Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([NH:8][C:9](=O)[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[OH-:20].[Na+].OO.[ClH:24]>C(O)(C)C.O>[ClH:24].[CH:4]([C:3]1([CH3:7])[NH:8][C:9]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[N:2][C:1]1=[O:20])([CH3:6])[CH3:5]
Reactant: CC(C)C(C)(C#N)NC(=O)c1ccccc1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)C1(C)NC(c2ccccc2C(=O)O)=NC1=O
Temperature: 80 °C
Yield: 60.3 %

Procedure:
To 5.22 g (0.020 mol) of N-(1-cyano-1,2-dimethylpropyl)phthalamic acid in a mixture of 35 mL isopropyl alcohol and 10 mL of water is added 6.41 g (0.080 mol) of aqueous 50% sodium hydroxide. External cooling is applied to hold the temperature at 20°-30° C. and 4.80 g (0.042 mol) of aqueous 30% hydrogen peroxide is added. The mixture is heated at 80° C. for five hours then cooled to 20°-25° C. Aqueous 36% hydrochloric acid is added to adjust the pH to 1. The volatile solvent is removed in vacuo to give 8.35 g of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoic acid, hydrochloride salt. The solid is analyzed by high performance liquid chromatography. The real yield is 60.3%.
Reaction SMILES: S(Cl)(Cl)=O.C([O:9][C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:14]=1[C:15]([OH:17])=[O:16])=O)(C)(C)C>O1CCCC1>[F:23][C:18]1[C:14]2[C:15](=[O:17])[O:16][C:10](=[O:9])[NH:12][C:13]=2[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
A solution of 108 ml of thionyl chloride in 300 ml of tetrahydrofuran was added dropwise while cooling with ice to a solution of 100 g (366 mmol) of 2-(tert.-butoxycarbonyl)amino-5,6-difluorobenzoic acid in 1.5 I of dry tetrahydrofuran, whereupon the mixture was stirred at room temperature for 16 hours. The brown solution was evaporated and the brown solid obtained was triturated with methylene chloride. The beige powder obtained was filtered off and dried in a high vacuum. There were obtained 56.5 g (77%) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione as a beige powder of m.p. >240°.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])[CH:23]=2)[CH2:18][CH2:19][CH2:20]1)(=[O:33])[CH3:32]
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)NCCC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccc(C(C)NC(=O)C=Cc3ccccc3)cc21

Procedure:
To a solution of 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-acrylamide (Example 233) in CH2Cl2 at 0° C. was added triethylamine followed by acetyl chloride. Work up and flash chromatography provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][OH:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][C@@H:35]3[CH2:39][OH:40])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: OC[C@H]1CCCN1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC[C@@H]4CO)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 182.6 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) then (R)-(−)-2-pyrrolidinemethanol (0.516 g) was added and the mixture heated to 110° C. for 50 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.341 g) as a pale yellow gum; NMR Spectrum: (CDCl3) 1.761 (m, 3H), 1.88 (m, 1H), 2.12 (m, 2H), 2.30 (m, 1H), 2.48 (m, 1H), 2.63 (m, 1H), 3.04 (m, 1H), 3.21 (m, 1H), 3.39 (dd, 1H), 3.46 (s, 3H), 3.64 (dd, 1H), 3.98 (s, 3H), 4.25 (m, 2H), 4.35 (s, 2H), 6.07 (s, 2H), 7.01 (s, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.28 (s, 1H), 8.62 (s, 1H). Mass Spectrum: M+H+ 555/557.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15].N1C=CC=CC=1>CN(C=O)C>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:15]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
To a solution of 5-aminoindan (4.66 g, 35.0 mmol) in anhydrous DMF (26 ml) was slowly added methoxyacetyl chloride (5.70 g, 52.50 mmol) followed by pyridine (8.5 ml, 105.0 mmol). The red solution was stirred at room temperature for 3.5 hours under argon, then it was partitioned between ethyl acetate (200 ml) and 1N HCl (120 ml). The organic layer was washed with more 1N HCl (120 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with diethyl ether; the white precipitate was collected by filtration, washed with diethyl ether to afford the title compound (5.93 g, 83%), m.p. 104-105° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.06 (m, 2H, 2-CH2), 2.87 (m, 4H, 1-CH2 and 3-CH2), 3.50 (s, 3H, OCH3), 4.00 (s, 2H, 2-CH2OMe), 7.22 (m (overlap with CHCl3 peak), 2H, 6-H, 7-H), 7.52 (s, 1H, 4-H), 8.18 (s, 1H, CONH); MS (ESI, m/z): 432 [(2M+Na)+, 30%], 206 [(M+H)+, 100%]. Found C, 70.10; H, 7.38; N, 6.81; C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18].C(O[C:22](=[NH:24])[CH3:23])C.[C:25]([OH:28])(=[O:27])[CH3:26]>C(#N)C>[C:25]([OH:28])(=[O:27])[CH3:26].[NH:24]=[CH:22][CH2:23][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18]
Reactant: CCOC(C)=N
Reactant: CCOc1cc(Cl)c(-c2c(C)n[nH]c2N)c(Cl)c1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOc1cc(Cl)c(-c2c(C)n[nH]c2NCC=N)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazole (4.8 g) (prepared from 4-ethoxy-2,6-dichloro benzaldehyde according to Example 1 C-F) in acetonitrile (50 mL) add ethylacetimidate (free base, 2.3 mL) followed by acetic acid (0.96 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 5.02 g of (iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol−5-yl]amine acetate salt as a white powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: ON=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 397.2 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-one (50.3 g, 322.1 mmol) and hydroxylamine hydrochloride (89.5 g, 100.3 mmol) in water (450 mL) was added portionwise sodium carbonate (102.4 g, 966.2 mmol). The reaction mixture was stirred for 40 minutes at room temperature then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 68.2 g of crude 1,4-dioxaspiro[4.5]decan-8-one oxime.
Reaction SMILES: O[CH:2]([CH3:21])[CH:3]([NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7](C)=[CH:6][CH:5]=1.[P+3]=O.[CH2:24]1C2C(CCCC2)CCC1>>[CH3:24][C:8]1[CH:9]=[C:4]([C:3]2[C:2]3[C:18](=[CH:17][CH:16]=[C:15]([CH3:19])[CH:21]=3)[C:13]([CH3:14])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(NC(=O)c2cccc(C)c2)C(C)O)cc1
Reactant: C1CCC2CCCCC2C1
Agent: O=[P+3]
Product: Cc1cccc(-c2ncc(C)c3ccc(C)cc23)c1
Reaction time: 5 h

