Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:35][CH:34]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (83 mg) in N,N-dimethylacetamide (1.6 ml) were added ethyl-4-(bromomethyl)benzoate (56 mg) and cesium carbonate (72 mg). The mixture was stirred for 4 h at room temperature. Ice water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>3:2) to give the title compound (96 mg) as colorless foam. MS (m/e, ISP neg. ion)=578.3 [M−H+].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[ClH:11].O=[C:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19](O)=[O:20]>>[ClH:11].[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[C:19](=[O:20])[O:10][C:6]=2[CH:5]=1)[CH3:3]
Reactant: O=C(O)C1CNCCC1=O
Reactant: CC(C)c1cccc(O)c1
Agent: Cl
Product: CC(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 28.2 %

Procedure:
Prepared by the method described in Example 1 from 3-isopropylphenol (150 g, 0.66 moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (114 g, 0.59 moles). Recrystallization from dilute aqueous hydrochloric acid yielded the product (46.6 g) as the hydrochloride, mp 257°-261° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].C(CN)O>O.C(O)(=O)C.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(I)cc1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: NCCO
Solvent: O
Solvent: CO
Product: COc1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 6 hours and 30 minutes, add 1-iodo-4-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 ml) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 7N ammonia in methanol to give the title compound: mp 88–91° C.; mass spectrum (ion spray): m/z=401.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[C:28]([O:41][CH3:42])=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[C:28]([O:41][CH3:42])=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (779 mg, 4.1 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (671 mg, 3.5 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). 4-Fluoro-3-methoxy-N2-phenylbenzene-1,2-diamine (283 mg, 1.2 mmol) was added and the reaction heated at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (349 mg, 74%). LCMS (Method C): RT=3.52 min, [M+H]+=386.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH:19]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:20])=[CH:14][CH:13]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C(C)c2ccc(OC)cc2)cc1
Yield: 100.7 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (142.7 mg, 1.0 mmol), 1-(4-methoxyphenyl)-1-propanone (195.8 mg, 1.2 mmol), palladium acetate (6.6 mg, 0.029 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.2 mg, 0.045 mmol), t-BuONa (115.9 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 18 h. 1,2-Di(4′-methoxyphenyl)-1-propanone (272.1 mg) was obtained with a yield of 100% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.99-7.92 (m, 2H, ArH), 7.24-7.18 (m, 2H, ArH), 6.87-6.79 (m, 4H, ArH), 4.61 (q, J=6.9 Hz, 1H, CH), 3.76 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 1.50 (d, J=6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 198.9, 163.0, 158.2, 133.8, 130.8, 129.2, 128.5, 114.1, 113.5, 55.1, 54.9, 46.3, 19.4; IR (neat) v (cm−1) 2969, 2932, 2837, 1668, 1600, 1574, 1514, 1455, 1419, 1371, 1303, 1258, 1169, 1114, 1032; MS (70 eV, EI) m/z (%): 270 (M+, 4.28), 135 (100).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:20])([F:19])[C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])=[O:11])=[CH:8][CH:7]=1>C(OCC)C>[OH:11][C:10]([CH:12]1[CH2:14][CH:13]1[C:15]#[N:16])([C:9]1[CH:17]=[CH:18][C:6]([C:5]([F:19])([F:20])[F:4])=[CH:7][CH:8]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 ml (9.09 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 1.45 g (6.06 mmol) of the compound from Example 122A in 25 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 1.40 g (90% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)[NH:22][C:16]=2[CH:15]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH:29]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)[N:22]([S:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:36])=[O:35])[C:16]=2[CH:15]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(C)C(=O)c1ccc(Nc2cc3[nH]c(-c4cnn(C)c4)cc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C)c2)n3S(=O)(=O)C2CCCC2)c(Cl)c1
Temperature: 60 °C
Yield: 18.1 %

