Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:15]([C:16]([O:18]CC)=[O:17])=[C:5]2[CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[C:15]([C:16]([OH:18])=[O:17])=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1ccn2nc(C)c(C(=O)OCC)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nn2ccc(C(=O)O)cc2c1C(=O)O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of diethyl 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate (100 mg), a 50% aqueous sodium hydroxide solution (160 mg), water (0.5 ml) and ethanol (1.0 ml) was refluxed under heating for 30 min. Then, the reaction mixture was adjusted to pH 4 under ice-cooling and stirred at the same temperature for 30 min. The precipitate was collected by filtration and washed with water to give the objective compound (50 mg) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1
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+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (906 mg, 1.978 mmol), pyridin-3-ylboronic acid (267 mg, 2.176 mmol), potassium carbonate (1367 mg, 9.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.099 mmol). The vial was flushed with argon and dioxane (9.89 mL) and water (5.1 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 4 h. The mixture was cooled to rt, diluted with EtOAc (45 mL), and brine (45 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×35 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of CH2Cl2/MeOH/NH4OH in CH2Cl2 to give (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4C)[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])C[CH2:3]1.C(NC(=O)NC1C=CC(C2N=C(N3CCOCC3)C3CN(C(OC(C)(C)C)=O)CC=3N=2)=C(F)C=1)C>>[ClH:1].[CH2:2]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:18]3[CH2:23][NH:22][CH2:21][C:19]=3[N:20]=2)=[C:11]([F:31])[CH:10]=1)=[O:7])[CH3:3]
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC(C)(C)C)C3)c(F)c1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)c(F)c1
Yield: 60 %

Procedure:
Method as described for (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) step 3 tert-butyl 2-(4-(3-ethylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 145). The resulting solid was triturated from methanol/ether to give a cream solid (60% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH:22][O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14][O:13]1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: COC=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: COCCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reaction time: 12 h
Yield: 19.2 %

Procedure:
A solution of 5-fluoro-3-[2-(2-methoxy-vinyl)-7H-furo[3,4-b]pyridin-5-ylidene]-1,3-dihydro-indol-2-one (27 mg, 0.08 mmol) in 10 mL MeOH is treated with palladium (10% on activated carbon, 27 mg) under an argon atmosphere. The resulting mixture is subject to hydrogenation at a pressure of 35 psi for 12 h. The reaction mixture is filtered, concentrated, and the residue is chromatographed (silica gel, MeOH-Chloroform). The product containing fractions are concentrated to give the title compound as yellow solid (5 mg, 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@H:13]1[O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.3 mmol) and triethylamine (4.5 g, 43.0 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.9 g, 43.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The solution was washed with water (150 mL×3) and brine, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure to give the title compound (6.0 g, crude) as a yellow oil. MS (ES+) C19H28H2O7S requires: 428, found: 329 [M+H−100]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3.85 g (7.00 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldiphenylsiloxy)methyl]-1,1'-biphenyl (Step E) in 25 mL of dry tetrahydrofuran under a nitrogen atmosphere was added by syringe 10.5 mL (0.530 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for two hours then diluted with 700 mL of diethyl ether. The mixture was washed with water (3×150 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), then dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography on silica gel eluting with hexanesthyl acetate (55:45) to afford 2.02 g (92%) of the product as a white solid (mp 89°-93° C.). 1H NMR (200 MHz, CDCl3): δ 1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated for C19H23 NO3 313; found 314 (M+H).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:25]>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)(=[S:25])[NH2:2]
Reactant: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Reactant: S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NC(C(N)=S)c2ccco2)sn1
Temperature: 25 °C

