]2)=[CH:23][N:22]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:29][C@H:27]([OH:28])[C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[N:22][CH:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Clc1ccc([C@@H]2CO2)cn1
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2ccc(Cl)nc2)cc1OC
Temperature: 25 °C

Procedure:
A solution of α-(3.4-dimethoxyphenyl)benzeneethanamine (257 mg, 1 mmol, 2 eq) and (R)-(2-chloropyrid-5-yl)oxirane (Example 3, 77 mg, 0.5 mmol) in dry methanol in a gas tight vessel was heated at reflux in an oil bath overnight. The reaction was cooled to room temperature and then the solvent was stripped under vacuum. The yellow residue was purified by flash chromatography on silica gel (eluent: ethylacetate: hexanes:9:1) to give the adduct as a white solid. 1H NMR (400 MHz, CDCl3)δ 8.20 (m, 1H), 7.53 (m, 1H), 7.07-7.30 (m, 6H), 6.71-6.8 (m, 3H), 4.38-4.58 (m, 1H), 3.87 and 3.86 (s, 3H. OCH3), 3.82 (s, 3H, OCH3), 3.70-3.85 (m, 1H), 2.80-3.0 (m, 2H), 2,64-2.73 (m, 1H), 2.35-2.51 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[CH:21](Cl)([Cl:23])[Cl:22].C(O)(=O)C.CO>O1CCCC1.[Cl-].[Na+].O.CCCCCC.C(OCC)(=O)C>[Cl:22][CH:21]([Cl:23])[C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]([C:17]([F:18])([F:19])[F:20])=[C:8]([F:7])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1C(Cl)Cl
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a solution of potassium t-butoxide (1.25 g, 11.1 mmol) in tetrahydrofuran (25 ml) was slowly added dropwise a solution of 2-fluoro-5-nitrobenzotrifluoride (1.00 g, 4.78 mmol) and chloroform (599 mg, 5.02 mmol) in tetrahydrofuran (2.5 ml) at −78° C. After stirring for 15 minutes at the same temperature, acetic acid-methanol (1:1, 5 ml) was added and the temperature was raised to room temperature. Ethyl acetate and saturated brine were added to the reaction mixture, which was extracted with ethyl acetate. After washed with brine, the organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [hexane→hexane-ethyl acetate(300:1)] to obtain 714 mg of title compound as pale yellow liquid. Yield 51%.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[CH:25][N:26]=4)[CH:17]=3)=[N:14][N:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:18]3[CH:17]=[C:16]([C:13]4[O:12][C:11]([CH2:10][C:7]5[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=5)=[N:15][N:14]=4)[CH:21]=[CH:20][CH:19]=3)=[N:26][CH:25]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(Cc2nnc(-c3cccc(-c4ncc(-c5ccc(OC)cc5)o4)c3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc(-c3cccc(-c4nnc(Cc5ccc(C(=O)O)cc5)o4)c3)o2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 28.3 %

Procedure:
A solution of 0.25 g (0.53 mmol) 4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoic acid methyl ester from Example B2a in a 5:2:1 mixture of THF/methanol/water was added 1.0 mL (1.0 mmol) 1N NaOH. The mixture was stirred 14 hours at room temperature before concentrating on a rotary evaporator. Partitioned between ether and water. Separated layers and acidified aqueous layer with 6M HCl. Extracted aqueous layer with 1:1 Et2O/EtOAc (2×), combined organic layers and wash with saturated aqueous NaCl solution and dried (MgSO4). Obtained a solid from MeOH. Filter and dry in a vacuum oven overnight at room temperature to provide 0.068 g (28%) desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:22])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1COCC1.[Cl:33][Si:34](Cl)([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:22])[CH:8]2[Si:34]([Cl:33])([CH3:36])[CH3:35])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)=C2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 16.2 g (55.4 mmol) of 5-tert-butyl-6-methoxy-2-methyl-7-phenyl-1H-indene in 300 ml of toluene, 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 2 h, and then 15 ml of THF was added. The formed suspension was stirred for 12 h at room temperature, ca. 2 h at 60° C., then cooled to −20° C., and 35.8 g (277 mmol) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to 60° C. and stirred for 1 h at this temperature. The resulting mixture was evaporated to ca. ½ of its volume, then filtered through glass frit (G3). The precipitate was additionally washed by 20 ml of toluene. The combined filtrate was evaporated to dryness to give 21.2 g (99%) of viscous yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[CH2:24]([O:31][C:32]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1Cc2ccc(N)cc2NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O

