Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C(OC)=C(OC)C=CC=1CCN.FC(F)(F)C1C(OC)=C(OC)C=CC=1C.[F:33][C:34]([F:59])([F:58])[C:35]1[C:45]2[CH2:44][CH2:43][NH:42][CH2:41][CH:40]([C:46]3[CH:51]=[CH:50][C:49]([S:52][CH3:53])=[CH:48][CH:47]=3)[C:39]=2[CH:38]=[C:37]([O:54]C)[C:36]=1[O:56]C.B(Br)(Br)Br>>[F:59][C:34]([F:33])([F:58])[C:35]1[C:45]2[CH2:44][CH2:43][NH:42][CH2:41][CH:40]([C:46]3[CH:47]=[CH:48][C:49]([S:52][CH3:53])=[CH:50][CH:51]=3)[C:39]=2[CH:38]=[C:37]([OH:54])[C:36]=1[OH:56]
Reactant: COc1cc2c(c(C(F)(F)F)c1OC)CCNCC2c1ccc(SC)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(C)c(C(F)(F)F)c1OC
Agent: COc1ccc(CCN)c(C(F)(F)F)c1OC
Product: CSc1ccc(C2CNCCc3c2cc(O)c(O)c3C(F)(F)F)cc1

Procedure:
Substituting a stoichiometric quantity of 2-fluoro-3,4-dimethoxyphenethylamine in the synthetic procedures of Example 1 gives 6-fluoro-7,8-dimethoxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine. Hydrolysis with boron tribromide as disclosed above gives 6-fluoro-7,8-dihydroxy-1 -(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine. Substituting 2-trifluoromethyl-3,4,-dimethoxyphenethylamine, prepared via 2-trifluoromethyl-3,4,-dimethoxytoluene, in Example 1 gives 6-trifluoromethyl-7,8-dimethoxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine and hydrolysis with boron tribromide gives 6-trifluoromethyl-7,8-dihydroxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=C)[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[O:35]=O>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=[O:35])[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=O
Reactant: C=Cc1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2s1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C=O)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of 91A (170 mg, 0.353 mmol), DCM (5.0 mL), and MeOH (5.0 mL) was cooled to 78° C. and perfused with oxygen gas for 3 min. Then using an ozonator, a stream of O3 in oxygen gas was bubbled through the solution for 5 min. After this, the reaction was stirred for 10 min, then sparged with oxygen gas for 2 min to drive out unreacted ozone in solution. While the reaction was still at 78° C., dimethylsulfide (200 μL) was added and the reaction allowed to warm to 0° C. After 30 min, 10% w/v aq Na2S2O3 (5 mL) was added and the reaction was warmed to 23° C. and stirred for 10 min. The reaction was diluted with H2O (20 mL) and extracted with DCM (3×15 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. More DCM was added and the reaction was concentrated once more to remove residual methanol, giving 91B (165 mg, 97% yield). 1H-NMR: 400 MHz, (CDCl3) δ: 10.04 (s, 1H), 8.00 (s, 1H), 5.60 (s, 1H), 4.22-4.00 (m, 2H), 2.51 (s, 3H), 1.16 (s, 9H), 1.14 (t, J=6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDCl3) δ: −73.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(C)=O)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)Nc1nc2c(OC)ccc(C(C)O)c2s1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
0.05 g of (7-acetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.00018 Mol) were dissolved in ethanol (30 ml) and 0.028 g of NaBH4 (0.00072 Mol) were added. After stirring at 40° C. for 24 hrs. the reaction mixture was diluted with water, extracted with CH2Cl2, the organic phase washed with brine and dried over MgSO4. After chromatography on silicagel with CH2Cl2/MeOH 97:3 the title compound was obtained as a white solid (38%); F.p.: 179° C. (dec.).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].OS(O)(=O)=O.[OH-].[CH2:32]([N+:36]([CH2:45][CH2:46][CH2:47][CH3:48])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>CO.O>[C:1]1([S:11]([O-:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:45]([N+:36]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:46][CH2:47][CH3:48]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=S([O-])c1cccc2ccccc12
Temperature: 65 °C

