Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.FC(F)(F)C([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=O>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH:20]2[CH2:21][CH2:22][NH:18][C:19]2=[O:23])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCCN1C(=O)C(F)(F)F
Product: O=C1NCCC1Cc1ccc(OC(F)(F)F)cc1
Yield: 53 %

Procedure:
Following the procedure as described in Preparation 5, making variations as required to use 4-(trifluoromethoxy)benzaldehyde in place of 4-fluorobenzaldehyde to react with 1-(2,2,2-trifluoroacetyl)pyrrolidin-2-one, the title compound was obtained as a white solid in 53% yield: 1H NMR (300 MHz, CDCl3) δ 7.24-7.06 (m, 4H), 3.71-3.50 (m, 2H), 3.34-3.02 (m, 3H), 2.19-2.00 (m, 1H), 1.83-1.70 (m, 1H); MS (ES+) m/z 260.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>O.[Cu]>[C:22]([CH2:21][NH:20][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CNc1cc(Cl)ccc1C(=O)O
Yield: 71 %

Procedure:
To a solution of potassium carbonate (10.3 g), potassium hydroxide (10.3 g), 2,4-dichlorobenzoic acid (VI) (15 g) and glycine (VII) (10.31 g) in water (150 ml) was added copper powder (0.38 g) and the resulting mixture was refluxed for 2 hours. Hereinafter, the resulting reaction solution was treated in the same manner as in Example 1 to give 12.8 g of the desired compound (yield, 71.2%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:19])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:19][C:8]1[C:7]([CH2:6][O:5][C:26]2[C:25]([F:28])=[CH:24][C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:22][C:21]=2[F:20])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(Cl)nsc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methyl methanesulfonate (320 mg, 0.95 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (230 mg, 1.00 mmol, 1.06 equiv), potassium carbonate (420 mg, 3.04 mmol, 3.21 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with of H2O. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (17/83). The collected fractions were combined and concentrated under vacuum. This resulted in 340 mg (68%) of ethyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H17C12F2NO3S, 472.0 (M+H). found 472.0.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](OCC)=[O:6].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[N:15]=1.O(C)[Na].Cl>CO>[N+:10]([C:4]1[C:5]([OH:6])=[N:22][C:20]([C:16]2[N:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[N:21][CH:3]=1)([O-:12])=[O:11]
Reactant: N=C(N)c1cccnn1
Reactant: CCOC(=O)C(=CN(C)C)[N+](=O)[O-]
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(-c2cccnn2)nc1O
Yield: 86 %

