Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH:25]([C:10]1[CH:11]=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:13]=[CH:14][C:9]=1[OH:8])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: CCOc1ccc(Oc2ccc(OCc3ccccc3)c(C(C)C)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(Oc2ccc(O)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
Then, 4.4 g of 4-(4-ethoxyphenoxy)-2-isopropylphenyl benzyl ether and 100 ml of ethyl acetate were charged into a reaction vessel, and air in the vessel was replaced with nitrogen. Then, 0.50 g of 5% palladium-carbon was added, and nitrogen in the vessel was replaced with hydrogen, followed by vigorous stirring at room temperature for 24 hours. After hydrogen in the vessel was replaced with nitrogen, the reaction vessel was filtered with Celite, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 3.1 g of 2-isopropyl-4-(4-ethoxyphenoxy)phenol (yield, 93%).
Reaction SMILES: [CH3:1][N:2]([C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[C:3](=[O:35])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[C:3](=[O:35])[CH:4]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)=[CH:17][CH:18]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)O)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Yield: 110.4 %

Procedure:
Methyl 2-{N-methyl-N-[(R/S)-α-t-butoxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate 48e (1.46 g, 2.47 mmol) was treated with 50% TFA in CH2Cl2 (20 mL) for 1 hour and the solution was concentrated in vacuo to give the acid (1.46 g, 100%) as a syrup. MS (ESI): (M+H)+=535.9.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].O>CS(C)=O>[CH2:22]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Sodium hydride (343 mg, 14 mmol) was added to a stirring solution of 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (40 ml). After 15 minutes, 9-bromo-1-nonene (2.93 g, 14 mmol, available from Alfebro) was added and the resulting mixture stirred for 20 hours. The reaction was poured into water (40 ml) and extracted with three 50 ml aliquots of dichloromethane. The organic layers were combined, washed with water (40 ml) and saturated aqueous salt solution (20 ml). After drying the washed organic layers over sodium sulfate, the solvent was evaporated, leaving a colorless oil, 3-(8-nonenyl)-1-methylthymine, which solidified upon standing (2.76 g, 73% yield).
Reaction SMILES: [Mg].[CH3:2]I.[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl>CCOCC.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]([F:14])([F:15])[F:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Magnesium (3.71 g/0.153 mol) was placed into a flask of the egg-plant type, followed by the replacement of air by nitrogen and addition of 30 ml of ether. While gently stirring the mixture, a solution of methyl iodide (24.4 g/0.172 mol) in ether (20 ml) was slowly added dropwise to the mixture, and the resulting mixture was refluxed with heating for 30 minutes. The mixture was cooled to room temperature, and a solution of 4-trifluoromethylbenzaldehyde (25.1 g/0.144 mole) in ether (20 ml) was slowly added dropwise to the mixture. The mixture was refluxed with heating for 2 hours, 30 ml of water was added dropwise to the mixture with ice cooling, and hydrochloric acid (2N) was further added until the aqueous layer became transparent. The aqueous layer was separated from an ethereal layer, the aqueous layer was subjected to extraction with ether, and the ethereal layers were combined, and the combined layer was washed with an aqueous solution of common salt three times. After removal of ether, the layer was distilled at a reduced pressure, giving 1-(1-hydroxylethyl)-4-trifluoromethylbenzene [compound (I)] represented by the formula CF3C6H4CH(OH) CH3, b.p. 53°~55° C. (50.5 Pa), colorless transparent liquid, yield 98.3%.
Reaction SMILES: CCCCC[C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/C=C\CCCC(O)=O)[C@@H](O)C[C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:25][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH2:36])=[O:24])=[CH:13][CH:14]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2α, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.433 g. of p-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (3:7). The residue obtained by concentration of selected fractions, 0.455 g., is crystallized from acetone diluted with an equal volume of acetonitrile as the title compound, white, free-flowing crystals, m.p. 129.5°-130.8° C., having Rf 0.32 (TLC on silica gel in ethyl acetate-acetone (3:7)).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:7][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(Cc2c[nH]cn2)cc1
Product: O=[N+]([O-])c1ccc(Cc2c[nH]cn2)cc1

