Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]([S:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14].CI.Cl>O1CCCC1>[CH:13]([S:16][CH:17]([CH3:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CSC(C)C
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
A solution of diisopropylamine (15.4 mL, 0.11 mol) in tetrahydrofuran is cooled to 0° C., treated dropwise with a 2.04 M solution of n-butyllithium in tetrahydro-furan (51.4 mL, 0.105 mol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl (isopropylthio)acetate (16.3 g, 0.1 mol), stirred at 0° C. for 1 hour, treated with methyl iodide (15.6 g, 0.11 mol), stirred at room temperature for 20 hours, and poured into an ice-water mixture (100 g) containing 15 mL of 6 N hydrochloric acid. The resulting aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water, saturated sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown solution. Vacuum distillation of the brown solution gives the title product as a liquid (10.0 g) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)ccc1Br

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-bromo-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 262-264° C.). MS(ES+) m/z 356 (M+, 100).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 85 °C
Yield: 64 %

Procedure:
A mixture of tert-butyl (1R,2S)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (60 mg, 0.109 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.164 mmol) and bis(triphenylphosphine)palladium chloride (15 mg, 0.022 mmol) in DME (1 mL) was placed in a vial. The vial was purged with nitrogen and aqueous sodium carbonate (2 N, 0.219 mL, 0.437 mmol) was added. The vial was sealed and the reaction mixture heated in an oil bath at 85° C. for 3 h. The reaction mixture was filtered through a pad of Celite, which was rinsed with MeOH and DCM. The solvent was removed in vacuo and the residue was diluted with DMSO and MeOH (1/1). The resulting mixture was filtered to recover a white precipitate (31.3 mg). The mother liquor was purified via preparative HPLC. The fractions were collected and dried in vacuo to recover an additional white solid (10.2 mg). The two crops were combined to give the title compound as a white solid (41.5 mg, 64%). [M+H] calc'd for C31H39FN6O5, 595; found, 595.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O.CCOC(C)=O>CC#N.O>[F:26][CH:17]([F:27])[O:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CSc1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc(OC(F)F)cn1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
To a stirring solution of 2-(methylthio)pyrimidin-5-ol (from step B) (71 mg, 0.50 mmol) in CH3CN (2.5 mL) and water (2.5 mL) at room temperature under argon was added K2CO3 (0.69 g, 5.0 mmol) and followed by 2-chloro-2,2-difluoro-1-phenylethanone (286 mg, 1.5 mmol). The reaction tube was sealed and heated at 80° C. for 5 hours. The reaction was cooled to room temperature. EtOAc (10 mL) was added to the reaction mixture, which was washed with brine (15 mL×3). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 23 mg (23% for three steps) of 5-(difluoromethoxy)-2-(methylthio)pyrimidine was obtained as an off white solid. MS (ESI) 193 (M+H).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]2[CH2:22][CH2:21][CH2:20][CH2:19][C:12]=2[C:13]=1[C:14](OCC)=[O:15])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:23][NH:24][CH3:25]>>[C:1]([NH:8][C:9]1[S:10][C:11]2[CH2:22][CH2:21][CH2:20][CH2:19][C:12]=2[C:13]=1[C:14]([N:24]([CH3:25])[CH3:23])=[O:15])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Nc1sc2c(c1C(=O)OCC)CCCC2
Reactant: CNC
Product: CCCCCC(=O)Nc1sc2c(c1C(=O)N(C)C)CCCC2

