Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]#[N:12])=[N:5][C:4]=1[C:13]#[N:14])#N.[CH3:15][N:16]([C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH3:15][N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][C:1]([C:3]2[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]#[N:12])=[N:5][C:4]=2[C:13]#[N:14])=[CH:27][CH:28]=1
Reactant: N#Cc1nc(C#N)c(C#N)nc1C#N
Reactant: CN(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Product: CN(c1ccccc1)c1ccc(-c2nc(C#N)c(C#N)nc2C#N)cc1
Temperature: 100 °C
Yield: 9 %

Procedure:
A mixture of 18 g of tetracyanopyrazine and 18.3 g of N-methyl-N-phenylaniline in 200 ml of dimethylsulfoxide was heated at 100°C for 21 hours, the solution was cooled and poured onto 6 liters of ice water to give a sticky precipitate. The mixture was extracted with ethyl acetate. The ethyl acetate solution was back-extracted with water, dried over sodium sulfate and concentrated to give a dark brown solid. Unreacted tetracyanopyrazine was removed by recrystallization of the solid from toluene, from which TCP was the first to crystallize. The toluene solution was concentrated and the residue was rinsed with hexane to partially remove unreacted N-methyl-N-phenylaniline. The residue was dissolved in aqueous tetrahydrofuran (THF) (75% tetrahydrofuran) at 50°C, the THF removed by distillation, and the residual solid washed with water to remove water-soluble by-products. The remaining product was chromatographed on a column of neutral silicic acid using hexane/benzene/ acetonitrile eluents. Red fractions were combined, concentrated, and the product recrystallized from heptane-toluene to give 3.02 g of red-purple 6-[p-(methylphenylamino)phenyl]-2,3,5-pyrazinetricarbonitrile, mp 187.3°- 1.88.8°C after drying at 111°C (0.1 mm). Another 1.93 g of this product was recovered from mother liquors. Silica paper chromatography revealed only one colored product.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6])[CH:2]=[CH2:3].Cl.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:11][C:10](=[O:12])[C@H:8]([CH3:9])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)alanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)alanine methyl ester.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]1[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=1.C(=O)([O-])O.[Na+].C(=O)=O>COCCOCCOC.O>[F:15][C:16]1[C:17](=[S:2])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=c1[nH]cc(F)c(=S)[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of phosphorus pentasulfide (102.6 g, 0.46 mol) in diglyme (1 L) was added 5-fluoropyrimidine-2,4(1H,3H)-dione (30 g, 0.23 mol). Solid sodium hydrogen carbonate (NaHCO3; 77.3 g, 1.04 mol) was added at a rate determined by the evolution of carbon dioxide. The reaction mixture was stirred overnight at 110° C. The yellow mixture was cooled and poured into 1 L of cold water. The precipitated solid product was isolated by filtration and purified by normal phase chromatography (gradient, 10 to 50% EtOAc/Petroleum ether) to give 5-fluoro-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (13.4 g, 40%) as a yellow solid: mp 254-255° C.; 1H NMR (301 MHz, DMSO-d6) δ 7.81 (d, J=4.0 Hz, 1H); ESIMS m/z 145 ([M−H]−).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([C@H:27]2[CH2:32][CH2:31][C@H:30]([O:33][CH:34]([CH3:39])[C:35]([OH:38])([CH3:37])[CH3:36])[CH2:29][CH2:28]2)[C:19](=[O:40])[C:18]=1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([C@H:27]2[CH2:32][CH2:31][C@H:30]([O:33][CH:34]([CH3:39])[C:35]([OH:38])([CH3:37])[CH3:36])[CH2:29][CH2:28]2)[C:19](=[O:40])[C:18]=1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)=[CH:44][CH:43]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.59 g), sodium hydrogen carbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.093 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.16 g, 43%).
Reaction SMILES: [C@H:1]1([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][C:12]([NH2:19])=[N:13][C:14]=3N)[S:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>O>[C@H:1]1([N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:22])[NH:13][C:12]([NH2:19])=[N:11][C:10]2=3)[S:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3C[C@H](O)[C@@H](CO)S3)c2n1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Yield: 93 %