Procedure:
N-(2-hydroxy-1-p-tolyl-propyl)-3-methylbezamide (2.1 mmol), phosphorus (V) oxide (10 mmol) and decahydronaphtalene (50 mmol) were put in a dried two-neck round-bottom flask. Then, the mixture was stirred at 120 for 5 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 1-(3-methylphenyl)-4,7-dimethylisoquinoline.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: NC(=O)CBr
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CC(N)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 143, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with bromo acetamide and the crude product subjected flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 155 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.83 (d, J=2.18 Hz, 1H); 7.24 (d, J=2.21 Hz, 1H); 7.18 (d, J=8.31 Hz, 1H); 6.86 (s, 1H); 5.71-5.63 (m, 1H); 5.45 (s, 1H); 4.54 (t, J=5.98 Hz, 2H); 3.87 (t, J=7.28 Hz, 2H); 3.81-3.72 (m, 1H); 3.38 (t, J=6.84 Hz, 2H); 3.22 (s, 2H); 3.16 (t, J=5.99 Hz, 2H); 1.59 (d, J=6.62 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=5.84 min, M+H+=408
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1CCC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(CN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCC=C1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(CN)cc1
Temperature: 65 °C

Procedure:
A mixture of 4-azidomethyl-N-methyl-benzenesulfonamide (2.20 g, 10.0 mmol), cyclohexadiene (8.90 mL, 90.0 mmol) and palladium hydroxide (20% on carbon, 1.4 g, 2.0 mmol) in MeOH (20 mL) was warmed at 65° C. for 2 hours. The solution was cooled to room temperature and filtered through diatomaceous earth. The solvent was removed in vacuo to afford 4-aminomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:20][CH:19]=2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:33]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:31][C:30]([C:8]2[N:9]3[CH:12]([S:13][CH2:14][C:7]=2[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:22][CH:23]=2)[C:10]3=[O:29])=[O:32])=[CH:42][CH:41]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)Oc1ccc(CO)cc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCc2ccc(OC(=O)C(C)(C)C)cc2)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
To a solution of 1.8 g of 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride in 25 ml of dimethyl formamide is added 0.78 g of ρ-pivalyloxybenzyl alcohol followed by cooling to 0° C. after with 3.7 mole of dicyclohexylcarbodiimide in 7.5 ml of dimethyl formamide is added dropwise with stirring. The reaction mixture is stirred for 1 hours at 0° C. and for an additional 4 hours at room temperature. The formed dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform and washed with water. The organic layer is then dried over magnesium sulfate filtered and evaporated in vacuo to give an oil which is triturated with ether to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ρ-pivalyloxybenzyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(O)c3)ccn2c1=O

