Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:25][CH2:24]2)[N:17]=3)=[CH:10][CH:9]=1.Cl.[NH2:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]1([C:23]2([C:18]3[N:17]=[C:16]4[S:15][C:14]([C:11]5[CH:12]=[CH:13][C:8]([NH:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:9][CH:10]=5)=[N:22][C:21]4=[CH:20][CH:19]=3)[CH2:25][CH2:24]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Ic1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Temperature: 80 °C

Procedure:
Sodium tert-butoxide (21 mg, 0.213 mmol) was added to a mixture of 2-(4-iodophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (40.4 mg, 0.089 mmol), tert-butyl 3-aminopropanoate hydrochloride (19 mg, 0.107 mmol), Pd2(dba)3 (2.0 mg, 2.2 μmol), and Xantphos (5.1 mg, 8.9 μmol) in toluene (1.0 mL), and the resulting mixutre was heated under argon at 80° C. for 15 h. The reaction mixture was then cooled to 25° C. and concentrated onto silica gel. Chromatographic purificaiton (silica gel, 0-50% EtOAc/hexanes) furnished tert-butyl 3-(4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenylamino)propanoate as a yellow oil. MS (ESI) m/z: Calculated: 471.2; Observed: 472.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[C:4]([CH3:12])=[N:3]1.[N+](=[CH:15]C(OCC)=O)=[N-]>>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH2:15][C:5]=2[C:4]([CH3:12])=[N:3]1
Reactant: Cc1nn(C)c2c1C(=O)CCC2
Reactant: CCOC(=O)C=[N+]=[N-]
Product: Cc1nn(C)c2c1CC(=O)CCC2

Procedure:
1,5,6,7-Tetrahydro-1,3-dimethyl-4H-indazol-4-one is reacted with ethyl diazoacetate according to the procedure described in Example 3 to give 4,6,7,8-tetrahydro-1,3-dimethyl-5(1H)-cycloheptapyrazolone. This is reacted with N,N-dimethylformamide dimethyl acetal according to the procedure described in the first paragraph of Example 6 to give 4-(dimethylaminomethylene)-4,6,7,8-tetrahydro-1,3-dimethyl-5(1H)-cycloheptapyrazolone. The dimethylaminomethylene compound is then reacted with hydrazine according to the procedure described in Example 7 to give 4,5,6,7-tetrahydro-1,3-dimethyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:19][O:29]1)=[O:20])[CH3:2]
Reactant: C=C(CCCCCCCC1CCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCCCC2CCCCC2)CO1

Procedure:
5.25 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 9.2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester and 11.3 g of m-chloroperbenzoic acid in 100 ml of methylene chloride.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][C:20]([O:22]C)=O)[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])(=O)C.C(SCC(CC(OC)=O)C([NH:32][C@H](C(O)=O)CCCNC(=N)N)=O)(=O)C>>[C:20]([CH2:19][CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])(=[O:22])[NH2:32]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Product: NCCCC[C@H](NC(=O)C(CS)CC(N)=O)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-methoxycarbonylmethylpropanoyl]-L-lysine for the Nα -[3-acetylthio-2-methoxycarbonylmethylpropanoyl]-L-arginine in the procedure of Example 19, Nα -[2-(carbamoylmethyl)-3-mercaptopropanoyl]-L-lysine is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:25][C:16]1[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Cc1cccc(-c2nn3ccccc3c2C(=O)O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nn3ccccc3c2Br)n1
Yield: 87.7 %

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.92 g, 3.6 mmol), sodium bicarbonate (1.04 g, 12.4 mmol), and N-bromosuccinimide (0.71 g, 4.0 mmol) in DMF (25 mL) is stirred for 2 hours at room temperature. The reaction is then diluted with water (50 mL) and extracted with EtOAc (3×15 mL). The organic layer is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to afford 0.91 g (87%) of desired product as a dark green solid. UV (95% EtOH) λmax 282 nm (ε 12089), 233 nm (ε 21813). TOF MS ES+ exact mass calculated for C13H10BrN3 (p+1): m/z=288.0136. Found: 287.0058. Anal. Calcd for C13H10BrN3: C, 54.19; H, 3.50; N, 14.58. Found: C, 54.10; H, 3.60; N, 14.48.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O.O>C(Cl)(Cl)Cl>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 140 °C
Yield: 3.9 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (2.0 g), diethyl ethoxymethylenepropanedioate (3.15 g) and N,N-dimethylformamide (16 ml) was stirred at 140° C. for an hour and a half. To the reaction mixture was added diethyl ethoxymethylenepropanedioate (1.57 g). The reaction mixture was stirred for an hour and cooled to ambient temperature. To the mixture was added water to five crystals, which were filtered off and dissolved in a mixture of chloroform and methanol. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, to which was added chloroform. The mixture was heated and insoluble materials were filtered off to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (0.12 g) melting at 310°-312° C. Further, the filtrate was concentrated under reduced pressure and allowed to stand at ambient temperature to give crystals (1.63 g), which were purified by a column chromatography on silica gel (60 g) (developing solvent: 3% methanol-chloroform solution). The crystals were dissolved in 10% methanol-chloroform solution. The solution was treated with activated charcoal and concentrated under reduced pressure. The residue was recrystallized from chloroform to give crystalline diethyl [{6-methanesulfonamido-4-quinazolinylamino}methylene]propanedioate (1.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:40][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Temperature: 80 °C

