Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23](ON2C(=O)CCC2=O)=[O:24])=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:24])=[O:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1(C(=O)O)CC1
Reactant: O=C(CCCc1ccccc1)OCCOC(=O)ON1C(=O)CCC1=O
Product: O=C(CCCc1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 45.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.218 g, 2.08 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 4-phenylbutyrate (0.607 g, 1.73 mmol) were reacted to provide 0.264 g (46% yield) of the title compound (15) as a white semi-solid after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=7.32 (t, 2H), 7.19 (m, 3H), 6.81 (q, 1H), 6.22 (s, 0.3H), 5.43 (s, 0.7H), 2.62 (t, 2H), 2.31 (m, 2H), 1.98 (q, 2H), 1.61 (m, 2H), 1.42 (dd, 3H), 1.23 (m, 2H). MS (ESI) m/z 358.05 (M+Na)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[C:36]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11]
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Yield: 66.4 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.00 g, 9.08 mmol, RN-59216-82-9), oxalyl chloride (0.871 mL, 9.99 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.17 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (2.41 g, 9.08 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 2.82 g (66%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.40-1.44 (m, 2H), 1.57-1.73 (m, 4H), 1.79 (s, 3H), 1.87-1.93 (m, 2H), 2.16 (s, 3H), 3.21 (quintet, 1H), 3.86 (s, 3H), 3.93 (s, 2H), 7.04 (d, 1H), 7.11-7.18 (m, 2H), 7.29 (t, 1H), 7.51 (dd, 1H), 7.54-7.60 (m, 2H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12]1>C(OCC)(=O)C>[CH:5]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11]1)=[O:7]
Reactant: c1ccc2c(c1)CCCNC2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN1CCCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (20 ml) was added dropwise to formic acid (60 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro 1H-2-benzazepine (10.71 g, 72.75 mmol) in ethyl acetate (5 ml) was added dropwise at room temperature. This mixture was stirred for 3 hours, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of potassium carbonate (K2CO3), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide the title compound (11.35 g) as colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:6]/[C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)/[C:16]#[N:17])=[CH:11][CH:10]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1ccc[nH]1
Solvent: O
Product: N#C/C(=C\c1ccc[nH]1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A suspension of 1H-pyrrole-2-carbaldehyde (3.3 g, 34.7 mmol) and 4-chlorophenylacetonitrile (5.5 g, 33.0 mmol, 0.95 equivalents) in water (50 ml) was heated to 50° C. When all the solid material had melted, the vigorously stirred mixture was treated with 40% aqueous Triton B (14 ml, 5.6 mmol). Precipitation began almost immediately. Stirring was continued for 5 h at 50° C., breaking up lumps when necessary. The still warm suspension was filtered through a sintered glass funnel and washed with warm water. The yellow precipitate was dried at the pump (6.63 g). This is Compound 2 in TABLE 8.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OC(C)=O)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Yield: 99.8 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-acetoxybenzoic acid (0.300 g, 0.663 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.909 g, 1.658 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.248 g, 0.662 mmol, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19]C3CCCCO3)[CH:14]=[C:15]([CH2:16]OC)[C:7]1=2)[CH3:2].B(Br)(Br)[Br:28].C(O)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][Br:28])[C:7]1=2)[CH3:2]
Reactant: BrB(Br)Br
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(COC)c21
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [1-hydroxy-4-methoxymethyl-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester from step 1.10. (870 mg, 1.37 mmol) in DCM (10 mL) was added boron tribromide (0.46 mL, 3.02 mmol) slowly under −78° C. The reaction mixture was allowed to stir at room temperature for 1 h. Ethanol was added slowly and the solvent was removed under vacuum. The crude product was used for next step without further purification. 1H NMR (300 MHz, CD3CN) δ 7.13 (s, 1H), 7.01 (s, 1H), 5.62 (dd, 1H), 4.42-4.63 (dd, 2H), 4.14 (q, 2H), 3.18-3.24 (dd, 1H), 2.40-2.51 (m, 1H), 1.22 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:41])[NH:16][C:15]1[CH:17]=[CH:18][C:12]([O:11][C:10]2[CH:20]=[CH:21][C:22]([CH2:24][CH3:25])=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:19])[CH:14]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Agent: CCOC(=O)Cl
