Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([NH:17][C@H:18]([C:23](O)=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])(OC(C)(C)C)=O>>[ClH:1].[NH2:17][C@@H:18]([CH:19]([CH3:20])[CH2:21][CH3:22])[C:23]([N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1)=[O:24]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)N1CCC(F)(F)CC1

Procedure:
(S)-2-amino-1-(4,4-difluoro-piperidin-1-yl)-3-methyl-pentan-1-one hydrochloride was prepared from 4,4-difluoro-piperidine hydrochloride and Boc-(L)-isoleucine as described in Example 1 (mp 190-192° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:17]1([CH2:23][CH2:24][NH:25][CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCCC2NCCc1ccccc1

Procedure:
A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g), phenylethylamine (15.6 ml) and p-toluensulfonic acid (8.7 g) in 250 ml of toluene was refluxed with removal of water for twenty hours. The mixture was then treated with a dilute NaOH solution, and extracted with ethyl acetate (3x). The combined organics were washed with water and dried (saturated NaCl solution, MgSO4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[OH-].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:12](=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(C(=O)C(C)C)c2cc(OC)c(C)cc2Br)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To a solution of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (6.83 g) in DMSO (40 mL) was added powder KOH (2.68 g, 47.7 mmol) and 4-methoxybenzyl chloride (7.5 g, 47.7 mmol) under argon. The mixture was stirred at room temperature for 17 hours. Water (30 mL) was added and the mixture extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc/10:1 t0 3:1) to give 8.72 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide (90%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.00 (d, J=7.03 Hz, 3 H), 1.13 (d, J=6.45 Hz, 3 H), 2.17 (s, 3 H), 2.28 (m, 1 H), 3.48 (s, 3 H), 3.78 (s, 3 H), 3.84 (d, J=14.07 Hz, 1 H), 5.62 (d, J=14.07 Hz, 1 H), 6.06 (s, 1 H), 6.78–6.81 (m, 2 H), 7.10–7.13 (m, 2 H), 7.38 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C=O>[C:40]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]=[C:24]([C:22]([NH:21][C@@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]3[NH:14][C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)=[O:13])=[O:23])[S:25][C:26]=2[CH2:27]1)(=[O:42])[CH3:41]
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (100 mg) obtained in Example 34 was dissolved in N,N-dimethylformamide (3 mL), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue for partitioning the mixture. The resultant organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:3) to give the title compound (86 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.[C:32]([O:36][C:37]([C@@H:39]1[CH2:43][S:42][C@@H:41]([CH2:44]O)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:46]([OH:49])(=[S:48])[CH3:47]>C1COCC1>[C:46]([S:48][CH2:44][C@H:41]1[CH2:40][C@H:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:43][S:42]1)(=[O:49])[CH3:47]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@@H](CO)C1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1C[C@H](C(=O)OC(C)(C)C)CS1
Temperature: -20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of triphenylphosphine (391 mg) in THF (3 ml), azodicarboxylic acid diethylester (260 mg) dissolved in THF (1 ml) was added at -15°--10° C. under nitrogen atmosphere. To the mixture, trans-4-tert-butoxycarbonyl-2-hydroxymethyltetrahydrothiophene (compound No. 1-1, 150 mg) and thioacetic acid (114 mg) dissolved in THF (2 ml) were added at -20°--15° C., and the mixture was stirred for 1 hour at -20° C. and for 1 hour at room temperature. The mixture was concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 169 mg (82%) of the titled compound (compound No. 4-1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14]S[CH2:12][CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:27](S([O-])=O)([O-:30])(=O)=[O:28].[Na+].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][S:27](=[O:30])(=[O:28])[CH2:14][CH2:15]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(N2CCSCC2)c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)cc(N2CCS(=O)(=O)CC2)c1
Reaction time: 3 h

Procedure:
To a mixture of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine (239 mg, 0.83 mmol) in methylene chloride (10 ml) and methanol (5 drops) was added m-CPBA (409 mg, 1.83 mmol). After 1 hour methanol (10 drops) was added to enhance solubility. The mixture was stirred another 3 hours. Methylene chloride (25 ml) and a 10% solution of aqueous sodium metabisulfite (35 ml) were added and the material was shaken in a reparatory funnel. The organic phase was collected and washed consecutively with equal volumes of 5% aqueous sodium bicarbonate and then brine solution. The aqueous phases were back-extracted with methylene chloride (2×25 ml), the organic phases combined, dried (MgSO4), filtered and stripped to a crude residue. The material was loaded onto 2 preparative TLC plates, eluting with 40% ethyl acetate in hexanes. The product band was collected to afford 76 mg of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine 1,1-dioxide as a off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34].Br[C:42]1[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13]([C:42]3[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=3[CH3:48])[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34]
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c(OC)c1
Reactant: COc1nccc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)ccnc4OC)cc32)c(OC)c1

