Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CN(C)C=O>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:34][CH:33]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OCC1CCCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCCC2CSc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A solution of 57.92 g (0.504 mole) of 2-hydroxymethylpiperidine and 236 g (1.24 mole) of tosylchloride in one liter of pyridine was stirred at 25° C. overnight. The mixture was quenched in water and the aqueous mixture was extracted with several portions of methylene chloride. The combined methylene chloride extract was extracted with 1M sulfuric acid solution followed by 1M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give an oil which was shown by NMR and mass spectrometry to be 1-[(4-methylphenyl)sulfonyl]-2-piperidinemethanol ester with 4-methylbenzene sulfonic acid. A mixture of 40.78 g (0.0964 mole) of the oil, 24.60 g (0.171 mole) of p-chlorothiophenol and 25.4 g of sodium carbonate in 200 ml of dimethylformamide was stirred at 100° C. overnight and then quenched in dilute sodium hydroxide. The mixture was extracted with several portions of methylene chloride. The combined extract was extracted with several portions of 1M sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was crystallized from ether-hexane to give 29.73 g of the solid product. On standing at room temperature, the solid melted.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2N)sc2ccccc12
Yield: 62.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.5 g), ethyl acetate (140 ml), 10% palladium-carbon and hydrogen (500 mg, 60 atm kg/cm2), ethyl 2-(2-amino-4-methylanilino)benzo[b]thiophene-3-carboxylate (3.7 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[C:25]1([CH3:58])[C:26]([C:31]([CH2:33][N:34]2[C:40]3[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:39]=3[N:38]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:37][CH:36]([NH2:56])[C:35]2=[O:57])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.Cl>O1CCCC1.O.C(N(CC)CC)C>[C:25]1([CH3:58])[C:26]([C:31]([CH2:33][N:34]2[C:40]3[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:39]=3[N:38]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:37][CH:36]([NH:56][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:35]2=[O:57])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)OCc3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 0.5 h
Yield: 239.5 %

Procedure:
Ethyl 3-aminobenzoate (4.29 g) was dissolved in tetrahydrofuran (600 ml), triphosgene (2.54 g) was added under ice-cooling, triethylamine (2.19 ml) was added thereto five times every 3 minutes after divided into five portions. A solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (9.78 g) in tetrahydrofuran (200 ml) was added, the mixture was stirred for 30 minutes, subsequently, stirred overnight at room temperature. The reaction mixture was poured into water (3 L), acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=2:1), to thereby obtain 13.3 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:13][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c(C)c1
Product: CC(=O)OCc1ccnc(C)c1
Temperature: 25 °C
Yield: 15 %

Procedure:
2,4-Dimethyl-pyridine 1-oxide (24.6 g, 0.2 mol) was stirred in acetic anhydride (200 ml) in an oil bath (140-150° C.) for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (2:1)) to afford 5.1 g (15%) of acetic acid 2-methyl-pyridin-4-ylmethyl ester as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 2.15 (3H, s), 2.56 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J=5.0 Hz), 7.11 (1H, s), 8.48 (1H, d, J=5.0 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:49])([C:45]([F:48])([F:47])[F:46])[C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:49])([C:41]([F:42])([F:43])[F:44])[C:45]([F:47])([F:48])[F:46])=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: FC(F)(F)C(F)(c1ccc(CCl)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 150 mg (0.365 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (enantiomer 1, Example 51A) in 3 ml of dry acetonitrile is mixed with 139 mg (0.47 mmol) of 1-(chloromethyl)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]benzene [prepared as described in EP 0 009 787-A2] and 100 mg (0.73 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is then filtered and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 210 mg (0.31 mmol, 86% of theory) of an oil are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(Cl)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=395.1 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([N:5]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:3]=[CH2:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(O)C>[CH2:2]([N:5]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH:3]=[CH2:4]
Reactant: COC(=O)CCCCCCCCBr
Reactant: C=CCN(c1ncnc2nc[nH]c12)C1CCCCC1
Agent: [Na]
Solvent: CC(C)O
Product: C=CCN(c1ncnc2c1ncn2CCCCCCCCC(=O)OC)C1CCCCC1
Yield: 37 %

