Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C(C(F)(F)F)CC(OC)=O)=C(Cl)N=CN=1.COC1C=C(OC)C=CC=1CN.CN(C)C=O.[Cl:36][C:37]1[C:42]([CH:43]([C:49]([F:52])([F:51])[F:50])[CH2:44][C:45]([O:47]C)=O)=[C:41]([NH:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=2[O:63][CH3:64])[N:40]=[CH:39][N:38]=1>O>[Cl:36][C:37]1[C:42]2[CH:43]([C:49]([F:51])([F:52])[F:50])[CH2:44][C:45](=[O:47])[N:53]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=3[O:63][CH3:64])[C:41]=2[N:40]=[CH:39][N:38]=1
Reactant: COC(=O)CC(c1c(Cl)ncnc1NCc1ccc(OC)cc1OC)C(F)(F)F
Agent: COC(=O)CC(c1c(Cl)ncnc1Cl)C(F)(F)F
Agent: COc1ccc(CN)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(Cl)ncnc32)c(OC)c1
Temperature: 50 °C

Procedure:
Combine methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate (0.71 g, 1.98 mmol) diisopropylethylamine (0.38 mL, 1.1 eq), 2,4-dimethoxybenzylamine (0.32 mL, 1.05 eq), and dimethylformamide (6 mL). Heat at 50° C. overnight. Allow to cool to room temperature. Dilute with water and extract with methyl tert-butyl ether. Wash the organic layer with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give a mixture of the title compound and methyl 3-(4-chloro-6-(2,4-dimethoxybenzylamino)pyrimidin-5-yl)-4,4,4-trifluorobutanoate as an oil. Combine the crude mixture (0.78 g), diisopropylethylamine (0.63 mL), and ethanol (7.8 mL). Heat at reflux for four hours. Allow to cool to room temperature. Filter and rinse with ethanol to obtain the title compound as a white solid (0.43 g, 55%).
Reaction SMILES: I[C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CN([CH:26]=[O:27])C.CCCCCC>COC1CCCC1.C([Li])CCC>[CH3:11][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]2[N:6]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[C:2]=1[CH:26]=[O:27]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(C)c32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COC1CCCC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-5,7-dimethyl-1-tosyl-1H-indole (950 mg, 2.1 mmol) and DMF (0.33 mL, 4.2 mmol) in cyclopentyl methyl ether (22 mL), n-butyllithium in hexane (2.2 M, 1.3 mL, 2.8 mmol) was added at −78° C. After stirring for 1 h, additional n-butyllithium in hexane (2.2 M, 0.19 mL, 0.42 mmol) was added. After stirring for 15 min, the reaction was quenched with MeOH (2 mL) and 1M aq. NaHSO4 (4.5 mL), and diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by FCC [(10% DCM/heptane)/(20% EtOAc/DCM)=100/0 to 50/50] to give the title compound. MS (ESI+) m/z 328.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C#N)([O-:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+].[CH3:18][N:19](C)C=O>>[N+:1]([C:4]1[CH:5]=[C:8]([C:18]2[NH:19][N:14]=[N:13][N:12]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C

Procedure:
Nitrobenzonitrile (5 g) was dissolved in 50 ml of dry N,N-dimethylformamide and mixed with 10.97 g of sodium azide and 9.03 g ammonium chloride. The resulting suspension was heated to 110° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (50 ml). The aqueous solution was washed with ethyl acetate and acidified with 1 N HCl solution. The aqueous phase was then extracted with ethyl acetate and the organic extracts were dried (sodium sulfate) and concentrated to give 8.5 g of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:13]=1)=[O:7])([O-])=O>CO.ClCCl.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[CH:13]=1)=[O:7]
Reactant: O=C(Nc1cn(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cn(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)benzamide (600 mg, 1.11 mmol, 1.00 equiv, 85%) in methanol/dichloromethane (10/5 mL). The mixture was treated with Pd/C (600 mg) and stirred under an atmosphere of hydrogen overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 450 mg (85%) of product as a brown solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
123 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (79 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH:6]([OH:12])[CH2:5]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O>[CH3:10][C:8]1([CH3:11])[CH2:9][C:4]([CH3:13])([CH3:3])[CH2:5][CH:6]([O:12][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:7]1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2ccc([N+](=O)[O-])cc2)CC(C)(C)C1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
1.3 g of sodium hydride are added to a solution of 7.8 g of 3,3,5,5-tetramethylcyclohexanol in 50 ml of dimethylformamide, and the mixture is stirred at 40-50° C. for 30 min. A total of 7.0 g of 4-fluoronitrobenzene are then added a little at a time, and the mixture is subsequently heated at 100° C. for three hours and cooled to room temperature. 250 ml of ice-water are added, the mixture is stirred and the resulting solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N+:21]([O-])=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl[C:29]1C=CC2C(=CC=CC=2)N=1.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])[CH3:40]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:29][CH2:40][C:39]([O:42][CH2:43][CH3:44])=[O:41])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c[n+]([O-])ccc34)no2)cc1Cl
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Yield: 8 %

