Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:16][CH3:17])=[S:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:20]([CH:22]=[O:23])=[O:21].NC(N)=S>COCCOC.C(N(CC)CC)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([N:13]2[CH:20]([OH:21])[CH:22]([OH:23])[N:16]([CH3:17])[C:14]2=[S:15])[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:8]=1
Reactant: O=CC=O
Reactant: CNC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(N)=S
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CN1C(=S)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(O)C1O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
30.0 g of N-(3,5-bis-trifluoromethyl-phenyl)-N'-methyl-thiourea were stirred in 100 ml of 1,2-dimethoxyethane and 10 ml of triethylamine, and then 22 g of a 30% strength aqueous glyoxal solution were added. The thiourea thereupon dissolved, the reaction being exothermic. The solution was stirred for a further 12 hours at 20° C. and was concentrated in vacuo and the residue was stirred with water and a little acetic acid. The reaction product, which had solidified, was filtered off, washed and dried. Yield 32.0 g; melting point: 133°-135° C. after recrystallisation from toluene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[C:19](OCC)(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCO
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 145 °C
Yield: 48.7 %

Procedure:
A mixture of 22.1 g (0.09 mol) of N-(6-hydroxyhexyl) phthalimide and 10.2 g (0.08 mol) of ethyl acetoacetate was heated in an oil bath at 145° C. under nitrogen for 15 hours. After drying on high vacuum the residue was subjected to flash chromatography (silica gel, 7:3 petroleum ether/ether). The product was isolated as 12.9 g (75%) of a pale yellow oil b.p. 218°-226° C./0.15 mm. NMR: (CDCl3) w 1.5 (8H, m), 2.21 (3H, s), 3.35 (2H, s), 3.55 (2H, m), 3.99 (2H, t), 7.5 (4H, m).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)C[NH3+]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of 2-(tert-butoxy)-2-oxoethanaminium chloride (3.00 g, 17.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (20 mL) was stirred at room temperature for 2 min. To the reaction mixture was added 4-(bromomethyl)benzonitrile (3.19 g, 16.3 mmol) and stirring continued for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The combined organic extract was dried over MgSO4 then concentrated. Purification of the crude product by a silica gel column (DCM/MeOH) gave 2.77 g (68%) of tert-butyl 2-((4-cyanobenzyl)amino)acetate INT-31 as a yellow oil. LCMS-ESI (m/z) calculated for C14H18N2O2: 246; found 247 [M+H]+, tR=0.92 min (Method 3).
Reaction SMILES: C(CS[C:6]1[N:7]=[N:8][C:9]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]3)=[C:10]([CH3:12])[N:11]=1)(O)=O.[OH-:25].[K+].[I-].[K+].[CH2:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[CH3:23][N:19]1[C:20]2[C:15](=[CH:14][C:13]([C:9]3[C:10]([CH3:12])=[N:11][C:6](=[O:25])[N:7]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:8]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:24]
Reactant: ClCc1ccccc1
Reactant: [OH-]
Reactant: Cc1nc(SCC(=O)O)nnc1-c1ccc2c(c1)CCC(=O)N2C
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: Cc1nc(=O)n(Cc2ccccc2)nc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
A solution of 3-carboxymethylthio-5-methyl-6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazine (7.25 g) in a mixture of 10% aqueous solution of potassium hydroxide (47 ml) and methanol (47 ml) was heated at 60° for 4 hours with stirring. To the mixture were added potassium iodide (0.5 g), benzyl chloride (5.33 g), and methanol (150 ml), refluxed for 8 hours with stirring, and evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (300 g) with ethyl acetate as an eluent to give 6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-benzyl-5-methyl-1,2,4-triazin-3(2H)-one (4.47 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OC)c(OC)c(OC)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCOc1cc(OC)c(OC)c(OC)c1OC
Temperature: 45 °C

Procedure:
11.5 g of 2-methoxymethyloxy-4,5,6-trimethoxyphenol prepared in Referential Example 12 and 23.0 g of potassium carbonate were suspended in 100 ml of DMF. The suspension was heated at 45° C. while stirring, and 5.2 ml of iodomethane was dropwise added thereto. After the completion of the dropwise addition, the mixture was heated for 30 min, cooled and separated by filtration. 1 l of water was added to the mother liquor, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate=85 : 15) to prepare 6.2 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1
Reactant: CC(=O)c1cc(Br)ccc1Cl
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)ccc1Cl
Temperature: 170 °C
Yield: 61.5 %

