Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[NH2:12].[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[C:16][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[NH2:12]
Reactant: C#CC(C)(C)C
Reactant: Nc1c(F)cc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(F)c1N
Temperature: 80 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
To a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol) in dry Et3N (100 mL) was added CuI (445 mg, 5% mol), Pd(PPh3)2Cl2 (550 mg, 5% mol) and 3,3-dimethyl-but-1-yne (9.6 g, 120 mmol) under N2 protection. The mixture was stirred at 80° C. for 10 h. The reaction mixture was filtered, poured into ice (100 g), and extracted with EtOAc (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 36%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=1.2 Hz, 1 H), 7.84 (dd, J=2.4, 10.8 Hz, 1 H), 4.85 (brs, 2 H), 1.36 (s, 9 H).
Reaction SMILES: S=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[CH2:4][NH:3]1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>O>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:25][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[CH2:4][N:3]=1
Reactant: CCOC(=O)c1ncn2c1CNC(=S)c1ccccc1-2
Reactant: COC(CN)OC
Solvent: O
Product: CCOC(=O)c1ncn2c1CN=C(NCC(OC)OC)c1ccccc1-2

Procedure:
2.1. 6.0 g of ethyl 5,6-dihydro-6-thioxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate in 40 ml of amino-acetaldehyde dimethyl acetal are stirred at 85° C. for 48 h. The mixture is diluted with 150 ml of water and extracted four times with ethyl acetate. The organic extracts are washed with saturated aqueous sodium chloride solution and evaporated in a vacuum. The residue is chromatographed over silica gel. Elution is carried out with dichloromethane/ethanol 99:1, 98:2 and 97:3. The crude eluate is recrystallized from ethyl acetate/diisopropyl ether. There are obtained 4.3 g of pure ethyl 6-[(2,2-dimethoxy-ethyl)amino]-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of m.p. 121°-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.[O:23]1CCC[CH2:24]1>[Pt].C(O)C>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:24](=[O:23])[NH:20][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2[N+](=O)[O-])CC1
Reactant: C1CCOC1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C)ccc32)CC1
Reaction time: 7 h

Procedure:
A mixture of 8.23 g of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate, 200 mL of tetrahydrofuran, 225 mL of ethanol and 2 g of 5% platinum on carbon was stirred under an atmosphere of hydrogen for 7 h. The catalyst was filtered off and the filtrate concentrated to to a thick oil. To an ice cold, vigorously stirred solution of the resulting crude ethyl 4-(4-methyl-2-aminoanilino)-1-piperidinecarboxylate in 500 mL of ethyl acetate was added 500 mL of saturated sodium carbonate followed by 20 mL of 1.9M phosgene in toluene dropwise over 30 min. After stirring overnight at room temperature, the layers were separated and the organic layer dried over MgSO4 and concentrated to dryness. Trituration of the residue with ether-hexane gave 8 g of ethyl 4-(5-methyl-2-oxo-1-benzimidazolinyl)piperidine-1-carboxylate as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH2:11][O:12][CH3:13])[N:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]=2[C:36]=1[F:37].Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH2:11][O:12][CH3:13])[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]=2[C:36]=1[F:37]
Reactant: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of [(R)-1-(6,7-difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (290 mg, 0.57 mmol) in methanol (5 mL) was added HCl in dioxane (0.5 mL, 4M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in EtOAc (10 mL). The solution was washed with sat. aq. NaHCO3 and the product extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with diethyl ether, collected by filtration and dried in vacuo to yield 190 as a white solid (111 mg, 46%). 1H NMR 400 MHz (DMSO-d6): δ 8.13-7.98 (2H, m), 7.89 (1H, br s), 7.74-7.58 (2H, m), 7.59-7.39 (4H, m), 7.29-7.14 (1H, m), 5.47 (1H, br s), 3.87-3.77 (2H, m), 3.11 (3H, s). LCMS (Method K): RT=3.72 min, [M+H]+=422
Reaction SMILES: C(CCN[C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[NH2:33][C:34]1[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6]([NH:33][C:34]3[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Product: Cc1cc(NC(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)n[nH]1

