Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ccnc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ccnc(COS(C)(=O)=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-methanol (177 mg, 0.91 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.16 mL, 1.17 mmol) followed by DMAP (11 mg, 0.09 mmol) and Ms-Cl (0.09 mL, 1.14 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester as a red oil. The crude material (246 mg) was dissolved in acetone (12 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (114 mg, 0.90 mmol) was added followed by K2CO3 (628 mg, 4.50 mmol) and TBA bromide (58 mg, 0.18 mmol). The reaction mixture was stirred overnight at rt and concentrated to dryness. The residue was partitioned between water (5 mL) and EA (10 mL). The layers were separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1:1 hept-EA)=0.10. LC-MS-conditions 02: tR=0.85 min, [M+H]+=291.31.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23](=[O:32])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[O:20][N:19]=1)=[O:17].C(=O)([O-])O.[Na+]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH:23]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[OH:32])[O:20][N:19]=1)=[O:17]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(=O)c2cc(F)ccc2F)on1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(O)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
Sodium borohydride (0.02 g; 0.530 mmol) was added to a solution of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide (0.167 g; 0.388 mmol) in methanol (3 mL) and stirred at room temperature for 4 hours: as the reaction did not evolve anymore, some fresh sodium borohydride was added (0.02 g; 0.530 mmol) to the reaction and the resulting mixture was left stirring overnight. The mixture was diluted in a solution of sodium hydrogencarbonate saturated in water and extracted with ethyl acetate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (61%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)(hydroxy)methyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:50](O)[CH2:51]CC>>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:30])=[O:31])=[CH:6][N:5]=1)[CH2:2][CH2:50][CH3:51]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: CCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (360 mg, 1.81 mmol) and n-butanol (5 ml) was stirred at 100° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (5 ml) and dichloromethane (5 ml). The phases were separated and the aqueous layer extracted with dichloromethane (2×10 ml), then the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel, using dichloromethane: methanol (97.5:2.5) as eluant, to yield the title compound (145 mg, 69%) as a white solid. Found: C, 57.43; H, 6.29; N. 18.82. C28H36N8O4S; 0.20 H2O requires C, 57.56; H, 6.28; N, 19.18%. δ (CDCl3): 1.03 (6H, 2×t), 1.30 (3H, t), 1.55 (2H, m), 1.94 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.13 (4H, m), 4.67 (2H, t), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.56 (1H, d), 8.62 (1H, s), 9.01 (1H, s), 10.64 (1H, s). LRMS: m/z 581 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:7]2[N:6]=[CH:5][N:4]=[C:3]([O:15][C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)/[CH:19]=[C:20]3/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/3)[C:2]=2[CH3:1])[CH2:14][CH2:13]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Temperature: 30 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution Trifluoro acetate salt of (Z)-5-(3-((5-methyl-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione prepared in step 1 of example 5 (524 mg, 0.000974 mol) in dichloromethane (20 ml), triethyl amine (1.35 ml, 0.00974 mol) was added followed by the addition of acetyl chloride (0.104 ml, 0.001461 mol) at 0° C. and the reaction mixture was stirred for 5 hrs at 30° C. Then reaction mixture was diluted with dichloromethane, washed with water, dried over calcium chloride and evaporated under reduced pressure to collect the crude product. The crude product was then purified by column chromatography using 1.5% methanol in chloroform as eluent to yield the 300 mg product as yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])O)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:46])=O>O1CCCC1>[C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[Cl:46])[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 4-(triphenylmethylthio)-1-(benzyloxycarbonylhydroxymethyl)azetidin-2-one (1.0 g) and pyridine (240 μl) in tetrahydrofuran (THF) (15 ml) at 0° C. under nitrogen was added slowly thionyl chloride (180 μl ). After 15 minutes the precipitate was collected by filtration and the filtrate evaporated. The residue was rapidly eluted through a short plug of silica gel using a 15 to 30% ethyl acetate/hexane solvent gradient to afford 4-(triphenylmethylthio)-1-(benzyloxycarbonylchloromethyl)azetidin-2-one (900 mg) as a 4:3 mixture of diastereomers.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>CS(C)=O>[C:23]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC(C)(C)C
Yield: 18.2 %

