Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (4.60 g) in dry N,N-dimethylformamide (55 ml) at room temperature and under was added potassium carbonate (7.25 g) in one go. The reaction was heated to 60° C. for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (2.6 g) in dry N,N-dimethylformamide (3 ml) was added via a Pasteur pipette and the reaction heated at 70° C. for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-60%) to afford the title compound as a clear viscous oil (3 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[CH3:20][NH:21][C:22]1[C:27]([CH3:28])=[N:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]([CH3:20])[C:22]2[C:27]([CH3:28])=[N:26][CH:25]=[CH:24][N:23]=2)[N:4]=1)=[O:10]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reactant: CNc1nccnc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nccnc1N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 80 °C

Procedure:
A CH2Cl2 (5 mL) suspension of 1-(4-(chloromethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (Intermediate XXI) (90 mg, 0.30 mmol), N,3-dimethylpyrazin-2-amine (69 mg, 0.56 mmol) and finely powdered K2CO3 (83 mg, 0.60 mmol) was evaporated to dryness. This mix was heated at 80° C. for 60 hours. Upon cooling, the organics were taken up in CH2Cl2 (3×5 mL) and the insolubles were removed by filtration. The volatiles were then removed in vacuo. The crude product was purified with chromatography (silica 1-4% MeOH in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, CDCl3): 8.00 (s, 2H), 7.23 (m, 1H), 6.95 (m, 3H), 6.60 (s, 1H), 4.45 (d, 2H), 4.37 (s, 2H), 2.87 (s, 3H), 2.52 (s, 3H). MS (ES+): M/Z 387 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8](=[O:19])[CH:9]1[CH2:13][C:12](=[O:14])[CH2:11][N:10]1[C:15]([O:17][CH3:18])=[O:16]>>[CH3:6][O:7][C:8](=[O:19])[C@H:9]1[CH2:13][C:12](=[O:14])[CH2:11][N:10]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC(=O)[C@H]1CC(=O)CN1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 200 mL aqueous solution containing 0.200M sodium acetate (pH 5.0), 1.3325 g of Candida antartica lipase fraction B, and 4.02 g of racemic N-(methoxycarbonyl)-4-keto-D,L-proline methyl ester (100 mM) was stirred at 25° C. After 24 h, an 96% enantiomeric excess of N-(methoxycarbonyl)-4-keto-D-proline methyl ester was obtained at 50% conversion of the racemic mixture. The reaction mixture was filtered using a 10,000 MWCO membrane filter (Amicon) to remove the enzyme catalyst, and the filtrate extracted with three 200 mL portions of dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and the dichloromethane removed from the filtrate by rotary evaporation at reduced pressure. Residual dichloromethane was removed from the resulting colorless oil at high vacuum (50 millitorr) to produce N-(methoxycarbonyl)-4-keto-D-proline methyl ester as a white solid (1.99 g, 99% isolated yield, 99% purity (by GC), 97% ee).
Reaction SMILES: CC#N.[Na+].[I-].C[Si](Cl)(C)C.[Br:11][C:12]1[C:13]2[CH:14]=[C:15]3[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])(O)[CH2:23][CH2:22][N:16]3[C:17]=2[CH:18]=[C:19]([F:21])[CH:20]=1.C([O-])(O)=O.[Na+]>CCOCC>[Br:11][C:12]1[C:13]2[CH:14]=[C:15]3[CH:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22][N:16]3[C:17]=2[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: COC(=O)CC1(O)CCn2c1cc1c(Br)cc(F)cc12
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CC1CCn2c1cc1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To dry CH3CN (2.3 g, 56 mmol) at r.t. was added NaI (8.4 g, 56 mmol) and trimethylsilyl chloride (6.1 g, 56 mmol). Then a solution of the alcohol of Step 7 (1.9 g, 5.6 mmol) in Et2O (60 mL) was slowly added. The reaction mixture was stirred for 5 minutes at r.t. and poured into a 1:1 mixture of saturated aqueous NaHCO3/10% aqueous Na2S2O3 (100 mL) at 0° C. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The desired compound was obtained as a brown solid (1.3 g).
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:1]2([C:4]#[N:5])[CH2:3][CH2:2]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: N#CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropanecarbonitrile (2.5 g, 37.3 mmol) was added to a solution of lithium diisopropylamide (41 mmol) in THF (20 mL) at −78° C. and the reaction stirred for 1 hour. 1-Bromo-4-bromomethyl-benzene (10.25 g, 41 mmol) in THF (50 mL) was slowly added and the reaction was allowed to warm to room temperature over 30 minutes. The reaction was submitted to standard aqueous workup to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: CC=CCC1Cc2ccc(OCC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.5 h
Yield: 64 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 5.6 g of (RS)-2-(2-buten-1-yl)-6-ethoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.72 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 170 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 3.4 g (64%) of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone were obtained as a red-brown oil.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[C:12]([F:25])[CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CN(C=O)C>[F:25][C:12]1[CH:11]=[C:10]([NH:9][C:8]([NH:37][CH2:36][CH2:34][OH:35])=[O:26])[CH:15]=[CH:14][C:13]=1[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:23])([CH3:24])[O:17]1
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of phenyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 12) (1.0 g, 2.8 mmol) in DMF (2 mL) was added triethylamine (1.3 mL, 9.0 mmol) followed by ethanolamine (0.84 mL, 14.0 mmol) and stirred at 50° C. for 2 hours. The reaction mixture was concentrated in-vacuo to afford a white solid (1.84 g, quantitative).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.Cl[C:38]([O:40][CH3:41])=[O:39]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methyl chloroformate. LCMS (M+H)+: m/z=480.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[N:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[N:15]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([C:14]1[N:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[N:15]=1)=[O:41]
Reactant: O=C(OCc1ccccc1)n1c(Sc2ccccc2-c2ccccn2)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1c(S(=O)c2ccccc2-c2ccccn2)nc2ccccc21
Reaction time: 3 h

