Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:23]2[CH2:25][CH2:24]2)=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>>[CH:23]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[N:8]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1c(C2CC2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)c(C2CC2)nn1-c1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared from 3-Cyclopropyl-5-methyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester by hydrolysis with sodium hydroxide in analogy to intermediate 6. MS: 327.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[Cl:22])[CH2:9]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:28][O:29][C:30]([C:32]1[CH2:33][N:34]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:35][CH2:36][C:37]=1OS(C(F)(F)F)(=O)=O)=[O:31].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:29][C:30]([C:32]1[CH2:33][N:34]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:35][CH2:36][C:37]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[Cl:22])[CH2:9]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(Cl)c(O[C@H]2CCN(c3ccc(Br)cn3)C2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(N3CC[C@H](Oc4c(Cl)cc(C)cc4Cl)C3)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A sol. of (S)-5-bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-1-yl]-pyridine (8.52 g, 21.2 mmol) in THF (212 mL) at −78° C. was treated with BuLi (1.6M in hexane, 22.1 mL, 35.3 mmol). The mixture was stirred −78° C. for 30 min, and ZnCl2 (1.03M in THF, 41.1 mL, 42.4 mmol) was added. The mixture was allowed to warm up to rt. A sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 9.17 g, 23.5 mmol) in THF (5 mL), and Pd(PPh3)4 (816 mg, 0.701 mmol) were added. The mixture was rapidly heated to 75° C., and stirred at this temperature for 1 h. The mixture was allowed to cool to rt, and aq. sat. NH4Cl was added. The mixture was extracted with EtOAc. The org. extracts were washed with aq. sat. NH4Cl, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane→heptane:EtOAc 65:35) yielded the title compound (6.83 g, 52%). LC-MS: tR=0.92 min, ES+: 562.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:26])(=[O:25])[CH:22]([CH3:24])[OH:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:26])(=[O:25])[CH:22]([CH3:24])[OH:23]
Reactant: CC(O)C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Solvent: CCO
Product: CC(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol 0.7 g of lactic acid were added in 10 ml of ethanol, the mixture was stirred for 3 hours at room temperature and precipitated with diisopropyl ether. After decanting of the solvent the oil was dissolved in water and lyophilized. The result was a colorless, amorphous solid substance that was decomposed from 120° C onwards γC=N 1630 cm-1.
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH:4]([OH:5])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a solution of (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (10 g, 30.8 mmol) in MeOH (200 mL) was added NaBH4 (9.3 g, 246 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at rt for 2-3 hrs. The solvent was removed in vacuo to afford a residue which was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated to give the crude product (R)-tert-butyl 3-((2,3-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (10 g, 99%), which was used in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 7.22 (m, 1H), 7.08 (m, 2H), 4.85 (t, 1H), 3.94 (d, 0.5H), 3.78 (d, 1H), 3.55 (m, 0.5H), 3.28 (d, 1H), 2.65 (m, 1H), 1.90 (m, 2H), 1.68 (m, 3H), 1.44 (d, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])=[CH:17][CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(4-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (35 mg, 0.089 mmol, 1.0 equiv) in t-BuOH (0.09 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.11 mmol, 1.2 equiv) and diisopropylethylamine (31 μL, 0.18 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 6.1 mg of the title compound (13% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 79.1 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (140 mg, 0.357 mmol) was dissolved in acetonitrile (7 mL), and the solution was added with 1-(2-hydroxyethyl)piperazine (186 mg, 1.43 mmol), acetic acid (0.409 mL, 7.14 mmol) and sodium triacetoxyborohydride (151 mg, 0.714 mmol), followed by stirring at room temperature for 1.3 hours. The mixture was added with sodium triacetoxyborohydride (151 mg, 0.714 mmol) and further stirred for 3.8 hours. Further, the mixture was added with sodium triacetoxyborohydride (76.0 mg, 0.357 mmol) and stirred for 0.6 hours. The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-hydroxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (143 mg, yield 79%).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
Man 32.8; Glc 188.3
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 4B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 8.63-8.64 (m, 1H), 8.37-8.47 (m, 1H), 8.12 (dd, J=8.2, 2.5 Hz, 1H), 7.92-8.04 (m, 2H), 7.73-7.76 (m, 2H), 7.41-7.49 (m, 2H), 7.28-7.34 (m, 2H), 7.16-7.20 (m, 1H), 2.63 (s, 2H), 1.47 (s, 6H); MS (APCI) M/Z 433 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])=[CH:18][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of isatoic anhydride (20 g, 122 mmol) in dimethylformamide (DMF) was added to a suspension of NaH (60% in mineral oil, 5.39 g, 135 mmol) in DMF and stirred at room temperature for 1 h. Then, 4-fluorobenzyl bromide (16.8 mL, 135 mmol) was added and the mixture stirred at room temperature for 4 h. The solution was poured into water and the solids formed were filtered, washed several times by water and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 30 g (90%) of white solids. M.P. 167° C. 1H NMR (DMSO-d6): δ 5.27 (s, 2H), 7.17 (t, J=8.8 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.47 (m, 2H), 7.74 (t, J=7.0 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H). Anal. (C15H10FNO3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:28][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH:13]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Reactant: NC(=O)N1CCOCC1
Product: COC(=O)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1

