Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([NH:16][C:17]([NH:19][C:20]3[CH:38]=[CH:37][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[CH:26]=4)=[CH:22][CH:21]=3)=[O:18])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH2:2]1.C=O.O.[C:42]([O-])(O)=O.[Na+]>CO>[CH3:42][N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([CH:34]5[CH2:35][CH2:36]5)=[O:33])[CH:26]=4)=[CH:37][CH:38]=3)=[O:18])[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=2)[CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1)Nc1cc(OC2CNC2)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(Oc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Yield: 7 %

Procedure:
Dissolve N-[4-[4-[[3-(azetidin-3-yloxy)-5-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-2-pyridyl]cyclopropanecarboxamide (210 mg, 0.4 mmol) in methanol (10 mL), add 35% aqueous formaldehyde solution (205 mg, 2.39 mmol), sitr for 1.5 hrs. Add Na(CN)BH3 (150 mg, 2.39 mmol) and stir at room temperature for 3 hrs. After reaction, pour the reaction mixture to water (50 mL), adjust pH=7 with saturated NaHCO3 solution, extract with EtOAc (15 mL×3), combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, DCM:MeOH=20:1) affords the target compound (16 mg, 7%). MS: (M+1): 542.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:36]1([CH3:45])[C:37]([N:42]=[C:43]=[O:44])=[CH:38][CH:39]=[CH:40][CH:41]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:43]([NH:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])=[O:44])=[CH:26][CH:27]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(N)cc3)n2)c(OC)c1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(NC(=O)Nc4ccccc4C)cc3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-methoxy-4-[2-(4-aminobenzyl)-4-thiazolyl]methoxybenzoate (87.8 mg, 0.220 mmol) in THF (2.0 mL) was added triethylamine (30.5 ul, 0.220 mmol) and o-tolyl isocyanate (30 μl), and the reaction mixture was stirred at room temp for 21 hr. The reaction mixture was poured into ice-water and the resulting precipitates filtered off. The filtrate was extracted with CHCl3, washed with H2O, and brine. The extract was dried over Na2SO4. The solvent was removed under a reduced pressure to afford 110.4 mg (94%) ethyl 3-methoxy-4-[2-[4-[N′-(2-methylphenyl)ureido]benzyl]-4-thiazolyl]methoxybenzoate as a pale yellow crystalline powder. 1H-NMR (400 MHz, CDCl3) δ1.38 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 4.35 (q, J=7.3 Hz, 2H), 5.29 (s, 2H), 6.20 (s, 1H), 6.47 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.24 (s, 2H), 7.27 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.49 (d, J=7.3 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 532 M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN1CCCC1=O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: Brc1ccc2nccc(N3CCCCC3)c2c1
Temperature: 150 °C
Yield: 100.4 %

Procedure:
To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL of 1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol). The reaction was heated to 150° C. for 5 h. The solvents were removed in vacuo at 100° C. and the residue dissolved in methylene chloride and washed with water. The methylene chloride was dried with sodium sulfate and concentrated. The residue was triturated with hexane and the solid filtered off to give 6-bromo-4-(1-piperidinyl)quinoline (877 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:49](=[O:50])[C:48]([CH3:51])=[CH:47][N:12]([C@@H:13]2[O:37][C@H:17]([CH2:18][O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@:15]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([OH:16])[CH2:14]2)[C:11]1=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([NH3+])(C)(C)C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:49](=[O:50])[C:48]([CH3:51])=[CH:47][N:12]([C@@H:13]2[O:37][C@H:17]([CH2:18][OH:19])[C@@:15]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([OH:16])[CH2:14]2)[C:11]1=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)n(COCc2ccccc2)c1=O
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO)O2)c(=O)n(COCc2ccccc2)c1=O