Procedure:
A round bottom flask was charged with 1-naphthalenesulfonyl chloride (20.0 g), Na2SO3 (33.36 g), NaHCO3 (22.24 g) and deionized water (350 mL). The mixture was stirred and heated to 65° C. under a nitrogen atmosphere for 2 hours, after which time the mixture was allowed to cool to room temperature and was then further cooled in a refrigerator. The cold mixture was acidified with concentrated H2SO4 which resulted in the formation of a precipitate. The mixture was extracted three times with 100 mL of ethyl acetate. The organic extracts were combined and the solvent was removed with a rotary evaporator to give a colorless solid that was then dissolved in 240 mL of 1:1 (v/v) methanol-deionized water in a beaker. The solution was titrated with a solution of 40% aqueous tetrabutylammonium hydroxide until the pH of the solution was 7.2. The solvent was removed with a rotary evaporator and the product was further dried in a vacuum oven at room temperature to afford 36.4 g of a yellow waxy solid.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Reactant: Oc1ccc(S)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Br)cc1
Yield: 92 %

Procedure:
Ethyl(4-bromophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(4-bromophenyl)acetate (15 g, 45.6 mmol) and 4-mercaptophenol (5.75 g, 45.6 mmol); 15.39 g white solid. mp: 55.6° C.; Yield 92%; MS: 365.1 (M−H)−
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C.[Na+].[Cl-]>C1C=CC=CC=1>[C:1]1([C@H:7]2[C@H:12]([OH:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCNCC1c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: O[C@@H]1CCNC[C@H]1c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 0.9 g of the free base, 3-phenyl-4-piperidone of Example 50c, above, 0.19 g of sodium borohydride and 15 ml of absolute ethanol is stirred at room temperature for 6 hours under a nitrogen atmosphere. The mixture is then treated with 25 ml of saturated aqueous NaCl solution and extracted with dichloromethane. The combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous Na2 SO4 and concentrated in vacuo to a gum which TLC shows to be a mixture of cis and trans isomers, with the trans isomer predominant. Trituration of this material with benzene gives a well formed solid which is filtered off after allowing the mixture to stand 18 hours. The solid is washed with benzene and then hexane, and dried in vacuo to afford a solid, m.p. s 99°, 115°-127° C., which TLC showed contained only a small amount of the cis isomer. This material is taken up in 10 ml of boiling benzene, filtered, and boiled down to a volume of approximately 5 ml of solution to afford a solid of trans-3-phenyl-4-piperidinol, m.p. s 125.5°, 127°-128.5°, which TLC showed to be pure trans isomer.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:27]=[CH:26][C:15]4[N:16](C(OC(C)(C)C)=O)[N:17]=[N:18][C:14]=4[CH:13]=3)[C:6]=2[N:7]=1.C1COCC1.CNC>CO>[NH:16]1[C:15]2[CH:26]=[CH:27][C:12]([CH2:11][N:8]3[C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:28]5[O:29][CH:30]=[CH:31][CH:32]=5)[C:5]=4[N:10]=[N:9]3)=[CH:13][C:14]=2[N:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(Cn3nnc4c(-c5ccco5)nc(N)nc43)ccc21
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccc4[nH]nnc4c3)c2n1
Yield: 30 %

