Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[CH2:32]([NH:34][C:35](=[O:36])[NH:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:33]
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.05 mL, 0.63 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by HiTOPs to provide N-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1nnc(-c2ccc(C=O)cc2)n1

Procedure:
In an autoclave, 5.0 9 (28.7 mmol) of 4-(tetrazol-5-yl)-benzaldehyde (Step 35.1) in 33 ml of toluene are heated at 110° C. for 2 hours with -2.4 g of isobutene and 377 μl of methanesulfonic acid. When cold the reaction mixture is diluted with 50 ml of ethyl acetate, washed twice with sat. NaHCO3 solution, once with water and brine, dried (Na2SO4) and concentrated by evaporation. Crystallization from ethanol yields 4-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; 1H-NMR (DMSO-d6) 10.11 (s, HCO), 8.31 (d, J=8, 2H), 8.11 (d, J=8, 2H), 1.78 (s, 9H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][CH2:21][C:22]2[N:27]=[C:26]3[C:28]([N:30]=[C:31]([NH2:33])[NH:32][C:25]3=[N:24][CH:23]=2)=[O:29])[CH:2]=1.[H][H]>[Pt]=O>[CH:5]1[C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:1][CH:2]=[C:3]([NH:19][CH2:20][CH2:21][C@@H:22]2[NH:27][C:26]3[C:28]([OH:29])=[N:30][C:31]([NH2:33])=[N:32][C:25]=3[NH:24][CH2:23]2)[CH:4]=1
Reactant: [H][H]
Reactant: Nc1nc(=O)c2nc(CCNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1
Agent: O=[Pt]
Product: Nc1nc(O)c2c(n1)NC[C@H](CCNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1)N2

Procedure:
The preparation of N5 -methyltetrahydrohomofolic acid and alkali metal salts thereof is from homofolic acid starting material (HFA) by catalytic reduction with platinum oxide in the dark under hydrogen at a slight overpressure to produce tetrahydrohomofolate (THHF), them immediately reacting this product with formaldehyde to produce 5,11-methylenetetrahydrohomofolate and reducing this methylene intermediate without isolation with sodium borohydride to give the desired 5-methyltetrahydrohomofolate in the disodium salt form. The 5-methyl product is recovered by precipitating side products at a pH of about 3.8 with acetic acid and refrigerating the product filtrate overnight at about 3°-10°C. The filtrate containing the product 5-methyltetrahydrohomofolate (5-MeTHHF) is treated with charcoal, concentrated to an oil and the 5-methyl product is precipitated with absolute ethanol. The 5,11-methylenetetrahydrofolate may be separately recovered and in a second reaction an additional product known as the 5,11-methenyl is formed by reaction with formic acid. These products show increased stability over folate analogues and show biological promise in the treatment of cancer and leukemia as antifolates and specifically against L1210-FR8 tumor in mice.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22].O>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH2:16][CH2:17][CH2:18][C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:5]=[CH:4][C:3]=1[C:7]#[N:8]
Reactant: N#Cc1cn[nH]c1N
Reactant: C[Si](C)(C)C#CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCCCn1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.4 %

Procedure:
A suspension of 5-amino-4-cyanopyrazole (10 g) and finely ground anhydrous potassium carbonate (38 g) in dry DMF (100 ml) was treated with 5-iodo-1-trimethylsilyl-1-pentyne (25 g) and the mixture was stirred under nitrogen for two days at room temperature. The reaction mixture was then poured into water and the product extracted into ethyl acetate. The extract was washed with water and then with brine, dried over Na2SO4, and evaporated to give a semisolid brown residue. This solid was taken up in chloroform and filtered through a short plug of silica gel. Evaporation of the chloroform left a tan solid comprising a mixture of the isomeric compounds 5-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole and 3-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole. Fractional recrystallization from ethyl acetate/hexane gave 4.66 grams of the desired 5-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole: mp 125°-127°.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1.Cl>CCOCC>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([C:6]3([CH2:9][OH:10])[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C2(CO)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)-cyclohexan-1-one dimethyl ketal (0.15 g, 0.41 mmol) in ether (2 mL) was treated with 1N hydrochloric acid (2 mL) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with ether, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/chloroform, provided a wax (0.06 g, 56%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>C(O)C.O>[CH3:30][O:29][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[C:27]=1[CH3:28]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
18.0 g of 5.7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one were suspended in 400 ml of ethanol and treated while cooling with ice with 15.6 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 5.6 g of sodium hydroxide in 150 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 1000 ml of methylene chloride; the solution was washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3 x 500 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 300 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) - methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one of melting point 166-168° .
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(OCC)(=O)C.CN(C)C=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([CH2:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[O:23]
Reactant: O=C(CCl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Reaction time: 3.5 h
Yield: 90.2 %

