Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH:12](N2CCOCC2)[C:13](O)=[O:14])=[CH:6][C:5]=1[O:23][CH3:24])[CH3:2].O.[NH2:26][NH2:27]>C(O)CCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:14])[NH:26][N:27]=2)=[CH:6][C:5]=1[O:23][CH3:24])[CH3:2]
Reactant: CCOc1ccc(C(=O)CC(C(=O)O)N2CCOCC2)cc1OC
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC

Procedure:
4.5 g of 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyric acid are boiled under reflux in 30 ml of 1-butanol with 6.7 g of 100% pure hydrazine hydrate for 8 hours. The reaction mixture is then evaporated in vacuo; the residue is boiled up in 100 ml of 2N hydrochloric acid, filtered off with suction and washed with water until free from acid. After drying, 2.1 g (65.6% of theory) of the title compound of m.p. 182°-184° are obtained; after recrystallization from ethanol/ethyl acetate, the product has a melting point of 186°.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:16]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[C:6]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:35])=[O:2])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CN2CCCC2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(CN3CCCC3)cccc2C(=O)O)cc1
Yield: 67.6 %

Procedure:
To a solution of 0.754 g (1.523 mmol) of the product of Example 318 in 15 mL of THF/Methanol (1:1) was added 7.6 mL of 1.0N sodium hydroxide solution. The resulting mixture was heated to reflux for 15 h and then concentrated in vacuo. The residue was diluted with water, neutralized with 5% HCl solution and exited with dichloromethane. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.496 g (67%) of the product as a tan solid. Electrospray Mass Spec: 482.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH:25]=O)[CH:2]=[CH2:3].C(OC(=O)[NH:34][C@H:35]([C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH2:36][SH:37])(C)(C)C.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:23])([CH3:24])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:37][CH2:36][C@H:35]([NH2:34])[C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Reactant: Cc1noc([C@H](CS)NC(=O)OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 13.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid allyl ester in 38 ml of trifiuoroacetie acid, cooled to 0° C., were added within 15 min a solution of 13.7 g of (R)-2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylcarbamic acid tert-butyl ester and 6.2 g of triethylsilane in 38 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water, saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 14.1 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=4)(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 57.7 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10 mg, 0.032 mmol) obtained in Example 1, (3), and 3-methoxybenzenesulfonyl chloride (13 mg, 0.063 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (9 mg, yield 59%) as slightly brown amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].[H-].[Na+].O=O.I[CH2:16][CH3:17]>CN(C=O)C>[CH2:16]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH3:1])[C:6]#[N:7])[CH3:17]
Reactant: Cc1ccc(C#N)cc1O
Reactant: CCI
Agent: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)ccc1C
Yield: 72.8 %

Procedure:
10 g (75 mmol) of 4-methyl-3-hydroxybenzonitrile were deprotonated with 1 eq. of NaH in 100 ml of DMF and then ethylated on the oxygen with 112 mmol of iodoethane. 8.8 g of product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:27]5[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1cccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 46.9 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), 3-methylpyridine-2-carboxylic acid (126 mg, 0.917 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (187 mg, 0.978 mmol), 1-hydroxybenzotriazole (133 mg, 0.988 mmol), triethylamine (0.14 mL, 1.039 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (128 mg, 47%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:17]\[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)/[C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[CH:17]\[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)/[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)/C(=C/C1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)C(=O)O)cc1

Procedure:
LDA (24 mL of a 1.8M solution in n-C7H16-THF-PhEt, 43.3 mmol) was added dropwise to a stirred solution of DMPU (19 mL, 153.0 mmol) in anhydrous THF (100 mL) at −78° C. After 30 min, a solution of ethyl (4-methanesulfonylphenyl)-acetate (Preparation 15, 5.00 g, 20.6 mmol) in anhydrous THF (42 mL) was added dropwise. The mixture was stirred further for 1 h, before being treated dropwise with a solution of tetrahydropyran-4-carboxaldehyde (2.36 g, 20.6 mmol) in anhydrous THF (25 mL). After being allowed to warm up to 20° C. over 16 h, the reaction was quenched with saturated aqueous NH4Cl (210 mL). The THF was removed under reduced pressure, then the remainder was extracted with EtOAc (3×250 mL). The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated. Column chromatography (IH-EtOAc, 7:3) furnished (E)-ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=356.2 [M+NH4]+. A solution of this ester (6.46 g, 19.1 mmol) in MeOH (30 mL) and 1M NaOH (40 mL, 40.0 mmol) was heated under reflux for 1 h. On cooling, the mixture was washed with EtOAc. The aqueous phase was acidified with 1M HCl, before being extracted with EtOAc. The combined organic extracts were dried (MgSO4). Filtration and solvent evaporation afforded the title compound: m/z (ES+)=621.3 [2M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21](=[O:29])[CH2:20][N:19]=2)[CH:9]=1.CI>O>[CH3:3][N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([C:10]2[CH:9]=[N:8][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:19][CH2:20][C:21]1=[O:29]
Reactant: C1CCOC1
Reactant: O=C1CN=C(c2cnc3ccccc3c2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)CN=C(c2cnc3ccccc3c2)c2ccccc21
Reaction time: 0.33 h
Yield: 53 %

