Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Yield: 33.1 %

Procedure:
To a 5 mL Wheaton vial was added was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol) and morpholine (Aldrich Chemical Company) (0.18 mL, 2.1 mmol). A solution of K2CO3 (0.37 g, 2.7 mmol) in H2O (2.5.mL) was added, the vial was securely capped, and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature and the resulting light-pink precipitate was collected by filtration, recrystallized from EtOAc and dried overnight in a 60° C. vacuum oven to give 0.04 g (33%) of the title compound as a white solid. Mp: 276° C. (dec.) 1H NMR (CDCl3; 500 MHz): δ 2.62 (s, 3), 3.87 (s, 4), 3.90 (s, 4), 6.79 (s, 1), 7.41 (t, 1, J=6.8), 7.48 (t, 2, J=7.4), 7.67 (d, 2, J=6.8), 8.17 (br s, 1). MS m/z: 295 (M+1). Anal. Calcd for C17H18N4O.0.25H2O: C, 68.32, H, 6.24, N, 18.75. Found: C, 67.90, H, 6.02, N, 18.64.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:18]1[CH:22]=[C:21]([CH2:23][OH:24])[N:20]=[CH:19]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=[CH:19]1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Yield: 32.7 %

Procedure:
To a suspension of the compound of Example 36 (100 mg, 288 μmol) in ethyl acetate (5 ml) were added phenyl isocyanate (68.6 mg, 576 μmol) and successively triethylamine (58.3 mg, 576 μmol), and the mixture was refluxed for 24 hours. After cooling, the precipitated crystals were collected by filtration, washed with ethyl acetate and water in sequence, and then dried under reduced pressure, thereby obtaining 44.0 mg of title compound as colorless powder. Yield 33%.
Reaction SMILES: [PH:1](=[O:33])([O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:22])=[C:14]2[OH:32])[O:2]C(C)(C)C.CCCCCC>C(O)(C(F)(F)F)=O.ClCCl>[PH:1](=[O:2])([OH:33])[O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:22])=[C:14]2[OH:32]
Reactant: CC(C)(C)O[PH](=O)OCCCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CCCO[PH](=O)O)cc2c1O
Yield: 103 %

Procedure:
A solution of 50.0 mg of tert-butyl 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl phosphonate from Example No. 270 in 0.5 mL of 1:1 TFA-dichloromethane is stirred for 2 h, then added slowly to 20 mL of rapidly stirred hexane. The resulting solution was concentrated under reduced pressure to provide 45.6 mg of the title compound as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][C:16]3=[O:19])=[CH:12][CH:11]=2)[N:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(Oc3cncc(Cl)n3)cc21
Yield: 94 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 6-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (330 mg). Yield: 94%. 1H NMR (250 MHz, DMSO-d6) δ 2.74 (t, 2H, H3, J=5.8 Hz), 3.15 (t, 2H, H2, J=6.0 Hz), 7.50 (d, 1H, Harom 7, J=2.2 Hz), 7.60 (dd, 1H, Harom 5, Jm=2.3 Hz, Jo=8.3 Hz), 7.70 (d, 1H, Harom 4, J=8.3 Hz), 8.53 (s, 1H, HPz 5), 8.59 (s, 1H, HPz 3). m/z: 261.1 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: C([O:4][CH2:5][C@:6]1([O:28][C@H:27]([CH2:29][OH:30])[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]1([O:28][C@H:27]([CH2:29][OH:30])[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][OH:8]
Reactant: CC(=O)OC[C@@]1(CO)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC[C@H]1OC(CO)(CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 1.7 g portion of 2-C-[(acetyloxy)methyl]-2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-diacetate was treated with 1.6 g of potassium carbonate, 10 ml of water and 8.5 ml of methanol and the mixture heated at reflux for 40 minutes and then evaporated. The residue was taken up in ether/water. The water layer was extracted twice with ether. All ether layers were combined, washed with brine, dried and evaporated. The residual oil was flash chromatographed, eluting with 4% methanol in dichloromethane, giving 1.0 g of the desired compound.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccc(Cl)cc2)CCC(=O)CC1
Yield: 82 %

