Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[S:23])[CH:20]=1)=[O:12])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:38](Cl)(Cl)=[S:39]>ClCCl>[C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([N:21]=[C:22]2[N:24]3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[C:38](=[S:39])[S:23]2)[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(=O)OC1COCC1OC(=O)COc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Yield: 72 %

Procedure:
In 15 ml of dichloromethane was dissolved 1.43 g of 1-(5-(4-acetoxytetrahydrofuran-3-yloxycarbonylmethoxy)-4-chloro-2-fluorophenylaminothiocarbonyl)hexahydropyridazine, followed by addition of 0.59 g of pyridine, which was then cooled in an ice-cold bath. Under stirring, a solution of 0.52 g of thiophosgene in dichloromethane was added dropwise, and after addition was completed, the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 1.12 g of a compound (No. 42) described in Table 1 (72%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]>C(Cl)(Cl)Cl>[CH3:8][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]3=[N:20][C:12](=[O:13])[CH:11]=[CH:10][N:17]3[CH2:16]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2Cn3ccc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl)-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine employing the procedures as set forth in Step 3 of Example 1. [α]D25 −43.52 (c 0.551, CHCl3).
Reaction SMILES: [OH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:1][C@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]([O:5][CH3:6])=[O:4])(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](O)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
0.72 g (6 mmoles; 0.1 equivalent) of 4-dimethylaminopyridine, 12.0 g (60 mmoles; 1 equivalent) of methyl(R)-2-hydroxy-2(2-chlorophenyl)acetate and 7.8 g (78 mmoles; 1.3 equivalent) of triethylamine and 20 ml of dichloromethane were added to a dry reaction flask. The colorless solution obtained was cooled to 0° C. and then, operating at this temperature, 13.14 g (60 mmoles; 1 equivalent) of 4-nitrobenzenesulfonyl chloride as a solution in 30 ml of dichloromethane was added. The reaction mixture was stirred for 3 hours at 0° C. and 240 ml of 1N hydrochloric acid and 240 ml of dichloromethane was added drop wise, while stirring this mixture. After decanting, the dichloromethane phase is washed with dilute hydrochloric acid and then with water, before being concentrated under reduced pressure. An analytically pure sample is obtained after purifying on a silica column. In this manner, methyl(R)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate is obtained: Yield: 98%. Optical purity: 99%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH3:14])[CH:3]=1.Cl.[C:24](OCC)(=O)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[CH3:24])[CH3:14])[CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (1.35 g) was added 4 M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.00 g). 1H NMR (300 MHz, CDCl3) δ 1.27 (3H, d, J=6.4 Hz), 1.98 (3H, s), 4.33-4.55 (3H, m), 5.65 (1H, d, J=6.1 Hz), 6.94 (1H, s), 8.86 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1ccc(Cl)cc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 2-amino-4-chlorobenzamide (393 mg, 2.30 mmol) and DIEA (0.60 mL, 3.45 mmol) in THF (15 mL) at 0° C. was added ethyl chlorooxoacetate (0.28 mL, 2.53 mmol). The solution was allowed to warm to rt and stir for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate as a solid (545 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.97 Hz, 3H), 4.31 (q, J=6.97 Hz, 2H), 7.34 (d, J=8.48 Hz, 1H), 7.86-8.03 (m, 2H), 8.44 (br s, 1H), 8.62 (s, 1H), 13.24 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a suspension of 7-chloro-4-hydroxy-2-(4′-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (495 mg, 1.4 mmol) in tetrahydrofuran (25 mL) was added trifluoroacetic acid (4.5 ml, 58 mmol). The mixture was cooled to 0° C. with an ice bath and sodium borohydride (290 mg, 7.7 mmol) was added. The resulting solution was stirred at 0° C. for 15 minutes, the cooling bath removed, and the reaction mixture was allowed to warm to room temperature. This was then stirred at room temperature for 3 hours after which the reaction was diluted with cold water (65 mL) and stirred for an additional 10 minutes. After this time, the resulting white mixture was extracted with ethyl acetate (120 mL). The organic phase was washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated to dryness. The resulting residue was triturated and filtered twice from warm ethyl acetate/hexane (2:1, 15 mL) and ethyl acetate (6 mL). After drying, this afforded the title compound as a white solid (462 mg, 97%). MP=208-210° C. (d) MS(CI)340(m/e+1) NMR(d6-DMSO): 2.33(s,3H),3.79(s,2H), 6.92(dd,1H,J1=8.1Hz,J2=1.9Hz), 7.11(d,1H,J=8.2 Hz),7.24(app d, 3H), 7.43(d,2H,J=8.2Hz), 9.05(s,1H),11.99(s, 1H);
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH3:19]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCl
Yield: 71.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using triethyl orthopropionate (7.96 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.33 g of 1-(3-chloropropyl)2-ethyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-])=O)[N:8]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([NH2:17])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COc1ccccc1CNc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1CNc1ccc2c(N)cccc2n1

