Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=[N:8][S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].[CH2:15]([Mg]Br)[CH3:16].C(=O)([O-])O.[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@@H:7]([NH:8][S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH2:15][CH3:16].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@H:7]([NH:8][S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH2:15][CH3:16]
Reactant: CC(C)(C)[S@](=O)N=Cc1ncccn1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Product: CC[C@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-pyrimidin-2-yl-methylideneamide (18.2 g, 86.1 mmol) in dry tetrahydrofuran at −78° C. was added a 1.0 M solution of ethylmagnesium bromide in tetrahydrofuran (95 ml, 95 mmol) and the mixture was stirred at −78° C. for 45 min. 120 ml of aqueous sodium hydrogencarbonate was added, the mixture was extracted 3 times with dichloromethane (200 ml) and after evaporation of all solvents the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 1.47 g of (S)-2-methyl-propane-2-sulfinic acid ((S)-1-pyrimidin-2-yl-propyl)-amide (LC/MS (method 5): Rt=2.99 min; m/z=242.21 (M+H+)) and 2.6 g of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-pyrimidin-2-yl-propyl)-amide (LC/MS (method 2): Rt=0.97 min; m/z=242.07 (M+H+)).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[S:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C([Li])CCC.CCCCCC.[Cl:31][C:32]1[CH:43]=[CH:42][C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=1>O1CCCC1.O>[Cl:31][C:32]1[CH:43]=[CH:42][C:35]([C:36]([C:2]2[CH:6]=[C:5]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[S:4][C:3]=2[S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: COC(OC)c1cc(Br)c(Sc2ccc(Cl)cc2)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1cc(C(=O)c2ccc(Cl)cc2)c(Sc2ccc(Cl)cc2)s1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
In an argon atmosphere, 3-bromo-2-(4-chlorophenylthio)-5-dimethoxymethylthiophene (500 mg, 1.32 mmol) obtained in Example 90 was dissolved in tetrahydrofuran (6 mL) and cooled to −78° C. n-Butyl lithium (a 1.6 mol/L hexane solution, 0.81 mL, 1.3 mmol) and tetrahydrofuran (1 mL) solution of 4-chloro-N-methoxy-N-methylbenzamide (528 mg, 2.64 mmol) were added thereto, followed by stirring for 10 minutes. Water was added to the reaction liquid and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (15:1 hexane/ethyl acetate) to give 3-(4-chlorobenzoyl)-2-(4-chlorophenylthio)-5-dimethoxymethylthiophene (345 mg, 60%).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][CH2:21][CH2:22][OH:23])[C:14]=2[N:13]=[CH:12]1.O>C(Cl)Cl>[CH2:15]([N:11]([CH2:12][CH2:1][CH3:2])[CH:20]([C:19]1[C:14]2[N:13]=[CH:12][NH:11][C:15]=2[CH:16]=[CH:17][CH:18]=1)[CH2:21][CH:22]=[O:23])[CH2:14][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCCc1cccc2[nH]cnc12
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCN(CCC)C(CC=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (1.2 mL, 0.014 mol) was added with stirring to methylene chloride (20 mL) at -78° C. Ten minutes after addition was complete, DMSO (2 mL) was added and stirring was continued for an additional 10 minutes. β-Dipropylamino)-1H-benzimidazole-4-propanol (2.1 g, 7.5 mmol) in methylene chloride was added and, after 30 minutes, the solution was allowed to warm to room temperature. Water was added, the methylene chloride was separated and evaporated, and the residue was chromatographed on silica gel to give β-(dipropylamino)-1H-benzimidazole-4-propanal as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.CCN(CC)CC.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH3:15][S:16]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1)(=[O:18])=[O:17]
