Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]([CH:9]([OH:24])[CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O>[OH:24][CH:9]([C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:25][CH3:26])[CH:5]=1)[CH2:10][N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2)ncc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(O)CN2CCNCC2)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The slower eluting isomer of tert-Butyl 4-[2-(5-cyano-4-methoxy-2-pyridyl)-2-hydroxy-ethyl]piperazine-1-carboxylate (1.0 g, 2.76 mmol) was dissolved in 5 mL of TFA and stirred at room temperature for 2 hours. The mixture was concentrated to ¼ the original volume and diluted with 10 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to offer amine TFA salt. This intermediate was diluted with 5% aqueous sodium bicarbonate with follow up addition of 10 N NaOH to bring the pH of extraction above 10. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the product (Isomer B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CCO.CN(C=O)C.CN(C=O)C.CCO.[Pd]>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
A solution of tert-butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I138) (0.527 g, 0.906 mmol) in EtOH (10 mL) was added to a solution of 10% Pd/C (0.500 g) in DMF (6 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent was removed in vacuo to afford a yellow oil. This was taken up in DMF/EtOH (1:1, 10 mL) and a slurry of 10% Pd/C (0.500 g, 1 eq) in DMF was added. The reaction was stirred under an atmosphere of H2 at room temperature for an additional 24 hours. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent removed in vacuo to afford a yellow oil which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (1139) (0.126 g, 24%) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.30-7.17 (m, 6H), 3.91-3.72 (m, 2H), 3.75 (s, 2H), 3.68 (s, 3H), 3.66-3.52 (m, 1H), 3.47-3.21 (m, 3H), 3.17-3.04 (m, 4H), 2.23 (d, J=20.4 Hz, 1H), 1.97 (dd, J=21.1, 10.2 Hz, 1H), 1.48 (d, J=3.1 Hz, 9H). LCMS Method C: rt 6.91 min; m/z 585 [M+H]+, 607 [M+Na]+.
Reaction SMILES: [ClH:1].Cl.CO[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH:10]([NH2:22])[CH2:9][CH2:8]2.[C:23]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[ClH:1].[ClH:1].[C:23]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][N:29]([CH2:32][C:33]([NH:22][C@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[CH:5][CH:6]=3)[C@H:11]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:35])[CH2:30][CH2:31]1)(=[O:25])[CH3:24]
Reactant: CC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reactant: COc1ccc2c(c1)CCC(N)C2Cc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C1(c2ccccc2)CCN(CC(=O)N[C@H]2CCc3ccccc3[C@H]2Cc2cccnc2)CC1
Yield: 179.6 %

Procedure:
1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 (0.75 g, 2.41 mmol) was reacted with 2-(4-acetyl-4-phenyl-piperidin-1-yl)acetic acid (0.86 g, 2.65 mmol), N,N-diisopropylethylamine (2.0 mL, 11.3 mmol) and HBTU (1.01 g, 2.65 mmol) in N,N-dimethylformamide (15 mL) at room temperature for 2 h as described above in EXAMPLES 7-8. The product was collected by filtration from the aqueous work-up. This material was dissolved in isopropanol (˜30 mL) and treated with a saturated solution of hydrochloric acid in isopropanol (˜5 mL). The solvent was evaporated in vacuo, and the residue was triturated with diethyl ether to give 4-acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide bis-hydrochloride 21 as an amorphous pale yellow solid (1.2 g, 90%): MS m/e 482 (MH+) (Scheme 34).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(#N)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating and NaOH (0.28 g) was added. The mixture was stirred at about 60° C. for 1 h, cooled to room temperature, heated again to about 75° C. for 2 h, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.07 g (34.9%) of fluvastatin sodium crystal Form I.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:25][CH2:26][CH3:27])=[C:12]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=1>>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:25][CH2:26][CH3:27])=[C:12]([C:14]2[NH:15][C:16](=[O:24])[C:17]3[N:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Product: CCOc1ccc(NC(=O)C(C)C)cc1-c1nc2cccnc2c(=O)[nH]1

