Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4](CC=C)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH3:6])C=C.[NH4+].[OH-]>C(Cl)Cl.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>[NH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH3:6]
Reactant: C=CCN(CC=C)[C@H](C)c1ccc(C(C)(C)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(C(C)(C)O)cc1
Yield: 93 %

Procedure:
A mixture of 0.63 g (0.54 mmol) Pd(PPh3)4 and 25.3 g (162 mmol) NDMBA was combined and placed under N2. Thereafter, a solution of 7.0 g (27 mmol) (R)-2-[4-(1-diallylamino-ethyl)-phenyl]-propan-2-ol in 140 ml CH2Cl2 was added. The resulting mixture was then refluxed under N2 for 2 hours. The crude reaction mixture was then loaded onto coarse silica gel. Chromatography on silica gel using 7.5% MeOH/CH2Cl2 followed by 2% NH4OH/ 10% MeOH/CH2Cl2 yielded 4.5 g (93%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23]>C(NCC)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:23]#[C:22][C:21]([O:20][CH3:19])([CH3:25])[CH3:24])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: C#CC(C)(C)OC
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Procedure:
3.57 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 4 hours with 1.22 g (12.5 mmol) of 3-methoxy-3-methyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 149°-150°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2].[OH-:13].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[NH2:2][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:13]
Reactant: [OH-]
Reactant: Cc1cc(C#N)ccc1C(=O)O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To 4-cyano-2-methylbenzoic acid (0.071 g, 0.44 mmol) in 2 ml of t-butanol was added potassium hydroxide (0.13 g, 2.15 mmol). The reaction mixture was refluxed for 30 min and cooled to room temperature. To the reaction mixture was added 10 ml of brine and the reaction mixture was extracted with ethyl acetate (2×15 ml). The water layer was acidified to pH 1-2 with concentrated aqueous hydrochloric acid to give a white precipitate. The solid was collected by filtration, washed several times with water (3×15 ml) and dried in vacuo to provide 4-(aminocarbonyl)-2-methylbenzoic acid (0.038 g, 49% yield). 1H-NMR (400 MHz, DMSO-d6): 13.10 (br s, 1H), 8.07 (s, 1H), 7.87 (d, 1H), 7.78-7.72 (m, 2H), 7.50 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C1COCC1.ClCCl>[O:23]=[C:17]([CH2:2][C:1](=[O:3])[C:4]1[S:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(=O)c1ccc(C#Cc2ccccc2)s1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-acetyl-5-(phenylethynyl)thiophene (1.81 g, 8.02 mmol), diethyl oxalate (2.17 mL, 16 mmol), and sodium ethoxide (1.09 g, 16 mmol) in anhydrous THF (25 mL) was stirred at rt under an atmosphere of argon for 5 hr. The resultant mixture was diluted with dichloromethane, and washed successively with dilute HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide yellow solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:24]([O:26][C:27]([C:29]1[C@@H:30]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][N:32]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:31]2)=[O:28])[CH3:25]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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>[CH2:24]([O:26][C:27]([C:29]1[C@@H:30]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=1)[CH2:33][N:32]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:31]2)=[O:28])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sol. of [3-(4-bromo-phenyl)-propoxy]-tert-butyl-dimethyl-silane (102.1 g, 310 mmol) in THF (1.50 L) under nitrogen is cooled to −78° C. BuLi (1.5M in hexane, 212 mL, 318 mmol) is added. After 30 min, ZnCl2 (1M in THF, 465 mL, 465 mmol) is added. The mixture is allowed to warm up to rt. (rac.)-(1R*,5S*)-9-Methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (83.6 g, 155 mmol) in THF (100 mL) and then Pd(PPh3)4 (4.48 g, 3.87 mmol) are added. The mixture is heated to reflux for 30 min, and allowed to cool to rt. The mixture is diluted with EtOAc and washed with aq. 1M NaOH (1×). The org. extracts are dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Purification of the residue by FC (MeOH/CH2Cl2 1:49→1:24→3:47→2:23) yields the title compound (88.6 g, virtually quantitative). LC-MS: tR=0.98 min; ES+: 559.24.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:5]=3)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c2)n(C)n1
Yield: 55.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.03 g, 2.71 mmol) and triethylamine (563 μL, 4.07 mmol) in tetrahydrofuran (15 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (295 μL, 3.25 mmol), and the mixture was stirred at room temperature for 2 hr. Cyclopropanecarbonyl chloride (500 μL, 5.51 mmol) was further added thereto, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (750 mg), methanol (15 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=60/40→0/100) and recrystallized from ethanol-ethyl acetate-hexane to give the title compound (675 mg, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:18][CH:19]=1)=[O:29]
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
A mixture of 0.409 g of 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno [3,2-b]azepine and 0.60 g of 2-methylphenylisocyanate in 2 ml of tetrahydrofuran is heated in an oil bath at 110° C. for 16 hours. The mixture is concentrated under vacuum and the residue chromatographed on preparative silica gel plates with ethyl acetate-hexane (1:1) as solvent to give a solid. Crystallization from ethyl acetate-hexane gives 0.33 g of white crystals, m.p. 179°-182° C.
Reaction SMILES: [CH3:1][N:2](C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:35](=[CH:36][CH:37]=1)[O:34][C:12]1([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]4[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:38]>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:31][O:30][C:28]1[C:27]2[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([CH2:11][C:10](=[O:38])[C:9]4[C:35](=[CH:36][CH:37]=[C:7]([C:1]#[N:2])[CH:8]=4)[O:34]3)[CH2:17][CH2:16]2)=[O:19])[CH:29]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Br)ccc2O3)nc2c(OC)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Temperature: 80 °C
Reaction time: 39 h