Procedure:
To a suspension of tert-butyl 2-hydroxyimino-3-oxobutyrate (46.8 g) and potassium carbonate (51.8 g) in ethyl acetate (70 ml) and N,N-dimethylformamide (70 ml) was added 2,2,2-trichloroethyl chloroacetate (56.5 g), and the mixture was stirred at 45° to 48° C. for 3.5 hours. After the insoluble inorganic substance was filtered off, to the filtrate were added water and ethyl acetate. The separated ethyl acetate solution was washed with water and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave tertbutyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (84.9 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:15]=[C:16]1CC[CH2:18][CH2:17]1>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:3]1(=[CH:2][CH2:1][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: C=C1CCCC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC=C2CCCC2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 4-(allyloxy)benzoate 66.67A (3.00 g, 16.0 mmol) and methylenecyclopentane (1.9 g, 23.0 mmol) in DCM (5.0 mL) was added Hoveyda Grubbs reagent (0.39 g, 0.62 mmol) at room temperature. The resulting reaction mixture was degassed three times and stirred at 55° C. under nitrogen overnight. The reaction mixture was purified by Combi Flash silica gel chromatography (hexane/EtOAc 95/5) to give the compound 66.67B, (2.60 g, yield 68%). 1H NMR (500 MHz, CDCl3) δ ppm 7.82-7.93 (2H, m), 6.80-6.88 (2H, m), 5.44-5.56 (1H, m), 4.47 (2H, d, J=6.6 Hz), 3.80 (3H, s), 2.20-2.31 (4H, m), 1.50-1.71 (4H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:15][OH:16].[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25](Cl)=[N:24][CH:23]=1)=[O:21])[CH3:18].O>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25]([O:16][CH2:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH3:3])=[N:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnc(Cl)s1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a stirred suspension of sodium hydride (304 mg, 6.98 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (30 mL) at 0° C. under argon was added (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.0 g, 5.28 mmol) The mixture was warmed to room temperature and after 1 h the reaction mixture was cooled to 0° C. then a solution of 2-chloro-thiazole-5-carboxylic acid ethyl ester (1.01 g, 5.28 mmol) in THF (15 mL) added. The reaction mixture was warmed to room temperature and after 15 h, water (20 mL) was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 20% ethyl acetate in heptane) gave the title compound (940 mg, 52% yield) as an off-white solid. MS: m/e=345.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.99 mmol) and Et3N (0.85 g, 1.2 mL, 8.4 mmol) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (0.88 g, 0.60 mL, 7.7 mmol). After 1 h, brine was added and the reaction extracted with CH2Cl2 (2×). The combined organics were dried to give 1.65 g (94%) of 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester a yellow solid that was used without further purification. 1H NMR (CDCl3): 5.20 (tt, J=6.7, 4.2 Hz, 1H), 4.28 (ddd, J=10.3, 6.7, 1.2 Hz, 2H), 4.10 (ddd, J=10.4, 4.2, 1.1 Hz, 2H), 3.07 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([NH:19][C:20](=O)[CH2:21][CH2:22][CH3:23])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].N1C=CC=CC=1>CCCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:27][C:20]([CH2:21][CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2s1
Yield: 59 %

Procedure:
A mixture of the N-(7-benzyloxy-4-hydroxyquinolin-3-yl)butyramide prepared in Part E (2.97 g, 8.83 mmol), P2S5 (1.96 g, 4.41 mmol), and pyridine was placed under a nitrogen atmosphere and heated to reflux. The resulting solution was cooled and the excess P2S5 was quenched slowly with 10% aqueous Na2CO3 (10 mL). The reaction mixture was partitioned between water (40 mL) and CH2Cl2 (100 mL). The organic layer was washed with 0.1 M aqueous HCl (50 mL), dried over MgSO4, filtered and concentrated to yield a brownish-yellow solid. The solid was treated with boiling heptane (40 mL) and filtered. The filtrate was allowed to cool and a solid formed. The light yellow solid was isolated by filtration and washed with cold heptane to provide 7-benzyloxy-2-propylthiazolo[4,5-c]quinoline (1.74 g, 59%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.O>C(O)C>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Sc2ccccc2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(Sc2ccccc2)c1
Yield: 98 %