Procedure:
A solution of tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (as a mixture with the 6-substituted regioisomer) (135 mg, 0.31 mmol) in MeOH (5 mL) and THF (5 mL was treated with 40% aqueous dimethylamine (0.176 mL, 1.56 mmol), refluxed for 25 min, concentrated in vacuo and the resulting solid triturated with ether, filtered, triturated with MeOH, filtered and dried to give the title compound (31 mg, 30%) as a yellow solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:36]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:58][C:59](O)=[O:60])([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:36]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:58][C:59](=[O:60])[NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1)NCc1ccccc1
Yield: 90.6 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.120 g, 0.271 mmol) was added to a solution of benzyl amine (0.030 mL, 0.271 mmol), 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.247 mmol), triethylamine (0.103 mL, 0.741 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). Organic layer collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.099 g of 4-(benzylcarbamoyl-methyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester. LRMS m/z 443.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:29][Li]>C1COCC1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:14])([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH3:29])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [Li]C
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)O)c(O)c3)ccc21
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(C)(O)COc3ccc(C(=O)O)c(O)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 g (2.6 mmol) of 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoic acid and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 5.3 ml (8.3 mmol) of a solution of methyl lithium in THF (1.6M) are added dropwise at -78° C. and the reaction mixture is stirred for 12 hours at room temperature. It is poured into ice-water, acidified to pH=1 and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is recrystalised in cyclohexane and 900 mg (86%) of the expected product of melting point 170°-171° C. are collected.
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[CH3:41][O:42][C:43]1[C:48]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][NH:60][CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[CH:47][CH:46]=[C:45]([O:68][CH3:69])[N:44]=1>>[CH3:41][O:42][C:43]1[C:48]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][N:60]([C:36]4[S:37][CH:38]=[CH:39][N:40]=4)[CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[CH:47][CH:46]=[C:45]([O:68][CH3:69])[N:44]=1
Reactant: Brc1nccs1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC
Agent: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromothiazole and starting with 5-(2,6-dimethoxypyridin-3-yl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (400 MHz, CDCl3) δ) 7.54, 7.23, 6.52, 6.43, 5.21, 4.92, 4.25, 4.00, 3.97, 3.93, 3.80–3.73, 3.54, 3.44, 2.72, 2.52, 1.33–1.26, 1.18; IR (diffuse reflectance) 2963, 2327 (w), 2187 (w), 2056 (w), 1997 (w), 1604, 1580, 1567, 1538 (s), 1474 (s), 1397, 1377, 1311, 1235, 1031 cm−1 HRMS (ESI) calcd for C24H32N6O3S+H1 485.2335. found 485.2333.
Reaction SMILES: C([O:6][C:7]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1)=[O:8])CCCC>P([O-])([O-])([O-])=O>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH:9]1[C:7]([OH:8])=[O:6]
Reactant: CCCCCOC(=O)C1Cc2ccccc2N1
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)C1Cc2ccccc2N1

Procedure:
After adding 10 g of lipase (Steapsin made by Wako Purechemical Industries, Ltd.) having (R)-selective esterase activity to 100 ml of 0.1M phosphate buffer at pH 7.0, a mixture was stirred and the insoluble material was removed. To the filtrate was added 60 g wet weight (containing 71% of water) of the methacrylate porous adsorbent Amberlite XAD-7 (made by Rohm & Haas Co.), which was washed with methanol and then with water, and a mixture was slowly stirred in a cold room (4° C.) for a night to immobilize the enzyme on the support by adsorption. The suspension containing the immobilized enzyme was filtered with suction by means of glass filter and the the filtrate was washed with 0.1M phosphate buffer at pH 7.0 three times (100 ml×3), followed by filtration with suction to give the wet immobilized enzyme. The obtained immobilized lipase was filled in the column (inner diameter: 2.2 cm, length: 15 cm), which was kept at 33° C. On the column was loaded 5 g of racemic amyl-indoline-2-carboxylate [(R,S)-Ia] and 0.1M phosphate buffer at pH 7.0 was passed through the column at a flow rate of 6 ml/h. Each 12 ml of the eluate collected from the column by a fraction collector was subjected to a liquid chromatography analysis. Only hydrophilic indoline-2-carboxylic acid produced by the asymmetric hydrolysis was contained. 180 ml of the phosphate buffer fraction was saturated with ammonium sulfate and the pH of the mixture was adjusted to 5.0, followed by extraction of indoline-2-carboxylic acid with an equivalent amount of ethyl acetate three times. The obtained ethyl acetate layer was dehydrated and concentrated under reduced pressure, followed by recrystallization in acetone-hexane (5 ml-1 ml). After driness in vacuum, 1.26 g of (R)-indoline2-carboxylic acid [(R)-II] having a specific rotatory power [α]D25 -32.5° (c=1.0, DMFA) (the value described in the literature J. Med. Chem. 26, 394 (1983) by D. H. Kim et al. is [α]D25 +34.5° (c=0.91, DMFA) was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:26][CH2:27][C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:26][CH2:27][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:23][CH2:24]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 22, Step 2) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18](Cl)(=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1>[C:18]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -78 °C