Reactant: CN1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Hydroxy-1-methylpyrroldine (0.543 mL, 4.94 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Et3N (0.827 mL, 5.93 mmol), methanesulfonyl chloride (0.421 mL, 5.44 mmol) and DMAP (0.006 g, 0.05 mmol) were added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with CHCl3 (5 mL) and washed with sat. NaHCO3 (5 mL) and water (2×5 mL). The organic layer was concentrated in vacuo to give the title compound A22 as a yellow oil (0.717 g, 81% yield). 1H NMR (300 MHz, CDCl3) δ 1.85-2.24 (m, 6H), 2.38-2.74 (m, 3H), 2.76-2.91 (m, 3H), 4.95 (m, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[C:27]([O-])(O)=[O:28].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CO>[OH:26][C@H:4]1[CH2:3][C@@:2]2([CH3:1])[C@@H:7]([CH2:8][CH2:9][C@:10]2([OH:15])[C@@H:11]([OH:12])[C:13]([O:28][CH3:27])=[O:14])[C@H:6]2[C@H:5]1[C@:24]1([CH3:25])[C:18]([CH2:17][CH2:16]2)=[CH:19][C:20](=[O:21])[CH:22]=[CH:23]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: O=C([O-])O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 0.33 h

Procedure:
Prednisolone (10 g) was dissolved in 750 ml of methanol and 2.25 g cupric acetate in 750 ml of methanol was added. The solution was mixed and set aside for 20 min. While stirring, the reaction was continued with airation for 1 weak. After adding 500 ml of 0.1% NaHCO3 solution containing 4.5 g EDTA, methanol was evaporated under vacuum. The solution was extracted with ethyl acetate (1,000 ml), dried on anhydrous sodium sulfate and evaporated to dryness (7.5 g). The residue was dissolved in 150 ml methanol and 375 ml water containing 3.75 g NaHSO3 was added. After refluxing for 1 hour, water was evaporated and the residue was extracted with ethyl acetate (500 ml), washed with distilled water, dried on sodium sulfate and evaporated to dryness (3.5 g), which was purified with silica gel column with acetone:dichloromethane:hexane (3:2:5) as a mobile phase. The pooled fraction was evaporated to dryness. Recrystallization four times from methanol gave 1.1 g of methyl (20R)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate (Product 9A) as a colorless platelet, m.p.=254°-255° C., 1H-NMR (Me2SO-d6) δ1.05(s,3H,13-CH3), 1.40(s,3H,10-CH3), 3.62(s,3H,21-OCH3), 4.06(s,1H,20-H), 4.21(m,1H,11-H), 5.91(s,1H,4-H), 6.15(dd,1H,J=10 and 2 Hz,2-H), 7.32(d,1H,J=10 Hz,1-H); MS, m/e 390(M+). The combined remaining solution was evaporated. After dissolving in small amount of methanol, the solution was subjected to preparative HPLC using methanol:water (6:4) as a mobile phase. The eluate was evaporated and crystallized to give 0.8 g of methyl (20S)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate (Product 9B) as a white prism, m.p.=171°- 173° C. 1H-NMR (CDCl3) δ1.15(s,3H,13-CH3), 1.45(s,3H,10-CH3), 3.31(s,3H,21-OCH3), 4.36(s,1H,20-H), 4.43(m,1H,11-H), 6.01(s,1H,4-H), 6.28(dd,1H,J=10 and 2 Hz,2-H), 7.28(d,1H,J=10 Hz,1-H); MS, m/e 390(M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[ClH:1].[Cl:21][C:16]1[CH:15]=[C:14]([C:4]2[CH:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: NCCO
Reactant: COc1ccc2c(Cl)cc(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: COc1ccc2c(NCCO)cc(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 268-27° C., and MS: m/e=363.0 (M+H+), was prepared from 4-chloro-2-(3,4-dichloro-phenyl)-7-methoxy-quinoline and ethanolamine.