Procedure:
2-(3-Phenylsulfanyl-benzyl)-isoindole-1,3-dione described in Preparation Example 94 (123 mg, 0.356 mmol) was dissolved in ethanol (3 mL), hydrazine monohydrate (518 μl, 10.7 mmol) was added at 0° C., and the solution was stirred under reflux for 2 hours. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (75 mg, 0.35 mmol, 98%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])[C@H:5]([OH:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].C(N(CC)CC)C.[C:36]1([N:42]([CH3:46])[C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])[C@H:5]([O:13][C:43]([N:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:46])=[O:44])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](OC(=O)N(C)c1ccccc1)c1ccccc1C
Reaction time: 15 h
Yield: 52.7 %

Procedure:
0.4 g (0.001 mol) of (2S,3R)—N-methyl-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxy-3-o-tolylpropionamide was dissolved in methylene chloride, 0.13 g (0.0013 mol) of triethylamine and a spatula-tip of 4-dimethylaminopyridine were added, and 0.22 g of N-phenyl-N-methylcarbamoyl chloride in methylene chloride was added dropwise. The suspension was stirred for 15 hours and then extracted with 5% strength hydrochloric acid and NaHCO3 solution and dried. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 0.28 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of trans-4-aminocyclohexanol (7.90 g, 68.5 mmol) in acetonitrile (150 mL), was added cesium carbonate (51.4 g, 157.5 mmol) and benzyl bromide (18.2 g, 143.8 mmol). The solution was stirred at ambient temperature for 16 hours. The solution was complete by LC-MS and the mixture filtered through a frit, washed with additional acetonitrile, and condensed under reduced pressure. The solid was partitioned between water and dichloromethane (500 mL) and dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (17.14 g, 85%). ES-MS (m/z) 296.5 [M+1]+.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[F:30][C:31]([F:39])([F:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:20].[CH:25]1[N:24]2[CH:27]=[CH:28][CH:29]=[C:23]2[CH:22]=[C:21]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:35]2[CH2:36][CH2:37][CH:32]([C:31]([F:39])([F:38])[F:30])[CH2:33][CH2:34]2)=[CH:13][CH:12]=3)[N:26]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: FC(F)(F)C1CCNCC1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCC(C(F)(F)F)CC3)cc12

Procedure:
2-pyrrolo[1,2-c]pyrimidin-3-yl-6-[2-(4-trifluoromethyl-piperidin-1-yl)-ethoxy]chromen-4-one oxime, hydrochloride was prepared in 34% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 4-trifluoromethyl-piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38]Cl>CN(C=O)C.CCOC(C)=O>[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)OC(=O)OCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)OC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and KOH (46 mg, 0.82 mmol) in DMF (1.5 mL) was added a solution of chloromethyl isopropyl carbonate (62 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The reaction mixture was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (105 mg, 43%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([NH2:25])[CH2:21][C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(O)CCC>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:25][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CCN
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)=CCNc1nc(SCc2ccccc2)nc2nc[nH]c12
Temperature: 110 °C

Procedure:
A mixture of 2-benzylthio-6-chloropurine (1.2 g) and isopentenylamine hydrochloride (1.04 g) in 1-butanol (25 ml) containing triethylamine (2.2 ml) is heated in a sealed tube at 110° C. for 2 hours. The butanol is removed under vacuum and the mixture shaken with ice-water (100 ml). The product is filtered recrystallized from ethanol with charcoal decolorization and dried under vacuum with phosphorous pentoxide. Yield 0.64 g. Yield 1.3 g of 2-benzyl-thio-N6 -(2-iso-pentyenyl)adenine as a colorless solid. The crude product is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1
Reactant: BrCC1CCOCC1
Reactant: N#Cc1c[nH]c2cc(Br)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cn(CC2CCOCC2)c2cc(Br)cnc12
Temperature: 100 °C

Procedure:
To mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (500 mg, 2.252 mmol) in N,N-dimethylformamide (4.5 mL) was added sodium hydride (60% dispersion in mineral oil) (59.4 mg, 2.477 mmol) followed by 4-(bromomethyl)tetrahydro-2H-pyran (444 mg, 2.477 mmol). The mixture was heated at 100° C. for 2 hours. The reaction was diluted with 50 mL of ethyl acetate and the organic mixture was washed with a solution of aqueous sodium bicarbonate (1×50 mL), water (1×50 mL), and brine (1×30 mL), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 30-100% ethyl acetate/hexane to afford the title compound.