Procedure:
Sodium hydroxide (0.39 g, 9.6 mmol) and hydrazine monohydrate (0.56 mL, 11.5 mmol) were added to a solution of 1-(5-Bromo-2-chloro-phenyl)-ethanone (0.9 g, 3.85 mmol) dissolved in triethylene glycol (5 mL). The reaction mixture was heated to 170° C. for 24 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound (0.52 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.23 (t, J=7.6 Hz, 3 H), 2.72 (q, J=7.6 Hz, 2 H), 7.19 (d, J=8.6 Hz, 1 H), 7.25 (dd, J=8.3, 2.3 Hz, 1 H), 7.36 (d, J=2.5 Hz, 1 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:17]([CH2:18][S:19][C:20]2[CH2:24][C:23]([CH3:26])([CH3:25])[O:22][N:21]=2)=[C:16]([Cl:27])[N:15]([CH2:28][CH3:29])[N:14]=1.[OH2:30]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:17]([CH2:18][S:19]([C:20]2[CH2:24][C:23]([CH3:25])([CH3:26])[O:22][N:21]=2)(=[O:9])=[O:30])=[C:16]([Cl:27])[N:15]([CH2:28][CH3:29])[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: CCn1nc(Cl)c(CSC2=NOC(C)(C)C2)c1Cl
Solvent: ClC(Cl)Cl
Product: CCn1nc(Cl)c(CS(=O)(=O)C2=NOC(C)(C)C2)c1Cl
Reaction time: 1 h
Yield: 46.6 %

Procedure:
2.0 g of m-chloroperbenzoic acid (purity: 70%, 11.6 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.6 mmoles) of 3-(3,5-dichloro-1-ethyl1H-pyrazol-4ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.41 g (yield: 46.6%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 105.0 to 107.0° C.)
Reaction SMILES: CC1C=CC(C)=CC=1C(CC#N)=O.COC(OC)(OC)CCC.C(OC(=O)C)(=O)C.[C:31]([C:33]([C:40](=[O:49])[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[CH3:48])=[CH:34][CH:35](OC)[CH2:36][CH3:37])#[N:32].C(N(CC)CC)C.[Cl:57][C:58]1[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[C:60]([Cl:68])[C:59]=1[NH:69][NH2:70]>C(OCC)(=O)C>[NH2:32][C:31]1[N:69]([C:59]2[C:60]([Cl:68])=[CH:61][C:62]([C:64]([F:65])([F:66])[F:67])=[CH:63][C:58]=2[Cl:57])[N:70]=[C:34]([CH2:35][CH2:36][CH3:37])[C:33]=1[C:40](=[O:49])[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[CH3:48]
Reactant: CCC(C=C(C#N)C(=O)c1cc(C)ccc1C)OC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(C)c(C(=O)CC#N)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(C)ccc1C

Procedure:
A solution of 0.52 g (3.0 mmol) of 2,5-dimethylbenzoylacetonitrile, 0.45 g (3.0 mmol) of trimethylorthobutyrate and 0.632 g (0.58 mL, 6.2 mmol) of acetic anhydride in 5.0 mL of ethyl acetate was refluxed overnight and then cooled. The solvents were removed in vacuo and the residues were dissolved in 10 mL of ethanol. One-half of this solution, containing 1.5 mmol of 1-cyano-1-(2,5-dimethylbenzoyl)-3-methoxy-1-pentene was mixed with 0.7 mL (0.51 g, 5.0 mmol) of triethylamine and 0.37 g (1.50 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and refluxed for 2.5 hours. The reaction mixture was cooled and partitioned between dilute hydrogen chloride and ethyl acetate. The organic phase was washed with water and then dried with brine and with magnesium sulfate. The solvent was evaporated to give an oil which was chromatographed on silica gel by the flash method eluting with 4:1 hexane/ethyl acetate to give the title compound as an amorphous foam. Anal. Calcd. for C22H20ON3Cl2F3, 469.0935. Found: 469.0889.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:4]=2[O:3]1.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:15][CH3:14])[C:4]=2[O:3]1
Reactant: CN
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2c1OC(C)(C)C2
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbaldehyde (281 mg, 1.59 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.63 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (61.5 mg, 1.63 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (303 mg, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.02 (m, 2H), 6.76-6.71 (m, 1H), 3.52 (s, 2H), 2.97 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22].Cl>C(Cl)(Cl)Cl>[Cl:26][CH2:25][CH2:24][O:23][C:21]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:22]
Reactant: O=C(Cl)OCCCl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OCCCl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (5.00 g) obtained in Reference Example 2(1) is dissolved in chloroform (60 ml), and thereto is added triethylamine (11 ml) under ice-cooling, followed by dropwise addition of a solution of 2-chloroethyl chloroformate (3.3 ml) in chloroform (10 ml). After stirring at room temperature for 2.5 hours, to the reaction solution is added 5% hydrochloric acid and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and then evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in chloroform/diisopropyl ether. The precipitates are collected by filtration and dried to give methyl trans-4-{[(2-chloroethoxy)carbonyl]amino}cyclohexanecarboxylate (5.11 g). APCI-MS M/Z:264/266[M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=2)[C:20](=[O:34])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:19][C:20]2=[O:34])=[CH:27][CH:28]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Reactant: CNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(CCn2ccc(OCc3ccccc3)cc2=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 49 mg (0.38 mmol) methyl-carbamic acid tert-butyl ester in 4.0 mL THF is added at RT 48 mg (0.43 mmol) potassium-tert-butylate. The reaction mixture is stirred 20 min at RT and then 100 mg (0.25 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 1.1a) is added. The mixture is stirred additional 1 h at RT and is diluted with EtOAc and water. The layers are separated and the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:19]=[CH:20][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:12]([O:14][CH3:15])=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (1.28 g) in N,N-dimethylformamide (14 mL) were added potassium carbonate (0.98 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into water, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29](C)([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(Oc1cnc(-c2ccc(S(C)(=O)=O)cc2)cn1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(C(C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1

