Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8]Cl)(=[O:5])[CH:2]([CH3:4])[OH:3].C(OC)(=O)[CH2:11][OH:12].C([O:18]CC)C>>[C:1]([O:6][CH2:7][C:8]([O:12][CH3:11])=[O:18])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCOCC
Reactant: CC(O)C(=O)OCCCl
Reactant: COC(=O)CO
Product: COC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroethyl lactate (19.10 g, 0.125 mol) and methyl glycolate (11.26 g, 0.125 mol) in 250 mL of ethyl ether containing 0.125% tert-butylbenzene was added to 17.5 g Lipase P30 powder in duplicate reactions. The reaction mixtures were agitated on an orbital shaker (175 RPM) at room temperature for 8 hr and an additional equivalent of methyl glycolate was added. After agitation for a further 40 hr, the enzyme powders were removed by filtration and the filtrates were combined and evaporated. The resulting residue was chromatographed by flash chromatography (ethyl acetate/hexane, 22.5/77.5) to give the title compound as an oil (6.00 g, 15%--an approximately equal amount of product was recovered in fractions which also contained methyl glycolate): 1H NMR δ 1.49 (d, 3 H, J=7.0 Hz), δ 3.55 (bs, 1 H), δ 3.78 (s, 3 H), 8 4.43 (q, 1 H, i=6.9 Hz), δ 4.67 (d, 1 H, J=15.9 Hz), δ 4.76 (d, 1 H, J=15.9 Hz); 13C NMR 20.04, 52.09, 60.87, 66.67, 167.63, 174.62; HRMS calcd for C5H6O5Tms (M--CH3) 219.0688, obsd 219.0641.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:23]([O-:26])([OH:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[C:5]([N+:23]([O-:26])=[O:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCc2cccc(Cl)c2CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Product: CCOC(=O)N1CCc2ccc([N+](=O)[O-])c(Cl)c2CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.86 g of ethyl 6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 30 ml of chloroform was ice-cooled, and while maintaining the inner temperature at 10° C. or lower, 60 ml of concentrated sulfuric acid was added thereto. Then, 3.2 ml of concentrated nitric acid was added dropwise thereto, followed by stirring for 30 minutes. The reaction mixture was poured into ice, followed by extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 6.442 g of ethyl 6-chloro-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a reddish orange viscous substance and 5.201 g of ethyl 6-chloro-9-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Br[C:48]1[S:49][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][N:52]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[S:49][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][N:52]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Product: CCOC(=O)c1cnc(-c2ccc(N(CC(=O)NCCN(CC)C(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c(C)c2)s1
Yield: 13.6 %

Procedure:
Using the compound (1.69 g, 2.66 mmol) of Example 295, step A and ethyl 2-bromothiazole-5-carboxylate (754 mg, 3.19 mmol), and according to the method of Example 295, step B, the title compound (246 mg, yield 14%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22](=[O:33])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[O:26][N:25]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[C:29]([C:27]1[O:26][N:25]=[C:24]([NH:23][C:22]([C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[O:33])[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCNCC2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[(S)-2-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-piperidine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (655 mg; 1.413 mmol) in dichloromethane (100 mL) is added 4N hydrochloric acid in dioxane (1.25 mL; 5 mmol) and the reaction mixture is stirred at room temperature for 3 hours. More 4N hydrochloric acid in dioxane (1.25 mL; 5 mmol) is added and the stirring is continued for another 3 hours. After this time, the reaction mixture is concentrated to afford the product. The product is taken up in the mixture of ethyl acetate and saturated NaHCO3 aqueous solution to free base the product. The aqueous layer is extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound, m/z 364 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](O)=[O:11].NC1C=C(Cl)C=CC=1CN1C=CC=C1C#N>O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:3]2[CH2:4][N:5]3[CH:9]=[CH:8][CH:7]=[C:6]3[C:10](=[O:11])[NH:1][C:2]=2[CH:16]=1
Reactant: Nc1cc(Cl)ccc1Cn1cccc1C(=O)O
Agent: N#Cc1cccn1Cc1ccc(Cl)cc1N
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2Cn2cccc21
Temperature: 105 °C

