Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH:22]=O)([CH3:18])([CH3:17])[CH3:16].COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[C:28]([C:25]1[CH:24]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:26]=1[OH:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nc2c1
Yield: 41 %

Procedure:
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-di-tert-butyl-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (130 mg, 41%) was isolated as a light yellow solid. Selected data: MS (m/z): 411.17; MP 229.7-230.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:28]([Li])([CH3:31])([CH3:30])[CH3:29]>CCCCC>[C:28]([C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(C)C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 50 parts by volume of benzene under nitrogen atmosphere is added 30 parts of 1.6 M solution of tertiary-butyllithium in pentane. The resultant solution is stirred for about 24 hours and then quenched with the careful addition of 60 parts by volume of 10% ammonium chloride solution. After 1 hour, the organic layer is separated, washed with water and brine, dried with magnesium sulfate, and concentrated to give clear red oil. This oil is chromatographed on silica gel using successively methylene chloride and 10% ethanol-methylene chloride solution as eluents to give pale yellow solid which upon sublimation affords 4-tert-butyl-1-(2,2-diphenylethyl)-4-piperidinol. This compound melts at about 105°-110° C. and is represented by the following structural formula ##STR36##
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH:10]1[CH2:13][CH:12]([O:14][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH2:11]1
Reactant: OC1CNC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of tert-butylchlorodimethylsilane (12.01 g, 79.69 mmol) in DCM (20 mL) was added dropwise to a stirred solution of azetidin-3-ol hydrochloride (CAS no. 18621-18-6) (8.73 g, 79.69 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (34.1 mL, 199.22 mmol) in DCM (20 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (11.1 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.87 (9H, m), 2.80 (1H, s), 3.57-3.61 (2H, m), 3.67-3.71 (2H, m), 4.57-4.64 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:29])[CH3:28]
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 2 was suspended in pyridine (5 ml), and to the suspension was added acetic anhydride (0.14 ml), and the mixture was stirred at room temperature for 2 hours. A small amount of methanol was added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with methanol and ether in succession to produce the title compound (100 mg; 46%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([CH2:7]O)[S:5][CH:6]=1.CS(Cl)(=O)=O.C1COCC1.N12CCCN=C1CCCCC2>O>[Br:1][C:2]1[C:3]2[O:9][C@@H:10]([CH3:20])[CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:7][C:4]=2[S:5][CH:6]=1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Oc1c(Br)csc1CO
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of tert-butyl [(2S)-2-{[4-bromo-2-(hydroxymethyl)thiophen-3-yl]oxy}propyl]carbamate (1.83 g), methanesulfonyl chloride (0.58 ml,) and THF (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml,), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution (30 mL) of the residue in DMF was added sodium hydride (60% in oil, 0.4 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give the title compound (1.17 g, 67%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][S:7][CH2:8][C@H:9]([C:21]([OH:23])=O)[NH:10]C(OCC1C=CC=CC=1)=O)=[NH:3].[CH3:24][S:25]([Cl:28])(=[O:27])=[O:26].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[NH:3]=[C:2]([NH:4][CH2:5][CH2:6][S:7][CH2:8][C@H:9]([C:21]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:23])[NH2:10])[NH:1][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: N=C(N)NCCSC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC(=N)NCCSC[C@@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-3-(2-{[amino-(imino)-methyl]-amino}-ethylthio)-N-(benzyloxy-carbonyl)-alanine, methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:27]=2[N:35]2[CH:39]=[N:38][C:37]([CH3:40])=[N:36]2)[CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.CO.C1COCC1.[Cl-].[NH4+]>[Fe].O>[NH2:32][C:30]1[CH:29]=[CH:28][C:27]([N:35]2[CH:39]=[N:38][C:37]([CH3:40])=[N:36]2)=[C:26]([CH:31]=1)[O:25][CH2:24][CH2:23][CH2:22][CH:20]([NH:19][C:4]1[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH3:21]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)Nc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncn(-c2ccc(N)cc2OCCCC(C)Nc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Iron powder-325 mesh (0.63 g, 11.4 mmol) was added to a round bottom flask charged with a mixture of 2-chloro-7-(2,4-difluorophenyl)-N-(5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (0.65 g, 1.14 mmol), methanol (15 mL), THF (30 mL), water (15 mL) and ammonium chloride (0.61 g, 11.4 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated at 70° C. with vigorous stirring for 2 h. The reaction mixture was filtered and washed with methanol. The filtrate was concentrated in vacuo. EtOAc (250 mL) was added to the residue and was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the light yellow solid N-(5-(5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenoxy)pentan-2-yl)-2-chloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (500 mg, 81%). LC-MS (M+H)+=540.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1H, s), 7.32-7.30 (1H, m), 6.96-6.94 (1H, m), 6.81-6.75 (2H, m), 6.34-6.29 (2H, m), 4.83 (1H, br m), 4.44-4.43 (2H, m), 4.09-4.00 (2H, m), 3.77 (2H, br s), 3.13-3.12 (1H, m), 2.64-2.56 (2H, m), 2.47 (3H, s), 1.94-1.80 (3H, m), 1.63-1.61 (2H, m), 1.27-1.22 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])[N:5]=[N:4][N:3]=1.CN(C)C=O.[O-]CC.[K+]>C(O)(=O)C>[N:5]1[N:6]2[C:7]3[C:8]([C:9]([OH:10])=[CH:1][C:2]2=[N:3][N:4]=1)=[CH:14][CH:15]=[CH:16][N:17]=3
Reactant: CCOC(=O)c1cccnc1-n1nnnc1C
Agent: CC[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1cc2nnnn2c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole) was covered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5 g, 54 mmole) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into ice water containing about 17 mL of acetic acid. The resulting precipitate was isolated by filtration, washed with water then dried to provide 4.5 g of tetrazolo[1,5-a][1,8]naphthyridin-5-ol as an off white solid, m.p. 236° (decomposition). Analysis: Calculated for C8H5N5O: %C, 51.34; %H, 2.69; %N, 37.42; Found: %C, 51.23; %H, 2.77; %N, 37.25.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[Na+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.O.CCO>C(OC(=O)C)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[CH:6]\[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=C(O)/C(=C/c1ccccc1[N+](=O)[O-])c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
64.7 g (0.43 mol) of 2-nitrobenzaldehyde and 105.7 g (0.43 mol) of 4-bromophenylacetic acid sodium salt are dissolved in 500 ml of acetic anhydride and stirred at 80° C. for 2 h. When the reaction is complete, the mixture is extended with 1000 ml of water and 750 ml of EtOH and heated to 110° C., and, after 20 min, the orange solid is filtered off with suction, washed with water and MeOH and dried, giving 107 g (71.8%) of a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39]([NH:42][NH2:43])(=[O:41])[CH3:40]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]2[O:16][C:39]([CH3:40])=[N:42][N:43]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:39](=[N:42][NH:43][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26])=[O:41]
Reactant: CC(=O)NN
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2Cc3ccccc3C2=O)ccc1OC
Product: CCOc1cc(C(Cc2nnc(C)o2)N2Cc3ccccc3C2=O)ccc1OC
Yield: 145 %

