Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH2:25][CH:24]1[N:26]([CH3:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1.C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:21])[NH:33][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH:24]4[CH2:23][CH2:25]4)[CH3:34])=[CH:32][CH:31]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(c1ccc(N)cn1)C1CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CN(c1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1)C1CC1

Procedure:
4-{4-[6-(Cyclopropyl-methyl-amino)-pyridin-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was synthesized from 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and N-2-cyclopropyl-N2-methyl-pyridine-2,5-diamine in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. LCMS calcd for C25H33N5O3 (m/e) 451, obsd 452 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)(=[O:3])[NH2:2].O.[NH2:16]N.Cl.O>CN1CCCC1=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[NH:16][NH:10][C:11]2=[O:12])(=[O:3])[NH2:2]
Reactant: NN
Reactant: NC(=O)c1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Carbamoylphthalimide (2.00 g, 0.011 mol) was suspended in 12 ml of N-methyl-2-pyrrolidinone, followed by the dropwise addition of 0.8 ml of hydrazine hydrate. The obtained mixture was stirred at room temperature for 30 minutes, followed by the addition of 5.5 ml of 3N hydrochloric acid and 50 ml of water. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air. The title compound (2.0 g) was obtained as a light brown crystal (yield: 94%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)[CH:3]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 200 °C
Yield: 107.7 %

Procedure:
A mixture of 4-bromo-2,5-difluoro-1-nitrobenzene (1 g, 4.2 mmol), 1-(tetrahydro-2H-pyran-4yl)piperidin-4-amine dihydrochloride salt (D40, 1.08 g, 4.2 mmol), and di-iso-propylethylamine (2.2 ml, 1.26 mmol) in dimethylformamide (10 ml) was heated in microwave reactor for 5 min at 200° C. The mixture was washed with water, then extracted with dichloromethane and the extract dried over MgSO4 and concentrated under vacuum. The crude material was purified on silica column (100 g of silica, ethyl acetate/methanol: 1.0% to 0%, 3CV; 2.0% to 100% 2CV 3. 100% to 100% 5CV) to leave 1.82 g (96%) of a mixture of title compound and an unknown impurity (˜3:1 by HPLC).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([C:23]([C:15]2[N:16]([CH:20]([CH3:21])[CH3:22])[C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:9]([N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([N:2]([CH3:1])[CH3:26])[CH2:4]2)=[O:10])=[CH:19][CH:18]=3)=[O:25])[CH2:31][CH2:30]1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, 4,4-difluoropiperidine hydrochloride, triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a light-brown oil (79%).
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28]C(=O)OC(C)(C)C)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36]>C(OCC)(=O)C.CO>[ClH:36].[ClH:36].[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH2:28])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 90 %

Procedure:
A mixture of tert-butyl (1R,25)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexylcarbamate (2.71 g, 5.7 mmol), a 4N hydrogen chloride in ethyl acetate solution (10 ml) and methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (2.29 g, 90%) as a colorless powder.
Reaction SMILES: COC1C=C2C(CCC(=O)C2(C)C)=CC=1.Br[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[OH:24].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:41](=[O:42])[C:40]3C4C(=CC(C#N)=CC=4)N[C:32]=3[C:31](C)(C)[C:30]=2[CH:47]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[C:40]3[C:41](=[O:42])[C:29]4[C:30]([CH2:31][C:32]=3[O:24][C:18]=2[CH:19]=1)=[CH:47][C:26]([OH:25])=[CH:27][CH:28]=4
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: Oc1cc(Cl)ccc1Br
Agent: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Product: O=C1c2ccc(O)cc2Cc2oc3cc(Cl)ccc3c21