Procedure:
A mixture of 5.7 g. of 1-(2-amino-4-chlorobenzyl)-2-pyrrolecarboxylic acid (prepared by the method of Example 5, using 1-(2-amino-4-chlorobenzyl)-2-pyrrolecarbonitrile), 3.9 g. of N,N'-carbonyldiimidazole and 60 ml. of tetrahydrofuran is stirred with cooling for one hour, allowed to stand at room temperature, heated on a steam bath for one hour, diluted with 5 ml. of water and concentrated to remove the tetrahydrofuran. The residue is dissolved in methylene chloride, washed successively with water, 25 ml. of 1 N sodium hydroxide and water, dried over magnesium sulfate and concentrated to remove the solvent. The resulting viscous oil is dissolved in 20 ml. of ethyl acetate and cooled giving crystals. These crystals are heated at 105° C. for one hour and then triturated with ethyl acetate giving 8-chloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]-benzodiazepin-11-one.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]([F:40])[F:39])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:57][NH2:58]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:58][N:57]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]([F:40])[F:39])=[CH:32][CH:31]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)F)cc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)F)cc3)n2)ccc1-n1cnc(Cl)c1

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (1.108 g, 2.61 mmol, from preparation A) and 6-chloro-2-(4-(2,2-difluoroethoxy)phenyl)hexanoic acid (1.0 g, 3.26 mmol, from preparation AX) were coupled [N-methylmorpholine (1.43 mL, 13.0 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.410 mL, 13.1 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 551.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[Cl:32][C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[C:38]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15 step (e-f) using 4-chloro-5-trifluoromethylphenylboronic acid in step (e). 1H-NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.04 (s, 1H), 6.92 (m, 1H), 6.86 (m, 1H), 4.98 (br s, 1H), 3.68 (m, 4H), 1.97 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 0.92 (d, 6H); Mass Spectrum (m/z, ESI) 399 (M−H)
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=4)=[N:7][C:8]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-tert-butyl-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 558.2 [(M+H)+]; mp 258-259° C.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH2:38])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:43]([O:45][CH3:46])=[O:44].C(N(CC)C(C)C)(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1

Procedure:
A room temperature solution of Example 43B (30 mg, 0.051 mmol), methyl chloroformate (0.05 mL, 0.65 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and DMAP (3 mg, 0.02 mmol) in dichloromethane (1 mL) was stirred for 16 hours, treated with 4M HCl (0.3 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 635 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ8.89 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.92 (m, 3H), 7.43 (d, 2H), 7.35 (m, 3H), 7.12 (dt, 1H), 3.50 (s, 3H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(N)cc1

Procedure:
To a solution of 4-amino benzoic acid (100 grams, 729.18 mmol) in methanol (1000 mL) at 0° C. is passed dry HCl for 3 hours. The solution is then refluxed for 10 hours. Excess methanol is distilled, and water (1000 mL) is added. The solution is neutralized with dilute ammonia, filtered, and purified from an appropriate solvent.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C1[C@H]2C[C@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 65B (200 g, 0.90 mol, 1 equivalent) in 2-ethoxyethanol (3.2 L), benzylamine (120 mL, 1.09 mol, 1.2 equivalents) was added. To this mixture, triethylamine (152 mL, 1.08 mol, 1.28 equivalents) was added, and the mixture was refluxed for 20 hours. The reaction mixture was cooled and concentrated under reduced pressure to afford crude product. This crude material was purified by column chromatography on silica gel using a mixture of methanol-ethyl acetate gradient (0-10%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (m, 1H), 2.46 (m, 1H), 3.50 (m, 2H), 3.73 (d, 1H, J=16), 3.76 (m, 1H), 4.00 (d, 1H, J=16), 4.45 (d, 1H, J=15), 4.50 (m, 2H), 4.72 (d, 1H, J=15), 7.30 (m, 5H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:24][C:25]1([CH3:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.N1C=CC=CC=1>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([CH3:29])([OH:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(O)CNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(C)(O)C3)c(F)cc2c1=O
Yield: 86.6 %