Procedure:
To a solution of 0.7 g. (30 mmole) sodium in 100 ml. propan-2-ol are added 7.7 g. (30 mmole) 6-(N-allyl-N-cyclohexylamino)-purine (compound of Example 8 j), the reaction mixture is heated to 40° C. for 10 minutes, 7.5 g. (30 mmole) methyl 9-bromononanoate are added thereto, the reaction mixture is heated under reflux for 16 hours and evaporated and the residue is taken up in water, extracted with dichloromethane, dried and evaporated. After chromatography on silica gel (elution agent: dichloromethane/methanol 95:5 v/v), there are obtained 4.8 g. of the title compound (37% of theory) in the form of an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH2:21][NH2:22]>C(O)C>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([NH:21][NH2:22])[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NN
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Solvent: CCO
Product: CC[C@@H]1C(=O)N(C)c2cnc(NN)nc2N1C1CCCC1

Procedure:
Intermediate B and hydrazine (6 equivalents) in ethanol was heated in a microwave for 1 h at 120° C. The solvent was removed to give Intermediate B-2. This material was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][C:15]=2[F:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Nc1ncc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1-c1ccc(F)cc1F

Procedure:
A solution of 3,5-dibromopyridin-2-amine (2.95 g, 11.71 mmol) and 2,4-difluorophenylboronic acid (1.85 g, 11.71 mmol) in toluene was degassed via nitrogen bubble for 20 mins. The mixture was then added Pd(PPh3)4 (0.677 g, 0.585 mmol), K3PO4 (2 M, 11.8 mL, 23.4 mmol) and ethanol (1 mL) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (150 mL), washed with brine, separated, dried over Na2SO4 and concentrated to give a crude 5-bromo-3-(2,4-difluorophenyl)pyridin-2-amine (3) which was used directly in next step without purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(Cl)(Cl)[Cl:23].S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:23])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: ClC(Cl)Cl
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of dimethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-9 for the 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30].C1(C2[O:41]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH:28]([OH:41])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cc1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 4.6 mL, 4.75 mmol) in THF (12 mL) at −78° C. was added a solution of methyl 2-(7-chloro-5-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.48 g, 1.5 mmol) in THF (12 mL) over 20 mins. The reaction mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.6 g, 2.3 mmol) in THF (12 mL) was added over 10 min and the resulted reaction mixture was stirred for an additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2 mL). The mixture was allowed to warm up to room temperature and diluted with EtOAc (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (250 mg, 51%). 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.65 (3H, s), 3.7 (3H, s), 5.79 (1H, s), 6.62 (1H, s), 7.35-7.59 (3H, m), 8.95 (1H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][OH:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][OH:36])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=2)=[O:10])C>>[N:1]1([CH2:20][C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[C:11]([C:9]([OH:10])=[O:8])[NH:12]3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1cc2ccc(C)cc2[nH]1
Reactant: c1c[nH]cn1
Product: O=C(O)c1cc2ccc(Cn3ccnc3)cc2[nH]1

Procedure:
6-Imidazol-1-ylmethyl-1H-indole-2-carboxylic acid was prepared from imidazole and 6-methyl-1H-indole-2-carboxylic acid ethyl ester using the procedures described by Peter E Cross, et. al; Journal of Medicinal Chemistry 1986, 29(9), 1637-43.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].CO>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11]([OH:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Temperature: -10 °C