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: Cc1cccc(C(O)CN)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)CC(O)c2cccc(C)c2)cc1
Yield: 56.5 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described in Preparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 4.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.2 g of the title compound were obtained having an Rf=0.24 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[N:4]([CH3:13])[C:3]2=[O:14].N[C@H](C(O)=O)C[SeH].[Li]CCCC.C1CCCCC1.[C:33](=[O:35])=[O:34]>C1COCC1>[CH3:13][N:4]1[C:3](=[O:14])[C@@:2]2([CH3:1])[C:9]([CH3:10])([CH3:11])[C@:6]([C:33]([OH:35])=[O:34])([CH2:7][CH2:8]2)[C:5]1=[O:12]
Reactant: O=C=O
Reactant: CN1C(=O)C2CC[C@@](C)(C1=O)C2(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN1C(=O)[C@@]2(C(=O)O)CC[C@@](C)(C1=O)C2(C)C
Temperature: -95 °C
Reaction time: 0.25 h

Procedure:
To a solution of step 2 intermediate (2 g, 10.2 mmol) in THF maintained at −95° C. under N2 atmosphere, 1.2N Sec.BuLi in cyclohexane (9.5 mL, 13.3 mmol) was added. After stirring for 15 min at −95° C., small pieces of dry ice (2 g) were added and the reaction mixture was kept at this temperature for 1 h before quenching with water (3 mL). The reaction mixture was allowed to warm to room temperature. To this 5% NaHCO3 solution (100 mL) and diethyl ether (50 mL) was added, the aqueous layer was separated and acidified with KHSO4 to pH 2. This was extracted again with diethyl ether, washed with brine, dried with anhydrous Na2SO4 and concentrated. (1.85 g). 1H NMR (400 MHz, CDCl3) δ ppm: 1.0 (s, 3H), 1.1 (s, 3H), 1.26 (s, 3H), 1.88-1.98 (m, 2H), 2.64-2.72 (m, 1H), 2.8 (m, 1H), 3.13 (s, 3H). m/z (M−H): 238.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(=O)OCC.O>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][O:7][C:4]1[CH:5]=[CH:6][C:1]([OH:8])=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCOc1ccc(O)cc1
Temperature: 60 °C

Procedure:
A mixture of benzene-1,4-diol (20.0 g), DMF (100 mL), cesium carbonate (59.2 g) and 1-bromo-3-methyl-butane (13.7 g) was heated to 60° C. for 12 hours. After the mixture reached room temperature, it was distributed between water and EA. The organic phase was washed twice (water), dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:2) to provide the subtitle compound.
Reaction SMILES: [C:1](C1NC=CN=1)([C:3]1NC=CN=1)=[O:2].[NH2:13][C:14]1[C:29]([F:30])=[CH:28][C:17]2[O:18][C:19]([F:27])([F:26])[C:20](=[O:25])[N:21]([CH2:22][C:23]#[CH:24])[C:16]=2[CH:15]=1.C(N(CC)CC)C.[F:38][C@@H:39]1[CH2:43]N[C@@H:41]([C:44]([OH:46])=[O:45])[CH2:40]1.Cl>C(#N)C>[F:38][C@H:39]1[CH2:40][C@H:41]([C:44]([OH:46])=[O:45])[CH:3]([C:1](=[O:2])[NH:13][C:14]2[C:29]([F:30])=[CH:28][C:17]3[O:18][C:19]([F:26])([F:27])[C:20](=[O:25])[N:21]([CH2:22][C:23]#[CH:24])[C:16]=3[CH:15]=2)[CH2:43]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)[C@H]1C[C@H](F)CN1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NC(=O)C3C[C@@H](F)C[C@@H]3C(=O)O)cc21
Temperature: 80 °C
Yield: 90 %

Procedure:
Carbonyl diimidazole (1519 mg, 9.37 mmol) was added to a stirred solution of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 1.6 above, 800 mg, 3.12 mmol) and triethylamine (0.457 ml, 3.28 mmol) in anhydrous acetonitrile (15 ml) at room temperature under nitrogen. The resulting mixture was heated to 80° C. Then (2R,4S)-4-fluoropyrrolidine-2-carboxylic acid (416 mg, 3.12 mmol) was added. The resulting suspension was stirred at reflux. After 2 hours a red/brown clear solution was obtained. LCMS analysis indicated that full conversion had occurred. The reaction mixture was gradually cooled to room temperature, poured into 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to yield the desired compound (1.34 g, ca. 90% purity), which was used without further purification in the following step.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:26]3[CH:31]=[CH:30][C:29]([N:32]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:28][CH:27]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl.CCOCC.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:16]=3)=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]3[N:12]=2)=[CH:31][CH:30]=1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N=C(c4ccccc4)c4ccccc4)cc3)nn3c(NCCCC)cccc23)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1

Procedure:
To a solution of N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(diphenylmethylene)-amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine (1.0 g, 1.7 mmol) in tetrahydrofuran (50 mL) was added hydrochloric acid (10 mL, 4 N aqueous). The resultant solution was stirred at room temperature for 30 minutes. Ether was added and the solution was made basic by the slow addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate) provided N-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine as an orange oil. 1H NMR (CDCl3): δ 8.02 (d, 1 H), 7.81 (d, 1 H), 7.47 (d, 2 H), 7.31 (m, 1 H), 6.77 (d, 2 H), 6.42 (d, 1 H), 6.08 (m, 1 H), 6.00 (d, 1 H), 5.18 (broad, 1 H), 3.86 (broad, 2 H), 3.53 (m, 2 H), 3.39 (m, 2 H), 1.82–1.64 (m, 4 H), 1.58–1.46 (m, 4 H), 1.04–0.99 (m, 6 H); MS m/z430 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[S:6]1)#[N:4].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(OCC)(=O)C>CN(C)C=O.O>[C:3]([C:5]1([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:26]3[O:28][CH2:27]3)=[CH:21][CH:22]=2)[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[S:6]1)#[N:4]