Procedure:
A mixture of ethyl 3-(dimethylamino)-2-nitroacrylate, 35i-f, (1 g, 5.3 mmol) and pyridazine-3-carboximidamide (0.8 g, 5.3 mmol) in CH3OH (30 mL) was added with NaOCH3 (3.4 g, 6.36 mmol) and refluxed overnight. The pH of reaction mixture was adjusted to 7 by addition of concentrated HCl. The solids were filtered to afford the product, 35i-g, (1 g, 86%). 1H NMR (300 MHz, DMSO) δ 7.77 (dd, J=4.8, 7.5 Hz, 2H), 8.29 (d, J=8.4 Hz, 1H), 8.77 (s, 1H), 9.26 (d, J=4.5 Hz, 1H). LC-MS (M+H)+ 220.1
Reaction SMILES: C(N(CC)C(C)C)(C)C.[OH:10][C:11]([C:14]1[N:15]=[C:16]([CH2:22][CH2:23][CH3:24])[NH:17][C:18]=1[C:19]([OH:21])=[O:20])([CH3:13])[CH3:12].[CH3:25][C:26]1[O:30][C:29](=[O:31])[O:28][C:27]=1[CH2:32]Cl.C(OCC)(=O)C>CN(C)C(=O)C.O>[OH:10][C:11]([C:14]1[N:15]=[C:16]([CH2:22][CH2:23][CH3:24])[NH:17][C:18]=1[C:19]([O:21][CH2:32][C:27]1[O:28][C:29](=[O:31])[O:30][C:26]=1[CH3:25])=[O:20])([CH3:13])[CH3:12]
Reactant: Cc1oc(=O)oc1CCl
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
1.76 ml of N,N-diisopropylethylamine were added to a suspension of 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] in 10 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes, after which 1.12 g of (5-methyl -2-oxo-1,3-dioxolen-4-yl)methyl chloride was added, and the mixture was stirred at 60° C. for 4 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to give 1.14 g of the title compound as a viscous oil.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of bromine (0.9 ml, 17.45 mmol) in glacial acetic acid (10 ml) was added dropwise to a stirred solution of 4-(methanesulfonyl)phenol (Description 26; 3 g, 17.45 mmol). The resulting solution was stirred at ambient temperature for 16 h. Bromine (0.45 ml) in glacial acetic acid (5 ml) was added dropwise and the solution was stirred for 2 h. The excess acetic acid and bromine were removed in vacuo and the residue was azeotroped with toluene to give the desired compound as an off-white solid (3.54 g, 81%). 1H NMR (250 MHz, CDCl3) δ8.06-8.05 (1H, d, J 2.3 Hz), 7.73-7.69 (1H, dd, J 8.6, 2.3 Hz), 7.06-7.02 (1H, d, J 8.6 Hz), and 3.06 (3H, s).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].[Cl-].[NH4+].N>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(Nc1ccccc1)Nc1nc(C=C2SC(=O)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.52 g of 2,4-thiazolidinedione, 0.6 g of ammonium chloride, 0.6 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Cl:26][C:27]1[C:33]([O:34][CH3:35])=[CH:32][C:30]([NH2:31])=[C:29]([CH3:36])[CH:28]=1.Cl.N1C=CC=CC=1>>[Cl:26][C:27]1[C:33]([O:34][CH3:35])=[CH:32][C:30]([NH:31][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[C:29]([CH3:36])[CH:28]=1
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3c2sc2ccc([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of 286 mg (0.99 mmol) of 4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 10 mL of 2-ethoxyethanol containing 131 mg (1.42 mmol) of 4-chloro-5-methoxy-2-methylaniline (WO 8501939A1) and 131 mg of pyridine hydrochloride is heated at reflux temperature overnight. The reaction mixture is cooled slightly and an additional 100 mg (0.58 mmol) of 4-chloro-5-methoxy-2-methylaniline is added and the reaction mixture is heated at reflux temperature overnight. The mixture is cooled to room temperature and the solid is collected by filtration, then suspended in methanol. Aqueous ammonium hydroxide is added and the mixture is partitioned between ethyl acetate and water. The organic layer is washed with water, then dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration, and washed with diethyl ether to give 110 mg (26%) of a tan solid, mp>305° C.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6][CH:5]1C(OCC)=O>O.C(O)C>[O:3]=[C:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of potassium hydroxide (24.6 g, 375 mmol) in H2O (400 ml) was added to a solution of 1-benzyl 4-ethyl 5-oxo-1,4-azepanedicarboxylate (40.0 g, 125 mmol) in ethanol (400 ml). The resulting mixture was heated at reflux for 2.5 hours. Reaction was then cooled to rt., the ethanol was removed under reduced pressure, and was diluted with 200 ml brine and 300 ml ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to an orange oil in vacuo. The product was isolated by flash chromatography (silica gel, 40% EtOAc/hexane) yielding a clear, colorless oil (22.6 g, 73%). 1H NMR (CDCl3) δ 7.31-7.30, 5.12, 3.65-3.63, 2.68-2.60, 1.81-1.78; IR (liq.) 1698, 1475, 1454, 1442, 1423, 1331, 1320, 1295, 1270, 1241, 1191, 1165, 1091, 900, 699 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([B])[CH:30]=[CH:31][CH:32]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([S:24][CH3:23])[CH:32]=1)[CH3:2]
Reactant: [B]c1cccc(S(C)(=O)=O)c1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(SC)c1
Yield: 5.7 %

