Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Intermediate 73 (24 g, 0.096 moles) was taken in a RB flask and to this acetic anhydride (230 ml) and sodium acetate (55.2 g, 0.673 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as brown solid (26 g, quant. yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87(dd, J=8.2,3.0 Hz, 1H), 7.48-7.36(m,3H), 7.10-6.99(m, 3H), 2.33(s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](=O)[CH3:11].[NH3:13].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH:10]([NH2:13])[CH3:11]
Reactant: N
Reactant: CC(=O)C1Cc2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)C1Cc2ccccc2C1
Reaction time: 14 h

Procedure:
1-(2,3-dihydro-1H-inden-2-yl)ethanone (44 mg, 0.275 mmol) was dissolved in methanol (2 mL), and 7 M methanolic ammonia was added (1 mL, 7 mmol). This was allowed to stir at rt for 4 h, at which time sodium borohydride (31 mg, 0.824 mmol) and a catalytic drop of glacial acetic acid was added. Stirring continued for 14 h at rt, after which time the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with a small amount of 10% aqueous sodium carbonate, dried with magnesium sulfate, and concentrated. The residue was then taken on in subsequent reactions without further purification or characterization.
Reaction SMILES: [C:1]1([Mg])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.CN(OC)[C:15]([C@@H:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[C:1]1([C:15]([C@H:17]2[CH2:18][N:19]([C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20](=[O:22])[CH2:21]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Mg]c1ccccc1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In an atmosphere of nitrogen, phenylmagnesium bride (3 mol/l diethyl ether solution, 15 ml) was added dropwise to tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (2.49 g, 9.0 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (50 ml) under ice-cooling and then extracted with ethyl acetate (8 ml×2). The organic layer was washed with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.36 g (89%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CC(C)=O>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: CCOc1ccccc1N
Reactant: Cc1ccccc1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Product: CCOc1ccccc1NC(=O)c1ccccc1C
Yield: 94.5 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 13.7 g of o-ethoxyaniline were dissolved in 200 ml of acetone. A 4.7 g (0.033 mol) amount of phosphorus pentoxide was gradually added to the prepared solution at 30° - 40° C. After the addition, the reaction mixture was refluxed for 3 hours with stirring. The acetone was removed and the residual product was poured into water and was extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and the toluene was removed to obtain 24.1 g (94.5%) of a clear pink liquid, having a boiling point of 148° C/0.04 mm Hg and nD20 of 1.5929.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](I)=[C:7]([CH2:25][C:26]([N:28]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[CH2:37]([O:39]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:38].[F-].[NH4+]>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:37]([C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([N:28]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:30][O:31][CH3:32])=[O:27])(=[O:39])[CH3:38]
Reactant: COCCN(CCO)C(=O)Cc1c(I)c(OCOC)cc(OCOC)c1C(=O)c1ccc(OC)cc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COCCN(CCO)C(=O)Cc1c(C(C)=O)c(OCOC)cc(OCOC)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
2-[3,5-Bis(methoxymethoxy)-2-iodo-6-(4-methoxy-benzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-methoxyethyl)acetamide (0.56 g, 0.91 mmol) obtained in Example 135, Step 2 was dissolved in toluene (10 mL), and ethoxyvinyl tributyltin (0.46 mL, 1.4 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.05 g, 0.071 mmol) were successively added thereto in an atmosphere of argon. The reaction mixture was stirred for 3 hours under heating and reflux, and then cooled to room temperature. To the mixture was added a saturated aqueous solution of ammonium fluoride, followed by stirring at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (10 mL), and a 1 mol/L hydrochloric acid was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled and neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by liquid separation. After the aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (20 mL), and activated carbon (400 mg) was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/0-9/1 to obtain 2-[2-acetyl-3,5-bis(methoxymethoxy)-6-(4-methoxybenzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-methoxyethyl)acetamide (0.25 g, 51%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=O)[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]>C(OCC)C.C1COCC1>[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)[C@H](NC(=O)C(F)(F)F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC=C1CCN(c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (5.59 g, 15.8 mmol) (dried on vacuum overnight before use) was suspended in ethyl ether (65 mL). The suspension was cooled to −15° C. Potassium tert-butoxide (1.0 mol/L) in THF (12.6 mL, 12.6 mmol) was added slowly and the bright orange suspension was stirred at −25° C. to −10° C. for 1 h while the color persisted. 2,2,2-Trifluoro-N-[(4R)-1-(2-methyl-4-nitro-pyrazol-3-yl)-5-oxo-azepan-4-yl]acetamide (1.38 g, 3.95 mmol) was dissolved in THF (12 mL) and added to the ylide at −15° C. The mixture was slowly allowed to warm to room temperature and stirred overnight then quenched with saturated ammonium chloride, and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give 2,2,2-trifluoro-N-[(4R)-5-(methoxymethylene)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[F:7][C:8]1[CH:9]=[C:10]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)[CH:11]=[C:12]([F:14])[CH:13]=1>>[C:23]([O:22][C:21](=[O:27])[NH:20][C@@H:16]([CH2:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)[C@H:17]([OH:18])[CH2:19][N:1]=[N+:2]=[N-:3])([CH3:24])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN=[N+]=[N-]
Reaction time: 16 h

