Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11](OC)=[N:10]2)[CH2:6][O:5][N:4]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[F:1][C:2]([F:19])([F:18])[C:3]1[CH:7]([CH2:8][CH:9]2[NH:10][C:11](=[NH:21])[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:6][O:5][N:4]=1
Reactant: [NH4+]
Reactant: COC1=NC(CC2CON=C2C(F)(F)F)CCCC1
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(CC2CON=C2C(F)(F)F)N1

Procedure:
The title product of Example 117 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To an oven-dried round bottom flask was added 1.87 g of a 60% oil dispersion of NaH (46.8 mmol), DMF (50 mL), and methanol (1.89 mL; 46.8 mmol) under a N2 atmosphere. To this suspension was added a solution of 2-cyanoacetamide (1.97 g; 23.4 mmol) in DMF (10 mL) via syringe followed by a solution of the crude product of Step B (21.3 mmol) in DMF (20 mL). The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was the quenched with saturated aqueous NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=359 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:41]([O:43][C:44](=[O:48])[CH:45](Br)[CH3:46])[CH3:42]>C1COCC1.ClCCl>[CH2:41]([O:43][C:44](=[O:48])[CH:45]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:46])[CH3:42]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C(C)C)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.CO[C:26]1[CH:43]=CC(CNC2N=C(Cl)N=C3C=2NC=N3)=C[CH:27]=1.[H-].[Na+].IC(C)C>CN(C=O)C.O>[CH:26]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:43])[CH3:27]
Reactant: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2) The 6-(4-methoxybenzylamino)-2-chloropurine (496 mg, 1.7 mmol) was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine (508 mg, 89%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N+:11]([O-:13])=[O:12])=[N+]=[N-].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.O>[F:10][C:6]1[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]=[P:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=Nc1cccc(F)c1[N+](=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
To a solution of 1-azido-3-fluoro-2-nitrobenzene (500 mg, 2.75 mmol) in THF (4 mL) and water (1 mL) was added triphenylphosphine (720 mg, 2.75 mmol). The reaction mixture was stirred at room temperature for 45 min then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si—PCC, Et2O) to give the desired product as a yellow solid (844 mg, 73%). LCMS (Method A): RT 4.36 min; [M+H]+ 417
Reaction SMILES: [C:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:8]([O-:11])(=[O:10])[CH3:9].[CH:12]1C=CC=CC=1>>[C:1]1(/[CH:6]=[CH:9]/[C:8]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)[O-]
Reactant: O=CC1=CCCC1
Reactant: c1ccccc1
Product: COC(=O)/C=C/C1=CCCC1

Procedure:
1-cyclopentene-1-carboxaldehyde (9.60 g, 100 mmoles) was mixed with methyl (triphenylphosphoraylidene) acetate (40.1 g, 120 mmoles) in 80 ml of benzene and was brought to reflux under nitrogen for 5 hours. After cooling, the solids were filtered off, washed with ether and discarded. The solvent mixture was concentrated in vacuo, triturated with several volumes of pentane, filtered and stripped. Flash chromatography on silica gel afforded 14.8 g of the desired ester as a pure, white solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:33]([O:35][CH3:36])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].O.C(O)C(F)(F)F.C(=O)=O>CO>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:33]([O:35][CH3:36])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C=O
Solvent: O
Solvent: OCC(F)(F)F
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
8 g of Z-Ile-His-Lys(Boc)-OMe are suspended in a mixture of 80 ml of MeOH, 8 ml of H2O and 80 ml of trifluoroethanol, and hydrogenated with 800 mg of Pd-on-carbon (10% Pd) with CO2 -absorption until saturation, the initially undissolved material being dissolved. The catalyst is filtered off, the filtrate is concentrated to dryness and the resinous residue is crystallised from acetonitrile, yielding H-Ile-His-Lys(Boc)-OMe in the form of needles having a melting point of 129°-130°; Rf (I)=0.12; Rf (B)=0.14.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[CH:1]1([O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(F)c(F)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 6-cyclobutoxy-5-(3,4-difluorophenyl)nicotinic acid (example BZ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 455.1 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([C@@H:35]2[CH2:36][CH2:37][C:38]([CH3:47])([CH3:48])[NH:39]2)[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4)CC3)c21
Reaction time: 8 h
Yield: 79 %