Procedure:
A solution of 3-benzyloxymethyl-3′-benzyloxymethyl-5′-O-tert-butyldiphenylsilylthymidine (20 g, 28 mmol) in THF (200 10 ml) was treated with tert-butyl ammonium fluoride 1M/THF (40 ml, 40 mmol) at room temperature for 16 hrs. The solution was concentrated in vacuo and the resulting oil chromatographed on silica gel (EtOAc/hexane, 7/3→8/2) to afford the product, 10 g (75%). m.p. 83-84° C.; 1H NMR (CDCl3), 1.92 (s, 3H, C5—CH3), 2.20-2.50 (m, 3H, C2′H, C5′OH), 3.73 (dd, 1H, C5′HH), 3.89 (dd, 1H, C5′HH), 4.09 (m, 1H, C4′H), 4.49(m,1H, C3′H) 4.62 (s, 2H, OCH2Ph), 4.70 (s, 2H, OCH2Ph), 4.81 (s, 2H, OCH2O), 5.49 (s,2H, NCH2O), 6.19 (t, 1H, Cl′H), 7.26-7.37 (m, 5H, CH═,ArH). Anal. Calcd. for C26H30N2O7: C, 64.94; H, 6.26; N, 5.75. Found: C, 64.71; H, 6.27; N, 5.81.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]2=[CH:14][CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>CN(C)C=O>[NH2:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:10]
Reactant: COc1ccc(N)cc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 4-nitroisatoic anhydride (2.08 g, 10.0 mmol) and p-anisidine (1.35 g, 11.0 mmol) in N,N-dimethylformamide (10 mL) was heated at 80° C. for 2.5 h. After cooling, the reaction was poured into ice cold 3 N hydrochloric acid (60 mL). The resulting solid was filtered and washed with 1 N hydrochloric acid and water. Drying in vacuo gave 2.73 g (95%) of the title compound as a greenish yellow solid; mp 193-7° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CO[CH:13](OC)[CH2:14][NH2:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4]2[NH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:8])[CH2:7]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)c2cc[nH]c2C1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
A solution of 5,5-dimethyl-1,3-cyclohexandione (30 g, 0.21 mol), aminoacetaldehyde dimethyl acetal (35 mL, 0.32 mol) and p-toluenesulphonic acid hydrate (1.5 g, 8 mmol) in toluene (250 mL) were heated at reflux for 4 h using Dean-Stark apparatus to remove the water. The toluene was evaporated and the residue dissolved in 3N HCl (250 mL). The solution was heated at 60° C. for 6 h. After this time the mixture was cooled to room temperature and extracted with DCM (6×). The combined organic layers were dried (MgSO4), evaporated and the residue chromatographed on silica gel, eluting with isohexane: EtOAc (4:1→1:1). The fractions containing the desired product were combined, evaporated and the residue triturated with ether. The title compound (1.8 g, 5%) was isolated as a cream solid. mp 177-178° C. 1H NMR (360 MHz, d6-DMSO) 8 1.02 (6H,s), 2.19 (2H,s), 2.63 (2H,s), 6.23 (1H,t, J=3.9 Hz), 6.71 (1H,t, J=3.9 Hz). MS (ES+) 164 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:15].Cl.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)(C)C>[ClH:1].[OH:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH3:15])[C:7]=4[N:6]=[N:5][C:4]=3[CH2:3][CH2:2]2)=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1cc(O)ccc1N
Reactant: Cc1cccc2c(Cl)c(CCCl)nnc12
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(O)ccc1N1CCc2nnc3c(C)cccc3c21