Procedure:
Prepared similarly to that described in Example 260 using 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and tert-butylamine (0.214 mL, 2.032 mmol) in DMSO (2 mL) at RT for 30 min. The mixture was purified with rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-40% ACN in water with 0.1% TFA) to give 6-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (13.0 mg, 0.037 mmol, 18% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 349.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (brs, 1H), 11.87 (brs, 1H); 7.99 (1H, d, J=6.8 Hz), 7.87 (1H, s), 7.66 (1H, d, J=7.0 Hz), 7.38 (1H, t, J=7.8 Hz), 7.27 (1H, s), 6.08 (1H, s), 2.57 (3H, s), 1.58 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:22](=[O:24])[CH3:23])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCC(c2ccc(O)cc2)N1c1ccc(Cl)cc1
Product: CC(=O)Oc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 1.00 g of 1-(4-chlorophenyl)-6-(4-hydroxyphenyl)-2-piperidone was added 25 ml of acetic anhydride and the mixture was stirred at 120° C. for 1 hour. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give 910 mg of 1-(4-chlorophenyl)-6-(4-acetoxyphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#CCN
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of (4-Amino-but-2-ynyl)-carbamic acid tert-butyl ester (0.8 g, 4.34 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.32 g, 4.4 mmol) under nitrogen. To the reaction was added EDC (1.66 g, 8.68 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 72% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCCN4)c3)oc12
Yield: 33.3 %

Procedure:
2-(3-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (90 mg, 0.28 mmol) and platinum (IV) oxide monohydrate (45 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (petroleum ether/ethyl acetate=1:1). 30 mg of 2-(3-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 33%. 1H-NMR (400 MHz, DMSO-d6) δ 1.35-1.38 (m, 1H), 1.45-1.47 (m, 2H), 1.58-1.60 (m, 1H), 1.75-1.82 (m, 2H); 2.68-2.69 (m, 1H); 3.08-3.10 (d, J=9.6 Hz, 1H); 3.66-3.69 (m, 1H); 7.48-7.50 (t, J=6.0 Hz, 1H), 7.55-7.58 (d, J=6.4 Hz, 1H), 7.63-7.64 (d, J=5.6 Hz, 1H); 7.79-7.81 (m, 1H); 7.86 (brs, 1H); 7.94 (brs, 1H); 7.95-7.97 (m, 1H); 8.16-8.18 (m, 1H); 8.302 (s, 1H); LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:26].Cl[CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:24][CH2:25]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:26]
Reactant: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Reactant: OCC(O)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(NCCCCCCN2CCN(CC(O)CO)CC2)c2nccc(C)c2c1
Yield: 20.3 %

Procedure:
A mixture of 3 g (0.008 mole) of 6-methoxy-4-methyl-N-[6-(1-piperazinyl)hexyl]-8-quinolinamine (Example 1) and 0.72 ml (0.008 mole) of 3-chloro-1,2-propanediol was heated at 120° for 2 hours. An additional 0.2 ml of 3-chloro-1,2-propanediol and 1 ml of triethylamine were added and the mixture was heated at 130° for 3 hr and allowed to cool. The reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness in vacuo. The residual oil was chromatographed over 200 g of silica gel, eluting first with one liter of a 1:15:84 mixture of triethylamine:methanol:ethyl acetate and then with a 1:20:79 mixture of the same solvents. That portion of the eluant containing fairly pure product Rf (silica--25 parts of methanol:75 parts of ethyl acetate:1 part of triethylamine)=0.26 was concentrated to dryness, taken up in 2-propanol and treated with an excess of a 17% solution of hydrogen chloride in 2-propanol to afford 0.7 g of product. That portion of the eluant containing contaminated product was concentrated and rechromatographed over 50 g of silica with a 1:15:84 mixture of triethyl amine:methanol:ethyl acetate and the product was isolated as described above. The two crops were combined and recrystallized from ethanol to afford 1.0 g (23%) of the title compound, mp. 237°-241° (dec) with prior sintering.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2ccc(C#N)cc2)cc1
Yield: 98 %