Procedure:
4M HCl in dioxane (6 mL, 24 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(3-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.020 g, 0.034 mmol) in dry DCM (15 mL) and stirred overnight. The solvent was evaporated to dryness to reveal (S)-2-(3-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.015 g, 0.027 mmol, 79% yield). HPLC, 220 nm, retention time=1.91 minutes, 92% purity. LC/MS, retention time=2.15 minutes, (APCI+) m/z=484 [M+H]+. 1H NMR (400 MHz, D2O) 8.35 (s, 1H), 7.35-7.28 (m, 3H), 7.25-7.15 (m, 1H), 5.22 (t, J=8.20 Hz, 1H), 4.28-4.00 (m, 2H), 3.88-3.71 (m, 1H), 3.67-3.55 (m, 1H), 3.55-3.42 (m, 4H), 3.36-3.05 (m, 1H), 2.16 (dd, J1=7.81 Hz, J2=13.27 Hz, 1H), 2.10-1.93 (m, 1H), 1.88-1.70 (m, 4H), 1.36 (s, 3H), 1.30 (s, 3H), 0.94 (d, J=7.03 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[Br:23]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:23][CH:13]([C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1)=[O:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCC(=O)c1ccc(F)c2ccccc12
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)c2ccccc12
Temperature: 25 °C

Procedure:
Ethyl 6-(4-fluoro-1-naphthyl)-6-oxohexanoate (27.7 g) was dissolved in methylene chloride (100 ml), and bromine (14.6 g) was added dropwise with stirring at room temperature. After an hour of stirring at room temperature, a 10% aqueous solution of sodium sulfite was carefully added until disappearance of the red color of bromine, which was extracted with diethyl ether (300 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(4-fluoro-1-naphthyl)-6-oxohexanoate as an oil (34.9 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][CH:26]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[CH3:27])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].[CH3:35]CN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][CH:26]([C:28]2[O:29][C:30]([CH3:35])=[CH:31][CH:32]=2)[CH3:27])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(CCNCc1ccc(C(C)(C)C)cc1)c1ccco1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(C)CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)o1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
65 mg (0.33 mol) of 5-chloro-1H-indol-7-carboxylic acid, 89 mg (0.30 mmol) of [rac]-(4-tert-butyl-benzyl)-(3-furan-2-yl-butyl)-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel, heptane/EtOAc 4:1) to yield 94 mg (66%) product as a colorless viscous oil. MS (ISP) 477.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N+:3]=1[O-].C([O-])([O-])=[O:11].[Na+].[Na+].[C:16]([O:19][C:20](=[O:22])[CH3:21])(=O)[CH3:17]>>[C:20]([O:19][CH2:16][C:17]1[CH:1]=[C:2]([NH:3][C:4](=[O:11])[CH3:5])[CH:7]=[CH:6][N:8]=1)(=[O:22])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)cc[n+]1[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccnc(COC(C)=O)c1

Procedure:
6.5 g of the thus obtained 2-methyl-4-aminopyridine-N-oxide were dissolved in 80 ml of acetic anhydride and heated for 3 hours at 80° to 100° C. The excess anhydride was decomposed with ice, the solution adjusted with Na2CO3 to pH 8 and extracted with dichloromethane. After rotating in the organic phase, 5 g of 2-acetoxymethyl-4-acetylaminopyridine were obtained.
Reaction SMILES: N1C2CCCCC=2C=[C:2]1C=O.C[C:13]1[C:21]2[C:20](=O)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]=2[NH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:2][C:14]1[NH:15][C:16]2[CH2:17][CH2:18][C:19]([CH3:23])([CH3:24])[CH2:20][C:21]=2[CH:13]=1
Reactant: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Reactant: O=Cc1cc2c([nH]1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c([nH]1)CCC(C)(C)C2
Yield: 98 %

