Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9].CN(C)C1C=CC=CC=1.[Br:31][CH2:32][C:33](Br)=[O:34].[Cl-].[NH4+]>ClCCl>[Br:31][CH2:32][C:33]([NH:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9])=[O:34]
Reactant: O=C(Br)CBr
Reactant: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1NC(=O)CBr
Yield: 78 %

Procedure:
To a solution of 3-amino-2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthiopyridine (synthesized by the method disclosed in Example 30 in WO96/26925) (1.50 g, 4.35 mmol) in dichloromethane (30 ml) were added N,N-dimethylaniline (0.63 g, 5.22 mmol) and bromoacetyl bromide (1.05 g, 5.22 mmol) with ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was mixed with a saturated ammonium chloride solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 100 g, developing solvent; hexane:ethyl acetate=3:1) to provide 1.57 g (yield 78%) of 2-bromo-N-[2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthio-3-pyridyl]acetamide as colorless powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(C)cc3C)nc12

Procedure:
From 2,4-dimethylbenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+7.4° (c=0.77, CHCl3), ES-MS m/e (%): 399 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11]SCCN)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCS
Reaction time: 0.67 h
Yield: 106.4 %

Procedure:
A solution of bis N-(t-butyloxycarbonyl)-cystamine (77.37 g, 0.220 mole) from Example 1, in 1 L of ethanol was treated with NaBH4 (32.5 g, 0.859 mmole). Vigorous gas evolution ensued and subsided in 40 minutes. The reaction was stirred for an additional half hour and was poured into 2.5 L of a cold dilute solution of citric acid (pH 6). The mixture was then extracted with 3×1 L of chloroform. The combined organic extracts were dried with MgSO4 and the solvents were removed under reduced pressure. The resulting residue was distilled (66°-73° C. 0.25 torr) to obtain the product (41.5 g, 53% yield).
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[ClH:1].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]2[N:3]3[C:8]4[C:9](=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH2:4]3)[C:16]=2[CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: NN1CCOc2ccccc21
Agent: Cl
Product: CN1CCc2c(c3cccc4c3n2CCO4)C1

Procedure:
By a procedure similar to Example 110, 4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with 1-methyl-4-piperidone to yield the title compound, m.p. 245°-246°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[OH:19].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:21]
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 4a (0.56 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:26]=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH:37]([C:42]([F:45])([F:44])[F:43])[CH2:38][C:39](Cl)=[O:40].C(N(CC)C(C)C)(C)C>CN(C)C=O.ClCCl>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:39](=[O:40])[CH2:38][CH:37]([N:28]3[C:29](=[O:36])[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27]3=[O:26])[C:42]([F:45])([F:44])[F:43])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N3C(=O)c4ccccc4C3=O)C(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.565 mmol, prepared in analogy to the one in Example 2-1) in N,N-dimethylformamide (6 mL) was added a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoyl chloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed by N,N-diisopropylethylamine (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour and heated at 85° C. for additional 2 hours. After being cooled to room temperature, the resulting mixture was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford 230 mg of the product as a solid (yield was 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[N:33](C(OCC)=O)[CH2:34][CH2:35][N:36]=1.C([O-])(O)=O.[Na+]>CCO>[NH:36]1[CH2:35][CH2:34][N:33]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN=C1SC
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of N-(4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl)acetamide (150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate (78.9 mg), ACOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (17.9 mg) as an off-white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
N-(tert-butoxycarbonyl)-isonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. (ice-bath). Borane-tetrahydrofuran complex (1M, 25 mL, 25 mmol) was added slowly over 30 min. The reaction mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The reaction mixture was extracted into ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 hexane:ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2H), 1.42 (s, 9H), 1.67 (m, 4H), 2.67 (t, 2H), 3.46 (d, 2H), 4.09 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1)#[CH:13]>>[C:14]1([C:12]#[C:13][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: C#CC1=CCCCC1
Reactant: Brc1ccc2ccccc2c1
Product: C(#Cc1ccc2ccccc2c1)C1=CCCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 99 %