Product: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Yield: 107.8 %

Procedure:
According to the procedure of example 44(a) except substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (200 mg; 0.59 mmol) and ethylchloroformate by benzylchloroformate (150 μL; 0.73 mmol), the title compound (300 mg; quantitative) was prepared as a brown solid and used without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH2:43]Br>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:45]=[CH:46][C:47]([CH3:48])=[C:40]([F:39])[CH:41]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Reactant: Cc1ccc(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(C)c(F)c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.046 mmol) in Acetonitrile (0.45 mL) was treated with Cs2CO3 (59.4 mg, 0.182 mmol), 3-fluoro-4-methylbenzyl bromide (13.89 mg, 0.068 mmol), and then stirred at 70° C. for 90 min. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-60% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(3-fluoro-4-methylbenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21.5 mg, 0.038 mmol, 84% yield) as clear oil: LCMS (m/z) ES+=561 (M+1). The intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with LiOH (0.100 mL, 0.200 mmol), and stirred overnight at 60° C. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (13.5 mg, 0.024 mmol, 64.7% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.36-7.29 (m, 0.4H), 7.12 (t, J=7.8 Hz, 1H), 7.04-6.87 (m, 3.6H), 6.80-6.66 (m, 1H), 5.97-5.59 (m, 3H), 5.46-5.40 (m, 0.4H), 5.21-5.11 (m, 0.6H), 4.27-4.10 (m, 2H), 3.71-3.61 (m, 3H), 2.77-2.58 (m, 2H), 2.27-2.19 (m, 3H), 2.16-2.05 (m, 2H), 2.02 (s, 2H), 1.94 (s, 1H), 1.19-1.11 (m, 6H), 1.05-0.99 (m, 3; LCMS (m/z) ES+=547 (M+1).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.C[O:12][C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[CH:20][NH:19][CH:18]=1)=[O:14]>ClC(Cl)C>[C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[C:20]([CH:3]=[O:4])[NH:19][CH:18]=1)([OH:12])=[O:14]
Reactant: COC(=O)CCc1c[nH]cc1C
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(CCC(=O)O)c[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 90.2 %

Procedure:
Dimethylformamide was charged to a 500 mL, 3 neck round bottom flask equipped with mechanical stirring, a thermometer, and a dropping funnel, and maintained under a nitrogen atmosphere. The flask was cooled to 0° C., and 58.4 mL of phosphorus oxychloride was added dropwise over 80 min. Dichloroethane (280 mL) was added, and the mixture was allowed to warm to room temperature, and then was cooled to −10° C. 3-(2-Methoxycarbonylethyl)-4-methylpyrrole (55.7 g) dissolved in 80 mL of dichloroethane was added dropwise over 1 hr, and the mixture stirred for another 35 min. The mixture was rotary evaporated at <30° C. The fluid residue was poured into 2700 mL of ice-cold 2 N sodium hydroxide solution. The resulting solution was heated to 88° C. over 20 minutes and then was maintained at this temperature for an additional 30 minutes. The solution was cooled to ambient temperature and was extracted with 200 mL of ethyl ether. The aqueous solution was cooled to 0° C. and was acidified to pH 3.5 by slowly adding about 1350 mL of 5 N hydrochloric acid. The yellow precipitate was collected by vacuum filtration, was washed four times with 100 mL of water each time, and was dried in a vacuum oven at ambient temperature to give 54.4 g (90.2% yield) of crude 4-(2-carboxyethyl)-2-formyl-3-methylpyrrole.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Yield: 89.2 %

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (0.56 g, 2.3 mmol) prepared above in 5 mL of dichlormethane was added triethyl amine (1.6 mL, 2.7 mmol) followed by 4-(dimethyl amino)pyridine (2.8 mg, 0.23 mmol) and p-toluene sulfonyl chloride (0.52 g, 2.7 mmol). After 1 hr the reaction was quenched with a saturated aqueous solution of NaHCO3. The reaction was diluted and extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 40 g ISCO column, eluting with a gradient of 4%, 6%, and 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrate under reduced pressure to give the title compound (0.82 g, 93% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>O>[CH2:24]([O:31][C:32]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1C(=O)C2(CCN(Cc3ccccc3)CC2)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 15.1 g of 1'-benzyl-1-methyl-2-oxoindoline-3-spiro-4'-piperidine, 33.5 g of benzyloxycarbonyl chloride and 530 ml of toluene was refluxed for 6 hours. The resulting mixture was poured into water and extracted with ethylacetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thus obtained oil was washed with n-hexane to give 1'-benzyloxycarbonyl-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)SC)#[N:2].[CH2:17]([NH2:20])[C:18]#[CH:19]>CO>[C:1]([NH:3][C:4]([NH:20][CH2:17][C:18]#[CH:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1nccs1)NC#N
