Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Yield: 40.5 %

Procedure:
Stir a solution of 5-hydroxymethyl-isophthalic acid monoethyl ester (1.9 g, 8.4 mmol), N-methylpropylamine (947 μl, 9.2 mmol), 1-hydroxybenzotriazole (1.24 g, 9.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g, 9.2 mmol) in a mixture of dichloromethane (12 mL) and DMF (12 mL) at room temperature for 1.5 h. Concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (950 mg, 40% yield).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C1(CC(Cl)=O)CCCCC1.BrC1C=CC([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=CC=1.[H-].[Na+].[Na].NCl>CN(C=O)C.N1C=CC=CC=1>[CH:29]1([CH2:28][C:27]([NH:26][NH:6][C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(CC1CCCCC1)Nc1ccc(Br)cc1
Agent: NCl
Agent: O=C(Cl)CC1CCCCC1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)NNc1ccc(Br)cc1

Procedure:
Reaction of 4-bromoaniline with α-cyclohexylacetyl chloride in the presence of pyridine and reaction of the resulting N-(4-bromophenyl)-α-cyclohexylacetamide with sodium hydride in DMF followed by reaction of the resulting sodium salt with chloramine all according to the procedure described in Example 65 affords N'-cyclohexylacetyl-4-bromophenylhydrazine. Reaction of the latter with levulinic aldehyde diethylacetal in refluxing ethanol using the procedure described above in Example 1, and reduction of the resulting 1-cyclohexylacetyl-5-bromo-2-methylindole-3-acetaldehyde in the presence of a molar excess of 2-cyclohexylmethylpiperidine under 600 pounds p.s.i.g. of hydrogen at a temperature of 100° C. over a Raney nickel catalyst affords 1-cyclohexylacetyl-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-bromo-2-methylindole.
Reaction SMILES: ClC(OCC(C)C)=O.[CH:9]1([NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](=[O:34])[C:21]([C:31]([OH:33])=O)=[CH:22][N:23]3[CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][C:17]=2[F:35])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[CH3:37][NH:38][O:39][CH3:40].[Cl-].[NH4+]>C(Cl)(Cl)Cl.ClCCl.C(N(CC)CC)C>[CH:9]1([NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](=[O:34])[C:21]([C:31]([N:38]([O:39][CH3:40])[CH3:37])=[O:33])=[CH:22][N:23]3[CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][C:17]=2[F:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
0.87 ml of triethylamine and 0.4 ml of isobutyl chloroformate were added to a 20 ml of dichloromethane solution of 1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid at 0° C., followed by stirring at 0° C. for 30 minutes. Then, 315 mg of N,O-dimethylhydroxylamine hydrochloride was added thereto, followed by stirring at room temperature for 1 hour. Chloroform and aqueous saturated ammonium chloride were added to the reaction mixture, the layers were separated, and the organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent filtration, the solvent was evaporated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 950 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-N-methoxy-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[S:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[OH-].[Na+].[CH3:23]I>CO>[CH3:23][S:18][C:7]1[CH2:8][C:9](=[O:17])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: CI
Reactant: O=C1CC(=S)Nc2ccc(Cl)cc2N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
To 3.03 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in a solution of 0.40 g sodium hydroxide and 15 ml of methanol is added, with stirring a solution of 1.39 g of methyl iodide in 5 ml of methanol. Stirring is continued for 1 hour, the reaction is evaporated, diluted with 30 ml methylene chloride and filtered through a short Florisil column. After washing the column with ethyl acetate, the combined filtrates are evaporated to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][C@H:23]([CH3:30])[CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=O>C(Cl)Cl>[OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][C@H:23]([CH3:30])[CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CO)ccc2C(=O)O1

Procedure:
To the solution of (3S)-tert-butyl 4-(2-hydroxy-2-((R)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2630 mg, 6.25 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at rt for 1 h. After removing the volatile the residue was dissolved in methylene chloride (100 mL). To the above solution was added triethylamine (4.36 mL, 31.3 mmol) and benzyl chloroformate (0.986 mL, 6.56 mmol) at 0° C. for 0.5 h. The reaction was quenched by water followed by addition of saturated sodium carbonate. The mixture was extracted with methylene chloride, dried over sodium sulfate, concentrated and the residue was purified on Biotage using 40-100% EtOAc/hexane to give the title compound: LC/MS: (M+1)+: 455.10.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:10](OC)(=[O:13])[CH:11]=[CH2:12].C[Sn](Cl)(Cl)C.[OH-].[Na+].COC1C=CC(O)=CC=1.C1(C=CC(O)=CC=1)O>CCCCCCC>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)OC
Reactant: CC(C)CCCCCO
Agent: COc1ccc(O)cc1
Agent: C[Sn](C)(Cl)Cl
Agent: Oc1ccc(O)cc1
Solvent: CCCCCCC
Product: C=CC(=O)OCCCCCC(C)C
Yield: 97 %

