Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:14]C(OC)=O)=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4].ClCCl.CO.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:14])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4]
Reactant: COC(=O)Oc1nsc(S(C)(=O)=O)c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1c(O)nsc1S(C)(=O)=O
Temperature: 65 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
The 5-Methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester/dichloromethane extracts were combined, then displaced with methanol (150 mL, 15 volumes). A solution of 98% sulfuric acid (50 mL, 5 volumes) in water (100 mL, 10 volumes) was added and the mixture was heated at 65° C. for 6 hours. The foamy slurry became a clear solution with some insoluble white solids over time. The mixture was cooled to 25° C. and stirred for 16 hours. Most of the methanol was removed under vacuum. The aqueous residue was extracted once with 100 mL dichloromethane, then twice with 50 mL dichloromethane. The combined dichloromethane extracts were dried over anhydrous magnesium sulfate and filtered. The dichloromethane was displaced with hexanes (100 mL, 10 volumes) and stirred at 25° C. until solids formed. The solids were filtered, and the filter cake was rinsed with hexane and dried to give 9.27 g of 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (80% yield). 1H NMR (DMSO-d6): δ 13.07 (s, 1H); 3.83 (s, 3H); 3.55 (s, 3H). MS (API-ES pos): 238 (M+H)+; 206 (M−MeO)+, base.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:21])[C:8]([C@H:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][OH:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[NH4+].[Cl-]>C(Cl)Cl>[C:27]([O:15][CH2:14][C@H:13]([C:8]1[C:7]([CH3:21])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]=1[OH:12])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccc(Br)cc2c(O)c1[C@@H](CO)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of (S)-7-bromo-2-(1-tert-butoxy-2-hydroxyethyl)-3-methylnaphthalen-1-ol (1.84 g, 5.20 mmol) in CH2Cl2 (15 mL) added imidazole (426 mg, 6.25 mmol) and pivalyl chloride (705 μL, 5.7 mmol). The reaction was stirred at room temperature for 36 h. A saturated solution of NH4Cl was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.21 (s, 1H), 7.63 (m, 2H), 7.26 (s, 1H), 5.47 (dd, J=10, 3 Hz, 1H), 4.62 (dd, J=12, 10 Hz, 1H), 4.14 (dd, J=12, 3 Hz, 1H), 2.75 (s, 3H), 1.22 (s, 9H) 1.11 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:42]([CH2:45]C)CC)C.[OH2:47]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:22][C:45](=[O:47])[NH:42][CH:9]2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O
Reactant: COc1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CC2NC(=O)OC2c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionic acid (13.7 g, 45.0 mmol) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (12.6 ml, 58.5 mmol) and triethylamine (8.78 ml, 63.0 mmol) and the mixture was stirred for 30 min. The mixture was further heated under reflux for 4 hrs and allowed to stand at room temperature. Water (2.00 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=4:1-2:1) to give (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(methyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (13.0 g, 96%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4ccccc4)ccc23)c1
Temperature: 90 °C

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.080 g, 0.17 mmol), phenylboronic acid (0.042 g, 0.34 mmol), NaHCO3 (0.073 g, 0.85 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.02 mmol) were suspended in DME:H2O (1:1, 3 mL) and the reaction vessel was purged with N2 (g). The reaction was heated to 90° C. and after two hours the mixture was submitted to aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[CH3:22][S-:23].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH3:22][S:23][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4]
Reactant: C[S-]
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 74.8 %

Procedure:
A slurry of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (207 mg, 0.605 mmol) and sodium thiomethoxide (127 mg, 1.82 mmol) in ethanol (10 mL) was stirred at room temperature for 18 hrs. The reaction mixture was diluted with water (10 mL) and ethyl acetate (50 mL), the organic phase was separated, dried over sodium sulphate and evaporated in vacuo to afford 2-(methylthio)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (140 mg, 75% yield). LCMS calculated for C17H15N3OS (M+H): 310.39. found 310. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.30 (1H, br.), 9.53 (1H, s), 8.53 (1H, m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.84-7.95 (3H, m), 7.55-7.60 (1H, m), 3.35 (2H, s), 2.22 (3H, s).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16](O)[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:7])=[O:6].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[F:24][CH:2]([F:1])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16]([CH2:27][CH:26]=[CH2:25])[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)C(OC(F)F)c1ccc2c(c1)C(O)Oc1ccccc1-2
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1Oc2ccccc2-c2ccc(C(OC(F)F)S(N)(=O)=O)cc21
Reaction time: 1 h