Procedure:
(S)-(+)-4-Phenyl-2-oxazolidinone (4.77 g, 29.3 mmol, Aldrich) was dissolved in dry THF (100 mL), and the solution was cooled to -78° C. and flushed with N2. n-Butyllithium (2.5M in THF, 11.7 mL, 29.3 mmol) was introduced over 10 minutes. The compound from step 8a (in 30 mL of THF) was added over 10 minutes, and the mixture was stirred at -78° C. for half an hour. The mixture was stirred as it was allowed to warm to room temperature. Saturated aqueous NH4Cl solution was added, the mixture was stirred for 10 minutes and the THF was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water, 5% aqueous NaHCO3 and brine, then dried over Na2SO4. The solvent was removed to afford the title compound, which was recrystallized from ethyl acetate to give the title product (7.18 g). MS m/z 294 (M+H)+, 311 (M+NH4)+.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])[N:23]4[N:22]=3)=[C:16]([O:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[CH3:39][O:38][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:40])=[O:5])[CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[N:23]2[N:22]=1
Reactant: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C2CCN(CC(=O)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Reaction time: 18 h

Procedure:
A solution of] (4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetic acid tert-butyl ester (73 mg, 0.13 mmol) in 2 mL of 4N HCl in dioxane was stirred at RT. After 18 h, solvent was evaporated and the mixture was triturated with ether. A solid was obtained which was filtered, washed with ether (twice) and dried. The product, (4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetic acid was isolated as a pale yellow hygroscopic solid (54 mg, 82%). LCMS (E/I+) 488 (M+H). NMR 1H (DMSO-d6)-10.1 (br s, 1H), 8.96 (s, 1H0, 8.05 (d, 1H, J=8.24 Hz), 7.81 (d, 1H, J=7.49 Hz), 7.68 (s, 1H), 7.46 (m, 1H), 7.41 (d, 1H, J=7.96 Hz), 7.21 (d, 1H, J=8.34 Hz), 7.11 (d, 1H, J=7.45 Hz), 7.08 (m, 1H), 6.98 (m, 2H), 6.70 (d, 1H, J=7.32 Hz), 4.16 (br s, 2H), 4.05-3.1 (series of m and s along with the water peak, 10H), 2.8 (m, 1H), 2.03 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:47]([O:49]CC(=O)C1C=CC=CC=1)=[O:48])[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:46])[C@@H:23]([NH:25][C:26]([C@@H:28]([N:30]([CH3:45])[C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32])[CH3:29])=[O:27])[CH3:24])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:47]([OH:49])=[O:48])[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:46])[C@@H:23]([NH:25][C:26]([C@@H:28]([N:30]([CH3:45])[C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[O:32])[CH3:29])=[O:27])[CH3:24])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)[C@H](C)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, are introduced into a solution of 17.0 g (21.0 mmol) of the compound from example 8A in 90 pc. aqueous acetic acid and 10.3 g (158 mmol) of zinc. The reaction mixture warms slightly and is cooled to 25° C. It is stirred at this temperature for 3 h and the mixture is subsequently filtered off with suction through kieselguhr and washed with ethyl acetate. The solvent is removed on a rotary evaporator, and the residue is taken up in ethyl acetate and extracted by shaking twice with 1N aqueous hydrochloric acid. The organic phase is concentrated again, treated three times with toluene and evaporated to dryness in vacuo and finally dried in vacuo. 14 g (94% of theory) are isolated. The product is reacted without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH2:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH2:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN

Procedure:
In 50 ml of MeOH is dissolved 350 mg of Z-Tyr-(D)-Leu-Gly-Phe-NH-NH2, and following addition of 0.1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filteredoff, the filtrate is concentrated and the residue is dissolved in a small amount of 1N-aqueous acetic acid and put on a column of Sephadex LH-20(2.5×120 cm). Elution is carried out with 1 N-aqueous acetic acid and fractions from 320 through 340 ml are collected and lyophilized. 210 mg (60%); [α]D22 +22.6° (c=0.38, MeOH); Rf2 =0.34; amino acid analysis (acid hydrolyzate): Gly, 1.00, Leu, 1.00; Tyr, 0.90; Phe, 1.02; mean recovery rate 70%.