Procedure:
The title compound was prepared using isobutyryl chloride and 2-(5-amino-2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Example 20), following the procedure of Example 12, and was obtained as a white solid (80%), m.p. 256-259° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:4][CH3:5].[Br:13][CH2:14][CH2:15]Br>O1CCCC1>[Br:13][CH2:14][CH2:15][N:7]([O:6][CH2:3][CH2:4][CH3:5])[C:8](=[O:12])[O:9][CH2:10][CH3:11]
Reactant: BrCCBr
Reactant: CCCONC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCON(CCBr)C(=O)OCC
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
8.73 g (218 mmol) of 60% sodium hydride was suspended in 200 ml of dry tetrahydrofuran, and 50 ml of a dry tetrahydrofuran solution containing 26.7 g (182 mmol) of ethyl N-n-propoxycarbamate, was dropwise added thereto under cooling with ice at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was stirred at the same temperature for 20 minutes and again cooled with ice. Then, 121.4 g (646 mmol) of 1,2-dibromoethane was added all at once. The temperature was gradually raised and then the mixture was refluxed under heating for 2 hours. The mixture was left to cool to room temperature, and the solvent was partially distilled off under reduced pressure. The residue was poured into 100 ml of ice water and extracted three times with 100 ml of chloroform. The chloroform layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then 42.0 g of ethyl N-(2-bromoethyl)-N-n-propoxycarbamate was obtained by distillation under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]=O)[CH2:7][CH2:6][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:4][CH2:3]1.[F:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:6][CH2:7]2)[CH2:26][CH2:25]1
Reactant: FC1CCNCC1
Reactant: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1CCCN1CCC(F)CC1

Procedure:
The title compound was prepared from 3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-propionaldehyde (Example 34C) and 4-fluoropiperidine in analogy to example 34D. MS: 402.2 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:25](Br)([CH3:27])[CH3:26]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Br
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Product: CCCCN1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and isopropyl bromide according to the same process as in Example 12.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C1C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:2][C:3]([CH2:5][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:4]
Reactant: O=C(CBr)CBr
Reactant: Oc1ccccn1
Solvent: c1ccccc1
Product: O=C(COc1ccccn1)COc1ccccn1
Yield: 14 %

Procedure:
The bromomethyl ketone derivative X (3.2 g, 7.93 mmol), an intermediate in Preparation 5, was dissolved in benzene (30 ml), Ag2CO3 (2.62 g, 1.2 Eq) and 2-hydroxypyridine (0.93 g, 1.2 Eq) were added, and the mixture was stirred under reflux at 80□ for 3 days. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by column chromatography to give 2-pyridinyloxymethyl ketone derivative (XIf) (466 mg, Yield 14%).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([NH:19][CH2:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]=[C:31]=[O:32].C(N(CC)CC)C>C(#N)C>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:31]([N:19]1[C:16]2([CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20]2)[CH2:17][CH2:18]1)=[O:32]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2)C1
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CCN2C(=O)NCc2ccc(Cl)cc2Cl)C1
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-1,6-diaza-spiro[3.3]heptane oxalate (350 mg, 719 μmol) in acetonitrile (5 mL) was added 2,4-dichloro-1-(isocyanatomethyl)benzene (291 mg, 1.44 mmol) followed by triethylamine (201 μl, 1.44 mmol) and the mixture was stirred overnight. Further 2,4-dichloro-1-(isocyanatomethyl)benzene (100 mg, 0.49 mmol) was added. After 1 hour at ambient temperature, the reaction was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; heptane:ethyl acetate 1:4) to give the title compound (378 mg, 65%) as a colorless foam. MS (EI) m/e: 400.2 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Cl[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.Cl>[Cu].[Cu]I.CN1CCCC1=O>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccccc2C(=O)O)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 22.8 %

Procedure:
A mixture of thiosalicylic acid (928.1 mg), 5-chloro-1,3-dimethoxybenzene (1.139 g), copper (powder) (222.4 mg), copper(I) iodide (666.6 mg) and N-methyl-2-pyrrolidone (5 ml) was stirred at 200° C. for 5 hours. After cooling, the reaction mixture was adjusted to pH 2 with 4 N hydrochloric acid, extracted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solvent; chloroform:methanol=97:3, 0.1% acetic acid) to give 397.6 mg (23%) of a compound of the indicated formula (10). The compound had a melting point of 182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(C#N)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 93, Suzuki coupling of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-cyanophenylboronic acid gave 199. MS: (ESI+) 471.1
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: Cc1ccc([N+](=O)[O-])c(N=C2NC3(CCCC3)CS2)c1C
Product: Cc1ccc([N+](=O)[O-])c(N=C2SCC3(CCCC3)N2C2CCCC2)c1C

Procedure:
2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. The acetamide was converted to 2,3-dimethyl-6-nitroaniline, then deprotected according to Method A2a, step 2. The aniline was converted to 2,-dimethyl-6-nitrophenyl isothiocyanate according to Method A2a, step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3-dimethyl-6-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[O:10]1>>[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH:14][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:12][C:11]=2[O:10]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)[C@H](Nc1ccc2c(c1)OCO2)C(=O)O