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(5-methyl(1,3,4-oxadiazol-2-yl))ethyl]isoindolin-1-one was prepared by the procedure of Example 1. Reaction 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanoic acid (1.50 g, 4.22 mmol), carbonyldiimidazole (0.76 g, 4.7 mmol) and acetic hydrazide (381 mg, 5.16 mmol) in tetrahydrofuran (15 mL) gave crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanamide (1.22 9, 3.06 mmol), which (650 mg, 1.47 mmol) was then reacted with phosphorus pentoxide (2.0 g, 14 mmol) in chloroform (30 mL) at room temperature for 18 hours The product was obtained as a white solid (250 mg, 32% overall yield): mp, 125.5-128.0° C.; 1H NMR (CDCl3); δ 1.43 (t, J=7.0 Hz, 3H, CH3), 2.46 (s, 3H, CH3), 3.56 (dd, J=6.3, 15.1 Hz, 1H, CHH), 3.76 (dd, J=10.0, 15.0 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.02-4.11 (m, 3H, NCHH, CH2), 4.46 (d, J=16.6 Hz, 1H, NCHH), 5.97 (dd, J=6.3, 9.9 Hz, 1H, NCH), 6.83-6.87 (m, 1H, Ar), 6.95-7.01 (m, 2H, Ar), 7.35-7.53 (m, 3H, Ar), 7.77-7.81 (m, 1H, Ar); 13C NMR (CDCl3) δ 10.89, 14.64, 28.04, 46.18, 52.08, 55.89, 64.47, 111.32, 112.51, 119.03, 122.81, 123.74, 127.95, 130.13, 131.48, 132.11, 141.17, 148.64, 149.31, 163.86, 164.23, 168.30; Anal Calcd for C22H23N3O4+0.28 EtOAc: C, 66.42; H, 6.08; N, 10.05. Found: C, 66.47; H, 5.98; N, 10.04. (1H NMR showed that the sample contained 28% of ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13]C)=O.O.Cl>C(Cl)Cl.C(O)(=O)C>[F:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[Cl:8])[NH:1][C:11](=[O:13])[CH2:10]2
Reactant: COC(=O)Cc1cc(F)c(Cl)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2cc(F)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Compound (III) is obtained by cyclizing (II) with an acid as shown in step [b] of Scheme 1. Compound (II) is dissolved in a mixture of an acid and a cosolvent, preferably the acid is glacial acetic acid in which instance the preferred cosolvent is water or the acid is hydrochloric acid in which instance the preferred cosolvent is methylene chloride. With acetic acid the ratio of the acid and cosolvent mixture ranges from 2:1 to pure acetic acid respectively, the preferred ratio being 6:1. With HCl, much less acid is required, preferably 1:4 3N HCl to CH2Cl2. Once compound (II) is dissolved, the reaction mixture is stirred at ambient temperature for from 6 to 7 hours to produce 5-fluoro-6-chlorooxindole (III). Compound (III) is readily purified by recrystallization from ethyl acetate to yield an off-white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[ClH:31].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:39]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:40])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 32.8 mg (0.21 mmol) of 4-chlorophenyl isocyanate. After 16 h at room temperature, the mixture is concentrated in vacuo. The residue is dissolved in a 1:1 mixture of water and acetonitrile and purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 29 mg (55.2% of theory) of the title compound are obtained.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH2:35]Br)=[CH2:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.[CH3:42][O-:43].[Na+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH2:35][O:43][CH3:42])=[CH2:34])=[CH:29][CH:28]=1
Reactant: C[O-]
Reactant: C=C(CBr)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Na+]
Solvent: CO
Product: C=C(COC)c1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1