Procedure:
5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-methoxy-4-methylpyridine obtained in Preparation Example 37 (2) (55.6 mg), Pd(PPh3)4 (10.6 mg), cesium carbonate (179 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (30 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.C[O:14][B:15](OC)[O:16]C.Cl>C1COCC1>[CH3:7][C:4]1[S:3][C:2]([B:15]([OH:16])[OH:14])=[CH:6][CH:5]=1
Reactant: Cc1ccc(Br)s1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2-bromo-5-methylthiophene (2.5 g, 14.1 mmol) in THF (30 mL) was added n-BuLi (1.55 M solution in hexane, 10.0 mL, 15.5 mmol) at −78° C. under nitrogen, and the mixture was stirred for 1 hour. Trimethylborate (1.83 g, 17.6 mmol) was added to the mixture, and residue was allowed to warm up to room temperature overnight. The reaction mixture was cooled at 0° c and 2N HCl (10 mL) was added, and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo, to give the title compound (1.36 g).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N:13]1([CH2:19][CH2:20][O:21][C:22]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][C:23]=2[CH:24]=O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C[O-].[Li+]>CN(C=O)C.CO>[CH3:31][O:30][C:28]1[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23](/[CH:24]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[C:22]([O:21][CH2:20][CH2:19][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:29]=1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Reactant: COc1cc(OCCN2CCOCC2)c(C=O)cc1-c1cccs1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(C(N)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 4-acetyl-benzamide (Ex-92A, 0.25 g, 1.53 mmol) and 2-(2-morpholin-4-yl-ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.53 g, 1.53 mmol) in DMF (7 mL) and methanol (3 mL) was added lithium methoxide. The solution was allowed to stir at ambient temperature. The reaction was quenched with water after 2 hours. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NaHCO3, NH4Cl, brine, dried (Na2SO4) and concentrated. The residue was stirred in ethanol overnight to afford the title compound as a yellow solid (0.43 g, 57%), mp 183–184° C. 1H-NMR (CDCl3) δ 8.09–8.04 (m, 3H), 7.93 (d, J=8.3 Hz, 2H), 7.87 (s, 1H), 7.57 (d, J=15.7 Hz, 1H), 7.42 (d, J=3.9 Hz, 1H), 7.32 (d, 4.4 Hz, 1H), 7.11–7.08 (m, 1H), 6.55 (s, 1H), 6.25 (bs, 1H), 5.75 (bs, 1H), 4.25 (t, J=5.9 Hz, 2H), 3.98 (s, 3H), 3.71 (t, J=4.2 Hz, 4H), 2.92 (t, J=5.7 Hz, 2H), 2.59 (t, J=4.6 Hz, 4H). MS m/z=493 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (120 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B2) (204 mg, 1.3 equiv), DMF (1.4 ml) and DIPEA (0.183 ml, 3 equiv) was shaken at room temperature, then HATU (206 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 1.5 h. A further portion of Intermediate D5 (12 mg, 0.1 equiv) was added then shaking was continued for 2 days. Reverse phase HPLC (Preparative Method B) gave ethyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (173 mg).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([OH:9])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: ClCC1CO1
Product: CC(=O)OCC(O)CCl
Temperature: 65 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Epichlorohydrin (92.5 g, 1.0 mol) was dissolved in 61.2 g (1.0 mol) of glacial acetic acid and 0.35 g of ferric chloride was added. The mixture was stirred at 65° C. overnight. Another 0.35 g of ferric chloride was added and the mixture was stirred another day. It was then concentrated by evaporation under reduced pressure to obtain 153 g 3-chloro-2-hydroxypropyl acetate as an oil. A few crystals of p-toluenesulfonic acid were added and then 81.5 g (1.13 mol) of ethyl vinyl ether was added dropwise with stirring and cooling with an ice bath to keep the temperature below about 35° C. When the addition was complete, the mixture was stirred overnight at 40° C. The dark oily product was presumed to be 3-chloro-2-(1-ethoxyethoxy)propyl acetate. This oil was added dropwise with stirring to a mixture of 110 g (2.75 mol) of sodium hydroxide in 110 mL of water heated to 105° C. When the addition was complete, the mixture was heated at 105° C. with stirring for 4 hours. It was then cooled and poured into 500 mL of water. The resulting mixture was extracted with 2×500 mL of diethyl ether and the ethereal extract was washed with concentrated aqueous sodium chloride, dried over sodium sulfate, and concentrated by evaporation under reduced pressure at 30° C. to obtain a dark oil. This oil was distilled at 5 mm Hg (665 pascals) pressure. The 40 g portion boiling at 60-68° C., which was 3-(1-ethoxyethoxy)oxetane, was collected. This fraction was dissolved in 100 mL of methanol and 25 mg of p-toluenesulfonic acid was added with stirring at about 10° C. The mixture was stirred for 2 hours at ambient temperature and then 1.0 g of solid sodium bicarbonate was added with stirring. After 5 min, the mixture was filtered and concentrated by evaporation under reduce pressure. The colorless oil residue was distilled at 5 mm Hg (665 pascals) pressure and the 1.9 g fraction boiling at 50-56° C., which was the title compound, a colorless liquid, was collected.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[CH:6][C:4]=1[OH:5].[C:14]1([CH:20]2O[C:23](=[O:24])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:11][O:10][C:9]1[C:8]([OH:12])=[C:7]([CH3:13])[C:6]2[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23](=[O:24])[O:5][C:4]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(O)cc(C)c(O)c1OC
Reactant: O=C1CCC(c2ccccc2)O1
Product: COc1c(O)c(C)c2c(c1OC)OC(=O)CCC2c1ccccc1
Temperature: 0 °C
Yield: 18.6 %

