Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=[O:4].N([C@H]1[C@H](O)CCCN(C(OC(C)(C)C)=O)C1)=[N+]=[N-].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[O:44][CH2:45][O:46][CH3:47])=[O:35])=[CH:30][CH:29]=1>>[OH:4][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[O:44][CH2:45][O:46][CH3:47])=[O:35])=[CH:30][CH:29]=1
Reactant: COCOc1ccc(OC)cc1C(=O)c1ccc(CBr)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](N=[N+]=[N-])C1
Product: COCOc1ccc(OC)cc1C(=O)c1ccc(CO)cc1

Procedure:
Compound (W) used in Examples (U8) and (U9) was obtained from tert-butyl (3R,4R)-3-azido-4-(benzyloxy)-hexahydro-1H-azepine-1-carboxylate (see Example (S) by debenzylation with trifluoroacetic acid to tert-butyl (3R, 4R)-3-azido-4-hydroxy-azepane-1-carboxylate and O-alkylation of this compound with (4-bromomethyl-phenyl)-(5-methoxy-2-methoxymethoxy-phenyl)-methanone. The latter compound was obtained by the bromination of (4-hydroxymethyl-phenyl)-(5-methoxy-2-methoxymethoxy-phenyl)-methanone (M8).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.Cl>[NH2:18][C:12]1[CH:13]=[N:14][C:15]2[CH2:16][CH2:17][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CN(Cc1ccccc1)CC2
Agent: Cl
Solvent: CCO
Product: Nc1cnc2c(c1)CN(Cc1ccccc1)CC2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
6-Benzyl-3-nitro-5,6,7,8-tetrahydro-[1,6]-naphthyridine (790 mg; 2.93 mmol) was dissolved in ethanol (100 ml), the solution heated at 50° C. and treated with a solution of stannous chloride dihydrate (2.65 g; 11.73 mmol) in conc. hydrochloric acid (10 ml). After 10 min, the reaction mixture was concentrated under reduced pressure, neutralised by addition of 2M aqueous sodium hydroxide and extracted with DCM. The extracts were combined, washed with water, saturated brine, dried (MgSO4) and evaporated to dryness in vacuo. The brown residue was dissolved in methanol and SiO2 added. The volatiles were removed under reduced pressure and the dried SiO2 placed on the top of a silica column and subjected to chromatography, eluting with ethanol in ethyl acetate (020%) ethanol gradient. The title compound was obtained as a white powder (275 mg; 39%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)OCc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[CH2:32][CH2:31][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2]>[Ni].N>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:32][CH2:31][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:10][CH2:9]2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(C#N)cc1)CC2
Agent: [Ni]
Agent: N
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(CN)cc1)CC2
Reaction time: 4 h

Procedure:
Raney nickel (144 mg, 1.68 mmol, slurry in water) was placed under argon atmosphere. Methyl 4-[8-(4-cyanobenzyl)-4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate (260 mg, 0.56 mmol) was dissolved in ammonia saturated methanol (5 mL) and added to Raney nickel solution. After 4 h at room temperature, full conversion was achieved and the slurry was filtered over celite, rinsing with ethanol. The filtrate was concentrated in vacuo to afford a yellow oil. LRMS (M+1)=470.5.
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:68])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([O:30][Si](C(C)(C)C)(C)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:20]([O:38][Si](C(C)(C)C)(C)C)[CH2:19][C:18]=1[O:46][C:47](=[O:67])[C@H:48]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>>[CH3:8][O:9][C:10](=[O:68])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:20]([OH:38])[CH2:19][C:18]=1[O:46][C:47](=[O:67])[C@H:48]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C[C@H]1O
Yield: 50.8 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.3 ml) and methyl(11R,12S,13E,15S)-9-(N-benzyloxycarbonylphenylalanyloxy)-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienoate (140 mg), methyl(11R,12S,13E,15S)-9-(N-benzyloxycarbonylphenylalanyloxy)-11,15-dihydroxy-7-thiaprosta-8,13-dienoate (53 mg, 51%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[NH2:10][OH:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[NH:7]=[C:6]1[C:5]([CH3:9])([CH3:8])[CH2:4][CH2:3][CH2:2][N:10]1[OH:11]
Reactant: NO
Reactant: CC(C)(C#N)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCCN(O)C1=N
Temperature: 25 °C
Reaction time: 1 h
Yield: 140.6 %