Procedure:
Prepared according to Arch. Pharm. 1975, 308, 755-759 by reacting 4-benzyl-1H-imidazole in fuming 100% nitric acid at -10 to -5° C. (30 minutes).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=3)[C:24](=[O:25])[O:18][N:17]=2)=[N:4][O:5][N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
A mixture of 4-amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (65.7 g, 208 mmol), N,N-carbonyldiimidazole (Sigma-Aldrich) (50.6 g, 312 mmol, 1.5 equiv.), and ethyl acetate (750 mL) was heated to 60° C. and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N hydrochloric acid (2×750 mL), dried over sodium sulfate, and concentrated. The crude product was triturated with a mixture of dichloromethane, ethyl acetate, and diethyl ether to give the desired product (60.2 g, 85%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.05 (m, 1H), 7.69 (m, 1H), 7.57 (t, 1H, J=8.7 Hz), 6.58 (s, 2H); C10H5BrFN5O3 (MW 342.08), LCMS (EI) m/e 342/344 (M++H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]([O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14])[CH3:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Sodium carbonate (21.1 g, 199 mmol) was added to a suspension of β-alanine ethyl ester hydrochloride (10.2 g, 66.4 mmol) and benzyl bromide (16.2 mL, 136 mmol) in acetonitrile (265 mL). The reaction mixture was stirred at ambient temperature overnight and then filtered through a layer of CELITE filter aid. The filter cake was rinsed with acetonitrile (100 mL). The filtrate was concentrated under reduced pressure to provide 20.28 g of ethyl 3-dibenzylaminopropionate as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].S(Cl)([Cl:41])=O>>[Cl:41][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Yield: 88 %

Procedure:
6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7. The solid was collected by filtration, washed with water and dried in a vacuum dessicator over phosphorus pentoxide to give 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g, 88%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.Br[C:13]1[N:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]2[CH:5]=[N:1][N:2]([C:13]3[N:18]=[C:17]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[CH:7]=1
Reactant: c1cncc(-c2cn[nH]c2)c1
Reactant: Brc1cccc(-c2ncccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(-c2cccc(-n3cc(-c4cccnc4)cn3)n2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
DMF was added to 0.8 g (5.5 mmol) of 3-(1H-pyrazol-4-yl)pyridine (Angew. Chemie, 2006, 118 (8) 1304), 1.3 g (5.5 mmol) of 2-(6-bromopyridin-2-yl)pyrimidine (WO 2010/006713), 0.29 g (0.82 mmol) of copper-8-hydroxyquinoline complex (cf. Tetrahedron Lett, 2006, 149) and 2.28 g (16.5 mmol) of potassium carbonate, and the mixture was stirred at 120° C. under argon for 16 hours. The entire reaction mixture was then concentrated under reduced pressure. The residue was admixed with aqueous citric acid, aqueous sodium chloride, ethyl acetate and diluted aqueous sodium hydroxide solution until the mixture gave an alkaline reaction (pH=9), the mixture was extracted four times with ethyl acetate and the combined organic phases were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/acetone). This gave 0.56 g (32% of theory) of 2-{6-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:38]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C1C=CN=CC=1)C.ClCCl>[O:35]1[C:31]2([CH2:30][CH2:29][N:28]([C:26]([N:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)[CH2:15][CH:10]([NH:9][C:43]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH2:11]3)=[O:27])[CH2:37][CH2:36]2)[O:32][CH2:33][CH2:34]1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
177 μl of triethylamine (1.27 mmol) and 15.5 mg of DMAP (0.127 mmol) were added to a solution of the amine hydrochloride from Example 62A (200 mg, 0.422 mmol) in dichloromethane (10 ml), and 84 mg of cyclopentanecarbonyl chloride (0.633 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrogen chloride solution and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 112 mg (52% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (4.0 g) synthesized in Example 265-1 and 1-bromo-4-(bromomethyl)benzene (2.94 g) were dissolved in N,N-dimethylformamide (40 mL), potassium tert-butoxide (1.32 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (4.65 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(F)cc1F)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (7.93 g, 38.2 mmol) in pyridine (76 mL) was drop wise added 2,4-difluorobenzene-1-sulfonyl chloride (20.3 g, 96.0 mmol) at 0° C. The mixture was stirred for 1 h at room temperature. The resulting solid was filtered, and washed with water, and dried under vacuum oven to give the N-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4-difluorobenzenesulfonamide (19.6 g, 90%) as a white solid, which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzaldehyde (3.00 g, 22.9 mmol) ad ethyl cyanoacetate (2.59 g, 22.9 mmol) are dissolved in absolute ethanol (100 ml). Piperidine (0.097 g, 1.14 mmol) is added, and the solution is stirred at room temperature until no more starting material is apparent by tic. This takes approx. 2 hours during which time a precipitate is formed. The precipitate is filtered and recrystallised, or alternatively, the crude reaction mixture is concentrated in vacuo and chromatographed over silica with cyclohexane/ethyl acetate mixtures as eluent to yield a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH2:6]/[C:5]/2=[CH:12]\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[C:17]([OH:25])[CH:16]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:25][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][CH2:23][CH3:24])[CH2:14][NH:13]/[CH:12]=[C:5]1\[CH2:6][N:7]=[CH:8][C:9]2[C:4]\1=[CH:3][C:2]([C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)=[CH:11][CH:10]=2
Reactant: OB(O)c1ccsc1
Reactant: CCCOc1ccc(CN/C=C2\CN=Cc3ccc(Br)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\CN=Cc3ccc(-c4ccsc4)cc32)cc1O