Procedure:
The compound of example 3 (5.7 g, 0.021 mol) was dissolved in carbon tetrachloride (125 mL). AIBN (350 mg) and NBS (4.1 g, 0.0231 mol) were added and the reaction mixture was refluxed at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to obtain a crude material containing 85% mono bromo and 10% dibromo product and 5% starting material. The crude was used directly without purification for the preparation of the compound of example 5.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][C:29]([CH3:31])=[N:28][CH:27]=3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:7]=1)=[CH2:5])C.O.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.[Cl-].[Na+].O>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:9]=2)[CH:25]=[CH:24][C:23]=1[C:26]1[O:30][C:29]([CH3:31])=[N:28][CH:27]=1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnc(C)o3)c(OC)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnc(C)o1
Temperature: 50 °C

Procedure:
4-(1-Ethoxyvinyl)-N-(3-methoxy-4-(2-methyloxazol-5-yl)phenyl)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-2-amine (70 mg, 0.15 mmol) was dissolved in dioxane (10 mL). Water (0.5 mL) and hydrochloric acid (conc., 0.038 mL, 0.45 mmol) were added. The mixture was heated at 50° C. for 10 min. Sodium bicarbonate (s, 0.5 g) was added and mixture was stirred. Brine (2 mL) was added. The mixture was extracted with EtAOc (×2). The organic phase was dried (sodium sulfate) and evaporated to give the title compound as a dry film 64 mg (97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2].Cl.[F:24][C:25]([F:37])([F:36])[C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][NH:31][CH2:32]2)=[O:27].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:32][CH:33]4[N:28]([C:26](=[O:27])[C:25]([F:36])([F:37])[F:24])[CH:29]([CH2:35][CH2:34]4)[CH2:30]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Reactant: O=C(N1C2CCC1CNC2)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC4CCC(C3)N4C(=O)C(F)(F)F)c(F)cc2c1=O
Temperature: 60 °C
Yield: 22.1 %

Procedure:
A mixture of 653 mg (2 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 732 mg (3 mmoles) 8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan,hydrochloride and 985 mg (6.48 mmoles) 1,8-diazabicyclo[5.4.0] undec-7-ene in 30 mL acetonitrile was heated at 60° C. for 72 hours. The solution was cooled and evaporated to dryness. The residue was worked up with dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated to give an oil. Purification was achieved by silicagel column chromatography to obtain 220 mg of 7-(8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. MP 205° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5]P(=O)(OC)OC.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:5]=[CH:20]/[C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: CCOC(=O)CCCCCOc1c(C=O)occc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution, under nitrogen, of 0.187 g (3.9 mmole) of sodium hydride (50% dispersion in mineral oil) in 10 ml of dry THF was added dropwise 1.2 g (4.95 mmole) of dimethyl (2-oxo-4-phenylbutyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.0 g (3.54 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone, prepared by the procedure of Examples 1 and 2, in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.90 g (64%) of pure 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, m.p. 38.5°-40°. NMR (CDCl3): δ1.26 (3H, t, J=7 Hz); 2.35 (2H, t, J=6.5 Hz).
Reaction SMILES: CO[O:3][P:4]([O:9][CH2:10][CH2:11][O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:17](=[CH:24]/[C:25]2[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])/[C:16]1=[O:32])=[O:14])([O:6]OC)=[O:5].Br[Si](C)(C)C>C(#N)C>[P:4]([O:9][CH2:10][CH2:11][O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:17](=[CH:24]/[C:25]2[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])/[C:16]1=[O:32])=[O:14])([OH:6])([OH:5])=[O:3]
Reactant: COOP(=O)(OCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCOP(=O)(O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 42 h
Yield: 46.1 %

Procedure:
To the suspension of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester (180 mg, 0.4 mmol) in 12 mL of acetonitrile was added bromotrimethylsilane (120 mL, 0.91 mmol) and N,O-bis-(trimethylsily)acetamide (225 mL, 0.91 mmol) sequentially. The reaction mixture was then stirred at room temperature for 42 h and concentrated. The residue was then washed with ethyl acetate, water, and 0.1 N HClaq and dried in a vacuum oven to yield 75 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxy-ethyl ester as a red solid. 1H NMR (400 MHz, CDCl3) δ 12.40 (s, br, 1H, NH-1′), 7.84–7.86 (m, 1H, H-4), 7.76–7.79 (m, 1H, H-7), 7.63 (s, 1H, H-vinyl), 7.19–7.22 (m, 2H, H-5, 6), 6.11 (d, J=1.95 Hz, 1H, H-4′), 4.52–4.56 (m, 2H, NCOOCH2CH2OPO(OCH3)2-1), 4.15–4.19 (m, 2H, NCOOCH2CH2OPO(OCH3)2-1), 2.37 (s, 3H, CH3), and 2.33 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([S@:12]([NH-:14])=[O:13])([CH3:11])([CH3:10])[CH3:9]>[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1(/[CH:6]=[N:14]/[S@@:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@]([NH-])=O
Reactant: O=CC1CCCC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)[S@@](=O)/N=C/C1CCCC1
Temperature: 25 °C
Reaction time: 71 h