Procedure:
To a solution of 9-(2-deoxy-4-thio-α-D-ribofuranosyl)-2,6-diaminopurine (formula 8) (30 mg, 0.11 mmol) in distilled H2O (10 mL) was added a suspension of adenosine deaminase in 3.2M (NH4)2SO4 (0.1 mL) and reaction mixture was kept at room temperature. A 12-day TLC aliquot showed complete reaction. The solution was evaporated to dryness, the residue was crystallized from EtOH to give 9-(2-deoxy-4-thio-α-D-ribofuranosyl)-2-amino-1,6-dihydro-6-oxopurine (28 mg, 93%); mp 257°-260° C.; TLC 3: 1 CHCl3, MeOH, Rf 0.55; MS z/e 284 (M+1)+, UV λmax pH 1 254 (11.15), pH 7 254 (12.51), pH 13 267 (11.09); 1H NMR (Me2SO-d6, 300 MHz) δ2.30-2.40 (m, 1, H-2'), 2.52-2.62 (m, 1, H-2'), 3.30-3.40 (m, 1, H-5'), 3.46-3.58 (m, 1, H-5'), 3.60-3.66 (m, 1, H-4'), 4.46 (br t, 1, H-3'), 5.04 (br t, 1, 5'-OH), 5.50 (d, 1, 3'-OH, J=4 Hz), 5.94 (dd, 1, H-1', J=4 and 8 Hz), 6.50 (s, 2,NH2), 8.08 (s, 1, H-8); 13C NMR (Me2SO-d6, 300 MHz) δ42.57 (C-2'), 57.32 (C-1'), 59.63 (C-4'), 63.58 (C-5'), 74.34 (C-3'), 116.09 (C-5), 136.53 (C-8), 150.63 (C-4), 153.41 (C-2), 156.54 (C-6). Anal. (C10H13N5O3S) C, H, N, S.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:41][C:38]3[CH:39]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: BrCc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(Br)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 83.9 %

Procedure:
Using 1.3 g (2.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 1-bromo-4-bromomethyl-benzene (0.72 g, 2.88 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.2 (2H, s), 6.78 (1H, d), 6.88 (1H, s), 7.12 (2H, d), 7.2 (1H, s), 7.4 (3H, s), 7.6 (2H, d), 7.86 (2H, d), 8.28 (1H, d).
Reaction SMILES: C[C:2]1[C:3]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[C:9](N)[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[ClH:25]>O.[Cu](Cl)Cl>[Cl:25][C:9]1[CH:10]=[CH:2][C:3]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: Cc1cc(N)cc(C(=O)O)c1Oc1c(F)cccc1F
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of methyl 5-amino-2-(2,6-difluorophenoxy)benzoic acid (step 3, 234 mg, 0.88 mmol) in 6 N hydrochloric acid (2.6 mL) was added a solution of sodium nitrite (74 mg, 1.07 mmol) in water (0.5 mL) at 0° C. for 15 min. The mixture was added to a slurry of copper chloride (120 mg) in concentrated hydrochloric acid (1.2 mL). The mixture was stirred for 1 day at room temperature. The mixture was extracted with dichloromethane. The organic layer was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10/1) to afford 210 mg (84%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.77 (1H, d, J=2.7 Hz), 7.51 (1H, dd, J=9.0, 2.7 Hz), 7.40–7.20 (3H, m), 6.80 (1H, d, J=9.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.O1CCCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To an ice-cooled solution of 2-bromo-5-(trifluoromethyl)benzoic acid (5.16 g, 19 mmol) in THF (50 mL) was added borane-tetrahydrofuran complex (70 mL of 1M solution in THF, 70 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with methanol. Solvent was removed. The residue was partitioned between ethyl acetate (3×40 mL) and 1M sodium bicarbonate (50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated to yield the title compound as an oil (4.85 g). 1H NMR (400 MHz, CDCl3) δ 4.8 (s, 2H) 7.5 (m, 1H) 7.7 (d, J=8.2 Hz, 1H) 7.8 (d, J=1.6 Hz, 1H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Yield: 101.6 %

Procedure:
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (8.77 mmol, 2.6 g) was dissolved in a mixture of acetic acid (10 ml) and ethanol (190 ml). The mixture was run through H-Cube (10% Pd/C CatCart (8.77 mmol) flow 1.5 ml/min, +80° C., Full hydrogen mode). The collected fractions were combined and evaporated. The acquired solid was stirred in toluene and evaporated. This was repeated once more. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 4.35 (q, 2H), 7.38 (s, 1H), 8.07 (d, 1H), 9.14 (bs, 1H), 14.44 (bs, 1H). LC-MS: [M−1]=205.0.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[C:25]#[CH:26].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:11]([O:13][CH2:26][C:25]#[CH:24])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1
Reactant: C#CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
2-(benzoylamino)-3-(indol-3-yl)propanoic acid (1.9 g) was dissolved in 75 ml of dry methylene chloride (from phosphorous pentoxide). The solution was cooled to 0° C. in an ice bath and 0.72 ml of propargyl alcohol was added along with 1.39 g of DCC followed by 0.07 g DMAP. The reaction mixture was warmed to room temperature and maintained there for 16 hours. The solution was filtered into a separatory funnel, washed with 5% acetic acid (2×), water (1×) and 5% solution bicarbonate (1×). The separated methylene chloride layer was then dried over magnesium sulfate and evaporated to dryness. The residue was redissolved in ethyl acetate, filtered and the filtrate evaporated to dryness. The orangish residue was dried in vacuo to give propargyl 2-(benzoylamino)-3-(indol-3-yl)propionate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:1])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]
Reactant: COc1nc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)ccc1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(OC)n4)cc3n2C)c1
Yield: 49 %