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (178 mg; 0.43 mmol), 3-methylsulphonyl-phenylboron acid (140 mg; 0.86 mmol) and tetrakis-triphenylphosphine-palladium (69 mg; 0.060 mmol) in dimethoxyethane (4 ml), ethanol (3 ml) and sodium carbonate (387 mg; 3.6 mmol) in water (4.5 ml), 10 mg (63%) 5-(2,6-diethoxy-3′-methylsulphanyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a greyish powder analogously to example 2a after crystallization from methanol.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:12])[CH:6]=[N:7][CH:8]=1)[CH2:18][CH2:17]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 72.6 %

Procedure:
(5-Bromo-pyridin-3-yl)-acetic acid methyl ester (230 mg, 1.0 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182 mg, 1.0 mmol), CuI (40 mg, 0.21 mmol), Cs2CO3 (650 mg, 2.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.1 mL, 0.8 mmol) were dissolved in dioxane (4.0 ml) and the resulting reaction mixture was heated at 150° C. for 2 hours before it was poured into H2O (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (230 mg, 72.5%) as light brown oil. MS: 317.1 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:14]=2)=[O:11])=[CH:8][C:7]=1[O:28]C)(=[O:4])=[O:3].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:28][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][C:6]=1[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH:14]=1)=[O:11]
Reactant: COc1ccc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(O)c(NS(C)(=O)=O)c2)cc1O
Reaction time: 20 h
Yield: 12.2 %

Procedure:
To a stirred suspension of 4-methanesulfonylamino-3-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.25 g) in dry CH2Cl2 (50 ml) under nitrogen, was added boron tribromide (1.5 ml) then stirring continued for a further 20 hours. Methanol (50 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this was repeated 2 more times. Purification by column chromatography over silica gel eluting with chloroform containing methanol (10-20%) gave 3-hydroxy-4-methanesulfonylamino-N-(3-methanesulfonylamino-4-hydroxyphenyl)benzamide (143 mg, 15%) as an off-white solid.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14]([N-:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:15])#[N:12]>>[OH:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[OH:24])[CH2:17][NH:16][C:14](/[C:13](=[CH:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)/[C:11]#[N:12])=[O:15]
Reactant: O=CC=Cc1ccccc1
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Product: N#C/C(=C\C=C\c1ccccc1)C(=O)NCc1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding cinnamaldehyde (0.018 ml, 0.14 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (Example 2, 0.03 g, 0.14 mmol). Afer refluxing for 2 h and recrystallization from ethanol, a yellow solid was obtained (0.027 g, 59%). The product gave the following analytical data:
Reaction SMILES: CO.[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14]CC([O-])=O)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-:23].[K+].[K+]>O>[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14][OH:23])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=CCCC(=O)[O-])COc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=CCO)COc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 176.5 %

Procedure:
Into methanol (1,200 ml) and water (400 ml) were dissolved 120 g (0.25 mol) of [4-(p-nitrophenoxy)-3-methyl-2-butenyl]acetate. With stirring at room temperatures, 40 g (0.29 mol) of potassium carbonate were added therein, and stirred for one hour. The reaction liquid was added into water and extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off, whereby 98.5 g of the title compound were obtained. (Yield: 98.5%)
Reaction SMILES: C[Si](C)(C)[C:3]#[N:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O[CH2:26][C:27]1[NH:28][C:29]([C:33]2[C:34]([CH3:43])=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=2)[C:38]([OH:40])=[O:39])=[C:30]([CH3:32])[N:31]=1>C(#N)C>[C:3]([CH2:26][C:27]1[NH:28][C:29]([C:33]2[C:34]([CH3:43])=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=2)[C:38]([OH:40])=[O:39])=[C:30]([CH3:32])[N:31]=1)#[N:4]
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of trimethylsilanecarbonitrile (376 mg, 3.79 mmol) in acetonitrile (20 mL). Tetrabutylammonium fluoride (3.8 mL, 1 M in THF) was added to the reaction. This was followed by the addition of 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5, 190 mg, 0.73 mmol), in portions. The reaction mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as eluent to furnish 190 mg (97%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)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>[CH3:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 76 %