Procedure:
A solution of 1.4 g (3.13 mmol, 92% pure) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (Example 75A) in 7 ml of dry acetonitrile is mixed with 1.42 g (6.26 mmol) 4-(tert-butyl)benzyl bromide and 1.30 g (9.39 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is directly purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 1:5). 1.85 g (3.32 mmol, 93% purity, 98% yield) of an oil are isolated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[N:17][S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[S@](=O)N=Cc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a flame dried flask under N2, 3-cyanobenzaldehyde (7.050 g, 53.76 mmol) was dissolved in anhydrous dioxane (100 mL). Ti(IV) ethoxide (28.183 mL, 134.40 mmol) was added followed by (S)-(−)-2-methyl-2-propanesulfinamide (7.167 g, 59.14 mmol). The r×n was heated to 110° C. After 2.5 hr the reaction was cooled to RT and brine (150 mL) was added. A precipitate formed and the reaction was rapidly stirred for 1 hr. The suspension was filtered through celite and the filter cake was washed with brine and ethyl acetate. The layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate (1×). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide as a light orange solid. 1H NMR (CD3OD) (8.61 (s, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.94-7.92 (m, 1H), 7.72 (t, 1H, J=7.81 Hz), 1.28 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:17]1(=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of triethyl phosphono acetate (35.2 g) in 100 mL THF, at 0° C., was added slowly via a syringe a solution of NaH (6.2 g) in 60 mL THF. The mixture was stirred at 0° C. for 10 minutes, cyclobutanone (10 g) was added by a syringe, and the resulting mixture was stirred at room temperature for 2 hours, followed by addition of distilled water to quench the reaction. The aqueous solution was extracted by ethyl acetate (3×20 mL), the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude residue was eluted by column chromatography (10% ethyl acetate/hexane), to give ethyl 2-cyclobutylideneacetate (20 g). 1HNMR (300 MHz, CDCl3) δ=5.57 (s, 1H), 4.13 (q, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 2.08(m, 2H), 1.26 (t) ppm. MS: m/z 370 (100, M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.ClC(Cl)C.Cl>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=2[OH:31])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(-c2nc3ccccc3o2)cc1
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccc(-c3nc4ccccc4o3)cc2)c(O)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 12.8 g. (0.05 mole) of 4-(2-benzoxazolyl)benzoyl chloride in 200 ml. of 1,2-dichloroethane is added, in small increments, 14.8 g. (0.11 mole) of anhydrous alumimum chloride at room temperature. The resulting solution is cooled to 10° C. and a solution of 6.2 g. (0.05 mole) of m-methoxyphenol in 50 ml. of dichloroethane is added dropwise over a period of 10 min. The reaction mixture is stirred at 10° C. for 30 min., then allowed to warm to room temperature and stirred at reflux for 1 hr. The reaction mixture is cooled to room temperature and combined with 300 g. cracked ice containing 50 ml. of concentrated hydrochloric acid. The organic layer is separated and washed 2 times with warm water. The organic layer is filtered through filter-cel and the solvent is evaporated on a steam bath leaving a yellow solid residue. The crude solid product is recrystallized from toluene to give 10 g. yellow crystals, m.p. 177°-179° C. (61% yield). The structure and purity of the product are confirmed by IR, NMR, and elemental analysis.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[CH:6]\[C:7]([O:9]CC)=O.C[Si]([N:26]=[C:27]=[S:28])(C)C>C(OCCCC)(=O)C.CN(C=O)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:5]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:27](=[S:28])[NH:26][C:7](=[O:9])[CH:6]=2)[CH:17]=1
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Reactant: C[Si](C)(C)N=C=S
Solvent: CCCCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CC(N)=O
Temperature: 117.5 °C
Reaction time: 8 h

Procedure:
A slurry of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (20 g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) was treated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and the mixture was heated at 115-120° C. for 5-6 hours. The mixture was cooled to 0-5° C., butyl acetate (100 mL) was added and the mixture was slurried for 8 hours. The formed solids were filtered, and the filter cake was washed with butyl acetate (2×100 mL). The solid was dried in a vacuum oven at 50° C. for 12 hours to a tan solid. The solid was dissolved in a 5:1 mixture of DMF and water at room temperature and additional water was added slowly to crystallize the material. The slurry was cooled to 10° C. and stirred for 8 hours, followed by filtration and washing with water. The filter cake was dried in a vacuum oven at 50° C. for 8 hours. The solid was dissolved in a 1:1 mixture of methanol and water and the slurry was heated to 50° C. and held at this temperature for 2 hours. After cooling to 10° C. over 30 minutes, the slurry was held at this temperature for 1 hour, filtered and washed with water and dried in a vacuum oven at 50° C. for 8 hours to give the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(=O)C.N1[CH2:18][CH2:17][CH2:16][CH2:15]C1>C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:15][CH:16]1[CH2:18][CH2:17]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CC1CC1
Yield: 43 %

Procedure:
A solution of 14 g (0.2 mol) of cyclopropylcarbaldehyde, 22.6 g (0.2 mol) of ethyl cyanoacetate, 1.4 ml of glacial acetic acid and 0.4 ml of piperidine in 200 ml of toluene was refluxed for 6 hours. After cooling, the mixture was washed with in each case 300 ml of 10% strength hydrochloric acid and water. The organic phase was dried and concentrated and the residue was subjected to distillation in vacuo. This gave 14.2 g (yield 43%) of ethyl 2-cyano-3-cyclopropyl-2-propenoate (b.p. 95° C./0.3 mbar).