Procedure:
Methyl 3-({6-[(5-bromo-6-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (3a) (0.74 g, 1.47 mmol), sodium methoxide (5.0 M solution in methanol, 2.94 mL, 14.7 mmol), water (10 mL) and 1,4-dioxane (20 mL) were stirred with heating under reflux for three days. After leaving to cool, the reaction mixture was concentrated and water (50 mL) was added. This aqueous solution was neutralized by adding 1 M hydrochloric acid and the precipitated solid was collected by filtration to obtain crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. Trimethylsilyldiazomethane (2.0 M solution in hexane) was added to a solution of the crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid in toluene (20 mL) and methanol (10 mL) until the raw material disappeared. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to obtain the title compound (0.36 g, 49%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:55]([C:62]1[S:66][C:65]([NH2:67])=[N:64][N:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>ClCCl.CN(C)C=O>[CH2:55]([C:62]1[S:66][C:65]([NH:67][C:19]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]3)=[CH:23][CH:22]=2)=[O:21])=[N:64][N:63]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1

Procedure:
3 g of trans-4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid (9.42 mmol, 1 eq.) are placed in 35 mL of a mixture of dichloromethane and dimethylformamide in a 250 mL round-bottomed flask under a nitrogen atmosphere, at room temperature. 1.528 g of hydroxybenzotriazole (11.1 mmol, 2 eq.), 2.168 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.1 mmol, 2 eq.), 3.11 mL of diisopropylethylamine (18.84 mmol, 2 eq.) and 2.162 g of 5-benzyl-1,3,4-thiadiazol-2-amine (11.1 mmol, 2 eq.) are successively added with stirring. The reaction mixture is stirred for 4 days at room temperature. The reaction medium is evaporated to dryness and diluted in water. The precipitate obtained is filtered off and washed with water. The solid obtained is dissolved in a minimum amount of dichloromethane and chromatographed on silica gel, eluting with a gradient of ethyl acetate in dichloromethane ranging from 2.5% to 25%. 3.13 g of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl)cyclohexyl}acetate are obtained.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][O:6][Si](C(C)(C)C)(C)C.[C:17](#[N:19])[CH3:18].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[OH:6][CH2:5][C:4]([CH3:14])([CH3:15])[C:3](=[O:16])[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)CC#N
Temperature: 110 °C
Yield: 90.7 %

Procedure:
A solution of 9.22 g of 3-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acid methyl ester and acetonitrile (2.34 mL, 44.88 mmol) in toluene (25 mL) is added dropwise over 1 h at reflux to a suspension of 1.80 g (44.88 mmol) NaH (60% dispersion in mineral oil) in anhydrous toluene (50 mL). The reaction mixture is heated to 110° C. for 18 h. The reaction mixture is diluted with 1M aqueous HCl solution to pH 7 and extracted with ethyl acetate (3×200 mL). The organic layers are combined, washed with water and brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 4.79 g of 5-hydroxy-4,4-dimethyl-3-oxo-pentanenitrile as a dark biphasic oil which is used crude in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6H), 3.55 (s, 2H), 3.61 (s, 2H). Spectrum recorded on crude material, signals of TBMDS are present.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([CH:18]([OH:28])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH:18]([O:28][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CCCCC(O)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Phenyl chloroformate (14.1 g) was added dropwise to a mixture of ethyl 6-(4-chlorobenzoyl)-6-hydroxyhexanoate (24.5 g), pyridine(7.14 g) and tetrahydrofuran(200 ml) with cooling with ice. After stirring for 3 hours at room temperature, the reaction mixture was poured into ice water, and neutrized by 2N-hydrochloric acid. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanate(32.3 g, 94%) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12]Cl)=[O:11].[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCNCC1
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCC(=O)CC1

Procedure:
The crude [(2,6-dimethylphenyl)aminocarbonylmethyl]chloride, prepared in Preparation B (50 g., 0.25 moles) and 4-piperidone (86 g, 1 mole) are dissolved in 500 ml of ethanol. The mixture is refluxed for two hours, and then cooled and evaporated. The product is recovered by adding aqueous ammonia to the residue, and extracting with methylene chloride. Three portions of methylene chloride are used, which are collected, washed with water, and evaporated to a semi-solid. Upon addition of diethylether, the product crystallizes and is filtered. The resulting crude mixture is boiled with ether and then evaporated to a residue and triturated with hexane to yield pure material, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]-4-piperidone. This material is of sufficient purity for use in Reaction Sequences 2 to 5.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:18]([CH:19]=[O:20])[C:9]2=[O:8])=[CH:24][CH:23]=1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cc2ccccc2n(Cc2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Sodium hydride (60% in oil) (1.3 g) was added at 0° C. to a DMF solution (50 ml) of 2-oxo-1,2-dihydroquinoline-3-carboxaldehyde (5.13 g), followed by stirring for 30 minutes. 4-chlorobenzyl bromide (7.0 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, extraction with ethyl acetate was performed, and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:4). The purified product was recrystallized from a chloroform-diisopropyl ether mixed solvent to thereby obtain 6.57 g (yield: 72%) of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde as a white powder.