Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](N)=[O:4].[C:14]([Cl:17])(=[O:16])[CH3:15]>C(O)C>[ClH:17].[OH:1][C@@H:2]([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:16][CH2:14][CH3:15])=[O:4]
Reactant: CC(=O)Cl
Reactant: NC(=O)[C@@H](O)[C@@H](N)c1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H](O)[C@@H](N)c1ccccc1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 10.0 g of (2S, 3S) 2-hydroxy-3-amino-3-phenylpropionamide in 100 ml of ethanol was slowly added 16 ml of acetyl chloride at 0° C. The reaction mixture was refluxed for 40 h then cooled to room temperature. The reaction mixture was filtered to remove the ammonium chloride salt. The filtrate was concentrated to about one third of its original volume and diluted with 150 ml of ether. The precipitated product was filtered and washed with 100 ml of ether to give 10.9 g of ethyl (2S, 3S) 2-hydroxy-3-amino-3-phenylpropionate hydrochloride salt as a white powder, m.p. 149-151° C.; [α]D25 -25.6° (EtOH, c 1.1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]([O:19][CH3:18])=[O:21])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1

Procedure:
The procedure described in Example 3 is followed. Starting from 1.5 g (4.88 mmol) of 5-bromo-2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine, obtained according to the protocol described in Examples 1.3 or 2.3, 1.05 mg (5.83 mmol) of 3-methoxycarbonylphenylboronic acid, 4.6 g (14.61 mmol) of caesium carbonate, 0.400 g (0.49 mmol) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and 20 ml of a THF/water (9/1) mixture and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (9/1), 1.6 g (90%) of the expected product are obtained in the form of a yellow-white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([NH:46][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[CH:11]=2)=[O:21])[CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 60.2 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.098 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea as solid (0.113 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 7.54 (m, 6H), 7.39 (m, 3H), 7.18 (d, 1H), 6.93 (d, 1H), 6.41 (s, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 3.25 (q, 2H), 1.45 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 523 (M−OEt)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:12][NH:13][C:14]([NH2:16])=[O:15]>C(O)CCC>[CH3:8][CH2:9][CH2:10][CH2:11][O:7][C:2]([C:1]([NH:16][C:14]([NH:13][CH3:12])=[O:15])=[O:5])=[O:3]
Reactant: CNC(N)=O
Reactant: C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCO
Product: CCCCOC(=O)C(=O)NC(=O)NC

Procedure:
8.5 ml of oxalyl chloride was added to 200 ml of tetrahydrofuran, 9.2 ml of butylalcohol was added dropwise for 30 minutes with stirring in an ice-water bath, and the solution was stirred for a hour in an ice-water bath. 7.4 g of methylurea was slowly added thereto and the solution was stirred for 15 hours at room temperature. After tetrahydrofuran was distilled off under the reduced pressure, water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed three times with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The crude product was passed through a column of silica gel. Ethyl acetate was distilled off, and ether was added thereto. The precipitate was filtered off and recrystallized from ethyl acetate-hexane to give 11.2 g of 5-methyloxaluric acid butyl ester (compound 20).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]3[CH:22](O)[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14]3)=[O:11])=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]3[O:11][C:22]4[CH2:21][CH2:20][C:15]5([O:16][CH2:17][CH2:18][O:19]5)[CH2:14][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC2(CCC1O)OCCO2)c1ccc(OCC2CC2)c(F)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluoro-N-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzamide (14.2 g) in dimethyl sulfoxide (100 mL) were added triethylamine (16.3 mL) and sulfur trioxide-pyridine complex (18.6 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (100 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (14.0 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title compound (6.00 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.02 min; [M+H]+=420.12.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:26][CH2:25]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH3:36][S:37]([NH:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:25][CH2:26][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:28][CH2:29]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (27 mg) obtained in Example 426 is dissolved in pyridine (2 ml), and thereto is added methanesulfonyl chloride (7 μl) under ice-cooling. The mixture is stirred at room temperature overnight, and thereto are further added pyridine (3 ml) and methanesulfonyl chloride (500 μl) under ice-cooling. The mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is extracted with chloroform. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=9/1) to give the title compound (21.2 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:7](CC#N)[CH2:6][S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.Cl.[C:15]([OH:18])(=[O:17])[CH3:16]>>[O:1]=[C:2]1[CH:7]([CH2:16][C:15]([OH:18])=[O:17])[CH2:6][S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2
Reactant: N#CCC1CSc2sccc2C1=O
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)CC1CSc2sccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of 25 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetonitrile in 100 ml of acetic acid is added 50 ml of concentrated hydrochloric acid and the mixture is refluxed under heating for 2 hours. Then, the mixture is poured into 500 ml of ice-cold water. The precipitated crystals are collected by filtration, washed with water and recrystallized from a mixed solvent of toluene and isopropyl ether to give 16.5 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid as white crystals, melting at 124°-127° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:30][C:31]1[C:39]2[C:38]([CH2:40]Br)=[CH:37][S:36][C:35]=2[CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:13]([CH2:40][C:38]2[C:39]3[C:31]([CH3:30])=[CH:32][CH:33]=[CH:34][C:35]=3[S:36][CH:37]=2)[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[N:10]=1)[CH3:2].[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:10]([CH2:40][C:38]2[C:39]3[C:31]([CH3:30])=[CH:32][CH:33]=[CH:34][C:35]=3[S:36][CH:37]=2)[C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH3:2]
Reactant: CCOC(=O)CCCSc1nc2ccc(OC)cc2[nH]1
Reactant: Cc1cccc2scc(CBr)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCSc1nc2cc(OC)ccc2n1Cc1csc2cccc(C)c12
Product: CCOC(=O)CCCSc1nc2ccc(OC)cc2n1Cc1csc2cccc(C)c12
Temperature: 100 °C
Yield: 17 %
Yield: 10 %