Procedure:
A solution of Example 27G (0.14 g, 0.39 mmol) in dichloromethane (10 mL) at −78° C. was treated with allyltrimethylsilane (0.13 g, 1.16 mmol) and borontrifluoride etherate (0.156 g, 1.16 mmol), stirred for 1 hour, and treated with saturated sodium bicarbonate (10 mL) to provide two laters. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)Q1MS) m/z 380 (M−H)−.
Reaction SMILES: ClC1C=C(N(CC)C2CN(C)C2)C(C)=C(C=1)[C:7]([O:9]C)=[O:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:32]([CH2:38][CH3:39])[CH:33]2[CH2:36][N:35]([CH3:37])[CH2:34]2)[C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.C(N(C1CCN(C(C)C)CC1)C1C(C)=C(C=C(C(F)(F)F)C=1)C(O)=O)C.Cl.[NH2:67][CH2:68][C:69]1[C:70](=[O:79])[NH:71][C:72]([CH3:78])=[CH:73][C:74]=1[CH2:75][CH2:76][CH3:77].CC1C=C(C)NC(=O)C=1CNC(=O)C1C=C(C(F)(F)F)C=C(N(CC)C2CCN(C)CC2)C=1C>>[CH:7]([OH:9])=[O:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:32]([CH2:38][CH3:39])[CH:33]2[CH2:36][N:35]([CH3:37])[CH2:34]2)[C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27]([NH:67][CH2:68][C:69]1[C:70](=[O:79])[NH:71][C:72]([CH3:78])=[CH:73][C:74]=1[CH2:75][CH2:76][CH3:77])=[O:29]
Reactant: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CN(C)C1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CN(C)C1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Agent: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C(C)C)CC1
Agent: Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc(N(CC)C2CN(C)C2)c1C
Product: O=CO

Procedure:
Methyl 5-chloro-3-(ethyl(1-methylazetidin-3-yl)amino)-2-methylbenzoate was hydrolyzed to 5-chloro-3-(ethyl(1-methylazetidin-3-yl)amino)-2-methylbenzoic acid following the same preparation method for 3-{Ethyl[1-(propan-2-yl)piperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoic acid from its corresponding carboxylate. The crude 5-chloro-3-(ethyl(1-methylazetidin-3-yl)amino)-2-methylbenzoic acid was then coupled with 3-(Aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt prepared earlier following the preparation method described for N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. After purification by reverse phase HPLC/MS (CAN-H2O containing 0.1% formic acid), the titled compound was obtained. 1H-NMR (500 MHz, CD3OD) δ ppm 8.58-8.24 (br, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.14 (s, 1H), 4.48 (s, 2H), 4.41-4.34 (m, 1H), 4.25 (br, 2H), 3.85 (br, 2H), 3.00 (q, J=7.0 Hz, 2H), 2.92 (s, 3H), 2.72-2.66 (m, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.70-1.61 (m, 2H), 1.04 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.0 Hz, 3H); MS (ES) (M+H) 445.48.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, undecanoyl chloride (0.45 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}undecanamide (0.53 g, 63%) as a white solid: mp 138-139° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.42 (t, J=5.9 Hz, 1H), 7.85-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.18-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.96-2.83 (m, 1H), 2.64-2.47 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.55-1.50 (m, 2H), 1.24 (s, 14H), 0.85 (t, J=6.1 Hz, 3H); 13C NMR (DMSO-d6) δ 172.74, 172.63, 169.80, 167.47, 166.93, 139.55, 134.65, 133.10, 131.50, 127.04, 121.79, 48.83, 37.55, 35.21, 31.28, 30.92, 28.94, 28.74, 28.67, 25.20, 22.08, 21.97, 13.94; Anal. Calcd. For C25H33N3O5: C, 65.91; H, 7.30; N, 9.23. Found: C, 66.08; H, 7.13; N, 9.23.
Reaction SMILES: O=S(Cl)[Cl:3].[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:14])[C:11]=1[CH2:12]O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:14])[C:11]=1[CH2:12][Cl:3]
Reactant: OCc1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
SOCl2 (2.3 mL, 32 mmol) was added dropwise to a stirred solution of (3,5-dichloropyridin-4-yl)-methanol (2.83 g, 15.9 mmol) in DCM (20 mL) over 10 min. After stirring for 35 min at room temperature, saturated aqueous Na2CO3 solution (40 mL) and DCM (60 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/hexane 1:4) to give the title compound. MS (m/z): 196.0 [M+H+].
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O-])(O)=[O:17].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N:13]=[C:16]=[O:17])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])O
Reactant: COc1ccc(C2CCCCC2)cc1N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C2CCCCC2)cc1N=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-cyclohexyl-2-methoxy-phenylamine (106 mg, 0.49 mmol), CH2Cl2 (10 mL) and saturated NaHCO3 (5 mL) was added a 20% solution of COCl2 in toluene (0.39 mL) directly to the organic layer. The mixture was stirred for 15 min at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-cyclohexyl-2-isocyanato-1-methoxy-benzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)=[N:7][C:2]([N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)=[C:3]([C:28]#[N:29])[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N3CC(O)C3)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (0.12 mmol) of 4-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-N-methylpyridine-2-carboxamide Example 75A, 19.6 mg (0.18 mmol) of azetidin-3-ol hydrochloride and 36.2 mg (0.36 mmol) of triethylamine were dissolved in 1 ml of tetrahydrofuran, and the mixture was stirred at RT for 1 h. Water and tetrahydrofuran were added to the reaction mixture until a solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C=O)C.O>[CH:19]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([CH3:21])[CH3:20]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](Oc1ccc2c(c1)OCC2=O)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
To a solution of 9.8 g (65.3 mMol) 6-hydroxy-2H-benzofuran-3-one in 80 ml DMF, 10.6 g (157 mMol) imidazole and 16.6 ml (78.3 mMol) chloro-triisopropylsilane are added dropwise. After 1 h, the mixture is poured into 300 ml EtOAc and 300 ml water, the aq. phase is separated off and extracted with 3×100 ml EtOAc. The organic layers are washed 4 times with 10% citric acid solution, brine and dried (Na2SO4). Then char coal is added. Filtration, concentration and drying (10 mbar, 65-85° C.) give the oily title compound: MS: [M+1]+=307; TLC(hexane/EtOAc 2:1): Rf=0.61.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[ClH:29].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2Cl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
E or Z-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (1.0 g, 0.0024 mol) (prepared as described in Method A) was dissolved in ethanol (10 ml) and 10N sodium hydroxide solution (2.42 ml) was introduced. After stirring the solution at room temperature for 5 h, water (100 ml) was added and the mixture was neutralized with 2N hydrochloric acid solution. Evaporation of ethanol under reduced pressure gave an aqueous solution, which was acidified to pH 0.5 with 2N hydrochloric acid solution and extracted with dichloromethane (4×100 ml). The combined extracts were dried (Na2SO4) and evaporated to an oil, which was dissolved in a trace of methanol. Toluene (20 ml) was introduced, and the product solution was heated on a steam bath. On cooling the title compound (0.64 g, 62%), a white crystalline solid, was collected and dried in vacuo. M.p. softens at 170°, melts at 198°.
Reaction SMILES: FC(F)(F)[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CC1N=CC(CO)=C[N:16]=1>>[CH3:4][C:3]1[N:16]=[CH:5][C:6]([CH2:9][C:10]#[N:11])=[CH:7][N:8]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Cc1ncc(CO)cn1
Product: Cc1ncc(CC#N)cn1