Procedure:
The product of Example 33 and dimethylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.88-0.96 (m, 4H), 1.29-1.41 (m, 4H), 1.54-1.72 (m, 3H), 1.73-1.91 (m, 3H), 2.33-2.42 (m, 4H), 2.63-2.71 (m, 2H), 2.92 (s, 3H), 3.05 (s, 3H); MS (DCI/NH3) m/z 323 (M+H)+; anal. calculated for C17H26N2O2S.0.75C8H17NO.0.3H2O: C, 63.46; H, 9.11; N, 8.85. Found: C, 63.15; H, 9.46; N, 8.66.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: NC1(C(=O)O)CCc2c(Br)cccc2C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NC1(C(=O)O)CCc2c(Br)cccc2C1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of racemic 5-bromo-2 aminotetraline-2-carboxylic acid (882 mg, 3.27 mmole), triethylamine (0.60 ml, 4.30 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.32 g, 3.91 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature overnight. TLC analysis of the reaction the next day indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (0.25 g), triethylamine (0.6 ml) and acetonitrile (5 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion extracted twice with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→10% methanol/methylene chloride) to give racemic Fmoc-5-bromo-2 aminotetraline-2-carboxylic acid (1.09 g, 68% yield) as a white solid. HRMS (FAB): C26H22BrNNaO4 (M+Na) calc. 514.0630; observed: 514.0643.
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[CH:11]=[C:10](C)[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].O.O.O.[C:29]([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH2:21]([NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:29])=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)[O-]
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Reactant: CCCCN
Agent: I
Agent: [Pb+2]
Solvent: CCO
Solvent: O
Product: CCCCNC(=Nc1ccc(C)cc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml) was stored at ambient temperature of 4 months. Lead acetate trihydrate (9 g) was then added and the mixture heated under reflux for one hour to yield 1-(n-butyl)-2-(4-methyl-2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 150° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25]CC1C=CC(OC)=CC=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (25.5 g, 33 mmol) in CH2Cl2 (400 mL) at room temperature, was added trifluoroacetic acid (40 mL). After 1 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5% MeOH in CH2Cl2), to give 19.8 g of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][CH2:5][O:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:2][C:3]2[CH2:4][CH2:5][O:6][CH2:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:17]=1[CH:18]=[O:19]
Reactant: BrCC1=C(c2ccccc2)COCC1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(O)cccc1OCC1=C(c2ccccc2)COCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (110 mg, 0.45 mmol) and 2,6-dihydroxybenzaldehyde (120 mg, 0.90 mmol) in DMF (3 mL) was added K2CO3 (120 mg, 0.90 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:1) to give 2-hydroxy-6-((5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (120 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 10.36 (s, 1H), 7.35 (m, 4H), 7.18 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.13 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.32 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 2.41 (m, 2H); MS (ESI) m/z 309.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (40 g, 0.26 mol), potassium carbonate (40 g, 0.29 mol) and cyclopentyl bromide (32 ml, 0.31 mol) in dimethylformamide (0.25 l) was heated under an argon atmosphere at 100° C. After 4 hours, additional cyclopentyl bromide (8.5 ml, 0.08 mol) was added and heating was continued for 4 hours. The mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic extract was washed with aqueous sodium carbonate and was dried (potassium carbonate). The solvent was removed in-vacuo and the residue was purified by flash chromatography, eluting with 2:1 hexanes/ether to provide a pale yellow oil (52 g, 89%)[may also be distilled at ˜0.02 mm Hg].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.Cl.[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[CH:10][CH:9]=1>O1CCOCC1.O.ClCCl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C@@H:18]2[CH2:21][O:22][C@@H:5]([CH2:4][CH2:3][CH2:2][OH:1])[O:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: OCC(CO)c1ccc(Cl)c2ccccc12
Reactant: C1=COCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Reaction time: 5 h

Procedure:
0.75 ml (10 mmol) of 2,3-dihydrofuran and then 0.25 ml of a concentrated aqueous hydrochloric acid solution (37%) are added to a solution of 1.18 g (5 mmol) of 2-(4-chloronaphthalen-1-yl)-1,3-propanediol in 10 ml of dioxane. The mixture is allowed to react overnight at ambient temperature and then 5 ml of water are added. The mixture is stirred for 5 hours and is then diluted in 25 ml of water and 50 ml of dichloromethane. The mixture is separated after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 70/30 and then 60/40 mixture of cyclohexane and ethyl acetate. After recrystallization from diisopropyl ether, 0.557 g of product is obtained, in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:40])[CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 85.5 %

Procedure:
Using 7-(2,5-difluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.094 mmol) obtained in step 5 and acetic acid (0.027 mL, 0.471 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.046 g, 84%) was obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.[CH:15](O)=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:1]([O:6][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCCCCCC=CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: C=CCCCCCCCCCOC(=O)C(=C)C
Yield: 51.2 %

Procedure:
Monomer synthesis. In a 3 neck round bottom flask, methacrylic acid (51.4 g, 0.515 mol) and benzene (60 ml) were combined. P-TSA (0.90 g, 2.6 mmol), hydroquinone (1.56 g, 13.6 mmol) and undecene-1-ol (25.8 g, 0.150 mol) were added into the flask and a Dean Stark adapter was attached. The reaction was heated at reflux overnight. The benzene was removed from the solution by rotary evaporation at reduced pressure and ether (200 ml) was added. NaHCO3 (50 g) was added to the ether solution to remove any excess methacrylic acid. The product was decanted from the NaHCO3 and washed with H2O (200 ml) 3 times, with 5% by weight NaHCO3 (200 ml) solution 3 times, and again with H2O (200 ml) 3 times. The product was dried over MgSO4 and the ether was removed by rotary evaporation. The product was distilled at 110° C. at 150 mTorr to yield 18.3 g (51% yield) of undec-10-enyl methacrylate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([O:6]/[N:7]=[C:8](/[C:14](=O)[CH2:15]Cl)\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:18].[C:19]([NH:22][C:23]([NH2:25])=[S:24])(=[O:21])[CH3:20].CN(C)C1C=CC=CC=1>C(O)C>[C:19]([NH:22][C:23]1[S:24][CH:15]=[C:14](/[C:8](=[N:7]/[O:6][CH:3]2[CH2:4][CH2:5][NH:1][C:2]2=[O:18])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:25]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)NC(N)=S
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)C(=O)CCl
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(C)=O)n1
Reaction time: 4 h
Yield: 49.9 %