Procedure:
1.0 g of N-(alpha-cyanofurfuryl)-3-methylisothiazole-5-carboxylic acid amide was dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine was added. With stirring at room temperature, hydrogen sulfide gas was introduced into the mixture. Five hours later, the reaction solvent was evaporated under reduced pressure. Water was added to the residue. The precipitated crystals were separated by filtration to give 1.1 g of the desired N-[(alpha-thiocarbamoyl)furfuryl]-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:38]=[C:39]=S)[CH2:35][CH2:36][CH3:37].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:34]([NH:38][C:39]1[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]([OH:8])[CH:2]2[N:1]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN=C=S
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To a solution of Intermediate B (142 mg, 0.318 mmol) in dry THF (3 mL) was added a solution of butyl isothiocyanate (45.7 mg, 0.397 mmol) in dry THF (1 mL). The mixture was stirred at room temperature for 16 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (90 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 5 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (87.2 mg, 52%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 15H), 4.83 (d, J=11.5 Hz, 1H), 4.80-4.76 (m, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.2 Hz, 1H), 4.45 (s, 2H), 4.05 (dd, J=7.9, 4.4 Hz, 1H), 3.64 (t, J=5.9 Hz, 1H), 3.56 (dd, J=9.0, 4.2 Hz, 1H), 3.52-3.46 (m, 2H), 3.25-3.11 (m, 2H), 2.18 (dt, J=14.8, 3.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.88 (ddd, J=15.1, 12.1, 3.7 Hz, 1H), 1.53-1.46 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].C[Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)([OH:19])[C:2]([F:4])([F:3])[F:1])=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)Oc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(O)(c2ccc(Br)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ed) 4 ml of trifluoromethyltrimethylsilane are added to a a solution of 3.1 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 60 ml of THF at 0° C. under argon. After stirring at 0° C. for 30 min. 69.3 ml of 1M tetrabutylammonium fluoride solution in THF are added dropwise. The reaction mixture is warmed to room temperature and stirred, subsequently treated with 40 ml of water, again stirred and then extracted with methylene chloride. The extracts are washed with saturated sodium chloride solution, dried and evaporated. The crude product is purified over silica gel with toluene/acetone (98:2) as the eluent. 3.0 g of (RS)-4-[1-(4-bromophenyl)-2,2,2-trifluoro-1-hydroxyl-ethyl]-phenol, MS: m/e 290 (M--CO, 1 Br), are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:10]=1)[C:6]#[N:7].C(C1C=NC=C(CCC(C)C)C=1)#N>>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=1)[N:2]([CH3:14])[CH3:1]
Reactant: C=C(C)c1cc(C#N)cc(N(C)C)c1
Agent: CC(C)CCc1cncc(C#N)c1
Product: CC(C)c1cc(CN)cc(N(C)C)c1

Procedure:
3-(aminomethyl)-5-isopropyl-N,N-dimethylaniline was synthesized from 3-(dimethylamino)-5-(prop-1-en-2-yl)benzonitrile following the general procedure as described for the 3-cyano-5-isopentylpyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
A solution of 2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidine (0.5 g), propionic chloride (0.18 ml) and triethylamine (0.3 ml) in methylene chloride (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale-yellow substance (0.8 g). The obtained pale-yellow substance was crystallized from hexane/ethyl acetate (1:1, 50 ml) to give the title compound (0.5 g) as pale-yellow crystals.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>>[F:11][CH:2]([F:1])[C@@:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][NH:4]1
Reactant: FC(F)C1=NO[C@@H]2COC[C@H]12
Reactant: Fc1ccccc1Br
Product: Fc1ccccc1[C@@]1(C(F)F)NO[C@@H]2COC[C@@H]21

Procedure:
Intermediate VI-3: Starting from (3aS,6aS)-rel-3-difluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole and 1-bromo-2-fluorobenzene, the product (3S,3aS,6aS)-rel-3-difluoromethyl-3-(2-fluorophenyl)-hexahydro-furo[3,4-d]isoxazole was obtained as an orange oil. MS: m/z=260.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:22][NH:23][CH3:24]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](=[O:18])(=[O:17])[N:23]([CH3:24])[CH3:22])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CNC
Reactant: O=C1c2cc(Br)ccc2CCc2ccc(S(=O)(=O)F)cc21
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)c1cc(Br)ccc1CC2

Procedure:
3-Bromo-7-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (2.5 g., 0.00677 mole) together with 30 ml. of 25% aqueous dimethylamine and 30 ml. of p-dioxane is heated to refluxing for 3 hours. The brown solution is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. After washing with water, the benzene layer is evaporated to dryness under reduced pressure, leaving 3-bromo-7-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-one as a tan solid, m.p. 142°-145° C., in a yield of 2.1 g. (80%). An analytical sample melts at 146°-148° C. after crystallizations from mixtures of benzene and hexane and from methanol.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].Cl.[CH2:13](O)C>>[C:1]1([C:7]([O:9][CH2:10][CH3:13])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C1C=CCCC1
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C1=CCCCC1
Yield: 90 %