Procedure:
(2-Methoxy-benzyl)-(5-nitro-quinolin-2-yl)-amine (2.2 g, 7.1 mmol) was dissolved in 100 mL methanol. Palladium on charcoal (10%, 150 mg, 0.14 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a yellow solid (1.98 g, 100%), MS: m/e=280.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:21]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Cl)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cccc(Cl)c2)c(C(=O)O)c1
Temperature: 150 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-chlorothiophenol (20 g, 138 mol), and cupric acetate (1.8 g) and DMF (200 mL) was added K2CO3 (23 g). The mixture was heated to 150° C. for 15-20 minutes, then 2-bromo-5-methoxybenzoic acid (35.8 g, 0.155 mol) was added in portions. The mixture was heated overnight, poured into water (600 mL), filtered and the filtrate was treated with charcoal, filtered and diluted with HCl. The resulting precipitate was collected by filtration, washed with water, and dried at 50° C. in vacuo over P2O5 to afford 27.6 g of 2-[(3-chlorophenyl)thio]-5-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:44]([O:48][CH2:49][CH:50](O)[CH3:51])([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:50]([CH3:51])[CH2:49][O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:6]([Cl:11])[CH:5]=1
Reactant: CC(O)COC(C)(C)C
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)COC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g of 3-chloro-4-hydroxybenzoic acid methyl ester in 20 ml of THF, 1.8 ml of 1-tert-butoxy-2-propanol, 3.16 g of triphenylphosphine, and 1.9 ml of diethylazodicarboxylate were added, and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=100:1˜5:1) to obtain 2.3 g of 4-(1-tert-butoxy-2-propoxy)-3-chlorobenzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 46 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (27 mg, 0.0675 mmol) and 2-aminoethanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (13 mg, 46% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.28 (br s, 1 H), 8.52 (s, 1 H), 7.51 (1 H), 7.15-7.11 (m, 2 H), 7.01-6.96 (m, 2 H), 4.27 (m, 2 H), 4.10 (s, 2 H), 3.76 (m, 2 H), 3.57 (m, 2 H), 3.49 (m, 2 H), 1.79 (m, 2 H); HRMS m/z calcd for C21H23N3O5F: 416.1622. Found: 416.1634.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: CCOC(=O)CCCBr
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution of pyrrolidine (8.42 mL, 102 mmol, 4.0 eq) in toluene (30 mL), ethyl 4-bromobutyrate (3.8 mL, 26 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 10 hours. The mixture was allowed to cool down to room temperature, the white solid present was filtered off and washed with Et2O. The filtrate was concentrated under reduced pressure to give the title product which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:19][S:16]([C:12]1[CH:11]=[C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:28]4[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=4)[N:9]3[N:8]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 20.2 %

Procedure:
A mixture of 5-Iodo-2-(3-methanesulfonyl-phenyl)-imidazo[2,1-b][1,3,4]thiadiazole (0.091 g, 0.225 mmol, 1 eq), and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.097 g, 0.337 mmol, 1.5 eq), PdCl2(PPh3)2 (32 mg, 0.045 mmol, 0.2 eq) and 2M Na2CO3 (1 mL) and dioxane (5 mL). The reaction mixture was heated at 110° C. for 24 h. The solvent was evaporated, the residue was redissolved in DCM/water (150 mL) and extacted with DCM (2×80 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered off. The solid was purified by column chromatography (0-5% MeOH in DCM) to give the desired product (20 mg, 20%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.25 min, [M+H]+ m/z 440.0; 1H NMR (300 MHz, DMSO) δ 8.90 (d, J=1.8 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.84 (s, 1H), 6.74 (s, 2H), 3.32 (s, 3H).
Reaction SMILES: [OH-].[Na+].[O:3]=[S:4]1(=[O:36])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:19]([O:21]CC)=[O:20])[CH3:18])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1.CC(O)=O>CCO>[O:36]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:19]([OH:21])=[O:20])[CH3:18])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)O)cc2S(=O)(=O)C1
Yield: 65.7 %

