Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]([CH3:15])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[B:16]([OH:18])=[O:17].[OH2:19]>CCCCCC>[B:16]([OH:19])([OH:18])[OH:17].[B:16]([OH:19])([OH:18])[OH:17].[B:16]([OH:19])([OH:18])[OH:17].[B:16]([OH:19])([OH:18])[OH:17].[CH2:1]([N:13]([CH3:15])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=BO
Reactant: O
Agent: CCCCCCCCCCCCN(C)C
Solvent: CCCCCC
Product: OB(O)O
Temperature: 25 °C

Procedure:
Lauryldimethylamine (21.3 grams, 0.1 mole) and metaboric acid (4.4 grams, 0.1 mole) were placed in a three-opening flask equipped with an evaporating device and a stirrer and heated at 140° to 150° C. for 1 hour with stirring. About 20 minutes after the onset of the reaction, the reacting content turns to be a nearly transparent, viscous solution. Water produced during the reaction was removed outside the reaction system passing through the evaporating device. After completion of the reaction, the reaction content was cooled down to room temperature, stirred with an addition of 200 ml of hexane to extract unreacted amine and then filtered. Insoluble cakes were crushed in a mortar in a powder form; 200 ml of hexane was added again and filtration was repeated 2 times after stirring at about 50° C. for 1 hour. The resulting residue was dried in air for 1 day and then at 60° C. for 2 hours in vacuo to obtain lauryldimethylamine tetraborate. Solubility of the above-mentioned compound in various solvents at 20° C. is shown in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](OCC)=[O:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[BH4-].[Na+].CC(C)=O>C(O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][OH:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(Nc2nc(CO)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carboxylate (0.38 g, 0.82 mmol) in ethanol (20 mL), was heated to 45°. Citric acid (1.255 g, 6.53 mmol) and sodium borohydride (0.309 g, 8.16 mmol) were added in portions (of 5-10 mg each) keeping pH within a range of 5-7 over 3 h. Acetone (2 mL) was added and reaction mixture was stirred for 15 min. Chloroform (40 mL) was added. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica column eluting with a gradient of MeOH and DCM to give the title compound as a solid, 0.24 g (69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][O:27][CH2:28][CH2:29][CH3:30]>>[CH3:26][O:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: CCCOCBr
Product: COCCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 27 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 1-bromomethoxypropane (0.0306 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (10.5 mg, yield 27%) as a white solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: C=Cc1ccc(C(C)(C)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(C(C)(C)OC(C)=O)cc1
Yield: 48 %

Procedure:
A mixture of 6.7 g of 1-(1-hydroxy-1-methylethyl)-4-ethenyl-benzene and 4.0 g of pyridine in 100 ml of dichloromethane was stirred while 4.0 g of acetyl chloride in 20 ml of dichloromethane was added dropwise. After the addition was complete, the mixture was refluxed gently overnight. After cooling, an additional 30 ml of dichloromethane was added and the mixture was then washed with 50 ml of cold 5% aqueous HCl, and then several times with 30 ml portions of water. After drying over magnesium sulfate, filtering, and concentrating, the crude product was purified by HPLC using ethyl/acetate hexane as eluent. This method affords 4.05 g (47.5% yield) of the desired compound.