Procedure:
Methyl 2-cyclohexene-1-carboxylate (5.6 g; 40 m. moles) was added to a solution of sodium (1.1 g; 47.8 m. moles) in ethanol (35 ml) and the mixture was allowed to stand at room temperature for a period of 11/2 hours. The mixture was poured into dilute hydrochloric acid extracted with ether (4×25 ml) and the combined extracts washed with dilute aqueous sodium carbonate. The dried (MgSO4) extract was evaporated and the residue distilled to give ethyl 1-cyclohexene-1-carboxylate (5.5 g; yield 90%), b.p. 92° C./15 mm (N.M.R.: 6.7-7.0 (m,1,CH=C), 3.9-4.25 (q,2,CH2CH3), 1.95-2.42 (m,4,allylic CH2), 1.13-1.42 (t,3,CH2CH3) 1.45-1.92 (m,4,CH2 --CH2)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][C:38]([O:40][CH3:41])=[O:39])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[N:7][CH:8]=1>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][C:38]([O:40][CH3:41])=[O:39])=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A slurry of 10% Pd/C (53% water; 0.100 g) in DMF (2 mL) was added to a solution of tert-butyl 4-(4-((5-methoxy-4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A99) (0.112 g, 0.201 mmol) in DMF (8 mL) and TEA (1 mL), and the resulting mixture stirred under an atmosphere of hydrogen at room temperature for 16 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc (50 mL). The solvent was removed in vacuo and the resultant residue purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-65% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A100 as a pale yellow oil (0.110 g, 98%); 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.24-7.14 (m, 4H), 7.11 (d, J=8.5 Hz, 2H), 7.02 (s, 1H), 4.34-4.13 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H), 3.65 (s, 3H), 3.06-2.98 (m, 2H), 2.98-2.90 (m, 2H), 2.77 (t, J=12.1 Hz, 2H), 2.58 (tt, J=11.9, 3.3 Hz, 1H), 1.78 (d, J=13.0 Hz, 2H), 1.57 (qd, J=12.9, 4.5 Hz, 2H), 1.46 (s, 9H). LCMS-A: rt 6.77 min; m/z 561.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([C:15]([F:18])([F:17])[F:16])=[CH:4][N:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[C:36]([CH3:38])[C:35]([NH2:39])=[CH:34][C:33]=2[CH3:40])[CH2:28][CH2:27]1)=O)(C)(C)C>Cl.CC(O)C>[CH3:38][C:36]1[CH:37]=[C:32]([CH:29]2[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]2)[C:33]([CH3:40])=[CH:34][C:35]=1[NH:39][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([C:15]([F:18])([F:17])[F:16])=[CH:4][N:3]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (513.0 mg, 0.9 mmol), tert-butyl-4-(4-amino-2,5-dimethylphenyl)piperidine-1-carboxylate (282.7 mg, 0.9 mmol), and concentrated aqueous HCl (10 drops) in i-PrOH (12 mL) was heated at 150° C. in a microwave reactor for 30 min. The crude product was purified by RP-HPLC to afford N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; ESMS m/z 446.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[C:15]=[O:16]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:15]([NH:14][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[CH:22]4)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorophenyl)piperazine (206 mg, 1.05 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.84 (s, 1H), 8.49 (d, 1H, J=7.1 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.78 (d, 1H, 6.8 Hz), 7.61-7.72 (m, 2H), 7.25 (t, 1H, J=8.1 Hz), 6.96-7.04 (m, 2H), 6.81-6.84 (m, 1H), 3.68 (m, 4H), 3.29 (m, 4H); MS (ESI+) m/z 367 (M+H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37](OCC1SC=CN=1)=[O:38])([CH3:27])[CH3:26]>C1COCC1>[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[O:38])([CH3:27])[CH3:26]
Reactant: OCCOCC(F)(F)F
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCCOCC(F)(F)F
Reaction time: 0.17 h
Yield: 0.5 %

Procedure:
2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH2:21][CH3:22]>>[CH2:20]([O:23][C:24](=[O:29])[C:25]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:27])[CH3:26])[CH2:21][CH3:22]
Reactant: CCCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2cccc(Cl)c2)c2cc(O)ccc2n1C
Product: CCCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(Cl)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid propylester using a procedure analogous to that of Example 102.