Procedure:
60% sodium hydride (62.8 mg, 1.57 mmol) was added to 25 mL of THF solution of 5-(3-quinolinyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (0.30 g, 1.04 mmol) at 0° C., followed by stirring at the same temperature for 20 minutes. Moreover, methyl iodide (0.18 g, 1.25 mmol) was added to the resulting solution, followed by bringing back to room temperature and stirring for 12 hours. 20 mL of water was slowly added to the reaction solution to stop the reaction. The resulting solution was extracted twice with 50 mL of ethyl acetate, and the extracted organic layers were mixed, followed by washing with 50 mL of brine and drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain the target compound (0.17 g, yield: 53%), which was slightly yellow amorphous.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) according to the general procedure K. Obtained as a yellow solid (113 mg).
Reaction SMILES: CO[C:3]([C:5]1[S:12][C:11]2[CH:10]=[N:9][N:8]([C:13](=[O:15])[CH3:14])[C:7]=2[CH:6]=1)=O.[CH3:16][C:17]1S[C:20](C(O)=O)=[CH:19][CH:18]=1>>[C:3]1([C:5]2[S:12][C:11]3[CH:10]=[N:9][N:8]([C:13](=[O:15])[CH3:14])[C:7]=3[CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c(cnn2C(C)=O)s1
Reactant: Cc1ccc(C(=O)O)s1
Product: CC(=O)n1ncc2sc(-c3ccccc3)cc21

Procedure:
1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [Intermediate (44), LC/MS: 243.1 (M+H), RT=3.45 minutes; 1H NMR (300 Mhz, CDCl3): δ 7.84 (s, 1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.43-7.31 (m, 3H), 2.75 (s, 3H)] is prepared using procedures similar to those described hereinabove for Intermediate (25) substituting 2-phenyl-5-methyl-thiophene for 5-methylthiophene-2-carboxylic acid in step 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)CC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of N-(tert-butoxycarbonyl)-piperidin4-ol (800 mg, 3.98 mmol), 3-hydroxypyridine (378 mg, 3.98 mmol) and triphenylphosphine (1.148 g, 4.38 mmol) in dry tetrahydrofuran (20 mL) was treated drop-wise via syringe with diethyl azodicarboxylate (0.75 mL, 830 mg, 4.76 mmol). The mixture was allowed to stir and warm to ambient temperature over 16 h. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography over silica gel, eluting with hexane-ethyl acetate (9:1, v/v). Selected fractions were collected and concentrated to produce 800 mg (72.2%) of a thick syrup.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:11]([O:14][C:15](=[O:24])[CH:16]([NH2:23])[CH2:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:12]>>[CH:11]([O:14][C:15](=[O:24])[CH:16]([NH:23][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)OC(=O)C(N)CSC(C)(C)C
Agent: Cl
Product: CC(C)OC(=O)C(CSC(C)(C)C)NC(=O)c1ccccc1
Yield: 72.5 %

Procedure:
With General procedure D, starting from 21 (5.6 g, 40.4 mmol) and 16 (7.33 g, 28.65 mmol), 6.72 g (73%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.54-7.43 (m, 3H), 6.97 (br d, 1H), 5.12 (m, 1H), 5.02 (m, 1H), 3.14 (dd, 2H), 1.30 (m, 15H). MS m/z 324 (M+1). HPLC: 96.61% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCCC(=O)c2ccccc2)CC1
Yield: 34.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 8-bromo-1-phenyl-1-octanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(8-oxo-8-phenyloctyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH:1]1([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH:1]1([C:5]2[N:6]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(C3CCC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 90.3 %