Procedure:
3-Chloro-N,N-dimethyl-4-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-ylamino)benzamide (Example 127, 25 mg, 0.063 mmol) was dissolved in dry DMF. The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.1 ml of a 1M solution in THF, 1 mmol) was added. After 20 minutes reaction, cyclopentyl sulfonyl chloride (17 mg, 0.1 mmol) was added and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified by silica gel column chromatography eluting with 5% methanol in ethyl acetate to afford the title compound as white foam (6 mg, 18%). 1H-NMR (500 MHz, d6-DMSO): δ 1.5 (m, 2H), 1.6 (m, 2H), 1.75 (m, 4H), 2.97 (s, 6H), 3.11 (m, 1H), 3.89 (s, 3H), 6.77 (s, 1H), 7.33 (dd, J=2 Hz, 8.6 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.68 (s, 1H), 7.76 (s, 1H), 8.01 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.51 (s, 1H), 8.7 (s, 1H). ESI-HRMS Found 527.1621, calculated for C25H27ClN6O3S (M+H+): 527.1627. MPS1 IC50 (uM): 0.092
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)[CH3:3]>O=[Mn]=O.C(Cl)(Cl)Cl>[C:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2c(c1)NC(=O)CC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CHCl3 (120 mL) solution of the compound (1.00 g) obtained in Step 51-1, MnO2 (13.6 g) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtrated through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase MeOH/CHCl3=0/100 to 10/90; v/v) to obtain 7-acetyl-3,4-dihydroquinolin-2(1H)-one (0.58 g, a colorless solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:12])[CH3:11].C[O:14][C:15]1C=CC=C[C:16]=1C1CC(=O)CC(=O)C1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15](=[O:14])[CH2:11][C:10](=[O:12])[CH2:9]1
Reactant: CC(=O)C=Cc1ccccc1F
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Product: O=C1CC(=O)CC(c2ccccc2F)C1

Procedure:
The title compound was prepared from 4-(2-fluoro-phenyl)-but-3-en-2-one (7.3 g, 44.5 mmol), stage 1, following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:26])(=[O:25])[NH:13][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:7]=1.CO>>[C:15]1([CH2:14][NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:26])=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methyl ester (14a) (0.44 g, 1.15 mmol) in methanol (5 ml) 1N NaOH solution (3.45 ml, 3.45 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.32 g, 76%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[CH3:31]>C1COCC1.ClCCl>[CH3:31][C:17]1[N:16]=[CH:21][C:20]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[CH:6][N:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OCc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(CO)cn2)cn1
Temperature: 85 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-methanol (0.614 g, 3.27 mmol) in 10 mL of THF under an atmosphere of nitrogen was added cesium carbonate (3.27 mL, 2 N aqueous, 6.53 mmol), 2-picoline-5-boronic acid pinacol ester (0.477 g, 2.18 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (0.178 g, 0.218 mmol). The reaction was heated at 85° C. for 1 h, cooled to rt, and diluted with dichloromethane. The organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The aqueous fraction was concentrated in vacuo, triturated 3× with 20% methanol in dichloromethane, and collected via filtration. The combined solids were purified via silica gel chromatography, eluting with 100% ethyl acetate to provide (6′-methyl-2,3′-bipyridin-5-yl)methanol that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 201.1 for [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1cc(Cl)ncn1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To 4,6-dichloropyrimidine (0.533 g, 35.8 mmol) in MeOH (15 ml) was added tert-butyl N-(2-aminoethyl)carbamate and the reaction stirred at room temperature for 6.5 hours. Reaction concentrated in vacuo, solids triturated with EtOAc/petrol. Filtrate which contains the desired product was concentrated and EtOAc and sat. NaHCO3 added.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[CH2:31](I)[CH3:32]>C(#N)C>[CH2:10]([N:1]([CH2:31][CH3:32])[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[CH3:11].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCI
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: CC#N
Product: CCN(CC)[C@H](C(=O)O)C(C)C
Temperature: 80 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (92 mg) was dissolved in acetonitrile (18 mL). Ethyl iodide (74 mg) was added. The mixture was stirred at 80° C. and allowed to react overnight. The solvent was removed by rotary evaporation in vacuo. White solid (30 mg) was obtained after the crude product was purified by silica gel column (eluted with acetic ether: petroleum ether=1:1). 1H NMR (CDCl3, ppm) δ 7.86-7.90 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.15-3.25 (m, 1H), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.45-2.58 (m, 4H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 7H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:39]([O:42][C:43](=[O:47])[O:44][CH2:45]I)[CH2:40][CH3:41]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:45][O:44][C:43]([O:42][CH2:39][CH2:40][CH3:41])=[O:47])=[C:17]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:16]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: CCCOC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CCCOC(=O)OCOc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (E)-3-(3′-adamantan-1yl-4′-hydroxybiphenyl-4-yl)acrylic acid tert-butyl ester (250 mg, 0.581 mmol) and K2CO3 (241 mg, 1.74 mmol) in water (2.9 ml) was stirred at RT for 30 min. Tetrabutylammonium hydrogen sulfate (197 mg, 0.581 mmol) and DCM (1.4 ml) were then added and the stirring maintained for further 10 min. A solution of carbonic acid iodomethyl ester propyl ester (184 mg, 0.755 mmol) in DCM (1.4 ml) was then added dropwise. The biphasic solution was stirred overnight at RT. After standard work-up and removal of the solvent under reduced pressure, the residue was taken up in Et2O. Tetrabutylammonium iodide was filtered off and the solvent was evaporated. (E)-3-(3′-Adamantan-1-yl-4′-propoxycarbonyloxymethoxy-biphenyl-4-yl)acrylic acid tert-butyl ester was obtained (117 mg, 36%) after purification on silica gel (EtOAc/hexane 12:88).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14](=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(O)C.CO.[Pd].CN(C=O)C>[NH2:19][C:15]1[C:14]2=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCn1cc2c(n1)c(N)nc1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1cc2c(n1)c(N)nc1cc(O)ccc12
Yield: 54.1 %