Procedure:
Sodium hydroxide (0.045 g, 1.13 mmol) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1-(ethoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 1; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%) and heated under reflux. After 1.5 hours AcOH (0.2 ml) was added and most of the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2O), dried (MgSO4) and evaporated to give the title compound 0.031 g (65%) as white solid. NMR (500 MHz, CD3OD) 0.70–0.85 (m, 6H), 0.95–1.25 (m, 4H), 1.35–1.70 (m, 4H), 2.65 (d, 3H), 3.10–3.35 (m, 2H), 3.45–3.95 (m, 2H), 4.70 (q, 1H), 6.90–7.35 (m, 6H), 7.45 (s, 1H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2ccccc2Cl)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccccc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 60%, with a melting point of 176° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:24](=[O:25])[CH2:23][O:22][CH2:21][C:11]=3[NH:12][C:13]3[CH2:19][O:16][C:15](=[O:17])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Solvent: ClCCl
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Temperature: 25 °C
Yield: 30.9 %

Procedure:
The product from Example 25B (0.30 g, 0.63 mmol) was heated neat to 130° C. for 15 minutes and cooled to ambient temperature. The residue was treated with methylene chloride and the resulting solid was collected by filtration, washed with methylene chloride and dried to provide the title compound (0.074 g) as a white solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].[N+:10]([C:13]1C=[CH:20][CH:19]=[CH:18][C:14]=1C(Cl)=O)([O-:12])=[O:11].O>C1(C)C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:18][CH:19]=[CH:20][C:2]=1[C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])=[O:3])([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)C1CCOC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 372 %

Procedure:
A mixture of Mg(OEt)2 (63 g, 0.55 mole) in toluene, under N2, is treated with dihydro-3-acetyl-(3H)-furanone (141 g, 1.10 mole) at 7°-10° C. over a 15 minute period and stirred at 25°-30° C. for 2 hours. The resultant reaction mixture is treated with a solution of o-nitrobenzoyl chloride (185.7 g, 1.0 mole) in toluene at 25°-35° C. over a 45 minute period, stirred at ambient temperatures for 1.75 hours, treated with 400 mL H2O and heated at 60°-75° until reaction is complete by LC analysis. The resultant reaction mixture is cooled to room temperature and the phases are separated to give the title product as a toluene solution, 875 g, 18% desired product by LC analysis (67% yield). The product solution is used as is in Example 6.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[OH-].[Na+].[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH3:13]>O.C(O)C>[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][N:1]2[CH2:6][CH2:5]3)=[CH:23][CH:24]=1)[CH3:13]
Reactant: O=C1CN2CCC1CC2
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COc1ccc(C=C2C(=O)C3CCN2CC3)cc1

Procedure:
A solution of 16.0 g of 3-quinuclidinone (hydrochloride) in 100 ml of water is treated with 100 ml of a 32% sodium hydroxide solution. 36.0 g of 4-(2-ethylhexyloxy)benzaldehyde [can be prepared from p-hydroxybenzaldehyde by reaction with 1-chloro-2-ethylhexane], dissolved in 250 ml of ethanol, is then added with stirring and the mixture is heated under reflux for 3 hours. After the reaction is complete, it is worked up in the customary manner. 2-[4-(2-ethylhexyloxy)benzylidene]quinuclidin-3-one is obtained in the form of a pale yellow solid; m.p. 37°, λmax =331 nm, E=0.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
N-t-butyloxycarbonyl-L-proline (32.29 g, 150 mmole), L-proline benzylester hydrochloride (36.26 g, 150 mmole) and HOBT (20.27 g, 150 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (15.18 g, 150 mmole) and WSC hydrochloride (28.76 g, 150 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C., and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 mg, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-t-butyloxycarbonyl-L-prolyl-L-proline benzylester (yield: 60.70 g, 100%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([OH:19])([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:15]([F:18])([F:17])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 11 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.