Reactant: ClCC1CO1
Reactant: CN1C(=O)C(C#N)(c2ccc(O)cc2)Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(C#N)(c2ccc(OCC3CO3)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 54.5 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.7 g) in anhydrous dimethylformamide (5 ml), 2-cyano-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g, compound No. 10) dissolved in anhydrous dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 7 minutes at room temperature. Epichlorohydrin(2.6 ml) is added to the reaction mixture, and the mixture is stirred for 1 hour at 65°-75° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 3.2 g (54.5%) of the titled compound.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][C:13]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]3=[O:33])[C:18]([F:34])=[CH:17][C:16]=2[N+:35]([O-])=O)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][C:13]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]3=[O:33])[C:18]([F:34])=[CH:17][C:16]=2[NH2:35])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(N)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a mixture of 2.0 g of an iron powder, 6 ml of acetic acid and 0.6 ml of water was added dropwise a solution of 1.9 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 5.0 ml of acetic acid, while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel column chromatography to obtain 1.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: [NH2:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:4].[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:18]([N:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:10][C:6]([NH:5][C:3]([C:2]([NH:1][C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[CH3:27])=[O:34])([CH3:26])[CH3:25])=[O:4])=[N:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCC[C@H]1C(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100 mL rbf was charged DCM (14.29 ml) followed by addition of 2-amino-N-(1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-2-methylpropanamide (1.000 g, 2.83 mmol) and (S)-1-methylpyrrolidine-2-carboxylic acid (0.402 g, 3.11 mmol). And it was stirred at room temperature for 10 min, the clear solution save for a couple of particles, was placed in an ice bath at 2° C. Then HATU (2.152 g, 5.66 mmol) and triethylamine (0.789 ml, 5.66 mmol) were added. The yellow semi-solution was allowed to stir at 2° C. for 5 h. It was allowed to warm to room temperature over night. It was diluted with DCM (25 mL) and H2O (30 mL). The white precipitates were collected by filtration and washed with 1:1 water/sat. NaHCO3 solution. (2×60 mL), brine (2×40 mL). This afforded the title compound 1H NMR (400 MHz, DMSO-d6) d ppm 1.53 (d, J=1.52 Hz, 6H) 1.66-1.78 (m, 3H) 1.96-2.13 (m, 1H) 2.21-2.29 (m, 1H) 2.30 (s, 3H) 2.61-2.70 (m, 1H) 2.99-3.09 (m, 1H) 5.43 (s, 2H) 7.13 (d, J=6.95 Hz, 2H) 7.26-7.43 (m, 5H) 7.68-7.75 (m, 2H) 7.97 (s, 1H) 10.21 (s, 1H). Theoretical mass 464.23. found 464.23. MS (m/z) 465.00 M (+1), tR=1.23, Meth A. ee: 95%, using 30% EtOH Heptane.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=[O:21])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol produced in Example XV in dry CH2Cl2 at 0 degree C. there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine solution, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by SiO2 column chromatography yielded the p-toluenesulfonate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[OH-].[K+].Br[C:10]([CH3:24])([CH3:23])[C:11]([NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)=[O:12]>C(O)C>[C:19]([C:17]1[O:16][N:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]([CH3:23])([S:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH3:24])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: Sc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Sc1cccs1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a stirred solution of 0.16 mL (1.7 mmol) of thiophene-2-thiol in ethanol (5 mL) were added 102 mg (1.8 mmol) of KOH pellets, followed by 460 mg (1.6 mmol) 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in step 1, method C). The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (15 mL). The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent: heptanes, 0-10% ethyl acetate) to yield 504 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(thiophen-2-ylsulfanyl)-propionamide.