Procedure:
The solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(3-bromoprop-1-en-2-yl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BA) (110 mg, 0.169 mmol) and 4 mL of 0.3M NaOMe in MeOH (freshly-distilled) was stirred at 70° C. for 2.5 h. Then the reaction was quenched with H2O. After removing the volatiles, the aqueous layer was extracted 3× with AcOEt. The organic portion was washed 1× with a saturated solution of NH4Cl and 1× with brine prior to drying over Na2SO4. Concentration and purification of the crude product by preparative TLC gave intermediate BA (48 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:19]1([CH2:18][CH2:17][CH2:16][NH:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:4])=[O:2])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccccc2c1NCCCc1ccccc1

Procedure:
48 mg 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid methyl ester were reacted with 0.14 ml of 2 M sodium hydroxide in 1 ml methanol and 1 ml of THF at 65° C. for 2 h. The organic solvents were then removed in vacuo, and the residue was taken up in water and ethyl acetate. The pH was brought to 3-4 with 2 M hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, and concentrated. After purification by chromatography on silica (ethyl acetate/heptane) 18 mg of 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid were obtained.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][NH2:8].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[C:26]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)=[N:27][O:28][C:29]=2[CH2:30][OH:31])=[N:19][CH:18]=1>O1CCOCC1>[F:39][C:34]1[CH:33]=[C:32]([C:26]2[C:25]([CH2:24][O:23][C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:8][CH2:7][C:6]([F:13])([F:5])[C:9]([F:12])([F:11])[F:10])=[O:15])=[CH:18][N:19]=3)=[C:29]([CH2:30][OH:31])[O:28][N:27]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NCC(F)(F)C(F)(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)C(F)(F)F)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
Trimethylaluminium solution (2M in toluene, 0.80 mL, 1.60 mmol) was added to a solution of 2,2,3,3,3-pentafluoropropylamine (116 μL, 1.10 mmol) in dioxane (4 mL). The mixture was stirred for 45 min at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (4 mL) was added and the reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=1:1) to afford the title compound (96 mg, 73%) as a white solid. MS: m/e=492.1 [M−H]−.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: NN
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (493 mg, 1.1 mmol) produced in Synthesis Example 33 in DMF (4.5 mL) was added hydrazine monohydrate (purity of 80%, 175 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (418 mg, yield 86%).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=[O:7])(C)(C)C.C(Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]2=1)(=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4)cc3c2C1
Yield: 37.5 %

Procedure:
Beginning with 0.198 gm (0.60 mMol) 6-(t-butoxy-carbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 9.7 μL (0.84 mMol) benzoyl chloride, 0.075 gm (38%) of the title compound were prepared as a light grey foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)=[CH2:2].C(=O)([O-])[OH:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:12][CH2:10]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C=C)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C2CO2)cc1
Yield: 231.5 %

Procedure:
Into a 1-liter reactor provided with a stirrer, and a thermometer, were added 25 g of p-divinylbenzene, 40 g of sodium hydrogencarbonate, and 400 ml of toluene. To the mixture, while being kept at 5° C. and stirred, was added dropwise a solution of 100 g (40% by weight) of m-chloroperbenzoic acid in toluene. The resulting mixture was stirred at 5° C. for 10 hours. After completion of the reaction, the reaction mixture was washed with aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The mixture was filtered from the drying agent, then stripped of the toluene under reduced pressure, and purified by distillation to yield 65 g of 4-vinylstyrene oxide (1 Torr., 74° C.). In a similar manner, 3-vinylstyrene oxide was obtained from m-divinylbenzene.