Procedure:
The compounds described in the following Table 43 were synthesized according to the method shown below. According to the method used for the preparation of Compound Z10, Z11 and Z12, 3-chloro-8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was prepared from Compound A2 and 2-bromo-5-chlorophenol. Subsequently, demethylation was carried out according to the method that is used for the preparation of Compound A6, and thus 3-chloro-8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was obtained. Thereafter, according to Mitsunobu reaction that is used for the preparation of Compound A7-1 or the alkylation method that is used for the preparation of A7-17, a corresponding side chain was introduced and, if necessary, functional group modification such as deprotection, etc. was carried out to prepare the compounds listed below.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)[O:31][C:32]=2[CH3:33])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccco2)nc1COc1cc(CCl)ccn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (643 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][OH:26])=[N:3]1.[H-].[Na+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1.CN(C)C=O>[CH2:29]([O:31][CH2:32][O:26][CH2:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)[CH3:30]
Reactant: Cn1nc(CO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOCOCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.6 g) in dry tetrahydrofuran (30 ml) and dry dimethylformamide (3 ml), was added to a suspension of an 80% dispersion of sodium hydride in mineral oil (0.31 g), in dry tetrahydrofuran (10 ml).The suspension was heated under reflux for 0.5 h. and cooled to room temperature. Chloromethyl ethyl ether (1.0 ml) was added dropwise, and thesuspension was heated at reflux for 1 h. The solvent was removed under reduced pressure, and the residual yellow oil was partitioned between aqueous sodium carbonate and ethyl acetate. The organic phase was chromatographed on silica using a mixture of dichloromethane:ethanol:0.880ammonia (100:8:1) to give an oil (0.7 g). This oil was distilled to give the title compound (0.44 g) as a pale yellow oil b.p. 220°/0.06 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@@H:9]1[CH:14]=CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[O:23]=[O+][O-]>CO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[CH:14]=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCO[C@H]1C=O
Temperature: 23 °C
Yield: 98 %

Procedure:
Through a stirring solution of [(2R,3R)-2-styryl-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (27 mg, 0.089 mmol) in methanol (2 mL) at −78° C. was bubbled ozone until the reaction solution was blue in color. Excess triphenylphosine (500 mg) was added, and the reaction was allowed to warm to 23° C. The resulting mixture was concentrated and purified by flash chromatography (SiO2, 7-40% ethyl acetate in hexanes) to give the desired aldehyde (20 mg, 98%) as a pale yellow oil. MS (APCI), m+/z: (M+H)+=230.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O1CCC[CH2:16]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.CCCCCC.C(OCC)(=O)C>[CH2:16]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 986 mg of methyltriphenylphosphonium bromide in 20 ml of tetrahydrofuran, 1.87 ml of 1.63 M n-butyl lithium/hexane solution was added dropwise at 0° C., under cooling with ice. The temperature then was immediately raised to room temperature, and the system was stirred for 50 minutes. The reaction liquid was again cooled to 0° C., to which a solution of 500 mg of t-butyl 4-oxotetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran was added dropwise, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to provide 192 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:18]([NH2:17])=[S:19])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Product: Cc1cccc(NC(N)=S)n1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
6-Methyl-pyridin-2-ylamine (1.0 g, 9.2 mmol) is dissolved in ethanol (10 ml) and benzoylisothiocyanate (1.24 ml, 9.2 mmol) is added dropwise. The mixture is heated to 40° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (15 ml) and heated under reflux for 2 hour. The resultant suspension is filtered and the solid washed copiously with water and then with cold ethanol. The solid is dried in vacuo to yield the title compound. Mass Spec (APCI+) 168.
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[S:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-:19].[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>O>[CH:15]([N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:19])([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(Sc1nc2ccccc2s1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(C)N(C(C)C)S(=O)c1nc2ccccc2s1
Reaction time: 10 h
Yield: 84.5 %

Procedure:
133 parts of N,N-diisopropyl-2-benzothiazolesulphenamide are suspended in 400 parts of water in an apparatus provided with a stirrer and a thermometer. 20 parts of sodium carbonate and 20 parts of sodium bicarbonate are added. 400 parts by volume of a sodium hypochlorite solution titrating 180 g. per liter of NaClO are gradually introduced in a period of 1 hour, with good stirring, at a temperature of 25°-28° C. The mixture is stirred for a further 10 hours at 20°-25° C. The solid is filtered off, washed with water until neutral and dried in vacuo. 119 parts of 2-N,N-diisopropylbenzo-thiazole-sulphinamide are obtained, that is a yield of 84.5%. Melting point (uncorrected): 79.5° C. After recrystallising from ethyl alcohol, a product of melting point (uncorrected) 80.5° C. is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15](O)[CH3:16].S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:15]([O:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:16]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c2ccccc12
Yield: 72 %