Procedure:
539 mg (1.44 mmol) of 4-(5-methoxybenzimidazole-2-ylthio)butanoate ethyl ester were suspended in 4 ml of toluene followed by the addition of 616 μl (3.60 mmol) of diisopropylethylamine and 384 mg (1.59 mmol) of 4-methyl-3-(bromomethyl)benzo[b]thiophene and heating at 100° C. After allowing to react overnight, saturated sodium bicarbonate solution was added followed by extraction with ethyl acetate. The organic phase was washed with water followed by drying with magnesium sulfate and concentrating the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 114 mg of 4-(1-((4-methylbenzothiophene-3-yl)methyl)-5-methoxybenzimidazole-2-ylthio)butanoate ethyl ester (yield: 17%) and 68 mg of 4-(1-((4-methylbenzothiophene-3-yl)methyl)-6-methoxybenzimidazole-2-ylthio)butanoate ethyl ester (yield: 10%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[S:15]1[CH:19]=[C:18](B(O)O)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[S:15]1[CH:19]=[C:18]([C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[C:2]([Cl:1])[N:10]=2)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A round-bottom flask was charged with 6-chloro-2-iodo-9-isopropyl-9H-purine (prepared in Example 15c, 3.31 g, 0.0103 mol), benzo[b]thiophen-3-ylboronic acid (2.74 g, 0.0154 mol), and tetrakis(triphenylphosphine)palladium(0) (1.19 g, 0.0103 mol). To this mixture was added toluene (80 ml), ethanol (25 ml) and aqueous sodium carbonate solution (2M, 21 ml). The flask was sealed and the reaction mixture was stirred at 90° C. for 1 h. Water was added to the cooled mixture, which was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 20 to 50% EtOAc in hexane to afford the title compound as a solid, which was recrystallized from 1:1 methanol/water. 1H NMR (400 MHz, DMSO-d6): δ=9.15 (d, 1H), 8.85 (s, 2H), 8.17 (d, 1H), 7.62 (t, 1H), 7.53 (t, 1H), 5.06 (m, 1H), 1.71 (d, 6H); MS m/z 329.0 (M+1).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7](NC([C@H]2CC[C@H](O[N+]([O-])=O)CC2)=O)[CH2:6][CH2:5]1)=[O:3].N1CCC(NC([C@H]2CC[C@H]([O:38][N+:39]([O-:41])=[O:40])CC2)=O)CC1>C(O)C>[NH2:1][C:2]([N:4]1[CH2:5][CH2:6][CH:7]([O:40][N+:39]([O-:41])=[O:38])[CH2:8][CH2:9]1)=[O:3]
Reactant: O=C(NC1CCNCC1)[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: NC(=O)N1CCC(NC(=O)[C@H]2CC[C@H](O[N+](=O)[O-])CC2)CC1
Solvent: CCO
Product: NC(=O)N1CCC(O[N+](=O)[O-])CC1
Yield: 25 %

