Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.C(OC([N:45]1[CH2:50][C@@H:49]([CH3:51])[NH:48][CH2:47][C@@H:46]1[CH3:52])=O)(C)(C)C>>[CH3:52][C@H:46]1[CH2:47][NH:48][C@H:49]([CH3:51])[CH2:50][N:45]1[C:2]1[CH:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[CH:4][N:3]=1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)NC[C@@H]5C)cn3)C4)n[nH]c2c1
Yield: 37.4 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 193 μmol) and (2S,5R)-2,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester (84 mg, 386 μmol) using the method from Example 61. After purification by HPLC Method E and deprotection using HCl/dioxan, the title compound (43 mg, 37% yield over two steps) was obtained as off-white solid (HCl-salt).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl[CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[N:13]([CH3:18])[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1>C(#N)C>[CH2:16]([C:14]1[N:13]([CH3:18])[C:12]2[CH:19]=[CH:20][C:9]([CH2:8][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:10][C:11]=2[N:15]=1)[CH3:17]
Reactant: c1c[nH]cn1
Reactant: CCc1nc2cc(CCl)ccc2n1C
Agent: Cl
Solvent: CC#N
Product: CCc1nc2cc(Cn3ccnc3)ccc2n1C
Yield: 54 %

Procedure:
A mixture of 6.8 parts of 1H-imidazole, 4.9 parts of 5-(chloromethyl)-2-ethyl-1-methyl-1H-benzimidazole monohydrochloride and 80 parts of acetonitrile was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.6 parts (54%) of 2-ethyl-5-(1H-imidazol-1-yl-methyl)-1-methyl-1H-benzimidazole; mp. 127.3° C. (compound 1).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C.CN(C=O)C.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>O>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2 ml of trimethylamine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.4 g of 4-cyanobenzoyl chloride. After completion of addition, the reaction mixture was stirred at 40° to 50° C. for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.9 g of 5-[4-(4-cyanobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 266°-269° C., colorless granules.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[NH2:24][C:25]1[C:30]([F:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1>>[NH2:24][C:25]1[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]34[CH2:23][CH:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=53)[C:15]3[C:10]4=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:4][CH2:3]2)[N:26]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Nc1nc(Cl)ncc1F
Product: Nc1nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)ncc1F

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (prepared as described in Example 8b) and 4-amino-2-chloro-5-fluoropyrimidine, the hydrochloride salt of the title compound was obtained as a white solid (8%), mp 250°-254° C.; MS(CI): 416 (M+H); NMR (300 MHz, DMSO-d6): 10.25(br s, 1H), 8.60(br m, 1H), 8.10(m, 1H), 7.39-7.32(m, 4H), 7.03-6.95(m, 4H), 4.46(s, 1H), 4.36(s, 2H), 4.18-3.80(br m, 1H), 3.60-3.38(m, 4H), 2.75(s, 2H), 2.14-1.96(m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:21].Cl.N1C=CC=CC=1OC1CCNCC1.C(O)C>C(OCC)C>[ClH:21].[ClH:21].[N:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1
Agent: Cl
Agent: c1ccc(OC2CCNCC2)nc1
Solvent: CCOCC
Solvent: CCO
Product: c1cc(OC2CCNCC2)ccn1

Procedure:
Prepared from 1-Boc-4-(pyridin-4-yloxy)piperidine using methods substantially equivalent to those described for the synthesis of 4-(pyridin-2-yloxy)piperidine dihydrochloride, using ethanol in place of ethyl acetate. The product was isolated by trituration with diethyl ether.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].Cl>[OH-].[Na+]>[C:14]([S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([SH:1])([CH3:13])[CH3:12])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)SC[C@H](NC(=O)C(C)(C)S)C(=O)O
Temperature: 0 °C
Yield: 74.8 %

Procedure:
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine (11.2 g, 0.05 mol) is dissolved in N sodium hydroxide (50 ml) and then pivaloyl chloride (6.6 g, 0.055 mol) and N sodium hydroxide (60 ml) are added dropwise while stirring under a nitrogen atmosphere at 0° C. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6 N hydrochloric acid. The produced oil is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness to yield 11.5 g (75.0%) S-pivaloyl-N-(2-mercapto-2-methylpropanoyl)-L-cysteine.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:31][CH2:32][O:33]C(=O)C)[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.Cl.C[OH:39]>O.[OH-].[Na+]>[OH:4][CH2:5][C:6]([N:8]([CH2:31][CH2:32][OH:33])[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][OH:24])[C:19]=1[I:20])[CH2:12][OH:39])=[O:7]
Reactant: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)COC(C)=O)c1I
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CO)Nc1c(I)c(CO)c(I)c(N(CCO)C(=O)CO)c1I
Reaction time: 2 h