Procedure:
To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-methyl CBS oxaborolidine (7.4 mL of a 1 M soln in toluene, 7.4 mmol, Aldrich). Toluene 190 mL was added and the reaction was cooled in an ice-salt bath (bath temp.=−10° C.). BH3-SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the mixture was stirred for an additional 1 h. The mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temp. was kept below 0° C. The mixture was concentrated in vacuo. Et2O (1L) was added, and the mixture was washed with 1 M H3PO4 (3×), satd NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with 1M H3PO4 (3×200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ion ESI) m/z=207 (MH+), 189 (MH+-H2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].F[C:25]1[C:30]([F:31])=[C:29]([I:32])[CH:28]=[CH:27][N:26]=1.CS(C)=O>C(OCC)(=O)C>[F:31][C:30]1[C:25]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)=[N:26][CH:27]=[CH:28][C:29]=1[I:32]
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1nccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3nccc(I)c3F)ccc2=O)cc1
Temperature: 85 °C

Procedure:
To a 20 mL microwave vial (Biotage) was added 0.70 g (3.03 mmol) 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 1.26 g (9.08 mmol) potassium carbonate, 1.10 g (4.54 mmol) 2,3-difluoro-4-iodopyridine and 15 mL DMSO, A yellow suspension formed and the vial was sealed and heated at 85° C. for 48 h on a heat block. The suspension was cooled, diluted with ethyl acetate, and washed twice with 10 mL brine. The organic layer was dried over sodium sulfate, filtered, and evaporated onto silica gel. Purification by flash chromatography (silica gel 0-100% hexanes/EtOAc gradient, followed by 10% MeOH in EtOAc) afforded 3′-fluoro-4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one as a yellow solid. LCMS (M+H)+ 453.3.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](OC)=[O:24]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:24]=[C:23]([CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1cccs1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A solution of 37.2 g (0.3 mole) dimethyl methylphosphonate (Aldrich) in 400 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 194 ml of 1.6 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 23.4 g (0.15 mole) methyl 2-(2-thienyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water the aqueous phase extracted with 100 ml portions of chloroform (3) the combined organic extracts were backwashed (50 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-152° (<0.5 mm) to give 4.8 g dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2a).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C1=CCCCC1
Product: CC(=O)OC1CCCCC1
Reaction time: 0.5 h

Procedure:
The procedure of Example 16 was repeated to conduct the reaction of acetic acid with cyclohexene except that the reaction temperature was 130° C. and the reaction time was 0.5 hour. The result is shown in Table 3, that is, cyclohexyl acetate was produced in high yield within a short time.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2.[OH-].[K+].[CH3:20][CH:21]1[CH2:26][C:25](=[O:27])[O:24][C:23](=[O:28])[CH2:22]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:25](=[O:27])[CH2:26][CH:21]([CH3:20])[CH2:22][C:23]([OH:28])=[O:24])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2
Reactant: CC(C)CCCCc1cc2cc(Cl)ccc2[nH]1
Reactant: CC1CC(=O)OC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)CCCCc1cc2cc(Cl)ccc2n1C(=O)CC(C)CC(=O)O
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-(5-methyl-hexyl)-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, 4-methyl-dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: I[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)#[CH:14]>C(#N)C.[Cu]I>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:14]#[C:13][C:15]3[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=3)[S:3][C:4]=2[CH:10]=1
Reactant: C#Cc1ccc(NC)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(I)sc2c1
Agent: [Cu]I
Solvent: CC#N
Product: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A 5 mL microwave tube is charged with 2 (1 equiv), 4-ethynyl-N-methyl-2-nitroaniline (1 equiv) [Pd(PPh3)4] (0.05 equiv), CuI (0.05 equiv) and TEA (5 equiv) in ACN (5 vol). The suspension is irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 5 min. After cooling to room temperature, the solvent is evaporated in vacuo. The residue is purified over silica gel using Hexanes:DCM (0-100%) as the eluent to afford the coupling product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH3:33]>C(OCCO)C>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:29]=[CH:28][C:27]=1[CH3:33]
Reactant: Cc1ccc(N)cc1Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(Cl)c3)c2cc1OC
Yield: 99.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 170.0 mg (1.2 mmol) of 2-chloro-4-amino-toluene to give 350.9 mg (99.4%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 353.9,355.8.