Procedure:
2.77 g of ethyl (Z)-2-[(2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate and 1.2 g of acetylthiourea are added to 20 ml of ethanol, and 2.0 g of N,N-dimethylaniline are added thereto. The mixture is stirred at 20° to 30° C. for 4 hours. Then, the mixture is concentrated under reduced pressure to drynss. The residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropanol, and the crystals are collected by filtration. 1.7 g of ethyl (Z)-2-(2-acetamidothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)[CH3:4].[CH3:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:20]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH:12][C@@H:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[CH3:31])[CH2:8]1)[CH3:4]
Reactant: CC1COCCC1=O
Reactant: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N[C@@H]2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of (1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100.0 mg, 0.211 mmol), 3-methyltetrahydro-4H-pyran-4-one (72.3 mg, 0.634 mmol) and triethylamine (0.118 mL, 0.845 mmol) in dry methylene chloride (5 mL) was added sodium triacetoxyborohydride (134.3 mg, 0.634 mmol). After being stirred at room temperature under N2 overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organics were combined, dried over MgSO4, filtered, purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column) to give the desired product (34 mg, 34%). MS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.3.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][O:14][C:15](=[O:39])[CH2:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][C:19]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:39])[CH2:16][N:17]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][C:19]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)CNc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(Oc2ccccc2)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of chlorosulfonyl isocyanate (0.274 g, 1.93 mmol) in DCM (2 mL) is added dropwise a solution of t-butanol (0.143 g, 1.93 mmol) in 1 mL DCM. The solution is stirred at ambient temperature for 45 min. A solution of (2-benzyloxy-4-phenoxyphenylamino)acetic acid methyl ester (0.50 g, 1.38 mmol) and triethylamine (0.278 g, 2.75 mmol) in DCM (1 mL) is added dropwise. The mixture is stirred at ambient temperature for 30 min., then washed with Water. The organic phase is dried over Na2SO4 and the solvent removed under reduced pressure. The residual oil is purified by flash chromatography using DCM to elute N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-phenoxyphenyl)glycine methyl ester as an oil: 1H NMR (CDCl3) δ 7.50 (d, J=8.84 Hz, 1H), 7.34-7.23 (m, 8H), 7.08 (t, 1H), 6.92-6.88 (m, 2H), 6.50 (d, J=2.53 Hz, 1H), 6.43 (dd, J=11.12, 2.53 Hz, 1H), 5.22 (s, 2H), 5.01 (s, 2H), 3.62 (s, 3H), 1.36 (s, 9H); MS (M−H)−=541.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:33](OCC)=[O:34])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][Si](C(C)(C)C)(C)C)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].NC1C(C(OCC)=O)=NC(NC2C=CC=CC=2CO)=NC=1NC1C=CC=C[C:47]=1[O:52]C.[Si](Cl)(C(C)(C)C)(C)C.[NH:76]1C=CN=C1>C(Cl)Cl>[OH:25][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:5]1[N:6]=[C:7]2[C:2]([NH:1][C:47](=[O:52])[N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:3]([C:33]([NH2:76])=[O:34])[N:4]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO)nc(Nc2ccccc2OC)c1N
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO[Si](C)(C)C(C)(C)C)nc(Nc2ccccc2OC)c1N
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
Ethyl 5-amino-2-(2-((tert-butyldimethylsilyloxy)methyl)phenylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate. Ethyl 5-amino-2-(2-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.227 g, 0.555 mmol), tert-butyldimethylsilyl chloride (0.104 g, 0.693 mmol), imidazole (0.047 g, 0.693 mmol) were combined in methylene chloride (10 mL) and stirred for 16 h at room temperature. The solution was condensed under reduced pressure and purified using Biotage chromatography (0 to 100% EtOAc in hexanes) to afford the title compound (0.200 g, 69%). MS (ESI) m/z 524.7 [M+1]+.