Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)c(F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In DMF (90 ml) was dissolved 4-bromo-3-fluorophenol (9.0 g), and to the solution were added at room temperature potassium carbonate (9.8 g), sodium iodide (7.8 g) and 2-chloroethylpropylether(7.7 ml). The mixture was stirred at 90° C. for 16 hours and cooled to room temperature. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-2-fluoro-4-(2-propoxyethoxy)benzene (8.8 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=O)[CH3:8].[CH3:10][NH:11][C:12]#[C:13][CH3:14].[Al].[Cl-].[Na+].[OH-].[Na+]>O.C(O)C>[CH3:10][N:11]([C:12]#[C:13][CH3:14])[CH:7]([CH3:8])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CNC
Reactant: CC(=O)Cc1ccco1
Agent: [Al]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC#CN(C)C(C)Cc1ccco1

Procedure:
12.4 g. (0.1 mole) of 2-furyl-acetone are dissolved in 100 ml. of ethanol, whereupon 7.25 g. (0.105 moles) of methyl-propinyl amine are added. 3.5 g. of aluminium foiles are degressed with ethanol and thereafter activated with a solution of 1 g. of mercuric chloride and 15 g. of sodium chloride in 30 ml. of water. The activating solution is decanted after 6-8 minutes and the activated aluminum foils are washed with cold water and added to the alcoholic solution previously prepared under stirring. An exothermic reaction takes place and the temperature is kept at 15° to 30° C. by cooling. The reaction mixture is stirred for 24 hours, whereupon 30 ml. of 40% sodium hydroxide are added. The two phases are separated, the lower aqueous phase is extracted three-times with benzene. The benzene solutions are united with the previously separated alcoholic phase and evaporated. The residue consists of an organic oily layer and an aqueous phase which is extracted with benzene and the benzene solution is dried over potassium carbonate. The benzene is removed and the residue is distilled off in vacuo. Thus 6.7 g. of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are obtained. BP.: 113°-115° C./20 Hgmm; nD20 =1.4905.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-:4])=O.[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].OS(O)(=O)=O>C(O)C.O>[O:4]=[C:2]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCCCC(C)=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of ethyl oxalate (97.21 g) and hexan-2-one (66.58 g) was added dropwise to a solution of sodium ethoxide (50.1 g) in ethanol (160 ml) at reflux. The resultant mixture was heated at reflux for 2 h. The cooled reaction mixture was poured into a stirring mixture of ice (500 g) and water (100 ml) and the resultant slurry adjusted to pH 1.5(conc.H2SO4). The two layers were separated and the bottom layer extracted with toluene (2×200 ml). The combined organics were washed with brine (200 ml), dried and concentrated in vacuo to give a residue (107 g) which was purified by distillation to afford the title compound as a colourless liquid (67.2 g).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].[CH2:25]=[O:26].Cl>CCCCCC.O1CCCC1>[OH:26][CH2:25][C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CCO)cc2)CC1
Reaction time: 1 h

Procedure:
6.75 ml (10.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is saturated with formaldehyde, acidified by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:2) gives 1.80 g of 1-(hydroxymethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR7## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.94 g of 1-(fluoromethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene. ##STR8##
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH2:15]=[O:16].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH2:15][OH:16])[C:3]1=[O:13]
Reactant: C=O
Reactant: CC1(C)CN(c2ccccc2)NC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CN(c2ccccc2)N(CO)C1=O
Temperature: 25 °C

Procedure:
4,4-Dimethyl-1-phenyl-3-pyrazolidone (152 g) was dissolved in 600 ml of acetic acid. To the solution as prepared above, 97 g of an aqueous solution containing 37% of formaldehyde was dropped with stirring at room temperature. The resultant mixture was stirred for 2 hours. At the end of the time, the solvent was distilled away under reduced pressure. To the residue thus obtained, 100 ml of toluene was added, and water was separated at the toluene azeotrope under reduced pressure. A mixture of 900 ml of hexane and 700 ml of ethyl acetate was added to the residue as obtained above which was then dissolved therein by heating. The resultant solution was allowed to cool to room temperature. Crystals precipitated were collected by filtration to obtain 120 g of 4,4-dimethyl-2-hydroxymethyl-1-phenyl-3-pyrazolidone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1)#[N:2].CP(C)C.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:31][C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1)#[N:2]
Reactant: OCc1ccsc1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccsc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
Add sequentially to a slurry of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (100 mg, 0.36 mmol) in THF (2 mL) at 0° C.: trimethylphosphine (1.0 M in toluene, 530 μL, 0.53 mmol), 3-thiophenemethanol (61 mg, 50 μL, 0.53 mmol), and 1,1′-(azodicarbonyl)-dipiperidine (ADDP, 134 mg, 0.53 mmol). Warm up to room temperature and stir in a sealed vial for 18 h. Evaporate the reaction solvent and dissolve the residue in EtOAc (5 ML). Add water (2 mL) and load onto a Varian Chem Elut CE1005 solid-phase extraction cartridge (Varian part number 12198006). Elute with EtOAc, collect, and concentrate (about 50 mL). Purify the crude product on silica gel (12 g) eluting with 30-90% EtOAc/hexanes to give the title compound in 11% yield as a colorless oil. MS (ES): m/z 378 (M+1), 376 (M−1); 1H NMR (CDCl3): δ 7.81 (s, 1H), 7.40 (dd, 1H, J=8.4, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.30 (m, 1H), 6.86-6.81 (m, 2H), 5.60 (d, 1H, J=7.5 Hz), 5.29 (s, 2H), 4.41 (m, 1H), 3.16 (dd, 1H, J=15.2, 5.1 Hz), 2.90-2.72 (m, 2H), 2.63 (dd, 1H, J=15.4, 7.5 Hz), 2.36 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.18 (dd, 7H, J=6.8, 3.7 Hz), 1.18 (dd, 6H, J=6.8, 3.7 Hz).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]=[C:35]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:10]([CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:9]=[C:8]([C:14]2[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=2)[N:7]=4)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 90 °C
Yield: 98.9 %