Procedure:
The contents of the three vials were pooled with the reaction mixture from a previous preparation of D6 (using the same method and 100 mg of chloroquinoline starting material), and the mixture diluted with ethyl acetate and washed sequentially with brine (×2) and water (×2). The organic layers were concentrated in vacuo to give a red oil that was dissolved in dichloromethane, and purified by flash chromatography on silica gel, eluting with a dichloromethane/ethyl acetate (2% to 20% EtOAc) gradient. The relevant fractions were pooled and concentrated in vacuo to give a red solid that was triturated with diethyl ether. The resulting brick coloured solid was collected by filtration and dried in vacuo to give the title compound (80 mg, 8%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([C:24]([F:27])([F:26])[F:25])=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:30])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.CCOC(C)=O>[CH2:28]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[C:24]([F:26])([F:25])[F:27])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reaction time: 4 h
Yield: 66.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) and 10% palladium on carbon (50% wet, 68 mg) in MeOH (6.5 mL) and EtOAc (6.5 mL) was hydrogenated under balloon pressure at room temperature for 4 h. The solid was filtrated and washed with MeOH (10 mL) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (103 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].N1CCOCC1>CN(C=O)C.C(OCC)(=O)C.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:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: C=CCCCBr
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: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: C=CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h

Procedure:
8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.44 mmol) was dissolved in DMF (1.5 ml) containing sodium carbonate (0.12 g, 0.49 mmol) and 5-bromopentene (0.07 g, 0.49 mmol) and the mixture stirred for 18 h. On completion of alkylation, morpholine (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.08 g, 0.07 mmol) were added and stirring continued for 3.5 h. The reaction was diluted with ethyl acetate (10 ml) washed sequentially with 2N hydrochloric acid (2×5 ml) and brine (3×5 ml) and the organic isolated, dried (MgSO4) and concentrated. The crude product was suspended in methanol (2 ml) and purified on an aminopropyl SPE (5 g) eluting with methanol first then 5% acetic acid in methanol to elute the title compound which was isolated as a white solid after concentration (0.039 g, 35%). NMR; (400MHz, d6-DMSO) 1.75 (m, 2H), 2.05 (m, 2H), 3.85 (t, 2H, J=7 Hz), 4.95 (m, 1H), 5.05 (m, 1H), 5.8 (m, 1H), 11.1 (br s, 1H), one exchangeable proton not observed to δH 13; m/z 255[MH+]
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:5]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Yield: 50.3 %

Procedure:
A solution of 1-methyl-4-(4-nitrophenoxy)-4-phenylpiperidine (4.4 g, 14.1 mM) in methanol (250 ml) was hydrogenated at 1 atmosphere and ambient temperature over 5% palladium on charcoal (500 mg) until the theoretical uptake of hydrogen had occurred (about 2 hours). The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (2 g) m.p. 174°-5°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl.[F:33][C:34]1([F:41])[C:38]([F:40])([F:39])[CH2:37][NH:36][CH2:35]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:36]4[CH2:37][C:38]([F:40])([F:39])[C:34]([F:41])([F:33])[CH2:35]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: FC1(F)CNCC1(F)F
Agent: Cl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC(F)(F)C(F)(F)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 30.8 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (43 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (40 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]2[N:6]=[C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[Cl:1])[O:18][C:8]=2[CH:9]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2nc(-c3ccncc3Cl)oc2cc1Cl
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.63 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.39 g of 6-chloro-2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 81”).
Reaction SMILES: C([C:3]1[NH:4][CH:5]=[C:6](C=O)[N:7]=1)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCCC1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C:38]1=[O:46]>CN(C=O)C>[NH:4]1[CH:5]=[CH:6][N:7]=[C:3]1[N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C:38]1=[O:46]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCc1nc(C=O)c[nH]1
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C1Cc2ccccc2N1c1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-ethyl-4-formylimidazole attached to 2-chlorotrityl resin (4, 78 mg, 0.052 mmol based on 0.67 mmol/g loading), DMF (0.9 ml) and piperidine (0.1 ml) was gently stirred for 45 min. at ambient temperature, afterwhich was added 2-indolinone (5, 70 mg, 0.523 mmol). The resultant mixture was gently stirred and heated at 80° C. for 20 h. The resin was filtered and washed with 30 ml each of acetone, water, dichloromethane, methanol, and another portion of acetone. Finally, the resin was air dried for 20 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[CH:12]=1.[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH:34]=O)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([BH3-])#N.[Na+]>CO>[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH2:34][N:7]2[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][C:11]3[CH:20]=[CH:19][C:14]4[C:15](=[O:18])[O:16][CH2:17][C:13]=4[CH:12]=3)[CH:3]([C:2]([F:1])([F:21])[F:22])[CH2:8]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C1OCc2cc(CCN3CCNCC3C(F)(F)F)ccc21
Reactant: COc1cc(CC=O)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)C(C(F)(F)F)C2)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.3 [M+1]+. 1H-NMR (500 MHz, CD3OD) δ ppm 7.82 (m, 1H), 7.60 (overlapping m's, 3H), 7.15 (s, 1H), 7.02 (m, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 3.90 (m, 1H), 3.58 (m, 2H), 3.51 (m, 2H), 3.43 (m, 2H), 3.20 (m, 4H), 3.12 (m, 2H), 3.08 (m, 2H). (0.65 μM)
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])(O)=[O:2].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:14][C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(Cl)c(C(=O)O)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a suspension of 2-carboxy-3-chloro-5-methylthiophene (1.2 g, 6.6 mmol) in methylene chloride (16 mL) at 0° C. were added oxalyl chloride (0.6 mL, 7.3 mmol) and a drop of DMF. The mixture was stirred at ambient temperature for 5 hours, then concentrated of all volatiles and dried in vacuo to afford 1.3 g (quantitative yield) of 2-chlorocarbonyl-3-chloro-5-methylthiophene as a pale yellow solid; NMR (DMSO-d6/TFA) 7.4 (s, 1), 2.5 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:19]=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[OH-:22].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([C:19]([OH:22])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde (1.00 g, 3.22 mmol) in methanol (40 mL) was added 1.0 M sodium hydroxide in water (16 mL, 16 mmol), followed by 1.0 M sodium hydroxide in water. After stirred at rt overnight, the mixture was slowly acidified to pH 5 with 1 N HCl, then extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dry under reduced pressure. The crude residue was used directly in next step (1.05 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[C:6]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:5]=1)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2NCC(C)C)c1
Solvent: CC(=O)O
Product: CCOc1cccc(OCc2nc3ccc(OCC)cc3n2CC(C)C)c1
Yield: 83.2 %