Procedure:
4-Fluoro-1-naphthoic acid (190 mg, 1.0 mmol) was transferred to a Pyrex tube and ethanol (0.6 mL) was added followed by conc. sulphuric acid (0.1 mL). The tube was capped and the reaction tube was exposed two times to microwave irradiation (2×120° C., 5 min). The reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 4-fluoronaphthalene-1-carboxylic acid ethyl ester (154BG85-11, 156 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+:8]([C:11]1[CH:21]=[CH:20][C:14]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>[OH-].[Na+].CCOCC>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:18])=[CH:20][CH:21]=1)([O-:10])=[O:9]
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 3.10 g portion of 4-aminobutyric acid was dissolved in 15 ml of 2N sodium hydroxide, to the solution were simultaneously added dropwise 6.48 g of p-nitrobenzyloxycarbonyl chloride dissolved in ether and 7.5 ml of 4N sodium hydroxide while cooling on an ice-bath. After 2 hours of stirring at the same temperature, the solution was washed with ether, the resulting aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and a precipitated. solid material was collected by filtration, washed with water and then dried to yield 7.64 g of 4-(p-nitrobenzyloxycarbonyl)aminobutyric acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]2[CH2:21][CH:22](O)[CH2:23][CH:17]1[CH2:18][CH2:19]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH:22]2[CH2:21][CH:20]3[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]3)[CH2:23]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CN1C2CCC1CC(OC(c1ccccc1)c1ccccc1)C2
Reaction time: 2 h

Procedure:
The starting material is prepared as follows. The intimate mixture of 9.20 g of benzhydrol 7.05 g of tropine and 10 g of p-toluenesulfonic acid monohydrate is placed in a flask which is fitted with an air condensor and a vacuum take-off. The flask is evacuated and maintained in vacuo while being heated in an oil bath to 165°-170°, whereby the liberated water is removed. After 2 hours, the mixture is cooled and partitioned between 100 ml of water and diethyl ether each. The aqueous solution is separated, washed once more with diethyl ether and made basic with 50% aqueous sodium hydroxide. It is extracted repeatedly with diethyl ether, the extract washed with brine and evaporated to give 3-diphenylmethoxy-8-methyl-8-azabicyclo[3.2.1]octane, which is sufficiently pure to be used in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 92.8 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrirnidinyl)-L-phenylalanine methyl ester hydrochloride salt (3.12 mmol, 1.15 g) and 2,6-dichlorobenzoyl chloride (3.51 mmol, 0.735 g) in dichloromethane (40 mL) was added diisopropylethylamine (9.36 mmol, 1.63 mL) at room temperature. After 1 min, everything went into solution and the clear yellow solution was stirred for 20 h at room temperature. The resulting brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 1.46 g (93% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23Cl2N3O5 (M+H) 504.1093, found 504.1083.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[C:5]([CH:23]2[CH2:25][CH2:24]2)=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]2>C(O)CCC.C(O)(C(F)(F)F)=O>[NH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]2[C:5]([CH:23]3[CH2:24][CH2:25]3)=[CH:4][N:3]=[C:2]([NH:26][C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]4)[N:7]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2C2CC2)CC1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C2CC2)CC1
Temperature: 140 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
A solution of tert-butyl (1-(2-chloro-5-cyclopropylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (99 mg, 0.27 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.30 mmol) in nBuOH (3 mL) was stirred at 116° C. for 20 h. It was then stirred at 140° C. for another 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give a powder, which was then dissolved in TFA (3 mL). After being stirred at room temperature for 20 h, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (16 mg). MS 393.5 (M+H); UV 208.9, 264.5 nm