Procedure:
Using 2-cyclobutyl-1H-benzo[d]imidazole (72 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (170 mg, 90%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:4][CH2:3]1)(=[O:29])=[O:28]
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(CCCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine (1.23 g. 0.005 m) was suspended in a solution of dichloromethane (10 mls) containing triethylamine (2 mls). Methanesulphonyl chloride (0.570 g, 0.005 m) in dichloromethane (5 mls) was added dropwise over 5 minutes and the reaction stirred overnight at room temperature. The solution was then washed with five aliquots of water and dried over magnesium sulphate. Evaporation yielded the free base in 90% purity. This was triturated in ethyl acetate and warmed. The mother liquor was decanted off and evaporated to yield the title compound m.pt 141.4° C. This was recrystallised from ethanolic HCl as the hydrochloride salt (0.510 g), m.pt 167.4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(-c3ccc(F)cc3)nc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Yield: 96.3 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-pyrido[3,2-d]-pyrimidin-4(3H)one (482 mg, 2 mmol) in toluene (20 ml), was added diisopropylethylamine (1.0 ml, 6 mmol) and phosphorus oxychloride (0.56 ml, 6 mmol). The reaction mixture was refluxed for 1 hour. After concentration under reduced pressure, the residue was extracted with dichloromethane (100 ml), and washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure yielding the title compound as a yellowish solid (0.50 g, yield 96%) which was characterised as follows: Rf=0.90 (MeOH/CH2Cl2=1/9).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH3:17]>CS(C)=O>[NH2:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Reactant: N
Solvent: CS(C)=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1N
Temperature: 0 °C
Reaction time: 60 h

Procedure:
A solution of 2-chloro-5-(4-chlorophenyl)-3-pyridinecarbonitrile (2.0 grams) in 30 ml DMSO was heated in an oil bath at 80°-90° C. and then treated with gaseous NH3 for 21/2 hours. The reaction mixture was allowed to stand at room temperature for about 60 hours and then additional starting material (4 g) in 35 ml DMSO was added. The mixture was then treated with NH3 at 80°-90° C. for about 28 hours and poured into ice water. The tan solid precipitate which formed was filtered and used without further purification, yield 5.5 grams, m.p. 202°-204° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:11]1[C:19]2[C:14]3[C:15](=[CH:20][CH:21]=[CH:22][C:13]=3[C:12]=1S)[CH:16]=[CH:17][CH:18]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][NH:10][C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[C:15]4[C:14]=3[C:19](=[CH:18][CH:17]=[CH:16]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NOCCCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NOCCCn1ccnc1)=N2
Yield: 51.3 %

Procedure:
A mixture consisting of 2.33 grams of 3-(1H-imidazol-1-yl)propoxyamine, 2.84 grams of benz(cd)indol-2-thiol, 4.9 grams of mercuric acetate, and 150 ml of ethanol as stirred and heated under reflux by the conditions of Example 55. The crude product was purified by the chromatographic procedure of Example 46. The resultant orange syrup was recrystallized from ethyl acetate-hexane to give 2.3 grams of the title compound; mp 102° C.-104° C.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:6]([CH3:9])([Cl:8])[CH3:7])[C:3](=[O:5])[CH3:4].[Br:11]Br>CO>[Br:11][CH2:4][C:3](=[O:5])[C:2]([CH3:10])([CH3:1])[C:6]([Cl:8])([CH3:9])[CH3:7]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)C(C)(C)Cl
Solvent: CO
Product: CC(C)(Cl)C(C)(C)C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.2 Grams of 3,3,4-trimethyl-4-chloro-2-pentanone was dissolved in 15 ml of methanol, and 2.50 g (1.2 times by mole) of bromine was added dropwise at 20° C. After stirring for 1 hour, the reaction solution was poured into ice water and extracted twice with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated to obtain 3.1 g of the desired 1-bromo-4-chloro-3,3,4-trimethyl-2-pentanone (a halogeno-ketone compound of the foregoing formula (II) wherein a substituent X is a bromine atom) (yield, 96%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[N:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.050 g, 0.089 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (10 mg, 95%). LCMS for C17H17ClFN6 (M+H)+: m/z=359.0.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1ccc(C)c(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (500 mg, 3.29 mM) and p-xylene (0.56 ml, 4.79 mM) were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.9 ml, 8.2 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 2',5'-dimethylbenzoin was obtained as crystal (587.7 mg, 73.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Agent: O=S(=O)(O)O
Product: O=c1[nH]cnc2cc(Br)c([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
A solution of 7-bromo-4-quinazolinone (2.6 g) in 5 mL of concentrated H2SO4 and 5 mL of fuming HNO3 was heated at 100° C. for 1 h. After the reaction was cooled to room temperature, the mixture was poured into ice-water. The solid was collected via filtration, and used without further purification, 7-bromo-6-nitro-4-quinazolinone (mixed with 7-bromo-8-nitro-4-quinazolinone, LCMS ESI(+) m/z: 270/271 (M+1).