Procedure:
118 mg of zinc cyanide, 69.3 mg of Pd(PPh3)4 and 3 mL of DMF were added to 511 mg of the bromo compound obtained in Example 9, and heated under a nitrogen atmosphere at 80° C., and the reaction mixture was stirred for 39 hours. After cooled, the reaction mixture was diluted with 30 mL of ethyl acetate, washed successively with diluted aqueous ammonia, water and saturated brine, then dried over sodium sulfate, and concentrated. Ethyl ether was added to the resulting residue, and the insoluble solid thus formed was taken out through filtration. This was washed with ethyl ether and dried under reduced pressure to obtain the intended compound as a pale yellow-brown solid. 1H-NMR (300 MHz, CDCl3) δ: 8.20 (1H, d, J=2.0 Hz), 7.71 (1H, d, J=8.2 Hz), 7.74 (1H, dd, J=8.6, 2.0 Hz), 7.42 (1H, t, J=8.2 Hz), 7.19 (1H, s), 7.13 (1H, d, J=8.6 Hz), 7.08 (1H, d, J=8.2 Hz), 4.63-4.54 (1H, m), 4.26-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.64-3.52 (1H, m), 3.42-3.29 (1H, m), 2.88 (1H, d, J=16.8 Hz), 2.81 (1H, d, J=16.8 Hz), 2.23-2.13 (1H, m), 2.09-1.85 (3H, m). MS [M+H]+=458.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH3:29][C:30]1[S:31][CH:32]=[C:33]([CH2:35][O:36][NH2:37])[N:34]=1>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:37][O:36][CH2:35][C:33]1[N:34]=[C:30]([CH3:29])[S:31][CH:32]=1)=[O:10])=[O:5]
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1nc(CON)cs1
Product: Cc1nc(CONC(=O)c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)cs1

Procedure:
Compound 424 (50 mg, 0.12 mmol) and O-(2-Methyl-thiazol-4-ylmethyl)-hydroxylamine (36 mg, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 1H NMR (CDCl3) δ 10.0-9.0 (bs, 1H), 7.76 (dd, 1H), 7.67 (d, 1H), 7.42-7.30 (m, 3H), 7.15 (s, 1H), 7.00-6.84 (m, 3H), 6.75 (dd, 1H), 5.98 (bs, 1H), 5.04 (s, 2H), 2.64 (s, 3H), 2.45 (s, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(O)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1OCCOc1ccc(Cl)cc1Cl

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-isopropoxypropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[C:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)[C:16]#[N:17])[CH3:23]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(C(=O)c2ccccc2)CC1

