Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:19](=O)([O-])[OH:20].[Na+]>CO>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:20][CH3:19])=[O:7]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-Bromomethylbenzoyl chloride (1.96 g, 10.37 mmol) was dissolved in methanol (20 ml), and triethylamine (1.5 ml) was added thereto. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a saturated sodium hydrogencarbonate solution and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.90 g, 10.29 mmol, yield: 97%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[C:4]([C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6])=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)C1CC1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=CN(C)C)C(=O)C1CC1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
3-Cyclopropyl-3-oxo-propionic acid methyl ester (1.25 g, 8.79 mmol) was dissovled in 6.25 mL of CHCl3 and 1.17 mL (8.79 mmol) of dimethylformamide dimethyl acetal was added. The mixture was heated to 60° C. in a sealed vessel overnight. The mixuture was then cooled and concentrated to provide 1.67 g of 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 8-fluoro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-fluoro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: c1ccc(-c2cnco2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
(182) A solution of 2-(oxazol-5-yl)pyridine (113 mg, 0.77 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.85 mmol, 0.34 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.54 mmol, 3.1 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.77 mmol, 147 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with stearic acid (2 equiv, 1.54 mmol, 440 mg) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 7.7 mmol, 0.98 g, 0.68 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of stearoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)octadecan-1-one (182) (97 mg, 0.24 mmol, 31% yield) as a white powder: mp 86-87° C.; 1H NMR (CDCl3, 250 MHz) d 8.66 (br d, J=5.4 Hz, 1H), 7.89-7.76 (m, 3H), 7.34-7.27 (m, 1H), 3.10 (t, J=7.7 Hz, 2H), 1.82-1.74 (m, 2H), 1.44-1.19 (m, 28H), 0.87 (br t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 157.4, 153.2, 150.1 (2C), 137.1, 126.8, 124.1, 120.3, 39.2, 31.9, 29.7 (5C), 29.6 (2C), 29.6, 29.4, 29.3 (2C), 29.2, 24.0, 22.7, 14.1; IR (KBr) umax 2942, 2871, 1701, 1601, 1429, 1376 cm−1; MALDI-FTMS (DHB) m/z 413.3170 (C26H40N2O2+H+ requires 713.3162).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[S:29](Cl)(=[O:31])=[O:30])[CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)(=[O:30])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc2cccnc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
The product has already been described in: V. M. Dziomko et al., Azotsoderzhashchie Geterotsikly 1967, 281-284; but by a different method of synthesis. Several grains of activated 4 Å molecular sieve are added to a solution under argon of 8-aminoquinoline (200 mg; 1.39 mmol) and triethylamine (0.30 ml; 2.15 mmol) in 10 ml of CHCl3 and the mixture is stirred slowly for 1 hour. 8-quinolinesulfonyl chloride (350 mg; 1.54 mmol) is added and the mixture is heated to 65° C. for 15 hours. After cooling, 50 ml of CHCl3 are added and the mixture is washed in water (2×50 ml) then dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure. The solid is washed with 5 ml of CH2Cl2 to yield after drying 25 in the form of a beige powder (108 mg; 0.32 mmol, yield=23%). NMR-1H (250 MHz, DMSO-d6) δ, ppm: 10.44 (s, 1H); 9.11 (dd, 3J (H, H)=4.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.83 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.47 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.40 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.22 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.20 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.80 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.70 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H); 7.62 (dd, 3J (H, H)=8.5 and 4.5 Hz, 1H); 7.51 ((dd, 3J (H, H)=8.5 and 4.0 Hz, 1H); 7.50 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.0 Hz, 1H); 7.42 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H). NMR-13C (63 MHz, DMSO-d6) δ, ppm: 151.5 (CH); 148.9 (CH); 142.1 (Cq); 137.6 (Cq); 136.9 (CH); 136.3 (CH); 134.4 (CH); 134.2 (Cq); 133.7 (Cq); 131.7 (CH); 128.2 (Cq); 127.8 (Cq); 126.6 (CH); 125.5 (CH); 122.6 (CH); 122.3 (CH); 122.1 (CH); 113.8 (CH). MS (CID, NH3): m/z=336 (MH+). Analysis (%) for C18H13N3O2S.0.2H2O: calculated C, 63.78. H, 3.98. N, 12.40. found C, 63.53. H, 3.70. N, 12.23.
Reaction SMILES: N.C(O)C.[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][C:17]#[N:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1>C(O)C.[Co]>[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1
Reactant: COc1ccc2nc(Cl)cc(CC#N)c2c1
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2nc(Cl)cc(CCN)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A saturated ammonia/ethanol solution (40 ml) and Raney cobalt (4 g) were added to a solution of (2-chloro-6-methoxyquinolin-4-yl)acetonitrile (1.0 g, 4.3 mmol) in ethanol (150 ml), and the reaction mixture was stirred under an atmosphere of hydrogen (5 kgf/cm2) at room temperature for 3 hours. The Raney cobalt was filtered off, and then the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to obtain the title compound (855 mg, 84%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.[CH2:34](N(CC)CC)C.CI.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:34])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C3CCN(C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolysed and then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol (98/2) as eluent to give (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 50% yield (96.8% purity by HPLC).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[N:3]=[N:2]1.[CH3:11][O:12][C:13]1[C:14](=O)[C:15](=[O:19])[C:16]=1[O:17]C>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:14]3[C:15](=[O:19])[C:16](=[O:17])[C:13]=3[O:12][CH3:11])[C:4]=2[NH:3][N:2]=1
Reactant: Nc1cccc2[nH]nnc12
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(Nc2cccc3nn[nH]c23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
A mixture of 2.045 g (15.2 mmol, 1 eq) of 1H-1,2,3-benzotriazol-4-amine and 1.80 g (12.7 mmol, 1 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 30 ml of methanol was stirred at ambient temperature for 2 days. The reaction medium (set solid) was filtered. 2.04 g of a mixture of 3-(3H-benzotriazol-4-ylamino)-4-methoxycyclobut-3-ene-1,2-dione and 3,4-bis(3H-benzotriazol-4-ylamino)cyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. Mixture of products (29% correct product). Yield=19%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=CC(O)=CC=1)C.C1(O)C=CC=CC=1.C1C(O)=CC=C(C)C=1.N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O>CO.O>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: CCc1ccc(O)cc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Agent: Cc1ccc(O)cc1
Solvent: O
Solvent: Oc1ccccc1
Solvent: CO
Product: C#Cc1ccc(O)cc1