Procedure:
A suspension of 7-benzyloxy-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-ylamine (prepared as described in Example 1320) (0.80 g, 2.51 mmol) in ethanol (80 mL) and methanol (20 mL) and palladium on carbon (10% palladium w/w on carbon) (0.4 g,) were combined in a pressure vessel and placed under hydrogen pressure ((50 psi (3.4×105 Pa)) for 24 hours. The reaction mixture was diluted with DMF (50 mL), filtered through CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue was purified via column chromatography on silica gel (eluting with 20-50% CMA/chloroform), concentrated under reduced pressure, and crystallized from acetonitrile to yield 0.31 g of 4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-7-ol as a light-yellow solid, mp 214-215° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:25]1([N:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)[CH2:10][CH2:9]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)(=[O:13])=[O:14])[CH2:26][CH2:27]1
Reactant: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: OC1CCNCC1
Product: O=C(CCN1CCC(O)CC1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
N-(1-Acryloyl-piperidin-4-yl)-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (1) (125 mg, 0.31 mmol), 4-hydroxypiperidine (313 mg, 3.1 mmol) and ETOH (2.5 ml) were mixed together in a sealed tube and heated to 150° C. with microwave equipment for 30 min. After the reaction, the reaction mixture was evaporated in vacuum and the residue was purified by column chromatography on silica gel (CHCl3/MeOH/NH3 aq.=100/10/1) to afford the desired compound as free base, which was dissolved in AcOEt (2 ml), and treated with 4N—HCl in AcOEt (2 ml) solution. The resulting mixture was concentrated in vacuo, and dried under reduced pressure for 24 hours at 60° C. to afford the title compound 2 as a HCl-salt (white amorphous, 151 mg, yield 90%) LC: 100%. MS: m/z=503.8, 504.49 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>O.C(OCC)C.C(O)C.O1CCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: c1ccccc1
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(N2CCOCC2)CC1
Yield: 30 %

Procedure:
A reaction mixture consisting of 2.63 gm. (0.01 mole) 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone (prepared as in Preparation I, Part i, above), 0.87 ml. morpholine, 0.05 gm. para-toluenesulfonic acid, and 40 ml. benzene is heated at the reflux temperature for 7 hours in a reaction vessel fitted with a Dean and Stark trap. The benzene is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in 10 ml. tetrahydrofuran, to which solution is added 0.76 gm. (0.02 mole) sodium borohydride in 35.0 ml. absolute ethanol. This reaction mixture is heated at the reflux temperature for 17 hours, after which heating the tetrahydrofuran and ethanol are removed by evaporation under pressure. The residue thus obtained is dispersed in a mixture of water and diethyl ether. After vigorous shaking and allowing the aqueous and organic phases to separate, the organic phase is recovered. It is washed first with water and then with brine. The ether is then allowed to evaporate. The residue thus obtained is transferred onto a 1 inch by 4 foot column of silica gel averaging 20 to 50 microns in size, for purposes of high pressure liquid chromatographic (HPLC) purification. The chromatogram is developed with a solvent system consisting of 5% methanol in chloroform with 1% triethylamine. The fractions of eluate containing the object compound yield a solid which is recrystallized from aqueous methanol to give 0.95 gm. (30% yield) of 1-(p-chlorophenyl)-1-dimethylamino-4-morpholinocyclohexane having a melting point at 103° to 105° C.