Procedure:
Methyl 8-(3-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-hydroxyphenyl)-boronic acid (56.6 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: C([Li])CCC.O1CCCC1.[F:11][C:12]1[CH:13]=[C:14]([C:19]2([CH2:24][CH3:25])[O:23][CH2:22][CH2:21][O:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1.[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>O>[Br:26][C:17]1[C:12]([F:11])=[CH:13][C:14]([C:19]2([CH2:24][CH3:25])[O:20][CH2:21][CH2:22][O:23]2)=[CH:15][C:16]=1[F:18]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CCC1(c2cc(F)cc(F)c2)OCCO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC1(c2cc(F)c(Br)c(F)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
Under a nitrogen atmosphere at −78° C., n-butyllithium (1.56 M hexane solution, 4.84 ml) was added to a tetrahydrofuran (20 ml) solution of 2-(3,5-difluorophenyl)-2-ethyl-1,3-dioxolane (1.01 g). The reaction liquid was stirred at −78° C. for 15 minutes, then a tetrahydrofuran (10 ml) solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.07 g) was added. After stirred at room temperature for 45 minutes, water was added to it, and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain the entitled compound (1.20 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1)[CH2:27][CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of N-phenylbenzene-1,2-diamine (1.0 g, 5.43 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (1.21 g, 5.97 mmol), HOAt (813 mg, 5.97 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.15 g, 5.97 mmol) and 4-methylmorpholine (1.31 mL, 11.95 mmol) in DCM (20 mL) was stirred at RT for 2 h. The crude reaction mixture was diluted with DCM (100 mL), then washed with a saturated solution of NaHCO3, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated to 70° C. for 18 h. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was dissolved in EtOAc (150 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was absorbed onto HM-N and purified twice by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording [(S)-1-(1-Phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tertbutyl ester (1.76 g). LCMS: RT 3.23 min [M+H-tBu]+ 352.2
Reaction SMILES: O1CCCC1.[CH:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH3:14][N:15]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[CH:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16](=[O:17])[N:15]([CH3:14])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: O=CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)C(=O)N1CCN(C=O)CC1
Yield: 49.7 %

Procedure:
Into 600 ml of tetrahydrofuran, were dissolved 41 g of 1-formylpiperazine and 54.5 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 56 g of 2,4,4-trimethylallophanyl chloride. The mixture was allowed to react at room temperature for 6 hours and the precipitate was removed by filtration. The filtrate was concentrated and the residue was recrystallized from tetrahydrofuran to obtain 41 g of 1-formyl-4-(2,4,4-trimethylallophanoyl)piperazine. This compound was mixed with 800 ml of 6N hydrochloric acid and the mixture was heated with stirring at 60° C. for one hour. The reaction mixture was concentrated and the residue was recrystallized from ethanol to obtain 35.2 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 215° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:19](=[O:36])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)[C:19](=[O:36])[C:18]=1[I:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)cc2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)c(I)c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
N-Iodosuccinimide (2.85 g) was added at room temperature to an acetic acid (57.6 mL) solution of tert-butyl 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (4.43 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was rendered basic by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.83 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[Br:20]Br>C(O)(=O)C>[Br:20][C:12]1[C:11]([F:14])=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3](=[O:17])[C:2]([F:1])([F:18])[F:19])[CH:13]=1
Reactant: COc1cc(F)ccc1C(C)(C)CC(=O)C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(F)c(Br)cc1C(C)(C)CC(=O)C(F)(F)F
Yield: 97.4 %

Procedure:
To a solution of 300 mg (1.078 mmol) of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 26) in 0.5 mL of acetic acid was added 70 μL (1.35 mmol) of bromine. The reaction was monitored by TLC (EtOAc-hexanes (1:9)) by partitioning an aliquot between saturated aqueous sodium bicarbonate and EtOAc. A new slightly more polar product was observed. The reaction was made basic with saturated aqueous sodium bicarbonate and extracted with three 15 mL portion of EtOAc. The combined organic layers were washed with two 10 mL portions of saturated aqueous sodium bicarbonate and 10 mL of brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in hexanes and passed through a pad of silica gel, eluting with EtOAc-hexanes (0.5:99.5) to afford 375 mg (97%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>O1CCCC1>[CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([S:41]([CH3:44])(=[O:43])=[O:42])[C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:32]=[N:31][C:30]([NH2:33])=[N:29][CH:28]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (140 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 ml) followed by the addition of triethylamine (68 μl) and mesyl chloride (28 μl) with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:5 to 0:10) to give a white solid (135 mg, 62%).