Procedure:
trans-N-(1-aminocarbonylpiperidin-4-yl)-4-nitroxycyclohexanecarboxylic acid amide from trans-4-nitroxycyclohexanecarboxylic acid piperidin-4-ylamide; yield 25% of theory; solvent: ethanol; m.p. 187°-188° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Br:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>C(#N)C>[Br-:15].[CH2:6]([S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: C1CCSC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: O=C(C[S+]1CCCC1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
Tetrahydrothiophene (53.2 g) was dissolved in 400 ml of acetonitrile, and thereto was slowly added a solution obtained by dissolving 100 g of phenacyl bromide in 300 ml of acetonitrile, and the solution was stirred at room temperature for 3 hours, thereby a powder was precipitated. The reaction solution was poured into 1,500 ml of ethyl acetate, and the powder was filtered out and dried, thus 137 g of phenacyltetrahydrothiophenium bromide was obtained.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30]Br>C(O)C>[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:30][CH2:29][Br:28])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccccc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 16.7 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-(1-methyl-3-oxo-3-phenyl-propenylamino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.22 g, 17%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=O.P([Cl:32])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]=[C:3]([Cl:32])[C:2]([F:15])([F:14])[F:1]
Reactant: COc1ccccc1NC(=O)C(F)(F)F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1N=C(Cl)C(F)(F)F
Temperature: 82 °C
Yield: 84 %

Procedure:
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide, 12.24 g (45.6 mmol) of diphenyl chlorophosphate, 4.64 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22.5 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.55 g of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 84.3%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[O:9][CH:10]=[C:11]([CH3:13])[N:12]=1.C(N(CC)CC)C>CCOCC>[CH3:13][C:11]1[N:12]=[C:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:9][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1coc(N)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Nc1nc(C)co1
Reaction time: 2 h

Procedure:
Ethyl chloroformate (1.05 ml, 0.011 mol) was added dropwise to a stirred solution of 2-amino-4-methyloxazole (1.0 g, 0.010 mol) and triethylamine (1.5 ml, 0.011 mol) in dry ether (50 ml) at 5°-10° C. The mixture was stirred for 2 hours at 0°-5° C. then the white solid was filtered off and washed well with water to remove triethylamine hydrochloride. Residue (0.5 g) was recrystallised from chloroform-petroleum spirit, m.p. 126° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:18])[N:6]2[CH3:17].[C:19]1(C)C=CC=C[CH:20]=1.C(O)C.C(C=P(CCCC)(CCCC)CCCC)#N>ClCCl.[Cl-].[Na+].O>[CH2:19]([O:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:18])[N:6]2[CH3:17])[CH3:20]
Reactant: Cc1ccccc1
Reactant: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOc1c(-c2cccnc2)ccc2c1CC(=O)N2C
Temperature: 105 °C

Procedure:
A microwavable vial was charged with 4-hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (48.1 mg, 0.2 mmol), toluene (2 ml), and ethanol (23.3 μL, 0.4 mmol). Cyanomethylene-tri-n-butylphosphorane (CAS#157141-27-0, 169 mg, 0.700 mmol) was then added to the vial. The reaction vial was sealed and was heated by microwave irradiation at 105° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted an additional two times with dichloromethane. The organic layers were combined dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 100%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1% NH4OH) to afford 4-ethoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1289 (M+H)+, 1H NMR (400 MHz, CD2Cl2) δ ppm 1.16 (t, J=6.95 Hz, 3H), 3.20 (s, 3H), 3.60 (s, 2H), 3.85 (q, J=6.91 Hz, 2H), 6.68 (d, J=8.08 Hz, 1H), 7.28 (d, J=8.08 Hz, 1H), 7.32 (dd, J=7.83, 4.80 Hz, 1H), 7.85 (dt, J=7.89, 1.99 Hz, 1H), 8.51 (dd. J4.80, 1.77 Hz, 1H), 8.71 (d, J=2.78 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17][CH2:18]C.ICCC.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC.CCN(C(C)C)C(C)C>C1COCC1>[CH3:27][O:31][N:32]([CH3:33])[C:12]([C:9]1[S:10][C:11]([CH2:16][CH2:17][CH3:18])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:14]
Reactant: [Li]CCCC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)N(C)OC)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At −75° C., a solution of 4-phenylthiophene-2-carboxylic acid (1.20 g, 5.88 mmol) in THF (15 mL) is treated with tert.-BuLi (10 mL, 1.6 M in pentane). The mixture is stirred at −70° C. for 1 h before 1-iodopropane (1.5 mL) is added. The reaction mixture is allowed to warm to rt and is stirred overnight. The reaction is quenched with sat. aq. NH4Cl (100 mL) and extracted with DCM (2×200 mL). The solvent of the organic extracts is evaporated and the residue is dissolved in DCM (15 mL). TBTU (2.03 g, 6.33 mmol), N,O-dimethylhydroxylamine (760 mg, 7.80 mmol) and DIPEA (2 mL) is added and the mixture is stirred at rt for 72 h before it is washed with water. The organic layer is separated and evaporated. The residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 4-phenyl-5-propyl-thiophene-2-carboxylic acid methoxy-methyl-amide (900 mg) as colourless oil; LC-MS: tR=1.05 min, [M+1]+=290.15.