Procedure:
A solution of intermediate 8, 5-chloro-2,2-dimethylpentanenitrile, (725 mg, 5.0 mmol) and 50% aqueous NH2OH (1.0 g, 15 mmol; Aldrich) in ethanol (1.5 mL) was stirred at room temperature for 5 days, and then treated with Na2CO3 (265 mg, 2.5 mmol). The mixture was stirred at room temperature for 1 h, and concentrated in vacuo to provide 1.0 g of the title compound as crude brown oily solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm: 1.29 (6H, s, Me), 1.59 (2H, m, CH2), 1.85 (2H, m, CH2), 3.62 (2H, t, J=6 Hz, NCH2); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 18.23, 26.63, 33.57, 35.09, 51.85, 162.76.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[O:10][C:9]([NH2:11])=[N:8][CH2:7]1.[CH3:16][C:17]([CH3:19])=O>>[CH2:16]([NH:11][C:9]1[O:10][CH:6]([CH2:5][O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])[CH2:7][N:8]=1)[CH2:17][CH3:19]
Reactant: Cc1ccccc1OCC1CN=C(N)O1
Reactant: CC(C)=O
Product: CCCNC1=NCC(COc2ccccc2C)O1
Reaction time: 48 h

Procedure:
In a reactor are introduced 0,01 mol of 5-[(2-methylphenoxy)methyl]-4,5-dihydro-oxazol-2-ylamine and 100 ml of acetone. Once dissolution is complete, 0,005 mol of 1-bromopropyl are added and the whole is heated to ebullition during 48 hours. After filtering off the formed solid and evaporating the solvent, the crude desired product is purified by separation by column chromatography (eluent: chloroform/ammonia, 95:5).
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1)#[N:2].[CH2:12]([NH2:15])[CH2:13][CH3:14]>C(#N)C>[CH2:12]([N:15]=[C:1]([NH2:2])[NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: CSc1nccc(NC#N)n1
Solvent: CC#N
Product: CCCN=C(N)Nc1ccnc(SC)n1

Procedure:
A mixture of 4-cyanoamino-2-methylthiopyrimidine (0.83 g.) and n-propylamine (0.6 ml.) was heated under reflux in acetonitrile (20 ml.) for 1 hour. The solvent was evaporated in vacuo and the residue suspended in dilute aqueous sodium hydroxide. The solid was collected, washed with water and dried to give 4-(2-propylguanidino)-2-methylthiopyrimidine, m.p. 177°-178°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:48]([O:50][C:51](=[O:55])[C@@H:52](O)[CH3:53])[CH3:49].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[CH2:48]([O:50][C:51](=[O:55])[CH:52]([O:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9])[CH3:53])[CH3:49]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Reactant: CCOC(=O)[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.076 g, 0.18 mmol), triphenylphosphine (0.076 g, 0.29 mmol) and (2S)-2-hydroxy-propionic acid ethyl ester (0.036 g, 0.31 mmol) in tetrahydrofuran (1 mL) was added diethyl-azodicarboxylate (0.049 g, 0.29 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was concentrated in-vacuo. Chromatography on silica gel gave the title compound (0.078 g)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[C:30]([N:34]1[C:38]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[C:37]([C:46]2[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=2[OH:53])[CH:36]=[N:35]1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:30]([N:34]1[C:38]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[C:37]([C:46]2[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=2[O:53][C:8]2[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:14]3[S:18][N:17]=[CH:16][N:15]=3)(=[O:11])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[CH:36]=[N:35]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)n1ncc(-c2cc(Cl)ccc2O)c1NC(=O)C(F)(F)F
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3cnn(C(C)(C)C)c3NC(=O)C(F)(F)F)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 150 mg, 0.35 mmol) in dimethyl sulfoxide (10 ml) was added N-[1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl]-2,2,2-trifluoroacetamide (Preparation 209, 131 mg, 0.36 mmol) and potassium carbonate (135 mg, 0.86 mmol) and the flask was purged with nitrogen (×3). The resulting suspension was stirred at room temperature for 18 hours before pouring into sodium hydroxide (1 M aqueous solution) and extracting with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a pale yellow oil. This was purified by column chromatography (80 g silica gel column) eluting with ethyl acetate:heptane (1:1, by volume) to furnish the title compound as a pale yellow oil, 157 mg, 59% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32]>O1CCCC1>[CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]1[CH:9]=[CH:8][C:7]([CH:31]=[O:32])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCCCCCOC1CCCCO1)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCN(CCCCCCOC1CCCCO1)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
50.0 g (130 mmols) of N-ethyl-N-[6-(tetrahydropyran-2-yl)oxyhexyl]-4-bromoaniline was dissolved in 180 ml of anhydrous tetrahydrofuran in an atmosphere of argon, and the solution obtained was cooled to -78° C. To the reaction solution obtained, 174.4 ml (2.2-fold equivalent weight) of t-butyl lithium (1.64 M, n-pentane solution) was dropwise added, followed by stirring for 1 hour. To the mixture obtained, 12.3 g (1.3-fold equivalent weight) of N,N-dimethylformamide was dropwise added, which was then stirred at room temperature for 2 hours and 30 minutes. The resultant reaction solution was concentrated, and dissolved in 500 ml of ethyl acetate, followed by washing twice with 300 ml of water. The organic layer thus formed was dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=4/1) to obtain 34.7 g of N-ethyl-N-[6-(tetrahydropyran-2-yl)oxyhexyl]-4-formylaniline (yield: 80%; a pale-yellow oily liquid). 1H-NMR Spectrum [δ(ppm)]: 1.20(t, 3H, J=7.0 Hz), 1.35-1.95(m, 14H), 3.20-3.55(m, 6H), 3.73(m, 1H), 3.86(m, 1H), 4.57(t, 1H, J=3.6 Hz), 6.65(d, 2H, J=9.7 Hz), 7.71(d, 2H, J=9.7 Hz), 9.69(s, 1H).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12](=[S:14])[NH:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH2:24](N(CC)CC)C.CI>C1COCC1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([S:14][CH3:24])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 40 °C