Procedure:
A mixture of 0.9 g (2.9 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.54 g (4.3 mmoles) of 3-hydroxy-3-methylazetidine hydrochloride, 1 g (10.8 mmoles) of triethylamine and 10 ml of pyridine is heated under reflux for 10 hours. The product is cooled, and diluted with water. Filtering and washing yields 0.95 g (89%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-methyl-3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.38 g (1 mmole) of this ester with 1.5 ml of ethanol, and 8 ml of 0.5N sodium hydroxide under reflux for 3 hours. The mixture is cooled, filtered and acidified with acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A solution of acryloyl chloride (0.522 mL, 1M in CH2Cl2, 0.52 mmol) was added dropwise to 4-(3-dimethylaminoazetidin-1-yl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxy-benzene-1,3-diamine (Intermediate 166, 224 mg, 0.52 mmol) in CH2Cl2 (10 mL) and the mixture was then stirred at −5° C. for 1 h. The mixture was then diluted with CH2Cl2 (100 mL), and the resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (25 mL) and then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (46 mg, 18%) as a beige solid; 1H NMR: 2.09 (6H, d), 3.09 (1H, s), 3.56 (2H, t), 3.85 (3H, s), 3.96 (2H, t), 5.68 (1H, dd), 6.20 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.14 (2H, dt), 7.18 (1H, t), 7.40-7.46 (1H, m), 7.82 (1H, s), 7.90 (1H, s), 8.23 (1H, d), 8.31 (1H, d), 8.38 (1H, d), 9.34 (1H, s), 11.76 (1H, s); m/z: ES+ MH+ 484.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][C@@H:12]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][N:5]12.[C:26](Cl)(=O)[C:27](Cl)=[O:28].[C:32]1([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([CH2:47][C:48]([OH:50])=[O:49])=[CH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(OCC)C.ClCCl>[C:21]([O:20][C:19]([NH:18][C@H:14]([C@H:12]1[CH2:11][CH2:10][N:5]2[C:6]3[C:2]([C:3]([C:26]4[C:27](=[O:28])[O:49][C:48](=[O:50])[C:47]=4[C:40]4[C:41]5[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:39]=4)=[C:4]2[CH2:13]1)=[CH:1][CH:9]=[CH:8][CH:7]=3)[CH:15]([CH3:17])[CH3:16])=[O:25])([CH3:23])([CH3:22])[CH3:24]
Reactant: O=C(O)Cc1cn(-c2ccccc2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H]1CCn2c(cc3ccccc32)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H]1CCn2c(c(C3=C(c4cn(-c5ccccc5)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
An ice-cooled solution of 3 g (8.77 mmol) of tert.butyl [1(S)-[6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl]-2-methylpropyl]carbamate, prepared as described in Example 11(iv), in 50 ml of anhydrous diethyl ether was treated dropwise under a nitrogen atmosphere over a period of 5 minutes with a solution of 0.85 ml (9.74 mmol) of oxalyl chloride in 5 ml of anhydrous diethyl ether. After an additional 5 minutes, the solvent was removed under reduced pressure and the residue was dissolved in 50 ml of dry dichloromethane. The solution was added dropwise at 0° C. to a stirred mixture of 2.2 g (8.77 mmol) of 1-phenylindole-3-acetic acid and 3.65 ml (26.3 mmol) of triethylamine in 50 ml of dry dichloromethane. The mixture was stirred for 17 hours and then the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution followed by crystallization from ethyl acetate/hexane gave 1.6 g of 3[8(S)-[1(S)-tert.butoxyformamido-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-furan-2,5-dione as an orange coloured solid of melting point 148°-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]3=[O:26])=[C:11]([N+:27]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:27][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]1=[O:26]
Reactant: [H][H]
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2N)C1=O

Procedure:
Prepared by reduction of 1-(4'-cyano-3-nitro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one with hydrogen at 5 bars in the presence of 5% palladium/charcoal in ethyl acetate at ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[NH:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:25][CH2:26]2)[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CCCC1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(C=O)cs1
Product: CC(C)(C)OC(=O)Nc1nc(CN2CCC(C(=O)NC3CCCC3)CC2)cs1