Procedure:
Using a procedure closely analogous to the preparation of 4,5,6,7-tetrahydroindole-2-carboxaldehyde, 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole 1.65 g (9.31 mmol) was reduced by 36-hour reflux with lithium aluminum hydride 2.0 g in anh. THF (100 mL) to provide 1.50 g (98%) of 2,5,5-trimethyl-4,5,6,7-tetrahydroindole (light tan crystalline solid) that was formylated with a mixture of anhydrous DMF 20 mL and POCl3 1.5 mL to provide the title aldehyde product 1.669 g (93% overall) as a tan solid. 1H-NMR (d6-DMSO, 400 MHz): 11.31 (br s, 1H), 9.43 (s, 1H), 2.51 (m, 2H), 2.14 (s, 3H), 2.13 (s, 2H), 1.49 (t, 6.6 Hz, 2H), 0.94 (s, 6H)
Reaction SMILES: [C:1]([Cu])#[N:2].[Na+].[I-].CN[C@@H]1CCCC[C@H]1NC.ClC1C=CC=CC=1.CCCCC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(OCC)(=O)C>[CH3:34][C:33]1[CH:28]=[CH:29][C:30]([C:1]#[N:2])=[CH:31][CH:32]=1
Reactant: N#C[Cu]
Reactant: CCCCCCCCCCCC
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: Cc1ccc(C#N)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A Schlenk tube was charged with CuCN (108 mg, 1.21 mmol), NaI (150 mg, 1.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (190 μL, 1.21 mmol) and 4-chlorobenzene (0.95 mL, 8.01 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 20 h. The resulting black suspension was allowed to reach room temperature. Ethyl acetate (3 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 60% yield of 4-methylbenzonitrile.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCCCC3)n2)cc1
Yield: 81.4 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (100 mg, 0.46 mmol) was acylated in CH2Cl2 using cyclohexane carbonyl chloride (85 μL, 0.57 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 123 mgs cyclohexanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[Cl:24])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4Cl)c3)csc12

Procedure:
3-[3-(2-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and 2-chlorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-bromo-3,3-dimethylbutan-2-one (0.52 mL) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. To the reaction mixture was added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.76 g, 61%).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:60])[CH3:59])[C@H:55]([CH:61]=O)[O:54][C:53]1([CH3:64])[CH3:63])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:59])[CH3:60])[C@H:55]([CH:61]=[C:11]([CH:17]([CH3:18])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:54][C:53]1([CH3:63])[CH3:64])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCOC(=O)C(C(C)C)P(=O)(OCC)OCC
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C

Procedure:
123 mg of lithium chloride was suspended in 10 ml of dry tetrahydrofuran under an argon stream, and 0.69 ml of ethyl 2-diethylphosphono-3-methylbutanoate was added under stirring. The mixture was stirred for 5 minutes at room temperature, and then 2.7 ml of a 20% dry tetrahydrofuran solution of diazabicycloundecene was added thereto. The mixture was stirred at room temperature for 10 minutes. Then, 2.0 ml of a dry tetrahydrofuran solution of 773 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine was added thereto, and the mixture was stirred overnight at room temperature. A precipitated inorganic salt was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in 300 ml of benzene and washed with 200 ml of water. The separated aqueous layer was extracted with 75 ml of benzene. The organic solvent layer thus obtained was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (32 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (10/1) to obtain 623 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate as a colorless oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)([OH:3])=[O:2].S1([CH2:25][CH2:24][CH2:23][CH2:22]1)(=O)=O.C[C:27]1[CH:42]=[CH:41][C:30]2[C:31](=[O:40])[C:32]3[CH:39]=CC=[CH:36][C:33]=3[CH2:34][CH2:35][C:29]=2[CH:28]=1>O>[C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:22][CH:14]=1)([OH:3])=[O:2].[CH2:23]([C:24]1[CH:25]=[CH:39][C:32]2[C:31](=[O:40])[C:30]3[CH:41]=[CH:42][CH:27]=[CH:28][C:29]=3[CH2:35][CH2:34][C:33]=2[CH:36]=1)[CH3:22]
Reactant: O=S1(=O)CCCC1
Reactant: Cc1ccc2c(c1)CCc1ccccc1C2=O
Reactant: Cc1cccc(CCc2ccccc2C(=O)O)c1
Solvent: O
Product: CCc1ccc2c(c1)CCc1ccccc1C2=O
Product: O=C(O)c1ccccc1CCCCc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
75 Gm. of 3-(o-carboxyphenethyl)toluene is dissolved in 400 ml. sulpholane and heated to 110°-120° C. 200 Ml. of polyphosphoric acid is added and the mixture is stirred at 100° C. for 90 minutes, and then poured onto ice and water. The mixture is extracted with hexane and the solution dried and evaporated to give 64 gm., 89%, of 2-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one as an oil. Use of 3-(o-carboxyphenethyl)ethylbenzene gives a similar yield of 2-ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one.