Procedure:
Following the general procedure using 2-bromonaphthalene (103 mg, 0.50 mmol) and 1-ethynylcyclohex-1-ene (100 μL, 0.85 mmol), the reaction was stirred for 21 h at rt. Column chromatography on silica gel (eluting with 1% EtOAc/hexanes) afforded the product as an off-white solid (115 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25]Cl)[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:5][C:4]=2[N:3]=1.[OH:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46].C(N(CC)CC)C.ClCCl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:35][N:36]3[C:40](=[O:41])[C:39]4[C:38](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:37]3=[O:46])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
A solution of tert-butyl 2-[4-amino-7-(benzyloxy)-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (2.70 g, 5.60 mmol) in DMF (10 mL) was added to a stirred solution of N-hydroxyphthalimide (1.10 g, 6.72 mmol) and triethylamine (1.56 mL, 11.2 mmol) in DMF (10 mL) at room temperature. A solid formed after 10 minutes. After 1.5 hours, dichloromethane (50 mL) was added and the solid was isolated by filtration, washed with dichloromethane followed by diethyl ether, and dried under vacuum to yield 3.15 g of tert-butyl 2-(4-amino-7-(benzyloxy)-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate as an off-white solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([C:63]([F:66])([F:65])[F:64])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([C:63]([F:66])([F:65])[F:64])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)(F)F)[nH]c54)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)(F)F)[nH]c54)c3=O)cc2)CCC1
Yield: 80 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(6-oxo-8-phenyl-2-trifluoromethyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow solid (25 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, J=9.0 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.50-7.47 (m, 2H), 7.45-7.31 (m, 7H), 2.65-2.56 (m, 2H), 2.53-2.44 (m, 2H), 2.21-2.09 (m, 1H), 1.88-1.76 (m, 1H). LCMS (Method E): RT=3.43 min, [M+H]+=476.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C.[OH-].[Na+].O>[CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5]
Reactant: CON=C(C)C1CCC(C)=CC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CONC(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone O-methyl-oxime (135 g; 0.69 mol), prepared as described in example P5, in acetic acid (650 ml) was added portionwise sodium cyanoborohydride (67 g; 1.04 mol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen atmosphere. Most of acetic acid was removed under reduced pressure. The yellow sticky oil obtained was poured in 2M sodium hydroxide (800 ml) and water (100 ml). The solution was extracted with dichloromethane (3×300 ml). Combined organic layers were washed with sodium bicarbonate (500 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 128 g (94% of theory) of O-methyl-N-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-hydroxylamine (mixture of two diastereomers) as a cloudy yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:11][O:10]1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13]
Reactant: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, 0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) and potassium carbonate (5.96 g, 0.043 mol) were added, followed by stirring at 60° C. for 2 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.5 g, yield: 25%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:5][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[O:3][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)=[CH:5][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1
Reactant: CCOC(=O)c1cnn(Cc2cc(-c3cccc(C(F)(F)F)c3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(C(F)(F)F)c2)cc1Cn1cc(C(=O)O)cn1
Yield: 77.1 %

Procedure:
The compound (0.35 g) obtained in Example 127c was dissolved in ethanol (3 mL), and 6N aqueous sodium hydroxide solution (0.77 mL) was added. The reaction mixture was heated under reflux for 2 hr, cooled in an ice bath, adjusted to pH 2 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, eluent: dichloromethane/methanol) to give the title compound (0.25 g) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: COCCn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (67 mg, 75%) as a colorless gum: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C22H28N4O4S (M+H)+ 445.1904, observed 445.1904; 1H NMR (300 MHz, DMSO-d6) δ 1.12 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.12 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.36 (s, 3H, SO2CH3), 3.61 (t, J=5.3 Hz, 2 H, OCH2), 3.89 (m, 1H, ArCHCO), 4.12 (t, J=5.3 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.11 (d, Jm=1.6 Hz, 1H, Ar), 8.11 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@H]1COCCO1
Agent: Cl
Product: O=C(C[C@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (107 mg, 93%), MS (ISP) m/z=459.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-[1,4]dioxan-2-yl-acetic acid.
Reaction SMILES: [OH-].[K+].[CH2:3]([NH:7][C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH3:6].[OH:20][CH2:21][CH:22](CO)[OH:23]>>[OH:20][CH:21]([CH2:22][OH:23])[CH2:15][O:14][C:12]1[CH:13]=[C:8]([NH:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]=1[OH:16]
Reactant: OCC(O)CO
Reactant: CCCCNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: CCCCNc1cc(OCC(O)CO)c(O)cc1[N+](=O)[O-]

Procedure:
0.128 mol (8.5 g) of 85% pure potassium hydroxide pellets is dissolved in 70 ml of double-distilled glycerol on a boiling water bath. 2-n-butylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 4, is added with stirring.