Reaction SMILES: P(=O)([O-])[O-].C[C:6](P(OC)(O)=O)([C:8]([O-:10])=[O:9])[CH3:7].[H-].[Na+].[CH3:18][N:19]([CH3:38])[CH:20]([CH3:37])[CH2:21][C:22]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C=O.[CH3:39]CCC>O>[CH3:38][N:19]([CH3:18])[CH:20]([CH3:37])[CH2:21][C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:7]=[CH:6][C:8]([O:10][CH3:39])=[O:9]
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CC(CC(C=O)(c1ccccc1)c1ccccc1)N(C)C
Reactant: CCCC
Agent: O=[PH]([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=CC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The phosphonate anion was generated by dropwise addition of a solution of trimethylphosphonoacetate (182 mg) in 1,2-dimethylethane (DME, 1 ml) to a slurry of 80% sodium hydride (24 mg, prewashed with hexane) in DME (3 ml). After stirring at room temperature for 30 min, a solution of 4-dimethylamino-2,2-diphenylpentanal (281 mg), as prepared in Example 1, in DME (1 ml) was added slowly. The mixture was allowed to stir for 24 hours. Water was added, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine (once each), and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was flash-chromatographed over silica gel. Elution with chloroform/methanol (20:1) yielded 93 mg of methyl 6-dimethylamino-4,4-diphenyl-2-heptenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:31])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([NH2:40])=[O:39].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:31])(=[N:40][C:38](=[O:39])[C:37]([F:42])([F:41])[F:36])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NC(=O)C(F)(F)F
Reactant: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylsulfinyl)ethyl]-1-naphthalenecarboxamide (i.e. the title product of Step B) (180 mg), 2,2,2-trifluoroacetamide (75 mg), MgO (53 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (160 mg) at room temperature. The resulting mixture was stirred for 5 h at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:7 to 1:9) as eluent to afford the title compound, a compound of the present invention, as yellow oil (100 mg, 46% yield).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.[Br:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:25][CH:26]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (2.02 g), 1,2-dibromoethane (20 ml), potassium carbonate (1.68 g) and N,N-dimethylformamide (20 ml) was stirred at 90° C. for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1530 mg, yield 58%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[N:15]1[C:24]2[C:19](=[N:20][C:21]([CH:25]=O)=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][C:11](=[CH:25][C:21]2[CH:22]=[CH:23][C:24]3[C:19](=[CH:18][CH:17]=[CH:16][N:15]=3)[N:20]=2)[C:12](=[O:14])[N:13]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a suspension of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.20 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min. The reaction mixture was then cooled to r.t. and diluted with toluene. The solid was collected by filtration and the solid was washed with toluene, MeOH and ether to give 2-[(3-Methyl-thiophen-2-ylmethyl)-amino]-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a light brown solid (25.7 mg, 43.9%). HR-ES (+) m/e calcd. for C18H14N4OS2: (M+H)+ 367.0682. Found: 367.0683.
Reaction SMILES: [C:1]([C:3](=[C:9]1[CH2:12][CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS(O)(=O)=O>CCOCC>[C:1]([CH:3]([C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C1CCC1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(c2ccccc2)CCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of Example 68A (3.0 g, 18.2 mmol) in ether (70 mL) was added dropwise phenyl magnesium bromide (9.0 mL, 3.0 M solution in diethyl ether, 27.4 mmol). The mixture was heated to 60° C. and stirred at this temp for 1 hour after addition was completed. The reaction mixture was cooled to ambient temperature. The resulting dark yellow solution was poured onto crushed ice and the pH was adjusted to about 5-6 with the addition of 20% H2SO4. The mixture was extracted with ethyl acetate/diethyl ether (1:1) (50 mL×2). The combined organic layers were washed with water and brine sequentially, dried over Na2SO4, filtered, and concentrated. The crude product was purified by reserve-phase C18 column chromatography (eluted with H2O/MeOH=1:4) to afford the desired compound (3.7 g, 15.2 mmol, 83.6%). LC-MS: m/e=261.1 (M++18). 1H NMR (400 MHz, CDCl3), 6 (ppm): 7.36-7.23 (m, 5H), 4.00 (q, J=6.8, Hz, J2=14.4 Hz, 2H), 3.91 (s, 1H), 2.80-2.73 (m, 1H), 2.65-2.55 (m, 3H), 2.21-2.07 (m, 1H), 1.99-1.88 (m, 1H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]([C@:4]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C@:6]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])=[O:3].O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:28]([C@@:4]([C@:6]([C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:10][OH:11])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
Crude 1-bromo-2,3,4-tri-benzoyl-L-ribose 21 (13.3 g, 25.3 mmol) was dissolved in acetone (150 mL) and water (5 ml, 277 mmol) at 0° C. Silver carbonate (6.28 g, 22.7 mmol) was added over 5 min. The reaction was brought to room temperature after 15 min and stirred an additional 30 min. The solids were removed by filtration and washed with acetone (100 mL) and the filtrate was concentrated in vacuo. The water was removed via azeotropic distillation with ethanol and toluene and the residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to EtOAc) to give 22 as white solid (9.8 g, 21.2 mmol, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Brc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-fluorobenzenesulfonyl chloride and bromobenzene.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20]([C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:22]1([C:20]([NH:19][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=3)[CH2:7]2)=[O:21])[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(C(F)(F)F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccc(C(F)(F)F)cc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