Procedure:
A suspension of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (1.2 g, 3.09 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.8 g, 5.82 mmol), PdCl2dppf.DCM (339 mg, 0.46 mmol) and potassium carbonate (1.9 g, 13.9 mmol) in DMF (10 mL) was degassed and then heated at 90° C. under an atmosphere of nitrogen for 1.5 h. The cooled reaction mixture was diluted with ethyl acetate and water, the aqueous extracted with ethyl acetate and combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane, 1% TEA in final eluent) to give 4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a tan foam (1.5 g, 99%). LCMS: RT=3.77 min, [M+H]+=491
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:32]([NH2:34])[CH3:33])[CH:20]=[N:21][C:22]=1[N:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:34]([CH:32]([C:19]3[CH:20]=[N:21][C:22]([N:23]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]4)=[C:17]([CH3:16])[CH:18]=3)[CH3:33])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1-n1cc(C(F)(F)F)cn1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cc(C(F)(F)F)cn1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (200 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (240 mg, 0.79 mmol, Amine-47, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH3:17])[S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[OH2:13].[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH3:17])[S:16][C:10]=3[S:9][CH2:8][CH2:7]2)[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc2c(s1)SCCN(CCCCCl)C2=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(s1)SCCN(CCCCN1C(=O)c3ccccc3C1=O)C2=O
Reaction time: 6 h
Yield: 212.4 %

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one in 30 ml of dimethylformamide was added 2.3 g of potassium phthalimide and stirred at 70°-80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo. The resulting crude crystals were recrystallized from methanol to give 4.6 g of 4-(4-phthalimidobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one hydrate as white crystals, melting at 120°-121° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH2:20][C:19]([CH:17]=[O:18])=[CH:4][C:3]=2[CH:6]=1
Reactant: C=CC=O
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(O)ccc2OC1

Procedure:
The starting material is prepared as follows: 2,5-Dihydroxybenzaldehyde (25.0 g, 0.18 mol) is dissolved in 375 ml of 1,4-dioxane. To this is sequentially added potassium carbonate (50.0 g, 0.36 mol) and acrolein (15.22 g, 0.27 mol). The mixture is heated at reflux overnight, cooled, and partitioned between water and ether. The aqueous layer is removed and extracted twice with ether. The combined organic layers are dried (MgSO4) and evaporated. Trituration of the residue with dichloromethane, followed by filtration and drying, yields 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde, m.p. 163°-165° C., as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:13]([C:16]1[CH:17]=[C:18]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:20][CH:21]=1)=[C:14]=[O:15]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:17]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 93.1 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (0.79 ml, 4.5 mmol) was added slowly to a stirred solution of 2-(3-isocyanato-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 g, 4.1 mmol) in dry THF (8 ml) at RT under N2 After 16 hours the volatiles were removed in vacuo and the residue was partitioned between EtOAc/H2O. The organic layer was washed with brine (×1), then dried (Na2SO4), filtered and evaporated to give the title compound (1.6 g) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 8.52 (1H, s), 7.77 (1H, s), 7.47 (1H, dt), 7.25-7.17 (2H, m), 6.80 (1H, t), 6.08 (1H, t), 3.13-3.02 (2H, m), 3.02-2.89 (2H, m), 1.57-1.48 (2H, m), 1.39 (9H, s), 1.29 (12H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.4 %