Procedure:
Phenylmethyl 2-[2-(pyridyl)-phenyl thio]benzimidazole-1-carboxylate (0.41 mmole) in dry dichloromethane (10 ml) was treated at 0° with a solution of m-chloroperbenzoic acid (0.48 mmole) in dichloromethane (5 cm3). The mixture was stirred for 3 hours at between 0° and 10° and then poured into aqueous sodium hydrogen carbonate. The organic phase was separated, dried (MgSO4), filtered and evaporated to give a pale brown foam. The foam was taken up into dichloromethane and flash chromatographed (4/1 CH2Cl2 /60:80 petroleum ether) to give the title compound as a yellow gum.
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:20].[Na]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:32][CH2:33]1)[CH3:20]
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Reactant: CCOc1ccccc1N1CCNCC1
Agent: [Na]
Product: CCOc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Yield: 60.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02 mmol) and 1-(2-ethoxyphenyl)piperazine (1.13 mmol) with sodium triacetoxyboranehydride (1.33 mmol) gave pure product 1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (270 mg) in 52% yield. To a solution of free base in methanol was added required amount of hydrochloric acid solution in diethyl ether. The solvents were removed by reduced pressure, and the product was dried under vacuum to give dihydrochloric acid salt.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].O>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
Benzaldehyde (1b, 1.00 ml, 9.8 mmol) and cyclohexanone (37, 0.51 ml, 4.9 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.99 g (73%) of yellow crystals: mp 118-119° C. [expected mp 117° C.]; 1H NMR: δ 1.77 (m, 2H), 2.92 (t, 4H, J=5.2 Hz), 7.39 (m, 10H), 7.80 (s, 2H); 13C NMR: δ 23.1, 28.5, 128.3, 128.5, 130.2, 135.9, 136.1, 136.8, 190.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1>O1CCCC1.O1CCOCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[N:2]([CH3:3])[CH3:1])([O-:17])=[O:16]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)c1ncnc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.40 ml of a solution of dimethylamine in tetrahydrofuran (2 M) are added to 500 mg 4-chloro-8-nitro-quinazoline in 3 ml dioxane and the reaction mixture is stirred for one hour at ambient temperature, then another 1 ml of a solution of dimethylamine in tetrahydrofuran (2 M) is added. The reaction mixture is stirred overnight and then evaporated down in vacuo. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (65:35 to 40:60).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[OH:25])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[C:14]([C:13]1[CH:22]=[CH:23][C:24]2[O:25][CH2:8][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:10][C:11]=2[CH:12]=1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2ccc(C(=O)c3ccccc3)cc2O1
Reaction time: 8 h