Procedure:
An amount of 18.4 g of 2,3-dimethoxy-5-methylhydroquinone and 16.2 g of γ-phenyl-γ-butyrolactone was stirred in 150 ml of polyphosphoric acid at room temperature for 5 hours. The reaction mixture obtained was poured into ice-water and extracted with ether, and the ether extract was washed with water and then dried over magnesium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography/hexaneethyl acetate (2:1), and thus 6.10 g (18.6%) of the desired compound was obtained.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12](O)=[O:13].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12]([N:22]([O:23][CH3:24])[CH3:21])=[O:13]
Reactant: CNOC
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.082 mL, 7.81 mmol) was added to a stirred solution of 4,4,5,5,5-pentafluoropentanoic acid (1.00 g, 5.21 mmol), N,O-dimethylhydroxylamine hydrochloride (0.559 g, 5.73 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.998 g, 5.21 mmol) in dry DCM (5.35 mL) at 25° C. under N2. The reaction was stirred at 25° C. overnight. The reaction was diluted with CH2Cl2 (60 mL) and washed consecutively with 1N aq. HCl (2×), satd aq. NaHCO3, dried (Na2SO4) and concentrated in vacuo to give the desired product, as a colorless liquid. 1H NMR (500 MHz, CHCl3-d): δ 3.72 (s, 3H); 3.21 (s, 3H); 2.74 (t, J=7.8 Hz, 2H); 2.51-2.37 (m, 2H). m/z=236.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1.O>[CH2:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([CH3:14])[CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:9]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (2.9 g, 13.53 mmol) was dissolved in 70 mL of a 1:1 mixture of dioxane and H2O and NaHCO3 (4.55 g, 54.13 mmol) was added. To the resulting suspension benzyl chloroformate (2.2 ml, 14.2 mmol) was added slowly. After 2 hours the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated. The remaining oil was purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0-20% EtOAc) to give 3.6 g of (3R,5R)-3-tert-butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil (76% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:37][C@H:38]1[C@H:42]([CH3:43])OS(=O)(=O)[O:39]1.Cl>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C@H:42]([CH3:43])[C@@H:38]([OH:39])[CH3:37])[CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (23 g, 52 mmol) in anhydrous DMA (160 ml) was added sodium tert-butoxide (12 g, 0.12 mol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (12 g, 78 mmol) in anhydrous DMA (20 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (80 ml) and concentrated on a rotary evaporator. To this residue was added anhydrous THF (0.12 L) and 5N HCl (0.14 L) and stirred at 60° C. for 80 min. The mixture was diluted with ethyl acetate and washed with water, satd NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (1:2, dichloromethane:ethyl acetate) to give an atropisomeric mixture of the title compound (14.3 g, 52%) as a pale yellow solid.
Reaction SMILES: C([C:4]1[C:9]2[N:10]=[N:11][S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=O.B(OCC)(OCC)[O:14][CH2:15]C.CO>O1CCCC1>[OH:14][CH2:15][C:7]1[C:8]2[S:12][N:11]=[N:10][C:9]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2snnc12
Reactant: CCOB(OCC)OCC
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cccc2nnsc12

Procedure:
To a suspension of 54 g of carboxybenzo-1,2,3-thiadiazole in 420 ml of tetrahydrofuran there are added dropwise under a nitrogen atmosphere with stirring at room temperature 110 ml of triethyl borate, the mixture is stirred for a further hour and subsequently treated dropwise with 45.6 ml of boranedimethyl sulfide complex in 60 ml of tetrahydrofuran, with gentle cooling, during which process gas is evolved vigorously. The mixture is stirred overnight and allowed to stand at room temperature and then cooled down to 5°-10° C. and treated dropwise with 200 ml of methanol with stirring and vigorous cooling, during which process gas is again evolved vigorously. The mixture is subsequently evaporated in vacuo, a further 300 ml of methanol are added, and the mixture is re-evaporated. The residue is purified on silica gel (solvent: ethyl acetate/hexane), and the product obtained is recrystallised from ethyl acetate/hexane. The title compound obtained melts at 79°-81° C.