Procedure:
Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added to tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75–80 degrees C. and stirred for 16 hours. The reaction is monitored by TLC to insure completion. The solvent is removed under reduced pressure. The concentrate is partitioned between ethyl acetate and water, the phases are separated and the organic phase is washed with bicarbonate and saline, dried over anhydrous sodium sulfate and concentrated to give the title compound, TLC (ethyl acetate/hexane) Rf=0.45; (MH+)=343.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(O)(=O)C>[CH2:13]([N:3]1[CH2:4][CH2:5][C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2]1)[C:14]([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)C=O
Reactant: Oc1cccc2c1CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)CN1CCc2cccc(O)c2CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (see Demarinis et al. J. Med. Chem. 1984, 27, 918-921) (60 mg, 0.37 mmol), trimethylacetaldehyde (400 μL, 3.7 mmol), trimethyl orthoformate (390 μL, 3.7 mmol) and glacial acetic acid (40 μL) in 1-methyl-2-pyrolidinone (2.5 mL) was stirred at rt for 2.5 h. Sodium triacetoxyborohydride (388 mg, 1.8 mmol) was then added and the mixture was stirred at room temperature for 16 h. The mixture was then loaded on top of a silica gel-SCX (sulfonic acid) column and eluted first with methanol, then with 2 M ammonia in methanol. The latter fraction was evaporated and the resulting 3-neopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol was used in the next step without further purification. (M+H)+=234.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.62 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1N aqueous sodium hydroxide solution (2.4 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.50 g, 85%) of 3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 112-113° C.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:26][C:22]1[CH:21]=[C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4cccc(C)c4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1cccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)c1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 15B for the product of Example 1H.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>>[ClH:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Reactant: C1CNCCN1
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(F)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-Chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-fluorophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (40% yield) as a cream solid. ESI/MS 324 (M+H); RT=2.44 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.71 (2H, m); 7.54 (2H, m); 7.23 (2H, m); 6.95 (1H, d, J=9 Hz); 3.33 (4H, br s); 2.95 (4H, br s).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][NH:6]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][NH:6]1
Reactant: COC(CN1NCc2ccc([N+](=O)[O-])cc21)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(CN1NCc2ccc(N)cc21)OC
Temperature: 25 °C

Procedure:
To a mixture of 1-(2,2-dimethoxyethyl)-6-nitro-2H-indazole (1.89 g, 7.52 mmol) and NH4Cl (337 mg, 6.01 mmol) in ethanol/H2O (2:1, 75 mL) at room temperature was added Fe (1.28 g, 23.7 mmol) and the mixture was heated for 2 hours at 70 C. The mixture was cooled to room temperature, filtered through celite, which was washed with hot methanol (5×20 mL), and the combined filtrate concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), filtered, the filtrate was concentrated under reduced pressure to provide 1-(2,2-dimethoxyethyl)-2H-indazol-6-ylamine as an amber oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.26 (m, 6 H), 4.23 (d, J=5.42 Hz, 2 H), 4.71 (t, J=5.42 Hz, 1 H), 5.30 (s, 2 H), 6.49 (m, 2 H), 7.35 (m, 1 H), and 7.73 (s, 1 H); MS (ESI) 222 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[C:16]([O-])([O-])=O.[K+].[K+].CO.O=C(C)C(P(=O)(OC)OC)=[N+]=[N-]>CCOCC>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 20 h

Procedure:
To a stirred suspension of tert-butyl 4-formylpiperidine-1-carboxylate (0.427 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and MeOH (25 mL) was added all at once the Bestman-Ohira reagent, dimethyl 2-oxo-1-diazo-propylphosphonate (0.461 g, 2.40 mmol, see Synthesis 2004, 1, 59-62). Stirring was continued for 20 hours under nitrogen. The reaction was diluted with Et2O (50 mL), washed with a 2:1 mixture of water and aqueous saturated NaHCO3 (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Yield: 253 mg (55%). 1H NMR (400 MHz, CDCl3) δ 3.72 (m, 2H), 3.19 (m, 2H), 2.58 (m, 1H), 2.10 (d, J=2 Hz, 1H), 1.77 (m, 2H), 1.61 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-3yl-acrylic acid ethyl ester was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [C:1]1([CH3:29])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH:12]([NH2:27])[C:11]2=[O:28])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>O1CCCC1>[C:1]1([CH3:29])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:13][CH:12]([NH:27][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)=[O:38])[C:11]2=[O:28])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 54.5 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (411 mg) was dissolved in tetrahydrofuran. m-Tolyl isocyanate (146 mg) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 300 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[S:10][C:3]=12.C([Mg]Cl)(C)C.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[S:10][C:3]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
In a round bottom flask, 7-chloro-2-iodothieno[3,2-b]pyridine (200 mg, 0.68 mmol) was suspended in THF (6 mL). The reaction mixture was cooled with a NaCl-ice bath (−12 to −8° C. internal temp) and isopropylmagnesium chloride (2.0 M in THF, 0.406 mL, 0.812 mmol) was added dropwise. The reaction mixture was stirred for 1 h at the same temperature, and then tributyltin chloride (0.29 mL, 1.08 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over ˜1 h then quenched with an aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude residue was purified by column chromatography (SiO2-11 g-Et3N 2%, hexanes 100% 5 min, to hexanes:EtOAc, 9:1 in 15 min) to isolate 162 mg (52%) of 7-chloro-2-tributylstannanyl-thieno[3,2-b]pyridine as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:6]=[S:5]1(=[O:7])[NH:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCNS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl] sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), was added potassium carbonate (71.0 mg, 0.514 mmol). The mixture was stirred at room temperature for 17 h, then diluted with water (7.5 mL). The reaction mixture was extracted with ethyl acetate (3×2 mL) and the extract was washed with water (2×2 mL), dried over MgSO4 and concentrated to give 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:26])([CH2:23][NH:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[O:15].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:23][N:24]([C:30]([C:29]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:28]=1[Cl:27])=[O:31])[CH3:25])([OH:26])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Product: CN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Similarly prepared to Example 6 from 5-amino-1-(4-fluorophenyl)-N-{3,3,3-trifluoro-2-hydroxy-2-[(methylamino)methyl]propyl}-1H-pyrazole-4-carboxamide and 2-chloro-6-fluorobenzoic acid.