Procedure:
2-({2-[(Morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and morpholine-4-carboxylic acid amide in analogy to the procedures detailed in WO2004/013102, particularly Example 6A, supra; 1H-NMR (300 MHz, d6-DMSO) 9.19 (1H, s), 8.15-8.19 (2H, m), 7.79-7.84 (2H, m), 7.29-7.34 (1H, m), 6.92 (1H, dd), 6.56-6.62 (2H, m), 4.50 (2H, d), 3.83 (3H, s), 3.57-3.60 (4H, m), 3.42-3.46 (4H, m).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([C:13]([NH2:15])=[O:14])=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[C@H:4]1[OH:24].[CH2:25]([CH2:32][C:33](=O)[CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH2:17]([O:16][C:8]1[CH:7]=[CH:6][C:5]2[C@@H:4]([OH:24])[C@H:3]([NH:2][CH:33]([CH3:34])[CH2:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11][C:10]=2[C:9]=1[C:13]([NH2:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CCc1ccccc1)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)[C@H]1O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
In 30 ml of methanol was dissolved 1 g of trans-6-amino-2-benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride, followed by addition of 5 g of benzylacetone. Then, under ice-cooling, 1 g of sodium cyanoborohydride was added and the mixture was allowed to stand at room temperature overnight. The reaction mixture was diluted with 300 ml of water and extracted 3 times with 30 ml of CHCl3. The CHCl3 layers were combined, washed with water, dried and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl ether, followed by addition of 5 ml of 20% ethanolic hydrochloric acid, whereby 0.84 g of trans-2-benzyloxy-5-hydroxy-6-(1-methyl-3-phenylpropylamino)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride was obtained as colorless crystals, m.p. 215°-218° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([N:17]([OH:19])C)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].ON1C2C=CC=C[C:26]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.O(N)C.C(N(CC)CC)C>C(Cl)Cl>[CH:1](/[C:11]1[CH:21]=[CH:20][C:14]([C:15]([NH:17][O:19][CH3:26])=[O:16])=[CH:13][CH:12]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCCCc1ccc(C(=O)N(C)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\c1ccc(C(=O)NOC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of the benzoic acid prepared in Example 1 Part C (2.0 g, 7.68 mM) in dry CH2Cl2 (20 ml) was added 1-hydroxybenzotriazole (1.25 g, 9.22 mM, 1.2 eq.) and N,N'-dicyclohexylcarbodiimide (1.90 g, 9.22 mM, 1.2 eq.) and the mixture stirred for 1 hour at room temperature. Methoxylamine hydrochloride (1.28 g, 15.36 mM. 2 eq.) and triethylamine (2.14 ml, 15.36 mM, 2 eq.) were added, the mixture stirred for 3 hours at room temperature, then filtered, evaporated, taken up in ethyl acetate and filtered again. The organic phase was washed successively with 5% KHSO4, saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to an oil. The crude oil was flash chromatographed on LPS-1 silica gel eluting with (7:3) hexane-ethyl acetate. Product containing fractions were evaporated to give 2.023 g (91%) of the desired title product, 1.664 g of cis isomer, 359 mg of trans isomer as a low melting white solid with consistent NMR (CDCl3, 60 MHz) spectral data. TLC (1:1) EtOAc-Hex, Rf =0.39 UV and PMA.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13](#[N:15])[CH3:14].[NH2-].[Na+]>CCOCC>[NH2:6][C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:11])([F:12])[F:1])=[CH:14][C:13]#[N:15]
Reactant: CC#N
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC=C(N)c1ccccc1C(F)(F)F
Yield: 67.2 %