Procedure:
11.63 ml of ethyl 2,3-dibromopropionate was added drop-by-drop over a 15-minute period to a mixture of 15.9 g of 5B, 58.5 g of anhydrous potassium carbonate and 250 ml of acetone. The stirred mixture was refluxed for 7 hours and stored overnight. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure (40° C.). The residue was suspended in 600 ml of ether and the mixture was washed with water, then with sodium bicarbonate solution, then dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform as eluent. Workup with ether and removal of the solvent gave a residue which was suspended in ethanol and placed in a freezer overnight. The solid was collected, washed with ethanol and dried to give 5, mp: 70°-71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=3)=[CH:10][CH:11]=2)[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (40 mg, 0.08 mmol) and DIPEA (69 μL, 0.40 mmol) in THF (5.0 mL) at 0° C. under N2 was added acetyl chloride (22 μL, 0.08 mmol) and the mixture maintained at 0° C. for 30 min and then warmed to RT for 16 hr. The reaction was quenched by the addition of a solution of NH3 in MeOH (1% w/v, 2.0 mL) and after 45 min at RT the volatiles were evaporated in vacuo. The residue was subjected to purification by SCX capture and release and then by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-70%, gradient elution). The impure material so obtained was subjected to re-purification by SCX capture and release and by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-65%, gradient elution) to afford the title compound, Example 3, as a white solid (12 mg, 27%); Rt 2.26 min (Method 2); m/z 549 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.01 (3H, s), 2.38 (3H, s), 6.39 (1H, s), 6.63 (1H, dd), 7.31 (1H, d), 7.36 (2H, d), 7.48 (2H, d), 7.56 (1H, m), 7.61-7.66 (2H, overlapping m), 7.83 (1H, d), 7.96 (1H, d), 8.16 (1H, d), 8.19 (1H, d), 9.02 (1H, s), 9.30 (1H, s), 10.52 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Li+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2[nH]ncc2c1
Yield: 94.3 %

Procedure:
A solution of 1H-indazole-5-carbonitrile (100 mg, 0.699 mmol) in tetrahydrofuran (4 ml) was added to a solution of lithium aluminum hydride (53 mg, 1.40 mmol) in tetrahydrofuran (4 ml) at room temperature, and the resulting mixture was refluxed for 2 hours. Subsequently, water (0.053 ml), a 2N-aqueous lithium hydroxide solution (0.106 ml) and water (0.212 ml) were added in that order to the reaction solution and stirred, followed by filtration. The solvent was distilled off under reduced pressure and the residue was dried under reduced pressure to obtain 1-(1H-indazol-5-yl)methanamine (97 mg, 94%).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH:27]1[CH2:29][CH2:28]1)C.C(C1CC1)#C.ClC(OCC)=O>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH:27]5[CH2:29][CH2:28]5)[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC1CC1
Agent: C#CC1CC1
Agent: CCOC(=O)Cl
Solvent: CCO
Product: O=c1cc(C2CC2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 170 °C
Yield: 95.2 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 28), in ethanol (5 mL) was added cyclopropyl-propynoic acid ethyl ester (0.377 g, 2.73 mmol) (prepared from ethynyl-cyclopropane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708). The reaction mixture was heated in a microwave oven at 170° C. for 30 min. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2) to afford 0.635 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-cyclopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −13.40 (c 0.5, CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=O)=[CH:5][CH:4]=1.[NH:15]([CH2:22][CH2:23][C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+].O>CS(C)=O.CO.C(O)C>[NH:15]([CH:22]=[C:23]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1ccc(C=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(C#N)=CNc2ccccc2)c2ccccc12
Yield: 60.9 %

Procedure:
To a solution of 4-methoxy-1-naphthaldehyde (10.0 g, 53.7 mmol)and 3-anilinopropionitrile (9.0 g, 61.6 mmol) in dimethylsulfoxide (25 mL) was added a solution of sodium methoxide (2.9 g, 53.6 mmol) in methanol (25 mL). The resulting mixture was heated to 133° with distillation of the methanol over 45 min. The reaction was then cooled, diluted with ethanol:water and the precipitate that formed was collected, washed with water, ethanol and hexane to give the title compound (10.28 g, 61%); mp 188°-189° after recrystallization from 2-methoxyethanol. Anal. Calcd for C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 79.80; H, 5.74; N, 8.87.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].N1C=CC=CC=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH:4]([C:5]#[N:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(C[C@@H](O)COCc1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
(4R)-4-hydroxy-2-phenyl-5-[(phenylmethyl)oxy]pentanenitrile (16.0 g, 57 mmol), accessed via the method of preparation 1, was dissolved in 116 mL CHCl3 and 116 mL Pyridine (25 eq) with DMAP (0.70 g, 5.7 mmol, 0.1 eq) and cooled to 0° C. 4-methylbenzenesulfonyl chloride (43.5 g, 228 mmol, 4 eq) was added to the reaction mixture and stirred 3 days at 0° C. The reaction mixture was washed successively with 1N HCl (4×250 mL) and brine, dried over MgSO4, filtered and concentrated to a red oil. The crude material was purified by flash chromatography (SiO2, 10→25% EtOAc/Hexanes) to give the diastereomeric product as a yellow oil (14.88 g, 34.2 mmol, 60%). ES-LCMS m/z 458.36 (M+Na).