The mixture of 2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-5-trifluoromethyl-indan-2-carboxylic acid ethyl ester (84) (437 mg, 1.0 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (50 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (85) as white solid (408 mg, 100%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.Cl>ClC(Cl)C>[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[C:25]([C:7](=[O:8])[CH:6]([CH3:10])[CH3:5])[CH:24]=2)[CH2:29]1
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)C(=O)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To 8.00 g of anhydrous aluminum chloride suspended in 100 ml of dichloroethane was added dropwise 3.20 g of 2-methylpropanoyl chloride dissolved in 50 ml of dichloroethane under ice cooling. Then, to the mixture was added 5.27 g of 2-(1,3-isoindolinedion-2-yl)indane, and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water containing hydrochloric acid, the organic layer was collected by separation, washed with water and dried, and then the solvent was removed. The resulting crystals were recrystallized from ethyl acetate-n-hexane to obtain 4.92 g of 2-(1,3-isoindolinedion-2-yl )-5-(2-methylpropionyl)indane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]#[N:35])[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(=O)([O-])[O-:37].[K+].[K+].OO>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]([NH2:35])=[O:37])[CH2:25][CH2:26][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:32][CH2:33]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCC4(CC3)OCCO4)s2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCC4(CC3)OCCO4)s2)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carbonitrile (250 mg, 0.50 mmol) in anhydrous DMSO (4 ml) were added potassium carbonate (172 mg, 1.25 mmol) and hydrogen peroxide (218 μL, 2.49 mmol). The resulting solution was stirred at 70° C. for 1.5 h, cooled to room temperature and diluted with water (70 ml) and washed with EtOAc (2×60 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude, oil was triturated with diethyl ether and hexanes, and the resulting tan solid was collected via filtration and air dried to provide 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carboxamide (171 mg, 0.31 mmol, 63% yield) as a tan solid. MS ESI: [M+H]+ m/z 520.1. 1H NMR (500 MHz, CD3OD): δ 11.0 (s, 1H), 9.64 (d, 1H, J=4.9 Hz), 8.79 (s, 1H), 8.76 (bs, 1H), 8.28 (bs, 1H), 8.12-8.05 (m, 3H), 7.97 (s, 1H), 4.68-4.64 (m, 4H), 3.23-3.15 (m, 2H), 3.12 (s, 3H), 2.95-2.85 (m, 2H), 2.44-2.38 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(C(C)C)CC)(C)C.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][N:27]([CH3:32])[CH2:28][C:29]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:30]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CN(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 100 mL round bottom flask was placed 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine 65 (438 mg, 2 mmol), dichloromethane (30 mL), diisopropylethylamine (517 mg, 4 mmol), and 2-(dimethylamino)acetyl chloride (267 mg, 2.2 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added (20 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified on a silica-gel column using 0 to 20% methanol in dichloromethane as the solvent gradient. The product fractions were collected and concentrated to afford the title compound 66 as an orange oil. Mass found by LC-MS(+): 305 (M+H); calc. for C16H25BN2O3: 304.19.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][OH:24]>>[CH3:23][O:24][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: CO
Product: COc1ccc2c(OC)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:16]=2[C:17](O)=[O:18])=[O:13])=[CH:10][C:9]=1[Cl:33].C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C.[CH3:58][O:59][C:60]1[CH:68]=[CH:67][CH:66]=[CH:65][C:61]=1[CH2:62][CH2:63][NH2:64]>CN(C=O)C>[Cl:33][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:8]=1[O:7][CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([NH:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][C:16]=1[C:17]([NH:64][CH2:63][CH2:62][C:61]1[CH:65]=[CH:66][CH:67]=[CH:68][C:60]=1[O:59][CH3:58])=[O:18])=[O:13]
Reactant: COc1ccc(COc2ccc(C(=O)Nc3ccc(Oc4ccccc4)cc3C(=O)O)cc2Cl)cc1OC
Reactant: COc1ccccc1CCN
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 1D (30 mg, 0.056 mmol) in DMF (2 mL) was treated with HOBt (15 mg, 0.11 mmol) and diisopropylcarbodiimide (13 μL, 0.084 mmol) at room temperature. The reaction was stirred for one hour then 2-methoxyphenethylamine was added. The resulting solution was stirred for three hours, concentrated and purified by chromatography (SiO2, 0.5% MeOH in CH2Cl2) to afford 1E (27 mg, 73%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(C=C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 55.00 g of N-t-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine was added 475 ml of an ice-cooled solution of 4 N hydrogen chloride in dioxane, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crystals were recrystallized from isopropanol to give 40.72 g of 4-(4-fluorobenzylidene)piperidine hydrochloride.