Procedure:
Compound 105 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 3-amino-5-methylpyrazole. LCMS (+ESI) m/z=473.3 [M+H]+. 1H NMR (CDCl3) δ 8.15 (d, J=9.8 Hz, 1H), 7.50-7.56 (m, 1H), 7.28-7.30 (m, 1H), 7.22-7.27 (m, 1H), 5.84 (d, J=9.9 Hz, 1H), 5.48 (s, 2H), 4.82 (s, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.18 (t, J=4.8 Hz, 2H), 2.17 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH:8]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9]1.C[O-].[Na+].Cl>CS(C)=O.C1(C)C=CC=CC=1>[CH:5]1([C:3](=[O:4])[CH2:12][C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:6][CH2:7]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Methylcyclopropanecarboxylate (20.2 ml, 286.3 mmol) was added to a stirred solution of 1-cyclopropylethanone (9 ml, 152.4 mmol) in dimethylsulfoxide (25 ml). Sodium methoxide powder (10.8 g, 200 mmol) was added, and the reaction was stirred at 55° C. for 8 hours. The mixture was cooled, diluted with toluene, neutralised with 6M hydrochloric acid, and then extracted with toluene. The combined extracts were washed with sodium carbonate, dried over magnesium sulphate and evaporated in vacuo to provide the title compound (14.9 g, 78%) as a mixture 2:1 enol:ketone forms. 1H NMR (CDCl3, 400 MHz): δ=0.79-0.87 (m, 4H), 0.98-1.01 (m, 4H), 1.46-1.51 (m, 2H-enol), 1.93-1.97 (m, 2H-keto), 3.70 (s, 2H-keto), 5.65 (s, 1H-enol); LRMS: APCl+: m/z 153 [MH+]; APCl− m/z 151 [M−H]−.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>O1CCCC1.CO>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCCC)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 312 mg of 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=83° C.). Yield=74% over the two steps.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1OCc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2ccc(OCc3ccccc3)c(Nc3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-(benzyloxy)phenyl)piperazin-1-yl)(phenyl) methanone (1 g, 2.58 mmol) and phenylboronic acid (0.94 g, 7.74 mmol) in DCM (100 mL) was added triethylamine (1.0 mL, 7.74 mmol) and Cu(OAc)2 (0.7 g, 3.87 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-(benzyloxy)-3-(phenylamino) phenyl) piperazin-1-yl) (phenyl)methanone (0.87 g), 82% yield. 1H NMR (500 MHz, DMSO): δ 3.01 (bs, 2H), 3.16 (bs, 2H), 3.59 (bs, 2H), 3.95 (bs, 2H), 5.10 (s, 2H), 6.20 (s, 1H), 6.42 (dd, J=2.5, 3 Hz 1H), 6.91 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.32 (m, 2H), 7.37 (m, 10H). HRMS (ESI) calculated for C30H30N3O2: 464.2333, Found: 464.2338.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16].[OH-].[K+]>>[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16]
Reactant: CC1(C)C(=O)CCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: [K+]
Agent: [OH-]
Product: CC1(C)C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 100 mL of HNO3 (90%) at −30° C. was slowly added 12 g 1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (Ref.: J. Am. Chem. Soc. (1993), 115, 10628). The mixture was stirred for 10 minutes and slowly poured onto 600 mL of ice water containing 120 g of KOH (more ice was added as necessary to keep the mixture cool). The mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated in vacuo. The isomers were separated iterative silica gel column using 20% ethyl acetate in hexanes followed by trituration with ethyl ether to provide 3.8 g of the higher Rf 1,1-dimethyl-6-nitro-3,4-dihydronaphthalen-2(1H)-one: 1H NMR (300 MHz, CDCl3) δ 8.1 (dd, 1H, C7-H), 8.0 (d, 1H, C5-H), 7.5 (d, 1H, C8-H), 3.2 (t, 2H), 2.7 (t, 2H), 1.5 (s, 6H), and 5.1 g of the lower Rf 1,1-dimethyl-7-nitro-3,4-dihydronaphthalen-2(1H)-one: 1H NMR (300 MHz, CDCl3) δ 8.2 (d, 1H, C8-H), 8.0 (dd, 1H, C6-H), 7.3 (d, 1H, C5-H), 3.2 (t, 2H), 2.7 (t, 2H), 1.5 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.Cl.[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:26][CH3:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C>C(O)CC.Cl.Cl.C(N(CC1CCCCN1)CC)C.C(#N)C>[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:26][CH3:27])[CH3:24]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A suspension of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (276 g, 0.959 mol), and 2-[(diethylamino)methyl]piperidine dihydrochloride (244.95 g, 100.7 mol), of sodium carbonate (223.9 g, 2.112 mol) and acetonitrile (1.92 liters) are stirred for 6 hours at a reaction temperature of 70° C. After this time, the 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one has 95-97% reacted (TLC). The mixture is left to stand overnight at ambient temperature, then suction filtered. The contents of the filter are washed three times, each time with acetonitrile (60 ml). The dark colored filtrates are discarded. The remaining solid is stirred for a further 2 hours with water (1.5 liters), suction filtered again and washed with another water (300 ml) and finally dried at 40° C. in a circulating air drier. The crude product thus obtained (390 g) is transferred into a 10 liter flask, taken up in 1-propanol (5.14 liters) and, after the addition of 2-[(diethylamino)methyl]piperidine dihydrochloride (13.5 g, 0.0555 mol) and anhydrous sodium carbonate (11.8 g, 0.1113 mol), refluxed for 16 hours. After the addition of activated charcoal (39 g) the mixture is heated to boiling for a further 30 minutes and the boiling hot mixture is then forced through a SEITZ filter. Clarification is repeated twice more in the same way using activated charcoal (20 g). The filtrate is left to stand for 12 hours at ambient temperature, the precipitated crystals are suction filtered and washed twice, each time with 1-propanol (50 ml). The product is again stirred with cold 1-propanol (0.5 liters), suction filtered and again washed twice, each time with 1-propanol (50 ml). It is then dried in a circulating air drier at 40° C. and almost colorless crystals (263 g) are obtained, mp. 226°-227° C.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][C:23]=2[F:30])=[CH:19][C:18]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:2]3[CH:14]=[C:6]4[N:7]([CH:11]5[CH2:13][CH2:12]5)[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:15])[N:3]=3)=[CH:24][C:23]=2[F:30])=[CH:19][C:18]=1[C:33]([F:36])([F:34])[F:35]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCCc2ccccc2F)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1CCNC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 91 (0.37 g, 0.81 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 0.21 g of the product 92. 1H NMR (DMSO-d6) δ 9.10 (t, 1 H), 8.43 (s, 1 H), 8.58 (s, 1 H), 7.40 (t, 1 H), 7.30-7.15 (m, 1 H), 7.15-6.90 (m, 8 H), 6.80-6.55 (m, 4 H), 5.15 (s, 2 H), 3.80-3.45 (m, 2 H), 3.10-2.85 (m, 2 H); MS: m/z 360 (M++1).
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]3=[O:31])=[CH:10][C:4]=2[O:3]1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]3[O:32][CH2:34][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=5)[C:12]4=[O:31])[C:9]3=[CH:10][C:4]=2[O:3]1
Reactant: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ncccc1C(F)(F)F
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OC(F)(F)O3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (23%) as a colorless solid: mp 200-201° C. (ether/hexanes); 1H NMR (300 MHz, acetone-d6) δ8.75 (d, J=4.1 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.62-7.55 (m, 1H), 7.30-7.22 (m, 2H), 7.10-6.84 (m, 4H), 5.42 (d, J=17.4 Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 5.01 (d, J=9.2 Hz, 1H), 4.91 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, acetone-d6) δ177.6, 158.1, 153.5, 153.4, 144.9, 144.0, 138.6, 135.7, 132.8, 129.9, 126.9, 125.3, 124.9, 124.6, 124.0, 123.7, 123.3, 109.9, 106.6, 98.4, 81.3, 58.7, 42.9; MS (ES+) m/z 477.0 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1)=[O:27]
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cn1cccc1C(=O)O
Product: Cn1cccc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methyl-2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 76% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC3)c(F)c2)c1
Yield: 38.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH2:23]>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:23][C:19]2[S:18][CH:22]=[CH:21][N:20]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncccc1=O
Yield: 29 %