Procedure:
Following the procedure of Example 1, the m-phenoxybenzyl ester of α-bromoisovaleric acid is reacted with 3,4-methylenedioxyaniline (3equivalents) at about 75° for about 14 hours to yield the m-phenoxybenzyl ester of N-(3,4-methylenedioxyphenyl)valine, MS m/e 419 (M+, 13.2), 192 (100).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[K+:10].O=[C:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(OC(C)C)(=O)C>[K+:10].[CH2:17]([O:16][C:14](=[O:15])[CH:13]=[C:12]([NH:1][C@H:2]([C:6]([O-:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[CH3:19])[CH3:18]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCOC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCOC(=O)C=C(C)N[C@H](C(=O)[O-])C(C)C

Procedure:
L-Valine (117.2 g, 1.0 mol), KOH (85%, 66.0 g, 1 mol) and ethyl 3-oxobutanoate (140.2 mL, 1.1 mol) are dissolved in isopropyl acetate (1 L). The reaction mixture is heated to reflux using a Dean-Stark apparatus. 32 mL water are isolated during 1.75 h. A small quantity of precipitate is formed. 500 mL are distilled off.
Reaction SMILES: CO.[O:3]=[C:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1.[BH4-].[Na+]>ClCCl>[OH:3][CH:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reaction time: 2 h

Procedure:
To a methanol (250 mL) solution of tert-butyl 4-oxoazepane-1-carboxylate (18.1 g, 85.0 mmol) at 0° C. was added sodium borohydride (8.01 g, 212 mmol). The reaction mixture was stirred for 2 hours before concentration in vacuo. The residue was dissolved in dichloromethane (250 mL) and washed with brine. The precipitate was removed by filtration, and the filtrate was dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) 3.87 (br s, 1H), 3.49-3.18 (m, 4H), 2.05-1.48 (m, 6H), 1.46 (s, 9H); LC-MS: m/z 238.2 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>C1COCC1>[Cl:7][CH2:8][C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: O=C(Cl)CCl
Reactant: Cn1cccc1
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)CCl
Yield: 106.4 %

Procedure:
A solution of 15 g (0.186 mole) N-methylpyrrole and 19.2 mL (0.186 mole) chloroacetyl chloride in 600 mL dry THF was heated under reflux overnight with a nitrogen stream bubbling through the reaction mixture. After cooling, the organics were washed with water, 1N NaOH, water, brine and dried (MgSO4). Evaporation of the solvent gave 31.2 g of a green solid: mp (decomp.) 280° C.; NMR 300 MHz (CDCl3) d 7.05 (d, 1H); 6.95 (s, 1H); 6.2 (m, 1H); 4.5 (s, 2H); 3.9 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73.9 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol), N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 11b (28.3 mg, 0.112 mmol) and piperidine (50 μL, 0.5 mmol) were dissolved in 2 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide 11 (46 mg, 74%) as a yellow solid.
Reaction SMILES: C([O:4][C:5]1[C:25]([OH:26])=[CH:24][C:8]2[C:9](=[O:23])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[CH:11][O:12][C:7]=2[CH:6]=1)(=O)C>Cl.C(O)C>[OH:26][C:25]1[C:5]([OH:4])=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CC(=O)Nc1ccc(-c2coc3cc(OC(C)=O)c(O)cc3c2=O)cc1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7-Acetyloxy-6-hydroxy-3-(4-acetylaminophenyl)-4H-1-benzopyran-4-one [see Example 65a] (20 mg) is dissolved in a mixture of 1N aqueous hydrochloric acid and ethanol 1:1 (10 ml) and stirred during 12 h at room temperature. The solution is then extracted with dichloromethane, the dichloromethane layer is washed with water and evaporated to dryness under vacuum to give 6,7-dihydroxy-3-(4-acetylaminophenyl)-4H-1-benzopyran-4-one, m.p.>310° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)(=[O:9])=[O:8]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2cccc(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Methyl 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (500 mg, 1.12 mmol) was dissolved in MeOH/THF (1:1, 40 mL) and treated with a solution of aqueous NaOH (10 N, 8 ml). The mixture was stirred at ambient temperature overnight, then MeOH and THF were removed by rotary evaporation. The resulting aqueous solution was washed with EtOAc (10 mL) and acidified with 6 N aq HCl (˜15 mL) to pH˜4. The aqueous solution was extracted with EtOAc (3×, 40 mL) and the combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by recrystallization from EtOH to afford the title compound 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (150 mg) in 30% yield.