Procedure:
To a solution of 13-4 (2.23 g, 6.9 mmol) in 40 mL of THF was added triethylamine (2.2 mL), followed by the dropwise addition of methyliodide (0.43 mL, 6.9 mmol). The reaction mixture was heated to 40° C. for 2 h. The solvent was then removed in vacuo and the residue was taken up in EtOAc and washed two times with 100 mL portions of saturated aqueous ammonium chloride and a 100 mL portion of brine. The combined organic layers were dried over MgSO4 filtered and concentrated to dryness in vacuo. Then 150 mL of CH2Cl2 were added and the resulting precipitate was collected by vacuum filtration to give title compound 13-5.
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:27]=2)=[O:21])[CH:11]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[C:12]([NH:19][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:27]=2)=[O:21])[CH:11]=1.[Na+:2]
Reactant: O=C(Nc1cc(-c2ccccc2F)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccccc2F)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethanol (1.5 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.087 mL) were sequentially added to the obtained 4-(2-fluorophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (36 mg), followed by stirring at room temperature for 3 hours. The solid substance was collected by filtration to obtain 22 mg of sodium 4-(2-fluorophenyl)-2-(5-phenylpyridine-3-carboxamido)-benzoate as a white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(S(=O)(=O)c2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to the procedures found in Intermediate 6 and Example 17 using 4-(phenylsulfonyl)-benzoic acid [CAS# 5361-54-6] and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCOCCO
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NCCOCCO)nc3N(C3CCCC3)C2=O)c1F
Yield: 91.3 %

Procedure:
1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 7 using 0.50 g (1.11 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.33 mL (3.32 mmol) of 2-(2-aminoethoxy)ethanol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (92%) of the title compound: mp 160° C.–163° C. MS (APCI) (m+1)/z 494.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6](Br)[CH2:7][CH2:8][CH3:9])[CH3:2].[Na].[OH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CCCC(Br)CC(=O)OCC
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCC(Oc1cccnc1)C(=O)OCC
Yield: 34 %

Procedure:
To a solution of ethyl-3-bromohexanoate, 5.0 g (22.4 mmol) in 200 mL of tetrahydrofuran was added 4.6 g (26.9 mmol) of 3-hydroxypyridine sodium salt. The mixture was refluxed for four hours and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 1.82 g (34%) of the desired mixture of isomers as a brown liquid. MS (ion spray) 238.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[N:17]([O-:19])=[O:18].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(OCCCl)c(OC)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 966.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 1.02 g (4.09 mmol) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate (purity: 98%) obtained in Example II-1, 0.03 g (0.40 mmol) of sodium nitrite, and 1.25 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 1.72 g (16.5 mmol) of nitric acid (60 wt. %), and the mixture was heated at 40-50° C. for 5 hours. After the reaction was complete, 5 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to give 1.12 g (isolated yield: 93.0%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C@@H:15]([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C@@H:15]([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The 1-(3-acetylthio-1-oxopropyl)-cis-4-methoxy-L-proline is hydrolyzed with an aqueous solution of ammonia according to the procedure of Example 2 to yield 1-(3-mercapto-1-oxopropyl)-cis-4-methoxy-L-proline.
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[C:10](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)CCc1ccccc1/C=C1/C(=O)Nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccccc1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To 300 mg of ethyl (E)-3-[(2-oxo-1,2-dihydroindol-3-ylidenemethyl)phenyl]-propionate in 3 mL of ethanol was added 2 mL of 2N sodium hydroxide. The mixture was stirred at 90° C. for 2 hrs, cooled and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration and washed with cold ethanol to give 30 mg of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-phenyl]-propionic acid as a yellow solid.