Procedure:
Using the method described in Example 78, Step 3,3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (prepared as in Example 78, Step 2) and thiazol-2-ylamine afforded 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide as a white solid (39.9 mg, 29%); ES+-HRMS m/e calcd for C15H18N4O2S [M+H+] 319.1223 found 319.1223. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.75 (m, 9H), 1.99 (m, 1H, CH), 2.28 (m, 1H), 5.60 (dd, J=4.5, J=10.3 Hz, 1H), 6.98 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.45 (dd, Jo=9.4, Jo=3.6 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 8.02 (dd, Jo=3.6 Hz, Jm=1.5 Hz, 1H), 12.58 (s, 1H).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([CH3:21])=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([CH3:21])=[N:19][CH:20]=1
Reactant: Cc1ncc(N=C(c2ccccc2)c2ccccc2)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncc(N)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of N-(5-(diphenylmethyleneamino)-2-methylpyridin-3-yl)methanesulfonamide (0.430 g, 1.177 mmol) in THF (10 mL) was added hydrochloric acid (JT Baker) (1.765 mL, 1.765 mmol) (1N). The reaction was stirred at rt in closed system for 20 min. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 5% to 10% MeOH in DCM) to afford the desired product as a brown solid (70.0 mg). MS (ESI pos. ion) m/z: 202.1. 1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H) 3.03 (s, 3H) 3.70 (br. s., 2H) 6.15 (br. s., 1H) 7.20 (d, J=2.34 Hz, 1H) 7.87 (d, J=2.34 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:8][CH:9]=1
Reactant: C=C(C)C(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=C(C)C(=O)NCCc1ccc(N)cc1
Reaction time: 4 h

Procedure:
Subsequently, N-[2-(4-nitrophenyl)ethyl]methacrylamide (1.20 g) was dissolved in ethanol (15 mL) and water (5 mL). Ammonium chloride (364 mg) and iron powder (933 mg) were added, and the reflux was performed at 80° C. for 4 hours. Iron powder was collected by the filtration, and the filtrate was evaporated under the reduced pressure. Water and ethyl acetate were added to the residual oil and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous sodium filfate, and evaporated to give the desired compound as a pale red oily substance. The yield was 1.01 g (97%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.