Procedure:
3-Bromo-2-methylpyridine (172 mg, 1 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (309 mg, 1 mmol) were dissolved in THF (10 ml) and combined with a solution of sodium carbonate (425 mg, 4 mmol) in water (1 ml). The mixture was purged with argon, PdCl2(PPh3)2 (35 mg, 0.05 mmol) was added and the mixture was stirred under reflux for three days, diluted with ethyl acetate (30 ml), the phases were separated and the organic layer was washed with brine and dried (sodium sulfate). After concentration under reduced pressure the residue was purified with column chromatography (silica, gradient of 0 to 30% ethyl acetate in DCM) to yield 209 mg (0.76 mmol, yield 76%) MS (multi-mode) m/z=275.2 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:15]=[C:16]([C:19](Cl)=[O:20])[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:22]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C(COC)OC>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:22]=1
Reactant: CSc1ccc2c(c1)C=Cc1ccc(C(=O)Cl)cc1S2(=O)=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CSc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2(=O)=O

Procedure:
Dissolve the crude 8-methylthiodibenzo[b,f]thiepin-3-carboxylic acid chloride-5,5-dioxide in glyme, and with stirring under dry nitrogen, add a filtered solution of 1.1 equivalents of lithium tri-tertiary butoxy-aluminum hydride in glyme dropwise with cooling (ice-bath). Stir the mixture for 1 hour after the addition is complete and pour into ice-cold dilute hydrochloric acid. Isolate the crude title compound by extraction with chloroform and purify the compound by column chromatography on silica gel usin toluene as the solvent.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][CH:39]=1)[O:29][Si](C)(C)C(C)(C)C.[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.C1COCC1.Cl.C(OCC)C>[C:12]1([C:10]2[N:11]=[C:7]([CH2:6][CH2:25][C:26]3[CH:27]=[C:28]([OH:29])[CH:37]=[CH:38][CH:39]=3)[S:8][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
n-Butyllithium (1.53 g, 24 mmol) in hexane (9.5 mL) was added dropwise to a stirred solution of 2-methyl-4,5-diphenylthiazole (5 g, 20 mmol) in dry THF (150mL,) maintained at -78° C. under an atmosphere of nitrogen. After 25 minutes a solution of [3-(bromomethyl)phenoxy]dimethyl(1,1-dimethylethyl)silane (6.60 g, 22mmol) in THF (10mL) was added dropwise, the mixture stirred at -78° C. for 10 minutes and the allowed to warm to room temperature. The reaction mixture was poured onto saturated ammonium chloride solution, extracted with CH2Cl2, the extracts combined, dried over sodium sulfate and concentrated in vacuo to leave an oil which was dissolved in THF (25 mL). A solution of tetra-n-butylammonium fluoride (6.77 g, 26 mmol) in THF (25.86 mL) was added and the mixture stirred at room temperature for 30 minutes before being diluted with 1N HCl solution (100 mL). The mixture was extracted with CH2Cl2, the combined extracts dried over sodium sulfate and concentrated to leave an oil. Chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (2:1) as eluent furnished 3-[2-(4,5-diphenyl-2-thiazolyl)ethyl]phenol (4.13 g, 58%), mp 166°-168° C. after recrystallization from a mixture of hexanes and CH2Cl2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[CH:13][CH:11]=[O:12]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1
Solvent: Cc1ccccc1
Product: COc1cccc(C=CC=O)c1
Temperature: 120 °C
Yield: 24.6 %

Procedure:
680 mg of m-anisaldehyde and 1.52 g of formylmethylenetriphenylphosphorane were dissolved in 10 ml of toluene and stirred under heating at 120 ° C. for 7 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography [hexane/ethyl acetate=9/1→4/1] to give 199 mg of the title compound as a yellow oily substance.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][C:25]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([CH:15]=[CH:16][C:17]([O:19][CH2:24][CH3:25])=[O:18])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(C(C)C)cc2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.20 g of 3-[4-(4-isopropylphenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 4.91 g of ethyl 3-[4-(4-isopropylphenoxy)-benzoyl]acrylate in the form of an oil.