Procedure:
N,N'-Bis(acetoxyacetyl)-N-(2-acetoxyethyl)-3,5-diamino-2,4,6-triiodobenzylacetate (0.50 g, 0.59 mmol) was dissolved in a mixture of methanol (5 ml), water (5 ml) and aqueous 1M NaOH (1 ml). The solution was stirred for 2 h, pH was adjusted to 2 using aqueous HCl and the product was purified by preparative HPLC. Yield: 240 mg (67%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=[O:18].O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:18])[CH3:12])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(C)oc2c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-yl acetate (5.05 g, 28.8 mmol) in THF (100 mL) a mixture of trifluoroacetic acid/water (4 mL/10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, saturated aqueous NaHCO3 (150 mL) was added. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo to give sub-title compound (4.0 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:14]1[O:18][C:17]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([NH:26][C:27](=[O:29])[CH3:28])[CH:20]=2)=[CH:16][C:15]=1[C:30]1[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:14]1[O:18][C:17]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([NH:26][C:27](=[O:29])[CH3:28])[CH:20]=2)=[CH:16][C:15]=1[C:30]1[NH:34][CH:33]=[N:32][N:31]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2cc(-c3nnc[nH]3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.20 g, 0.34 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was purified by column chromatography to give N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(4H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.14 g, 81%). LCMS (FA): m/z=477.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1
Yield: 79.5 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.5 g (11.6 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.09 g (79%) of 7-chloro-3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 105°-108°.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].CCN=C=NCCCN(C)C.[CH3:40][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH3:43])[NH2:42]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:42][C:41]([CH3:43])([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH3:40])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of {4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}acetic acid (Intermediate 5) (0.13 g, 0.34 mmol) in DCM/DMF (1:1, 6 ml) were added EDCI (0.07 g, 0.36 mmol), DMAP (0.004 g, 0.03 mmol) followed by the addition of tert-butyl 2-methylalaninate (Intermediate 8) (0.057 g, 0.36 mmol). The mixture was stirred at RT for overnight. The reaction mixture was diluted with EtOAc (20 ml), washed with water (2×20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (100% EtOAc) afforded the title compound as an off-white solid (78 mg, 44% yield).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].[NH2:22][CH2:23][C:24]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:24]([CH2:23][NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:14][CH:15]=2)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH2:34][CH2:35]1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC#CCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2 ml (14.2 mmol) of triethylamine then 2.9 g (14.2 mmol) of 4-but-2-ynyloxybenzoyl chloride diluted in 30 ml of tetrahydrofuran are added to a solution of 4 g (11.6 mmol) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate (prepared as described in example 1-3) in 40 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 1 h, then hydrolysed and the product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 4.2 g (70%) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzoylamino)methyl]malonate are obtained in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[C:13]3C(CC[C:8]=3[CH:9]=[CH:10][C:11]=2[Cl:14])=[CH:4][CH:3]=1.[C:15]([O:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].[OH-].[K+].Cl[O-].[Na+]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.[Na+].[Br-].O.ClC1C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[C:12]2[C:13](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:14])[C:16]([C:15]([O:18][C:19]([C:20]2[C:13]3[C:12](=[C:11]([Cl:14])[CH:10]=[CH:9][CH:8]=3)[C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:21])=[O:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c3c(ccc(Cl)c13)CC2
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(OC(=O)c1ccc(Cl)c2c(Cl)cccc12)c1ccc(Cl)c2c(Cl)cccc12
Temperature: 65 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
There was provided a 300 ml flask which was equipped with an agitator and a thermometer and provided with a gas feed port and a gas exhaust port attached with a condenser. The flask was charged with 22.3 g of 5,6-dichloroacenaphthene, 0.6 g of cobalt acetate tetrahydrate, 0.2 g of manganese acetate tetrahydrate, 0.2 g of NaBr, 10 ml of acetic acid, 90 ml of chlorobenzene, and 17 ml of acetic anhydride. The reaction system was heated to 65° C., into which air was blown for oxidation at a rate of 50 ml/min. The reaction was continued for 20 hours, during which the system was gradually heated up to 95° C. After completion of the reaction, the acetic acid was removed by distillation together with the chlorobenzene. To the remaining reaction mixture were added 50 ml of chlorobenzene and 400 ml of water dissolving therein 27 g of KOH, into which 32 ml of a sodium hypochlorite solution (13.6%) was dropped at 70°-100° C. The chlorobenzene was removed from the reaction solution, followed by treating with active carbon and filtering. The filtrate was treated with an acid to permit precipitation and the precipitate was filtered, washed with water and dried to obtain 23.5 g of 4,5-dichloronaphthalic anhydride. The yield was 88.0%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH2:19])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[C:20]([NH:27][C@@H:28]([C:30](O)=[O:31])[CH3:29])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[C:23]([O:22][C:20](=[O:21])[NH:27][C@@H:28]([C:30](=[O:31])[NH:19][C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=1[C:11](=[O:12])[NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)[CH3:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOc1ccc(NC(=O)C2=C(N)CCCC2)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)C2=C(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 63.3 %