Procedure:
(2-Methyl-pyrimidin-5-yl)-acetonitrile was prepared as described above for the synthesis of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile starting from (2-methyl-pyrimidin-5-yl)-methanol
Reaction SMILES: [Na].[CH3:2][OH:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[N:20]=[C:21](Cl)[CH:22]=[C:23](Cl)[N:18]2[N:17]=1)(=[O:15])=[O:14].[C:27]([OH:30])(=O)C>>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[N:20]=[C:21]([O:30][CH3:27])[CH:22]=[C:23]([O:3][CH3:2])[N:18]2[N:17]=1)(=[O:15])=[O:14]
Reactant: CC(=O)O
Reactant: CO
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(Cl)cc(Cl)n2n1
Agent: [Na]
Product: COc1cc(OC)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium (683 mg, 29.7 mmol) was added to 30 ml of methanol under nitrogen and allowed to react. The resulting solution was cooled and 4.06 g (9.83 mmol) of N-(2,6-dichlorophenyl)-5,7-dichloro-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide were added with stirring. After one hour, 2 ml of acetic acid was added and the mixture was poured into about 150 ml of ice water. The solids present were collected by filtration and dried to obtain 3.21 g (88 percent of theory) of the title compound, which is a white powder that melts at 232°-4° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]OS(C)(=O)=O)[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17]
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCOCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Yield: 30.8 %

Procedure:
A mixture of 0.512 g (0.00224 mol) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)-ethanone, 1.000 g (0.00224 mol) of [4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 0.620 g (0.00448 mol) of anhydrous potassium carbonate in 20 ml of anhydrous acetone and 10 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was filtered and concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The crude oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 20-30% ethyl acetate-hexane to yield 0.400 g (31% yield) of [4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]2-propylphenoxy]acetic acid ethyl ester as a pale yellow oil.
Reaction SMILES: ClC1C=CC2C3N=C(NC4C=CC=C(I)C=4)N=CC=3CC(=O)NC=2C=1.C(NC(=O)OC(C)(C)C)C#C.C(OC(=O)[NH:43][CH2:44][C:45]#[C:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)[CH:48]=1)(C)(C)C>>[NH2:43][CH2:44][C:45]#[C:46][C:47]1[CH:48]=[C:49]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)[CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Agent: C#CCNC(=O)OC(C)(C)C
Agent: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1
Product: NCC#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-58) and tert-butyl prop-2-ynylcarbamate was converted to {3-[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester, which was subsequently deprotected according to Method Kto give I-67 (62%): HRMS Calcd. for C21H16ClN5O: 390.1121, Found 390.1117.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[N:20]=[C:19]([CH:21](O)[CH3:22])[CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH:21]([F:7])[CH3:22])[N:20]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1cccc(C2OCCO2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(F)c1cccc(C2OCCO2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.81 ml of diethylamine trifluorosulfide (6.14 mmol) is added to a solution of 0.60 g of 1-(6-[1,3]-dioxolan-2-yl-pyridin-2-yl)ethanol (3.07 mmol) in 25 ml of dichloromethane cooled to -78° C. and maintained under a nitrogen atmosphere. The mixture is stirred for 30 minutes at -78° C. and then for 2 hours at room temperature. The mixture is poured slowly into a 10% aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.42 g of a yellow oil is obtained. Yield for the 2 stages combined: 53.4%