Procedure:
To 536.3 g of a p-vinylphenol fraction obtained by the same vacuum flash distillation as in Example 1, containing 32.9% of p-vinylphenol, 49.1% of p-ethylphenol, 1.6% of phenol, 7.0% of p-cresol and 9.4% of water were added 160.9 g of methanol as a solvent and 5.36 g of dimethyl 2,2′-azobisisobutyrate as an initiator. The resulting mixture was subjected to a polymerization reaction at 80° C. for 5 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain 98.2 g of a poly(p-vinylphenol). The polymer had a Mw of 8,800, a Mn of 5,200 and a light transmittance at 248 nm, of 76.9%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([OH:37])[CH2:11][CH:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[CH2:11][C@@H:10]([OH:37])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 107D (0.5 g, 0.840 mmol) in a mixture of methanol (4 mL) and ethyl acetate (4 mL) was treated with Pd(OH)2 on carbon (0.175 g, 20% Pd by wt.) and HCl solution (0.40 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 2 hours, filtered through a bed of celite®, rinsed with methanol, and concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: C(OC([N:8]([CH2:21][CH2:22][C:23]#[C:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[NH:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])=O)(C)(C)C>[Cu]I.CN(C)C(=O)C>[CH:33]([N:32]1[C:26]2[C:25](=[CH:30][C:29]([Cl:31])=[CH:28][CH:27]=2)[CH:24]=[C:23]1[CH2:22][CH2:21][NH:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 150 °C
Yield: 98.9 %

Procedure:
A solution of N-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide (400 g, 0.585 mol) and N,N-dimethylacetamide (800 mL) was added slowly over 1 h to a hot (150° C.), stirred mixture of copper (I) iodide (12.2 g, 0.064 mol) and N,N-dimethylacetamide (740 mL). The reaction mixture was stirred and maintained at 150° C. for an additional 2 h. The reaction mixture was cooled to 40° C. The mixture was filtered through a celite pad and the pad was washed with IPA (2×100 mL). An additional charge of IPA (1400 mL) was added to the filtrate. The mixture was stirred and warmed to 60° C. Water (2.2 L) was added to the mixture over 30 m, maintaining an internal temperature of 55-60° C. The mixture was held at 60° C. for 30 m, then it was cooled to 5° C. The solid product was collected by filtration and the cake was washed with cold IPA/water (3/2 v/v, 2×200 mL). The solid was vacuum dried at <50° C. to give N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide (338 g, 99%) with 98% purity (as determined by HPLC).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2C[CH:10](C)[CH2:11][CH2:12][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=1>>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC(C)C2
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanato-6-methylbenzo[b]thiophene-3-carboxylate (0.099 g. 0.37 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.051 g, 0.37 mmol) as described above.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)N>C(O)CCC>[NH2:4][C:3]1[NH:5][C:9](=[O:17])[C:10]2[C:16](=[CH:15][CH:14]=[CH:13][CH:11]=2)[N:2]=1
Reactant: COC(=O)c1ccccc1N
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc2ccccc2c(=O)[nH]1
Yield: 18.6 %