Procedure:
In a similar manner, a mixture of 520.9 parts isooctyl alcohol, 516.6 parts methyl acrylate, 183 parts heptane, 2.4 parts dimethyltin dichloride, 0.5 parts sodium hydroxide (molar ratio 1.14:1), 1.6 parts 4-methoxyphenol and 0.6 parts hydroquinone yielded, after reaction and work up as in Example 1, 715.2 parts (97 percent yield, based on isooctyl alcohol) of isooctyl acrylate with a purity of 99.9 percent, containing no detectable tin.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]([NH:19][CH:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:11][C:12]3[CH:13]=[CH:14][NH:15][C:16](=[O:18])[C:17]=3[C:8]=2[CH:7]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]([NH:19][CH:20]([CH3:25])[C:21]([CH3:22])([CH3:23])[CH3:24])=[N:11][C:12]3[C:13]([N+:1]([O-:4])=[O:2])=[CH:14][NH:15][C:16](=[O:18])[C:17]=3[C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1nc2c([N+](=O)[O-])c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (0.271 mL, 4.24 mmol) was added to 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (397 mg, 1.061 mmol) in TFA (10.600 mL) at room temperature. Reaction was then heated to 40° C. and stirred for 1.5 h. The reaction was then diluted with dichloromethane (150 mL) and quenched by pouring cautiously into saturated NaHCO3. The layers were separated and the aqueous phase was further extracted with a 75 mL portion of dichloromethane. The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, loading with THF/hexanes and eluting with EtOAc/Hexanes to give the title compound as an orange solid. 1H NMR (500 MHz, C2D6SO) δ 12.11 (s, 1H), 9.98 (d, 1H, J=2.0 Hz), 8.55 (d, 11-1, J=9.0 Hz), 8.44 (s, 1H), 7.95 (d, 1H, J=9.0 Hz), 7.85 (dd, 1H, J=8.5, 2.0 Hz), 4.69 (m, 1H), 1.17 (d, 3H, J=7.0 Hz), 0.94 (s, 9H). LRMS (ESI) calc'd for (C18H20BrN4O3) [M+H]+ 419.1; found 419.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([C:25](O)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.C1COCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([C:25](=[O:26])[NH:29][CH3:28])[N:11]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:12][C@H:13]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
(2R,5R)-5-Methyl-piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester (200 mg, 0.53 mmol) was dissolved in anhydrous DMF (2.65 mL). HATU (221 mg, 0.58 mol) was added and the reaction stirred for 20 min. DIPEA (184 μL, 1.06 mmol) and methylamine in THF (2.0M, 0.53 mL, 1.06 mmol) were added and the reaction stirred for 2 h. Water (10 mL) was added and aqueous phase extracted with EtOAc (3×5.0 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×15 mL), brine (3×15 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (0.12 g, 58%) as a colourless oil. 1H NMR (Me-d3-OD): 7.48-7.26 (5H, m), 5.30-5.04 (2H, m), 4.44 (1H, d), 4.21 (2H, s), 3.64 (2H, d), 3.44 (1H, d), 2.72 (3H, d), 1.46 (9H, s), 1.16 (3H, dd).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: NCC1CCOCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Br)cnc1NCC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 5-bromo-2-chloro-3-nitropyridine (Step B), 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.) and triethylamine.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:82])[CH3:81]>CN(C=O)C>[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:27](=[O:28])[C@@H:2]([NH:1][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]2[C:13]([CH3:14])=[C:15]([CH3:16])[C:17]3[O:18][C:19]([CH3:21])([CH3:20])[CH2:22][C:23]=3[C:24]=2[CH3:25])(=[O:10])=[O:11])[CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:81])[CH3:82]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-Arg(Pbf)-OH 1 (25.0 g, 38.5 mmol) in DMF (200 mL) at room temperature was added DIEA (13.41 mL, 77.1 mmol). After stirring at room temperature for 10 min, the reaction mixture was cooled to ˜5° C. To the reaction mixture was added HATU (16.11 g, 42.4 mmol) in portions and stirred for 20 min and a solution of tert-butyl-1-piperazine carboxylate (7.18 g, 38.5 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 5 min The mixture reaction was then allowed to warm to room temperature and stirred for 2 h. Solvent was removed in vacuo and the residue was dissolved in EtOAc (500 mL), washed with water (2×750 mL), 1% H2SO4 (300 mL) and brine (750 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to a total volume of 100 mL. Compound T was taken to the next step as EtOAc solution (100 mL). LC-MS [M+H] 817.5 (C43H56N6O8S+H, calc: 817.4).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[CH2:48][NH2:49]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:49][CH2:48][C:44]3[S:43][CH:47]=[CH:46][CH:45]=3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCc1cccs1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NCc4cccs4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and thiophen-2-ylmethanamine
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH2:12][CH3:13])[S:4]1(=[O:15])=[O:14].[Na].[SH:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[N:20][N:19]=1>CN(C=O)C>[C:23]1([N:22]2[C:18]([S:17][CH2:2][N:3]3[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH2:12][CH3:13])[S:4]3(=[O:15])=[O:14])=[N:19][N:20]=[N:21]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(CSc2nnnn2-c2ccccc2)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 1.96 mmol) and sodium salt of 5-mercapto-1-phenyl-1H-tetrazole (0.39 g; 1.98 mmol) (Formula III: M+ =Na+ ; X=S; R4 = ##STR24## in 10 ml of DMF was allowed to react at 80° C for 11 hours and then cooled. The mixture was poured into ice/water containing saturated sodium bicarbonate solution, extracted with ether/ethyl acetate (1:1; 250 ml), and the organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (35% ethyl acetate in hexane) to afford 0.56 g (72%) of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: ##STR25## as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6]C)=[O:5].CO.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][CH:2]([CH3:38])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 360 (150 mg, 0.293 mmol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (61.58 mg, 1.46 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([C@@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])(=[O:34])=[O:33])[CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:45])=[CH:15][C:14]=1[CH2:13][CH2:12]3)(=[O:3])[CH3:2].S([O-])(O[CH3:50])(=O)=O.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([C@@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])(=[O:33])=[O:34])[CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:45][CH3:50])=[CH:15][C:14]=1[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)[O-]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 1 h