Procedure:
A 250 mL flask fitted with a stir-bar, condenser, and an Ar inlet was charged with amine 50a (12.5 g, 32.3 mmol) and AcOH (120 mL). The resultant solution was heated in a 100° C. bath for 3 hr. The mixture was cooled and concentrated in vacuo to a pale, orange solid. The solid was partitioned with EtOAc (150 mL) and saturated NaHCO3 (100 mL). The organic phase was washed with brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to an orange oil. The oil was crystallized with hexanes (25 mL), filtered, and rinsed with hexanes (2×15 mL). The material dried to give 9.9 g of Compound #1 as an off-white solid (83%). 1H NMR (300 MHz, CDCl3): δ 7.66 (d, 1H), 7.21 (t, 1H), 6.94 (dd, 1H), 6.82 (d, 1H), 6.71-6.62 (m, 2H), 6.56 (dd, 1H), 5.33 (s, 2H), 4.10 (qt, 2H), 4.05 (t, 2H), 4.03 (qt, 2H), 2.35 (nonet, 1H), 1.48 (t, 3H), 1.43 (t, 3H), 0.98 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 99% with a retention time of 4.6 min.
Reaction SMILES: [CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]2[C:8]([CH3:14])([CH3:13])[CH:9]([O:11]C)[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].C(O)(=O)C>O>[CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]2[C:8]([CH3:13])([CH3:14])[CH:9]([OH:11])[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(cc1O)C(C)(C)C(OC)O2
Solvent: O
Solvent: CC(=O)O
Product: C=CCc1cc2c(cc1O)C(C)(C)C(O)O2
Yield: 94 %

Procedure:
A mixture of 6-allyl-3,3-dimethyl-5-hydroxy-2-methoxy-2,3-dihydrobenzofuran, E70a, (20 gm; 85 mmoles), acetic acid (160 mL) and water (40 mL) was refluxed for 18 hours. The mixture was concentrated in vacuo and the residue chromatographed on silica gel using 20% ethyl acetate in hexane as eluent to obtain 17.8 gm (94%) of 6-allyl-2,5-dihydroxy-3,3-dimethyl-2,3-dihydrobenzofuran, E79, m.p. 66°-67° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[CH:15][C:16]=1[NH2:17]>>[CH3:18][C:13]1[CH:14]=[CH:15][C:16]2[NH:17][C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)=[N:10][C:11]=2[CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1ccc(N)c(N)c1
Product: Cc1ccc2[nH]c(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 3,4 diamino toluene using the method described in Description 14. MH+ 216.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc2c(c1)CCCC2=O
Product: COc1ccc2c(c1)CCC(=CN(C)C)C2=O

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-6-methoxy-1(2H)-naphthalenone starting material was prepared from 6-methoxy-1-tetralone (5.29 g, 30 mmol) and N,N-dimethylformamide dimethyl acetal (24 ml, 180 mmol) to give the desired product as a brown oil (2.67 g). δH (CDCl3) 8.00 (1H, d, J 8.6 Hz), 7.67 (1H, s), 6.81 (1H, dd, J 8.6, 2.6 Hz), 6.65 (1H, d, J 2.6 Hz), 3.83 (3H, s), 3.11 (6H, s), 2.95-2.90 (2H, m) and 2.88-2.79 (2H, m).