Procedure:
A mixture of N-benzoyl-4-piperidone (20.0 g, 0.1 mol), ethyl cyanoacetate (10.9 ml, 0.1 mol), ammonium acetate (2.0 g) and acetic acid (6 ml) in benzene (100 ml) was heated at reflux temperature in a 3-nacked reaction flask equipped with a Dean-Stark water trap for 1 h. The cooled reaction mixture was diluted with ethyl acetate (100 ml) washed with water (3×100 ml), saturated aqueous sodium chloride (80 ml), dried (MgSO4) filtered and evaporated in vacuo affording quantitative yield of (1-benzoyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester as a slowly crystallising oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH:26]=[O:27].C(O)(C)C>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]([C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[OH:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(C(O)c2cccc(OCc3ccccc3)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
A stirred mixture of 1-benzyloxy-3-bromo-benzene (10.56 g, 40.1 mmol) and dry THF (35 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (17.7 mL, 44.1 mmol) and stirred for 20 min. Then a mixture of 3,5-dimethoxy-benzaldehyde (7.34 g, 44.1 mmol) in dry THF (30 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (18.5 mL, 241 mmol) and added water (30 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic phases were washed with water (2×80 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82% yield): 1H NMR (CDCl3) δ 2.21 (d, J=4 Hz, 1H, OH), 3.76 (s, 6H, 2OCH3), 5.04 (s, 2H, CH2), 5.72 (d, J=4 Hz, 1H, CH), 6.36 (t, J=2 Hz, 1H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.85-7.04 (m, 3H, Ar), 7.21-7.43 (m, 6H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Br
Yield: 46.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenylisocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(530 mg, 47%). EI-MS m/z 350(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)#[C:12][CH3:13]>C(NCC)C.[Cu](I)I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:17]2[CH:18]=[CH:19][C:14]([C:11]#[C:12][CH3:13])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CC#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(OC)cc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(OC)cc2)cc1

Procedure:
4-Methoxyphenyl acetylene (2.65 g, 0.02 mol) and 4-(1-propynyl)iodobenzene (5.0 g, 0.02 mol) were dissolved in diethylamine (20 ml), and then added copper iodide (0.06 g) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g) were added. The resulting mixture was subjected to reaction and purification operations in the same manners as in Example 1, to obtain the objective 4-methoxy-4'-(1-propynyl)tolan (No. 297) (1.35 g).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method A, Step 5 of Example 1, the title compound was prepared from 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.58 g, 3.73 mmol), sodium hydride (0.194 g, 4.85 mmol), and ethyl bromoacetate (0.51 mL, 4.5 mmol) in DMF (15 mL). Purification by flash chromatography using 10% acetone in hexane as an eluant yielded a yellow gum (0.993 g); 1HNMR (200 MHz, DMSO-d6): δ8.5 (s, 1H), 8.25 (d, 1H, J=8.5 Hz), 8.15 (d, 1H, J=10 Hz), 7.95-8.1 (m, 2H), 7.75 (d, 1H, J=7.5 Hz), 7.2-7.4 (m, 3H), 5.15 (s, 2H), 4.15 (q, 2H, J=6.7 Hz), 2.75 (t, 2H, J=7.5 Hz), 1.5-1.65 (m, 2H), 1.1-1.3 (m, 4H), and 0.7 ppm (t, 3H, J=7.3 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28][S:27][S:26][CH2:25][CH2:24]1>CC(C)=O>[C:23]([CH2:24][CH2:25][S:26][S:27][CH2:28][CH2:29][C:30]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:31])([OH:33])=[O:32]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C1CCSSCCC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)CCSSCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 2.0 g of (4R)-2-hydroxyphenyl-4-thiazolidinecarboxylic acid and 1.7 ml of triethylamine in 15 ml of anhydrous acetone, 2.0 g of dithiodipropanoic anhydride is added. The resulting mixture is continuously stirred for 40 min at room temperature and extracted with ethyl acetate after addition of 50 ml of water containing a small amount of potassium carbonate. The aqueous layer is acidified with N aqueous hydrochloric acid and extracted with ethyl acetate. The second organic layer is washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residual oil is purified by column chromatography on silica gel to give crystals of the titled compound. The yield is 0.6 g (15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[CH:21][C:20]([C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: C[C@@](O)(c1ccc(-c2ccc(S(=O)(=O)c3ccccc3)c(Cl)c2)nc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@](O)(c1ccc(-c2ccc(S(=O)(=O)c3ccccc3)c(Cl)c2)nc1)C(F)(F)F

Procedure:
(2R)-2-(6-(3-chloro-4-(phenylsulfonyl)phenyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ 8.95-8.88 (m, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.31-8.21 (m, 2H), 8.19-8.11 (m, 1H), 8.06-7.95 (m, 3H), 7.74-7.66 (m, 1H), 7.62 (s, 2H), 1.81 (s, 3H). m/z (ESI, +ve ion) 441.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.75 μM; GK-GKRP EC50 (LC MS/MS)=3.57 μM.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C@H:8]1[O:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C@H:8]1[O:12][C:11](=[S:25])[CH2:10][CH2:9]1)([CH3:4])[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=S)O1
Yield: 57.1 %

Procedure:
The title compound is prepared by the procedure of Example 353 using 0.868 g of product from Example 359, 10 ml of toluene and 0,763 g of Lawesson's Reagent to give 0.530 g of the desired product.