Procedure:
The title compound (0.21 g, 98%) was prepared as a white foam from (±)-1,1-dimethylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (Example 160, 0.22 g, 0.48 mmol) and TFA (0.37 mL) in CH2Cl2 (16 mL) then diisopropylethylamine (1.25 mL) and isopropyl chloroformate (1.0M in toluene, 0.57 mL, 0.57 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to afford (±)-1-methylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=1.0 Hz), 8.24 (d, 1H, J=1.2 Hz), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.6 Hz), 5.15-5.05 (m, 1H), 4.89 (septet, 1H, J=6.3 Hz), 4.30-4.15 (m, 2H), 3.07 (s, 3H), 2.75-2.65 (m, 2H), 1.85-1.65 (m, 3H), 1.40-1.25 (m, 5H), 1.22 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:10][CH:11]([NH:20][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(C)N
Reactant: COc1cc(Cl)ncn1
Product: CCCCCCCCC(C)Nc1cc(OC)ncn1
Yield: 60.3 %

Procedure:
7.2 g (0.05 mol ) of 4-chloro-6-methoxypyrimidine and 15.7 g (0.1 mol) of 2-decylamine were heated at 100° C. for 2 hours. The mixture was worked up using a water/methylene chloride mixture, and purification by chromatography (silica gel/ethyl acetate) gave 8.0 g (58.8% of theory) of 4-(2-decylamino)-6-methoxypyrimidine in the form of a yellow oil.
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH3:19]>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([CH3:10])[C:16]=1[CH3:17])=[O:9]
Reactant: COc1cccc(C)c1C
Reactant: O=C(O)c1cccs1
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccs2)c(C)c1C
Yield: 86 %

Procedure:
This compound was prepared in 86% yield by using step (A) of Example 1 with the chloride of 2-thiophene carboxylic acid and 2,3-dimethyl anisole.
Reaction SMILES: N1C=CN=C1.[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([OH:22])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C)C=O>[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([O:22][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Imidazole (203.7 gm, 2.28 mol) was added to a stirred suspension of 3-acetoxy-pregn-5-en-20-ol (361 gm, 1 mol, product of Step 1) in dimethylformamide (3.7 L). t-Butyldimethylsilyl chloride (228.9 mg, 1.52 mol) was added over a 10-15 min period. The mixture was stirred at room temperature for 3 days. The dimethylformamide was removed by decantation and methanol (50 mL) was added to it. Water (4 L) was added and the solution extracted with ethyl acetate (2×4 L). The precipitate remaining behind after decantation was dissolved in ethyl acetate and added to the above ethyl acetate extracts. The combined solvent extracts were washed with water, saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was removed by rotoevaporation and the product purified by column chromatography on silica gel eluted with 2:1 hexane-methylene chloride followed by 1:1 hexane-methylene chloride. The title compound was isolated as a mixture of 20α- and β-isomers.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]2[N:45]=[C:44]([CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][C:55]([OH:57])=O)[C:43]([C:58]([F:61])([F:60])[F:59])=[CH:42][N:41]=2)=[CH:35][CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1>[NH2:7][C:55](=[O:57])[CH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][CH2:46][C:44]1[C:43]([C:58]([F:60])([F:59])[F:61])=[CH:42][N:41]=[C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:34][CH:35]=2)[N:45]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HOBt (76 mg, 0.56 mmol) and EDCl.HCl (108 mg, 0.561 mmol) were added to a solution of 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A15) (251 mg, 0.468 mmol) and DIPEA (326 μL, 1.87 mmol) in DMF (2 mL) and THF (10 mL). The resulting mixture was stirred at room temperature overnight then the volatiles were removed in vacuo and the residue partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated and the organic layer was washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo and the residue adsorbed onto silica gel and purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A16 as a tan solid (0.22 g, 89%); 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 8.67 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.27-7.10 (m, 6H), 6.91 (s, 1H), 3.50 (s, 2H), 3.18 (d, J=5.3 Hz, 2H), 3.14-2.99 (m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.086 min; m/z 530 [M+H]+.