Procedure:
A mixture consisting of 9.3 g of 2-trifluoromethylbenzonitrile, 4.5 g of acetonitrile, 4.3 g of sodium amide and 100 ml of ether is stirred and refluxed under nitrogen over night. The resulting solid is collected on a Buchner-funnel, washed with ether and dissolved in approximately 100 ml of cold ethanol. Crushed ice is added to this solution until the total volume is about 700 ml. This mixture is allowed to stand for several hours. The resulting solid precipitate is collected by filtration then dissolved in methanol and decolorizing charcoal is added. The charcoal/methanol mixture is filtered and the filtrate is gradually treated with water until crystallization is judged complete. The crystalline solid is collected and dried under vacuum, to give 7.75 g of β-amino-2-trifluoromethylcinnamonitrile, mp 101°-103°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CC#N>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: COc1cc(OC)c(-c2nn[nH]n2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Product: COc1cc(OC)c(-c2nn[nH]n2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 19 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(2H-tetrazol-5-yl)-benzaldehyde (Ex-75A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 19% yield, mp 218° C. (dec). 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.20 (d, 2H), 8.03 (m, 3H), 7.85 (d, 1H), 6.90 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z=422 ([M+CH3CN+H]+, 100%). HRMS m/z: calc. 381.1199, found 381.1184.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:36])[CH2:9][N:10]([C:15](=[O:35])[C@H:16]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.[ClH:37].C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[ClH:37].[S:18]([NH:17][C@H:16]([C:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([OH:36])=[O:7])=[O:35])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.0 g of N2 -tosyl-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry ethyl ether to give 1.5 g of N2 -tosyl-L-arginyl-N-butylglycine hydrochloride as an amorphous solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>>[ClH:1].[NH:9]1[CH2:10][CH2:11][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Agent: Cl
Product: N#Cc1ccc(OC2CCNCC2)cc1
Reaction time: 2 h

Procedure:
Step-2: To a stirred solution of 100 mL (400 mmol) of 4N HCl in dioxanes was added the step-1 product, 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, (12.60 g, 0.0417 mol) and the mixture stirred 2 h, and 150 mL of 67% Et2O/hexanes added. The resulting slurry was filtered and dried under vacuum (1 torr, 60° C.) to afford the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, as a white solid (9.10 g, 91%): LCMS [MH+]203, Rt 1.23.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([CH2:25][O:26][CH3:27])[NH:11][CH2:12][C@H:13]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Reaction time: 3 h
Yield: 93.8 %

Procedure:
10% Pd/C (5.05 g, 4.76 mmol) and (2R,5R)-2-methoxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (18 g, 48 mmol) were mixed with MeOH (190 mL) at ambient temperature and the mixture was hydrogenated at ambient temperature and 1 bar for 3 h. The mixture was filtered through celite and the filtrate concentrated, to give the title compound (11 g, 99%) as a colourless oil. 1H NMR (Me-d3-OD): 4.16 (1H, dd), 3.80 (1H, d), 3.71-3.47 (1H, m), 3.47-3.40 (1H, m), 3.39 (3H, s), 3.30-3.17 (2H, m), 3.17-3.00 (2H, m), 2.60 (1H, dd), 1.48 (9H, s), 1.25 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:26][CH:28]3[O:30][CH2:29]3)=[CH:19][CH:18]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: BrCC1CO1
Reactant: O=C(c1ccc(Cl)cc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Product: O=C(c1ccc(Cl)cc1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12

Procedure:
When an equivalent amount of 3-p-chlorobenzoyl-2-p-hydroxyphenylbenzofuran was reacted with epibromohydrin as described in the procedure of Example 26 and the product 3-(4'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran thus formed was treated with isopropylamine as described in the procedure of Example 25, the title compound was obtained.
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][C@H:17]1[C@H:22]([NH:23][C:24]([C:26]2[NH:27][C:28]([CH2:32][CH3:33])=[C:29]([Cl:31])[N:30]=2)=[O:25])[CH2:21][CH2:20][N:19]([C:34]2[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=2)[CH2:18]1)=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[NH2:16][C@H:17]1[C@H:22]([NH:23][C:24]([C:26]2[NH:27][C:28]([CH2:32][CH3:33])=[C:29]([Cl:31])[N:30]=2)=[O:25])[CH2:21][CH2:20][N:19]([C:34]2[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=2)[CH2:18]1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NC(=O)OCc3ccccc3)C2)nc1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](N)C2)nc1C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
Hydrobromic acid/acetic acid solution (1 mL) was added to ethyl trans(±)-2-(3-{[(benzyloxy)carbonyl]amino}-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained by the method described in Example (79e) (62 mg, 0.11 mmol), and the mixture was stirred for 25 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution. Purification by reverse phase silica gel chromatography (elution solvent: distilled water, distilled water/THF=70/30, 60/40) gave 51.3 mg of the title compound (100%).