Procedure:
2.9 cm3 of water is added to 1.05 g of the phenol obtained in Example 94 in solution in 3.9 cm3 of acetone, agitation is carried out, 0.3 cm3 of methyl sulphate and 0.83 cm3 of an 2N aqueous soda solution are added and agitation is carried out for 1 hour at ambient temperature. The reaction medium is acidified with 1 cm3 of 2N hydrochloric acid, poured into an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried and the solvent is evaporated off. After chromatographing the residue on silica (eluant: ethyl acetate-cyclohexane 3-7), 959 mg of expected product is obtained.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:12])([CH:10]=[CH2:11])[CH2:4]1.Cl.[NH2:14]O>C(O)C.O>[CH3:12][C:5]1([CH:10]=[CH2:11])[CH2:4][C:3]2[CH:2]=[N:14][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: NO
Reactant: C=CC1(C)C=CC(=O)C(=CO)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C=CC1(C)C=Cc2oncc2C1
Temperature: 115 °C
Yield: 91.8 %

Procedure:
To a stirred solution of 21 (177 mg, 1.078 mmol) in ethanol (15 mL) under a nitrogen atmosphere was added a solution of hydroxylamine hydrochloride (741 mg, 10.66 mmol, 10 eq.) in water (1 mL). The reaction mixture was heated to reflux at 115° C. for 1 hour. Water was then added to the mixture until it became cloudy and the aqueous mixture was extracted with methylene chloride/ethyl ether (1:2, 4×). The organic layers were then combined and washed with saturated sodium bicarbonate solution (1×) and brine (1×), dried over magnesium sulfate, filtered and concentrated in vacuo to give 23 (159.7 mg, 0.99 mmol, 92%) as an oil. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 8.03 (1H, s), 6.52 (1H, dd, J=0.6, 10 Hz), 5.87 (1H, d, J=10 Hz), 5.81 (1H, d, J=10.6 Hz), 5.04 (1H, dd, J=0.6, 18.3 Hz), 5.00 (1H, dd, J=1.2, 11.4 Hz), 2.69 (2H, dd, J=16.2, 34.8 Hz) 1.23 (3H, s); 13C NMR (CDCl3) δ 165.0, 148.8, 143.6, 141.6, 114.4, 112.7, 109.5, 40.4, 31.4, 26.0; MS (ESI+) m/z 162.1 [M+H]+, HRMS (ESI+) calcd for C10H11NO+H 162.0919. found 169.0913.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:30][CH:31](Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][N:17]([CH2:32][CH2:31][Br:30])[CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(OCc1ccccc1)N1CCN(CCBr)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
From N,N′-bis(benzyloxycarbonyl)-1,4,7-triazacyclononane (1.3.13.9), dibromoethane and potassium carbonate.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[OH:15][C@@H:9]1[CH2:8][N:7]([CH2:6][CH2:5][C@H:4]([N:16]2[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[CH2:18][CH2:17]2)[CH2:3][OH:2])[CH2:14][CH2:13][C:10]21[CH2:12][CH2:11]2
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 64 %

Procedure:
In analogy to the procedure described in example 2, (S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4 gave the title compound in 64% yield as a white foam. MS: 456.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH3:27])[N+:12]=2[O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O:33]C(=O)CC)(=[O:32])[CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH2:27][O:33][C:29](=[O:32])[CH2:30][CH3:31])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCc1c(C)[n+]([O-])c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)OCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2c1CC

Procedure:
3.83 g (10 mM) of 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-6,7-dimethoxy-isoquinoline N-oxide is refluxed with 20 ml of propionic anhydride for 1.5 hours. The solution is evaporated at reduced pressure, the residue is suspended in 100 ml of water, filtered, washed with 3×15 ml of water, dried at reduced pressure at room temperature, recrystallized from 7 ml of 99.5% ethanol, filtered, washed with 3×8 ml of ethanol and dried at 80° to 90° C. Yield 2.70 g (61.5%), m.p. 125° to 127° C.