Procedure:
The title compound was synthesized according to General Method H utilizing cyclopentanecarboxaldehyde (15.0 g, 152.8 mmol, 1.0 eq.), (R)-t-butylsulfinylamide (24.1 g, 198.7 mmol, 1.3 eq.), and flame-dried CuSO4 (73.2 g, 458.5 mmol, 3.0 eq.). The resulting mixture was stirred at rt for 71 h. The reaction mixture was filtered through a pad of Celite and the pad was rinsed with CH2Cl2 (5×100 mL). The combined organic extracts were concentrated under reduced pressure yielding a clear yellow oil (37.2 g). Purification by flash chromatography (SiO2, h=6 cm, Ø=10 cm) using 1:9 EtOAc-cyclohexane as eluent gave the product (23.8 g, 78% isolated yield) as a clear pale yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.99 (d, J=5.5 Hz, 1H), 3.02-2.87 (m, 1H), 1.97-1.78 (m, 2H), 1.78-1.55 (m, 6H), 1.18 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:24]C(=O)C)=[C:8]2[C:16]([Br:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Br:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:3])[C:7]=2[OH:24])[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2-c2ccccc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)cn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-bromo-7-cyano-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 428 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(OC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.-butyl 4'[(2-n-butyl-6-dimethylaminocarbonyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1](=O)([O:5]CC)[O:2][CH2:3][CH3:4].CCOCC.[H-].[Na+].[CH3:16][C:17]1([CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[O:21][CH2:20][CH2:19][O:18]1>CCCCCC.C(O)C>[CH2:3]([O:2][C:1](=[O:5])[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][C:17]1([CH3:16])[O:18][CH2:19][CH2:20][O:21]1)[CH3:4]
Reactant: CC(=O)CCCC1(C)OCCO1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)CCCC1(C)OCCO1

Procedure:
11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrous ether was added to 4.55 g. (0.1 moles) of a 53 per cent dispersion of sodium hydride in mineral oil which was washed with anhydrous hexane and dried under nitrogen. This mixture was stirred under nitrogen and 8.6 g. (0.05 mole) of the ketal ketone, 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over a period of two hours. A gentle reflux was maintained throughout the addition and the refluxing was continued for an additional period of approximately 11/2 hours. The solution was then cooled with an ice bath, 20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was added and it was stirred for 45 minutes to destroy any unreacted sodium hydride. The suspension was diluted with an equal volume of ether and the ice cold suspension was then added to a rapidly agitated mixture of 6 ml. of glacial acetic acid and 200 ml. of ice water. The etheral layer was separated, and the aqueous layer was additionally extracted twice with ether. The extract was washed with saturated sodium bicarbonate and with a saturated sodium chloride, dried with sodium sulfate, filtered and evaporated in vacuo to give the crude β-keto ester, 6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p. 110°-112°C at 0.2 mm.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[C:19]([N:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:31][CH:30]=2)[CH2:37][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:20]=[CH:21][C:22]=1[F:29]
Reactant: O=CC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CCCC3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (800 mg, 1.93 mmol) in DCE (16 mL) was treated with cyclopentanecarboxaldehyde (Aldrich, 283 mg, 2.89 mmol) then with sodium triacetoxyborohydride (1.22 g, 5.78 mmol). The resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was allowed to cool down, dichloromethane (40 mL) was added and the organic layer was washed twice with water and with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silicagel afforded the title compound as a colorless oil (590 mg, 60%). HPLC, Rt: 6.47 min (purity: 97.1%), LC/MS, M+(ESI): 498.1. 1H NMR (CDCl3) δ: 7.42 (m, 4H), 7.22 (m, 1M), 7.14 (m, 4H), 6.92 (m, 1H), 6.75 (m, 1H), 4.55 (s, 2H), 3.89 (s, 3H), 3.33 (d, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.29 (m, 1H), 1.65 (m, 2H), 1.70-1.46 (m, 6H), 1.42-1.15 (m, 6H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C1COCC1>[C:9]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[C:23]3=[O:28])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCc2c1cccc2-c1cccc2ccccc12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(cccc3-c3cccc4ccccc34)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.50 mL, 1.0 mmol) was added to a solution of 4-(naphthalen-1-yl)-2,3-dihydro-1H-inden-1-one (254 mg, 0.98 mmol) in THF (3.4 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (230 mg, 1.0 mmol) in THF (1.7 mL) was added via cannula. After 1 h at −78° C., the mixture was allowed to slowly warm to 0° C. After 30 min at 0° C., the reaction was quenched with saturated aqueous NH4Cl (25 mL), diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 53 mg (13%) of methyl 4-((4-(naphthalen-1-yl)-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.