Procedure:
4-Bromo-3-nitroanisole (10.00 g, 43.1 mmol), ethyl acrylate (5.62 mL, 51.7 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.789 g, 0.862 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.500 g, 1.724 mmol), and N,N-dicyclohexylmethylamine (10.10 mL, 51.7 mmol) were mixed in 1,4-dioxane (170 mL) and placed under an argon atmosphere. The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were separated, washed with brine, dried over magnesium sulfate, and concentrated. The resulting crude product was purified via silica gel flash column chromatography eluting with 0 to 20% ethyl acetate in hexanes to yield (E)-ethyl 3-(4-methoxy-2-nitrophenyl)acrylate (5.05 g, 20 mmol, 46.5% yield) as an orange solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[CH3:5].[OH-].[K+]>C(O)C>[C:12]([C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:20])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The obtained ester (VI-7.5 g.) is dissolved in 75 ml. of ethanol and, under stirring, 3.75 g. of KOH are added. The mixture is stirred for further three hours at ambient temperature and evaporated on a rotation evaporator. The residue is dissolved in 30 ml. of water and extracted with two 10 ml.-portions of chloroform. The aqueous layer is stirred for 15 minutes with 0.8 g. of active carbon and, after the separation of the carbon, it is acidified by means of 5% w./w. HCl. The resinous product is extracted with two 70 ml.-portions of ether and washed with two 50 ml. portions of water. After the drying of the ether extract over Na2SO4, it is evaporated to dryness on a rotation evaporator. Yield: 6.0 g. of a resinous product (84.3% theor.), which is crystallized from acetonitrile.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[CH:21]([C:23]1[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[O:22]>O1CCCC1>[Si:6]([O:5][C:4]1[CH:3]=[C:2]([CH:21]([OH:22])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[O:28])=[CH:34][CH:35]=2)[CH:15]=[CH:14][CH:13]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Iodophenoxy-tert-butyldimethylsilane (48.85 g, 146 mmol) was placed in a 250 mL flask with 180 mL of dry tetrahydrofuran at room temperature under nitrogen, Isopropylmagnesium chloride (73 mL, 146 mmol, 2.0 M solution in tetrahydrofuran) was added through an addition funnel to form a light yellow solution. The reaction was stirred at room temperature for 1 hour. In the meantime, 30 g of 4-formyl-N,N-diethylbenzamide was dissolved in 300 mL of dry tetrahydrofuran in another 1000 mL flask and cooled to −72° C. under nitrogen. The freshly prepared 3-phenoxy-tert-butyl-dimethylsilane magnesium chloride was slowly added into the 1000 mL flask. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was quenched with 24 mL of saturated aqueous ammonium chloride, diluted with 600 mL of diethyl ether, and washed with 600 mL of water followed by 150 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent was removed to give crude 4-{[3-(tert-butyl-dimethylsilanyloxy)phenyl]hydroxymethyl}-N,N-diethylbenzamide as a yellow oil. Crude yield was˜100%. The crude product was slurried in a solution of 20% ethyl acetate in pentane. The resulting white precipitate was collected by filtration, washed with pentane, and dried overnight (30 mmHg, 40° C.).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[CH:8]=[O:9].CN(C)C=O.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>C(N(CC)CC)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:4]2[O:3][C:2]([NH:1][CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([CH:8]=[O:9])[C:6](=[O:10])[C:5]=2[CH:11]=1)[CH3:16]
Reactant: CCc1ccc2oc(N)c(C=O)c(=O)c2c1
Reactant: C#CC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CNc1oc2ccc(CC)cc2c(=O)c1C=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture consisting of 2.17 g of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde, 25 ml of dimethylformamide, 5 g of ethyl propiolate and 0.1 ml of triethylamine was stirred at 90° C. for one hour and then the mixture was allowed to stand at room temperature. The resulting crystals were collected by filtration and recrystallized from acetone to obtain 1.65 g of ethyl 3-(6-ethyl-3-formyl-4-oxo-4H-1-benzopyran-2-yl)aminoacrylate as colorless needles melting at 201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:34])[C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=3)=[O:19])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:34])[C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:19])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCOc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
32 mg (purity 89%, 0.06 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 11 mg (44% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (2.13 gm, 7.92 mmol) in anhydrous THF under nitrogen was added borane dimethylsulfide complex (15.83 mmol, 7.91 mL) and the mixture was stirred at room temperature for 16 hours. A further aliquot of borane dimethylsulfide complex (15.83 mmol, 7.91 mL) was then added and stirring was continued at room temperature for a further 4 hours. LC-MS indicated complete consumption of starting material. Methanol was added cautiously until effervescence ceased then 2N hydrochloric acid (20 mL) was added. The mixture was stirred at room temperature for 20 hours then concentrated to dryness under reduced pressure. The residue was extracted with diethyl ether and the solution washed with water. The organic layer was dried with anhydrous sodium sulfate and the solvent removed under vacuum. The residue was dissolved in a mixture of dichloromethane and methanol, silica gel was added and the solvent removed under vacuum. The solid was placed on a column of silica gel (50 gm) and eluted with hexane-ethyl acetate (85:15) to give the title compound as a yellow oil which crystallized on standing (1.16 gm, 57%).