Procedure:
To a suspension of ethyl 7-amino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (2.0 g) in THF(40 ml) was added aqueous sodium carbonate (4.5 g in 40 ml) and cooled, to which benzylchloroformate (1.8 ml) was added dropwise. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated. The precipitated crystals were washed with hexane to obtain the entitled compound (3.07 g).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]>>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([NH:31][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Reactant: CC(C)N=C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)NC(C)C)CCCCC1
Reaction time: 4 h

Procedure:
Isopropyl isocyanate (0.15 mL, 1.45 mmol) was added to a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (0.50 g, 1.45 mmol) dichloromethane (5 mL) at rt. After 4 h, the reaction was set up on a larger scale with 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (1.50 g, 4.43 mmol). Both reactions were allowed to stir overnight and additional isopropyl isocyanate (0.5 equivalent) was added to each reaction. After stirring another day, the reactions were combined and concentrated under reduced pressure to yield an oil. The oil was triturated with hexane and N-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N′-isopropylurea was isolated as a white solid (2.23 g, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[S:30])#[N:2]
Reactant: COC(=O)c1cccc(OCc2cccc(C#N)c2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2cccc(C#N)c2)c1
Yield: 80.5 %

Procedure:
In an analogous manner to that described in Example 1(B), 8.9 g(33.3 mmol) of methyl 3-[(3-cyanobenzyl)oxy]benzoate were heated at reflux for 17 hours with 13.5 g (33.4 mmol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel. Elution with an 8:2 and 7:3 mixture of hexane and methylene chloride yielded 7.6 g (65.8%) of O-methyl 3-[(3-cyanobenzyl)oxy]thiobenzoate as a yellow oil which gradually crystallized upon standing.
Reaction SMILES: [OH-].[Na+].CSC1C=C(CC(O)=[O:21])C=C2C=1NC(C(F)(F)F)CC2.[CH3:23][S:24]([C:26]1[CH:27]=[C:28]([CH2:40][C:41]([OH:43])=[O:42])[CH:29]=[C:30]2[C:35]=1[NH:34][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]2)=[O:25].OO.Cl>O>[CH3:23][S:24]([C:26]1[CH:27]=[C:28]([CH2:40][C:41]([OH:43])=[O:42])[CH:29]=[C:30]2[C:35]=1[NH:34][CH:33]([C:36]([F:38])([F:39])[F:37])[CH2:32][CH2:31]2)(=[O:21])=[O:25]
Reactant: CS(=O)c1cc(CC(=O)O)cc2c1NC(C(F)(F)F)CC2
Reactant: CSc1cc(CC(=O)O)cc2c1NC(C(F)(F)F)CC2
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(CC(=O)O)cc2c1NC(C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
Into 20 ml of 1N sodium hydroxide were dissolved 250 mg of 8-methylthio-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetic acid and 300 mg of 8-methylsulfinyl-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetic acid, and, after 10 ml of 35% aqueous hydrogen peroxide were added, the mixture was stirred at room temperature for 3 hours. To this were added 50 ml of water, and the reaction mixture was brought to pH2 with concentrated hydrochloric acid. The crystals deposited were collected by filtration, washed with water and dried to obtain 220 mg of white crystals. Further, the aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate and then solvent was distilled off to obtain 360 mg of faintly yellow crystals. When recrystallizing from ethyl acetate, the crystals obtained give a melting point of 124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -12 °C
Yield: 64 %

Procedure:
0.113 mole) in orthodichlorobenzene at -14° C. was slowly added over 5 minutes a mixture of 4-fluorobenzoyl chloride (4.0 g., 0.025 mole) and fluorobenzene (2.4 g., 0.025 mole). The mixture was then maintained at -12° C. for one hour and then allowed to warm up to room temperature overnight then worked up as described in example 1. The crude 4,4'-difluorobenzophenone obtained (3.5 g., 64% yield) had a 90% purity with 0.5% ortho impurities and 5 other small impurity peaks by 19F NMR. 1 HNMR indicated 95% purity with 5% unreacted acid chloride.