Procedure:
A mixture of 29.8 g. (0.102 mole) of methyl 5-cyano-5-(4-chlorophenyl)-2-oxocyclohexanecarboxylate (prepared in Example 7) in 660 ml. of acetic acid and 330 ml. of 10% sulfuric acid is stirred mechanically on a steam bath for about 24 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is washed successively with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from ether to give 19.49 g. (82% yield) of 4-cyano-4-(4-chlorophenyl)cyclohexanone, having a melting point of 94.5° to 97°C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[CH2:5][N:6]=[N+]=[N-])#[N:2]>[Pd].C(OCC)(=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[CH2:5][NH2:6])#[N:2]
Reactant: COc1ccc(C#N)c(CN=[N+]=[N-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyano-5-methoxybenzyl azide (1 g, 5.3 mmol) and 10% palladium on carbon (500 mg) in ethyl acetate (30 ml) was stirred at room temperature under an atmosphere of hydrogen for 1 h. The catalyst was removed by filtration through a bed of Celite and the filtrate concentrated to yield the product as an orange oil: 1H NMR (CDCl3) δ7.56 (d, J=8.5 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.82 (dd, J=2.5, 8.5 Hz, 1H), 4.05 (br s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-methoxyisatin (15.0 g, 84.7 mmol) in DMF (100 mL), sodium hydride (5.1 g, 127 mmol) and benzyl bromide (12.1 mL, 101.6 mmol) were added at 0° C., and the resulting mixture was stirred for 1 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the aimed product (yield: 96%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]3[C:21](=[CH:22][C:9]1=2)[CH2:20][CH2:19][CH2:18][CH2:17]3.[C:38](=O)(O)[O-].[Na+].ICl.[F-].[Cs+].CB(O)O>ClCCl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].CO>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][N:7]([C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[C:15]([CH3:38])=[C:16]3[C:21](=[CH:22][C:9]1=2)[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: O=C([O-])O
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)CCCC4)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CB(O)O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1c2c(cc3c1NCCC[C@@H]3N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine (Example 77, Step 3) (0.19 mmol) in dichloromethane (5 mL), add sodium bicarbonate (0.28 mmol) and methanol (2 mL). Add a 1.0 M solution of iodine monochloride (0.28 mmol) in dichloromethane dropwise. After stirring for 1 h at room temperature, quench the reaction with concentrated aqueous sodium metabisulfite. Dilute with dichloromethane (20 mL) and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Dissolve the crude intermediate in dioxane (5 mL) and purge with nitrogen. To this solution add palladium acetate (0.04 mmol), diphenylphosphinoferrocene (0.04 mmol), cesium fluoride (0.76 mmol), and methylboronic acid (0.76 mmol). Heat the mixture at 60° C. for 4 h, then cool to room temperature and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-25%) to afford the title compound. MS (ES+): 539 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[CH3:18][N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1.O.[Na]>CS(O)(=O)=O>[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:20]1
Reactant: OC(c1ccccc1)c1nc2ccccc2[nH]1
Reactant: CN1CCC(O)C1
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C

Procedure:
272A A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and 1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) is heated for 4 hours in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poored into water which is then made alkaline with concentrated sodium hydroxyde solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole melting at 53° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
DMAP (89 mg, 0.73 mmol), 2,3-dimethylaniline (98 mg, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional 2,3-dimethylaniline (0.049 mL, 0.40 mmol) and THF (2 nL) was added. The reaction was diluted with EtOAc after 25 h followed by washing with 10% aqueous citric acid (75 mL), saturated aqueous NaHCO3 (40 mL), and brine (40 mL). A precipitate in the combined organic layers was filtered to yield 0.22 g (58%) white solid: mp 232.5-233.0° C.; 1H NMR (DMSO, 400 MHz) δ 9.77 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 7.03 (m, 2H), 5.11 (s, 2H), 3.64 (m, 4H), 3.39 (m, 2H), 3.03 (m, 2H), 2.24 (s 3H), 2.09 (s, 3H), 1.41 (s, 9H); IR (diffuse reflectance) 2977, 1692, 1659, 1541, 1474, 1451, 1412, 1366, 1303, 1269, 1201, 1174, 1112, 791, 773 cm−1; MS (EI) m/z 515 (M+), 376, 226, 224, 212, 189, 149, 133, 119, 55, 52; HRMS (EI) calcd for C27H31Cl2N3O3 515.1743, found 515.1747.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Cl.[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:13]([CH3:12])[CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCOc1ccccc1Br
Reactant: CNCc1ccccc1
Product: CN(CCOc1ccccc1Br)Cc1ccccc1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from N-benzyl-N-[2-(2-bromophenoxy)ethyl]methyl amine in a similar manner to Example 1 (a) except that after evaporation of the dimethoxyethane, the aqueous residue was extracted with DCM (100 ml). The latter was then extracted with 5% aqueous acetic acid, the acetic acid extracts adjusted to pH 8 with 10N potassium hydroxide solution and the resulting precipitate collected by filtration, washed with water and digested in methanol (5 ml), affording the title compound as a solid. MS 425 (M+H)+. 1H NMR (DMSO-D6) 2.2 (s, 3H), 2.9 (t, 2H), 3.55 (s, 2H), 4.25 (t, 2H), 6.8 (s, 2H), 7.0 (t, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 7H), 7.6 (d, 2H), 7.8 (s, 1H), 11.0 (s, 1H). b) N-Benzyl-N-[2-(2-bromophenoxy)ethyl]methylamine This was prepared from l-bromo-2-(2-chloroethoxy)benzene and N-methyl benzylamine in a similar manner to Example (b) except that the mixture was stirred at 65° C. for 16 h. MS (ES) 320 (M+H)+. 1H NMR (CDCl3) 2.4 (s, 3H), 2.9 (t, 2H), 3.7 (s, 2H), 4.1 (t, 2H), 6.7-6.9 (m, 2H), 7.15-7.4 (m, 6H), 7.5 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23](=O)[NH2:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH:18]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH:18]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNc2cc(NCc3ccccc3Cl)ncc2C(N)=O)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC(CNc2cc(NCc3ccccc3Cl)ncc2C#N)CC1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a suspension of (4-{[5-carbamoyl-2-(2-chloro-benzylamino)-pyridin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester (31 mg, 0.062 mmol) in CH2Cl2 at ambient temperature was added Burgess reagent (40 mg, 0. 168 mmol) in portions over 3 h. The resultant mixture was stirred at 25° C. for another 1 h and then water was added. The mixture was stirred for 20 min and extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica-gel column chromatography (hexanes/EtOAc, 2:1 v/v then EtOAc) to afford (4-{[2-(2-chloro-benzylamino)-5-cyano-pyridin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white solid (12 mg, 40%).
Reaction SMILES: O1CCCC1.[C:6]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1.CN1CCCC1=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: Cl[Mg]c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccccc2)cc1