Procedure:
An amount of (4Z)-6-bromo-4-{[(3-hydroxy-4-propoxybenzyl)amino]methylene}isoquinoline}-1,3(2H,4H)-dione (135.0 mg, 0.32 mmol) is dissolved in 80% mixture of N,N dimethylformamide/water (4 mL). Tetrakistriphenylphosphine (44.0 mg, 0.04 mmol) is added followed by 3-thiopheneboronic acid (48.4 mg, 0.38 mmol) along with sodium carbonate (67.8 mg, 0.64 mmol). The reaction mixture is heated to 150° C.-180° C. for 3 minutes under microwave irradiation. The solvent is concentrated and the reaction mixture is partitioned between ethyl acetate (50 ml) and water (50 ml). The crude solid is then purified by high performance liquid chromatography to give 25.0 mg of a white solid. MS (ESI) m/z 549.8 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])(=[O:10])=[O:9].[CH2:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH2:19]>CN(C)C=O.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>[CH3:15][C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:19][CH:18]=[CH2:17])(=[O:10])=[O:9])([CH3:16])[CH2:13][CH3:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCC(C)(C)NS(=O)(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1ccccc1S(=O)(=O)NC(C)(C)CC
Temperature: 110 °C
Yield: 92.7 %

Procedure:
To a solution of 2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide (5.00 g, 16.3 mmol) in dimethylformamide (dry, N2-degassed, 20 mL) were added allyltribuylstannane (6.07 mL, 19.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (189 mg, 0.163 mmol). The mixture was heated at 110° C. for 15 h. The reaction was concentrated in vacuo and the residue was chromatographed (silica, 40% dichloromethane/hexanes to dichloromethane gradient) to provide N-(1,1-dimethylpropyl) 2-(2-propenyl)benzenesulfonamide (4.04 g, 92%) as an off-white solid: LCMS (neg. ion spectrum) m/z 266.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]OS(C)(=O)=O)(=O)=O.C(#[N:23])C.[OH-].[NH4+].Cl>O>[CH2:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:23][CH2:6]1
Reactant: CC#N
Reactant: CS(=O)(=O)OCCc1ccccc1CCOS(C)(=O)=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CCNCC2
Temperature: 100 °C

Procedure:
A 350 mL pressure vessel was charged with the methanesulfonic acid 2-[2-(2-methanesulfonyloxy-ethyl)-phenyl]-ethyl ester (3.2 g/10 mmol) in a 1:1 mixture of acetonitrile and ammonium hydroxide (100 mL total volume). The vessel was sealed and heated to 100° C. for one hour (pressure rises to ca. 40 psi) and then gradually allowed to cool. The reaction contents were poured into water and acidified to ca. pH 4 with concentrated hydrochloric acid. The aqueous solution was extracted with diethyl ether (100 mL), basified to pH 14 with 30% aqueous sodium hydroxide and finally extracted repeatedly with 10% methanol/methylene chloride (4×50 mL). The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to afford 2,3,4,5-tetrahydro-1H-benzo[d]azepine as a pale yellow oil (1.2 g/81%) that solidifies on standing. 1H NMR (400 MHz, CDCl3) δ 7.1 (m, 4H), 2.91 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(O)C=CC=CC=1.O>[C:18]1([N:17]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: Oc1ccccc1
Solvent: O
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1
Temperature: 190 °C
Yield: 82.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol and aniline (228 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium surface and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 240 mg of desired compound as solid in 83% of yield.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)([CH3:20])[CH3:19].O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC(C)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (4-fluorobenzoyl)acetate (23.21 g, 110.4 mmol) in 1,2-dimethoxyethane (150 ml) was added a suspension (4.42 g, 110 mmol) of 60% sodium hydride in liquid paraffin under ice-cooling and the mixture was stirred as it was for 0.5 hr. A solution of 4-isopropylbenzyl chloride (18.6 g 110 mmol) in 1,2-dimethoxyethane (50 ml) was added at room temperature and the mixture was stirred at 70° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.