Solvent: CO
Product: C#CCNC(=NCCSCc1nccs1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(thiazol-2-yl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in U.S. Pat. No. 3,950,333] (4.40 g, 16.1 mmole) and propargylamine (8.8 ml) in methanol (35 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 16 hours. The reaction mixture was evaporated under reduced pressure, the residue dissolved in warm isopropanol, and then cooled and filtered to yield 2.26 g of product. Recrystallization from isopropanol with Darco treatment gave the title compound; mp 137.5°-139.5°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cc(F)ccc2c(=O)n1-c1ccccc1Cl
Yield: 43.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2c (100 mg, 0.310 mmol), adenine (46 mg, 0.340 mmol), K2CO3 (47 mg, 0.340 mmol), and DMF (1 mL). The crude product was recrystallized from EtOH to provide 57 mg of a beige solid (44%), mp 216.8-217.2° C. 1H NMR (DMSO-d6) δ: 8.22 (dd, J=6.3, 8.7 Hz, 1H); 8.05 (s. 1H); 8.03 (s, 1H); 7.78-7.80 (m, 2H); 7.61-7.64 (m, 2H); 7.46 (dt, J=2.1, 8.6 Hz, 1H); 7.32 (d, J=9.8 Hz, 1H); 7.22 (s, 2H); 5.13 (d, J=17 Hz, 1H); 4.95 (d, J=17 Hz, 1H). 13C NMR (DMSOd6) ppm: 166.1 (d, J=253 Hz), 159.6, 155.8, 152.5, 149.7, 148.6 (d, J=14 Hz), 141.4, 132.8, 131.8, 131.6, 130.8, 130.5, 129.8 (d, J=11 Hz), 129.0, 118.1, 117.4, 116.2 (d, J=24 Hz), 112.7 (d, J=22 Hz), 44.6. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O.0.1H2O(0.15KCl: C, 55.25; H, 3.06; Cl, 9.38; N, 22.55. Found: C, 55.13; H, 2.92; Cl, 9.12; N, 22.30.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCCc1ccccc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCCc3ccccc3)C2)cc1

Procedure:
Phenethyl(1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and phenethyl carbonochloridate (52.9 mg, 0.18 mmol) according to General Procedure H to give 60 mg (80.4%) of pale yellow solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (d, J=9 Hz, 2H), 7.24 (m, 5H), 6.98 (d, J=7 Hz, 3H), 4.13 (t, J=6.8 Hz, 2H), 3.89 (d, J=12.6 Hz, 1H), 3.76 (d, J=12.5 Hz, 1H), 3.05 (bs, 1H), 2.82 (m, 3H), 1.90 (m, 1H), 1.80 (m, 2H), 1.68 (m, 1H), 1.61 (m, 2H), 1.46 (m, 1H), 1.18-1.2 (m, 4H), 1.01 (m, 1H).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39](OC)=[O:40])=[CH:35][N:34]=1>C1(C)C=CC=CC=1>[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:40])=[CH:35][N:34]=1
Reactant: COC(=O)c1cnc(N2CCN3CCCCC3C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.45 mL, 2.90 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (286 mg, 1.16 mmol) and methyl 2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate (320 mg, 1.16 mmol) in toluene (5.8 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution, until a freely stirred solution was obtained). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (238 mg, 42%) as a solid.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([O:59][CH3:60])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([O:59][CH3:60])=[C:54]([NH:55][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Yield: 27.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-methoxyaniline (26.1 g, 64.7 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.8 g, 64.7 mmol) the title compound of Step C was obtained (10.2 g, 27.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=5.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.38-7.45 (m, 1H), 7.15-7.30 (m, 4H), 6.40 (d, J=5.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.50-3.61 (m, 4H), 3.18 (s, 3H). MS (ES+): 580 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][OH:15].[C:21]1([S+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][O:15][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1.[C:34]1([S+:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)([O-])C(F)(F)CO
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Under ice cooling, 2.0 g (12 mmol) of the 4-vinylbenzoyl chloride in methylene chloride was added dropwise to a mixture of 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate in Synthesis Example 1-13, 1.21 g (12 mmol) of triethylamine, 0.24 g (2 mmol) of N,N-dimethylaminopyridine, and 20 g of methylene chloride. The resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, which was washed with dilute aqueous ammonia and then with water. Thereafter, methyl isobutyl ketone was distilled off in vacuum. Diisopropyl ether was added to the residue. By decantation, the target compound, triphenylsulfonium 1,1-difluoro-2-(4-vinyl-benzoyloxy)-ethane-1-sulfonate was obtained. Colorless oil, 5.1 g (yield 86%). The compound has the following structure.