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 1.090 g (8 mmol) of zinc chloride and 4 ml of N-methylpyrrolidinone were weighed in the flask. The flask was purged with argon, followed by stirring. 3.4 ml (7.5 mmol) of 2.2M tetrahydrofuran solution of phenylmagnesium chloride was added dropwise at 25° C. over a period of 30 minutes, followed by stirring at 25° C. for 30 minutes. The reaction liquid previously obtained was added, followed by stirring at 25° C. for 30 minutes. Further, 0.688 g (5 mmol) of 4-chlorobenzonitrile was added, followed by stirring at 120° C. for 9 hours. After the completion of the reaction, 10 ml of toluene and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.670 g of 4-cyanobiphenyl (yield: 75 mol % based on 4-chlorobenzonitrile). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[CH3:9]S(C)=O.[O:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>CS(C)=O.C1COCC1.O>[O:13]1[C:14]2([CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)[CH2:16][CH2:15]2)[CH2:9]1
Reactant: CS(C)=O
Reactant: CCOC(=O)c1ccc(C2CCC(=O)CC2)cc1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2CCC3(CC2)CO3)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
0.246 g of sodium hydride (9.74 mmol, 2 eq.) is placed in 25 mL of a 1/1.5 mixture of THF/DMSO with stirring at 10° C. 2.14 g of trimethylsulfoxonium iodide (9.74 mmol, 1.2 eq.) are added. After 5 minutes, 10 mL of DMSO are added dropwise. After the evolution of gas has ceased, 2 g of ethyl 4-(4-oxocyclohexyl)benzoate (8.12 mmol, 1 eq.) dissolved in a minimum amount of a 2/1 mixture of DMSO/THF are rapidly added at room temperature. After stirring for 1 hour at room temperature and for 1 hour at 50° C., the reaction medium is diluted with 75 mL of water and extracted with ethyl acetate. The organic phases are successively washed twice with water and with brine, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with a gradient of methanol in dichloromethane ranging from 1% to 2%. 1.8 g of ethyl 4-(1-oxaspiro[2.5]oct-6-yl)benzoate are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:27]([O:29][C:30]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:31])[CH3:28].O.C(OCC)(=O)C>CN(C=O)C>[CH2:27]([O:29][C:30]([C:32]1[CH:33]=[N:34][N:35]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:36]=1)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Under N2 atmosphere, potassium tert-butoxide (9.60 g, 85.5 m mol) and trityl chloride (21.9 g, 78.5 m mol) were added successively to a solution of 4-(ethoxycarbonyl)pyrazole (10.0 g, 71.3 m mol) in DMF (100 ml) at 0° C. After stirred for 1 hour, the mixture was poured into water/ethyl acetate. The aqueous layer was separated, and the organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting precipitate was recrystallized from ethyl acetate to afford 4-ethoxycarbonyl-1-(trityl)pyrazole (21.7 g).
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8]2[C:3](=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:7]1[C:8]2[C:3](=[CH:2][CH:1]=[C:10]([S:11]([O-:14])(=[O:13])=[O:12])[CH:9]=2)[C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 50.0 g amount of (61.5%) 1-naphthylamine-4,7-disulfonic acid is dissolved in 150 ml of water and 5 N sodium hydroxide is added until basic pH (10-11). The solution is warmed and ethyl alcohol is added until a precipitate forms. The solid is collected by filtration, washed with 85% ethyl alcohol, ethyl alcohol and ether and is dried in vacuo at 110° C. to give 31.0 g of 4-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])CCC.CCCCCC.Cl[C:23]([O:25][CH3:26])=[O:24].Cl>CCOCC.CC(O)C.CC(O)C.CC(O)C.CC(O)C.[Ti].C(OCC)(=O)C>[CH3:1][C:2]1([C:23]([O:25][CH3:26])=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)Cl
Reactant: CC1C=Cc2ccccc21
Agent: [Ti]
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: COC(=O)C1(C)C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.4 g of 1-methyl-1H-indene in 136 ml of ether was added 16.2 ml of a 1.62 M n-butyllithium/hexane solution at −78° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture were added 15.5 ml of tetra-iso-propyl titanate and 2.41 ml of methyl chloroformate at −78° C., followed by stirring at −78° C. for 2 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation, followed by drying over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.57 g of methyl 1-methyl-1H-indene-1-carboxylate.