Procedure:
Guanidine hydrochloride (47.77 g, 0.5 mol) was added portionwise to a stirred suspension of sodium methoxide (32.42 g, 0.60 mol) in n-butanol (450 ml) at ambient temperature over 0.5 hour. After a further 0.5 hour a solution of methyl anthranilate (15 g, 0.10 mol) in n-butanol (150 ml) was added dropwise and then slowly brought to reflux. After distilling off ca. 100 ml of solvent the reaction mixture was heated under reflux at 116° for 117 hours. The cooled suspension was filtered, excess solvent removed and the residue dissolved in water, acidified to pH 5 and extracted with diethyl ether. The aqueous suspension was reacidified to pH 5, filtered off, washed with water and dried. The solid was then triturated in methanol, filtered, washed with ether and dried to give 2-amino-4-(3H)-quinazolone (3.0 g, 19%) m.p. >300°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:24])[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[C:11]3[N:12]=[C:13]([NH:36][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:38][CH:37]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:24])[CH:3]=1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(S(C)=O)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 41.1 %

Procedure:
6-(4-Bromo-2-chlorophenyl)-8-ethyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (11, 0.60 g, 1.41 mmol) and 4-(4-methylpiperazino)aniline (0.27 g, 1.41 mmol) were stirred at 150° C. for 4 h. The cooled reaction mixture was taken up in dichloromethane (50 mL) and washed with 10% NaOH (1×25 mL) then with water (1×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using chloroform:methanol (100:3) as eluent to give the title compound as a yellow solid (0.32 g, 0.58 mmol, 41%). ESMS m/z 553 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.52-7.59 (m, 3H), 7.45 (dd, J=8.2, 1.9 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.48 (q, J=7.0 Hz, 2H), 3.17-3.26 (m, 4H), 2.55-2.70 (m, 4H), 2.37 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13].C(OCC)(=O)C>CN(C=O)C>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cnccc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccncc1C=O
Reaction time: 18 h
Yield: 86.9 %

Procedure:
Sodium azide (1.07 g, 16.5 mmol) was added to a mixture of 4-chloro-3-formylpyridine (2.22 g, 15.7 mmol) in DMF (15 mL) and the reaction mixture was stirred for 18 hours. Ethyl acetate was added and the organic layers were washed with water and brine. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in cyclohexane) to afford the title compound as a white solid (2.02 g, 87% yield). 1H NMR (300 MHz, CDCl3): δ 10.35 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 7.20 (d, J=5.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:49])[CH:33](OS(C(F)(F)F)(=O)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH:33]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32]([O:31][CH3:30])=[O:49])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 87.3 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.140 g, 0.373 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.175 g, 0.560 mmol) and cesium carbonate (0.243 g, 0.746 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 20% to 50% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.175 g, 88%), mp 57–62° C. Elemental Analysis for C37H31NO3 Calc'd: C, 82.66; H, 5.81; N, 2.61. Found: C, 82.39; H, 5.88; N, 2.46.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:18]O>C(O)(=O)C>[CH:14]1[C:9]([NH:8][C:6]([C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[N+:3]([O-:18])[CH:4]=2)=[O:7])=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=1
Reactant: OO
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)[n+]([O-])c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (2.06 g, 8.2 mmole) in 30 mL of acetic acid was added 30 mL of aqueous hydrogen peroxide (30%). The mixture was warmed to 70° C. and stirred for 18 hours, and then 20 mL of additional hydrogen peroxide (30%) was added and stirred for 2 hours. The mixture was then cooled, concentrated in vacuo and diluted with water (100 mL). Isolation of the precipitate by vacuum filtration afforded 0.43 g (20%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ7.19 (m 2H), 7.75 (M, 3H), 7.95 (M, 1H), 8.94 (d, 1H, J=2.2 Hz), 10.5 (s, 1H); MS (EI) m/z 267.19 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]2[C:20]=1[C:21]([CH:31]=O)=[CH:22][NH:23]2.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:21]3[C:20]4[C:24](=[C:25]([F:30])[C:26]([F:29])=[C:27]([F:28])[C:19]=4[F:18])[NH:23][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1c[nH]c2c(F)c(F)c(F)c(F)c12
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1c[nH]c2c(F)c(F)c(F)c(F)c12

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4,5,6,7-tetrafluoro-1H-indole-3-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine was suspended in 5 mL MeOH and sodium borohydride (3 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D22 as a light yellow powder as product. Product was washed with deionized water to remove excess sodium borohydride.