Procedure:
A mixture of 2-amino-cyclohex-1-enecarboxylic acid (4-ethoxy-phenyl)-amide (1.46 g, 5.60 mmol), N-Boc-D-alanine (1.06 g, 5.60 mmol), EDC (1.60 g, 8.4 mmol), HOBT (151 mg, 1.12 mmol) and 1.0 mL of N-methylmorpholine in 30 mL of methylene chloride was allowed to stir at room temperature for 28 h. Upon completion, the mixture was concentrated and 30 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with ethyl acetate (30 mL×3). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The material was purified by chromatography on a silica gel column using 30% ethyl acetate/hexane successively as the eluents to give 1.53 g of product H4. 1H NMR (400 MHz, CDCl3) δ: 12.95 (s, 1H), 7.36 (d, J=8.86 Hz, 2H), 7.25 (br s, 1H), 8.87 (d, J=8.95 Hz, 2H), 5.23 (br s, 1H), 4.13 (br s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.01 (br s, 2H), 2.37 (br s, 2H), 1.70 (m, 4H), 1.43 (s, 9H), 1.41 (dd, J=7.0, 7.0 Hz, 3H), 1.40 (obscured d, J=7.07 Hz, 3H). MS (ESI+) 432 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)C(=O)COc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)(COc1ccccc1)c1cncnc1
Temperature: -110 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A solution of 19.2 g (0.1 mol) of 3,3-dimethyl-1-phenoxy-butan-2-one in 110 ml of absolute tetrahydrofuran and 70 ml of absolute ether was cooled to -120° C. under a dry nitrogen atmosphere. A solution of 15.7 g (0.1 mol) of 5-bromopyrimidine in 50 ml of absolute tetrahydrofuran was added dropwise. 60 ml of a 15% strength solution of n-butyl-lithium (containing about 0.14 mol) in n-hexane were then slowly added dropwise at -120° C. The mixture was stirred further, first for 2 hours at a temperature of about -110° C. and then overnight at -78° C. The reaction mixture was then warmed to room temperature, mixed with 100 ml of 10% strength ammonium chloride solution and concentrated in vacuo. The aqueous suspension was then extracted with ethyl acetate. The ethyl acetate extract was washed successively twice with 1N hydrochloric acid, twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was recrystallized from cyclohexane. 10.5 g (39% of theory) of 3,3-dimethyl-1-phenoxy-2-pyrimidin-5-yl-butan-2-ol of melting point 127°-129° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:9]2=[O:25])=[CH:5][CH:4]=1)#[N:2].Cl>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:25])=[CH:26][CH:27]=1)#[N:2]
Reactant: N#Cc1ccc(C=C2NC(=O)N(CC(=O)OCc3ccccc3)C2=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc(C=C2NC(=O)N(CC(=O)O)C2=O)cc1

Procedure:
0.4 g (1.1 mmol) of benzyl (5-(4-cyanobenzylidene)-2,4-dioxoimidazolidin-3-yl)-acetate are heated under reflux with 5 ml of 6N HCl and 5 ml of acetic acid for 30 minutes, the mixture is filtered hot and the filtrate is cooled. The product which has precipitated is filtered off with suction, washed with water and dried.
Reaction SMILES: [Br:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=O)=[O:4].Cl.CN(CCCN=C=NCC)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH2:33].O>ClCCl>[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH:33][C:7](=[O:9])[C:6]([NH:5][C:3](=[O:4])[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[Br:1])([CH3:11])[CH3:10]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)Nc1cc(Cl)ccc1Cl
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution of 2-(α-bromophenylacetylamino)isobutyric acid (1.9 g) in dichloromethane (30 mL) was cooled to 0° C., to which dimethylaminopropylethylcarbodiimide hydrochloride (1.3 g) was added. The mixture was stirred for 10 minutes at 0° C. to room temperature. 2,5-Dichloroaniline (1.0 g) was added to the mixture, which was stirred overnight at room temperature. The reaction solution was poured into water and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, 2.3 g of N-(2,5-dichlorophenyl)-2-(α-bromophenylacetylamino)isobutyramide was obtained as viscous liquid.
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([O:29]CC3C=CC=CC=3)[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21](=[O:29])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(OCc3ccccc3)nc3ccccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(=O)[nH]c3ccccc23)CC1
Yield: 3.4 %

Procedure:
150 mg of 10% palladium-carbon was added to 11 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl}carbonyl-2-benzyloxyquinoline (obtained in Reference Example 2) in 20 ml of ethanol. The mixture was stirred at room temperature at a hydrogen pressure of 1 atm. for 1 hour. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether and then re- crystallized from ligroin-ethyl acetate to obtain 0.3 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl}carbonylcarbostyril as a white powder having a melting point of 155°-158° C.