Procedure:
The title compound is prepared according to the reactions described above starting from (4-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid cyclopentylamide J-4 yielding after reductive amination [4-(4-cyclopentylcarbamoyl-piperidin-1-ylmethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester; LC-MS A: tR=0.66 min; [M+H]+=409.13.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[C:8]=2[OH:20])=[CH:5][C:4]([OH:21])=[C:3]([OH:22])[CH:2]=1.[CH3:23][C@@H:24]1[O:29][C@@H:28]([O:30][CH2:31][C@H:32]2[O:37][C@@H:36]([O:38][C:39]3[C:48](=[O:49])[C:47]4[C:46]([OH:50])=[CH:45][C:44]([OH:51])=[CH:43][C:42]=4[O:41][C:40]=3[C:52]3[CH:53]=[CH:54][C:55]([OH:59])=[C:56]([OH:58])[CH:57]=3)[C@H:35]([OH:60])[C@@H:34]([OH:61])[C@@H:33]2[OH:62])[C@H:27]([OH:63])[C@H:26]([OH:64])[C@H:25]1[OH:65].C(O)(=[O:75])C=CC1C=CC=CC=1.C1C=CC(O)=C(/C=C/C(O)=O)C=1.C(O)(=O)C1C=C(O)C(O)=C(O)C=1.C1C=CC(N(NC2C([N+]([O-])=O)=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)C2C=CC=CC=2)=CC=1>>[CH:53]1[C:52]([C:40]2[O:41][C:42]3[C:47](=[C:46]([OH:50])[CH:45]=[C:44]([OH:51])[CH:43]=3)[C:48](=[O:49])[C:39]=2[O:38][C@@H:36]2[O:37][C@H:32]([CH2:31][OH:30])[C@@H:33]([OH:62])[C@H:34]([OH:61])[C@H:35]2[OH:60])=[CH:57][C:56]([OH:58])=[C:55]([OH:59])[CH:54]=1.[CH3:23][C@H:24]1[O:29][C@@H:28]([O:20][C:8]2[C:9](=[O:10])[C:11]3[C:12]([OH:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=3[O:17][C:7]=2[C:6]2[CH:1]=[C:2]([OH:75])[C:3]([OH:22])=[C:4]([OH:21])[CH:5]=2)[C@@H:27]([OH:63])[C@@H:26]([OH:64])[C@@H:25]1[OH:65]
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=c1c(O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Reactant: O=C(O)C=Cc1ccccc1
Agent: O=C(O)/C=C/c1ccccc1O
Agent: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(NN(c2ccccc2)c2ccccc2)c([N+](=O)[O-])c1
Product: C[C@H]1O[C@@H](Oc2c(-c3cc(O)c(O)c(O)c3)oc3cc(O)cc(O)c3c2=O)[C@@H](O)[C@@H](O)[C@@H]1O
Product: O=c1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12

Procedure:
UV spectra were measured on a Perkin-Elmer Lambda 35 UV/VIS spectrometer. NMR experiments were conducted on a Bruker Avance AV300 NMR spectrometer operating at 300.13 MHz for 1H and 75.48 MHz for 13C using standard Bruker software. Mass spectra were obtained on a ThermoFinnigan LCQ utilizing both ESI and APCI in the positive and negative modes. HRESIMS was performed on a Micromass Q-TOF Ultima mass spectrometer. HPLC was done on a Waters 2695 using a Phenomenex Aqua column (250×4.6 mm, 5 μm) and monitored using a Waters 996 PDA scanning from 240 to 600 nm. Column chromatography was accomplished using Sephadex LH-20 (Pharmacia, 25-100 μm), reversed-phase C18 silica gel (J. T. Baker, 40 μm), and Diaion HP-20 (Mitsubishi, Japan). Separations were monitored using silica gel 60 F254 and RP18 F254 TLC plates (1 mm thickness, EM Science, Germany). Quercetin, rutin, cinnamic acid, O-coumaric acid, gallic acid, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) were purchased from Sigma (MO, USA). Isoquercitrin and myricitrin were previously isolated in the laboratory (23).