Procedure:
3-(2-Chloroethyl)-4-chloro-8-methylcinnoline (2 g, 0.0083 mol) and 4-hydroxy-2-methylaniline hydrochloride (1.32 g, 0.0083 mol) in isopropanol (50 ml) were heated under reflux in a nitrogen atmosphere for 20 hours. The solid obtained was collected by filtration and dried. Recrystallization from isopropanol/ethanolic HCl gave the title compound as a partial hydrate, 0.64 g, m.p. 292-294°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:31][CH:30]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH2:14][CH2:15][C:16]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(#N)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][C:16](=[O:17])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:9]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CC(C)(C)NC(=O)CN
Solvent: CC#N
Product: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A suspension of 5-bromoisatoic anhydride (1.2 g, 5.0 mmol) and 2-amino-N-tert-butylacetamide (INTERMEDIATE I.2) (0.78 g, 6.0 mmol) in acetonitrile (8 mL) was stirred at room temperature for 20 h. The white suspension was filtered, and the white precipitate washed cold EtOH to give 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (1.06 g, 3.22 mmol, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:17]([NH:25][C:26]([NH:16][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([Br:15])=[CH:13][N:12]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(OCc2ccccc2)c(Br)cn1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A flask was charged with 4-(benzyloxy)-5-bromopyridin-2-amine (6.90 g, 24.7 mmol), and THF (250 mL). Benzoyl isothiocyanate (4.24 g, 26.0 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction mixture was concentrated, and 9:1 Hexanes:ethyl acetate (400 mL) was added to the residue. The suspension was filtered to give the desired product (10 g, 82.3% yield) as light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([N:21]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:34](=[O:36])[CH3:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2ccccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (100 mg, 0.22 mmol) in ethyl acetate (5 ml) were added acetyl chloride (225 ml, 3.3 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (45 mg, 41%).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[S:10]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])N1)(=[O:12])=[O:11].N.S(=O)(=O)(O)O>O.C(#N)C>[CH3:1][Si:2]([N:3]1[C:14](=[O:15])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:12])=[O:11])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)N1C(=O)c2ccccc2S1(=O)=O
Yield: 102 %

Procedure:
2 ml (9.6 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 1.83 mg (10 mmoles) of saccharin, 10 mg (0.02 mmole) of di-4-nitrophenyl N-(4-toluenesulfonyl)-phosphoramidate and 20 ml of acetonitrile under dry nitrogen and the ammonia evolved was led into water by the nitrogen stream and was titrated with 1 N sulfuric acid. The calculated amount of ammonia was evolved within 0.5 hour and the solvent and other volatile materials were removed by evaporation in a rotating film evaporator. Then, the residue was dried under vacuum to obtain 2.50 g (98%) of trimethylsilylsaccharin melting at 90°-92° C.
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([O:26]C)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[Li+].[OH-].O>CO>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe (SEQ ID NO: 2) were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 0° C. and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 30.62 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:37][C:38]([NH:40][CH3:41])=[O:39]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[N:20]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (mg, mmol) in CH3CN was added K2CO3 and 2-chloro-N-methylacetamide. The reaction was allowed to stir at reflux overnight. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (10-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined and concentrated in vacuo and gave the desired tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl][2-(methylamino)-2-oxoethyl]carbamate which was confirmed by MS: cal'd 481.2 (MH+), exp 481.2 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CN2CCCC2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (150 mg, 0.37 mmol), pyrrolidine (30 μL, 0.36 mmol) and AcOH (20 μL, 0.37 mmol) in THF (4 mL) was added NaBH(OAc)3 (235 mg, 1.11 mmol) and the mixture was stirred at room temperature for 1.5 hours. Purification of the crude white foam (205 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (160 mg, 96%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(OO)(=O)C.[CH:17](=[O:21])[CH2:18][CH2:19]C.OO>C1(C)C=CC=CC=1.C(O)(=O)C.Cl[Cu]>[CH2:17]([O:21][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:18][CH3:19]
Reactant: CCCC=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl[Cu]
Agent: CC(=O)OO
Agent: OO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g 2,2,6,6-tetramethyl-piperidin-4-ol (intermediate product of Ciba Specialty Chemicals Inc.) are suspended in 7 ml of toluene. 2.3 g of a 40% solution of peracetic acid in acetic acid are added at 0° C. and the reaction mixture is stirred at room temperature for 3 h. 4.2 ml butanal and 2.4 ml of a 30% aqueous hydrogen peroxide solution are added, followed by 50 mg CuCl after 15 min. The reaction mixture is stirred for 1.5 h at room temperature to give a greenish emulsion. The two phases are separated and the organic one is washed with 10% ascorbic acid solution, water, diluted sodium carbonate sol., diluted sodium chloride sol., and saturated sodium chloride sol. The organic phase is dried over sodium sulfate and finally evaporated to complete dryness under vacuum to afford 1.3 g product.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][CH:19]=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][C:19]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(S(=O)(=O)Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, to dimethylformamide (0.2 ml) was added dropwise sulfuryl chloride (0.17 ml), and the mixture was stirred, under nitrogen atmosphere, at room temperature for 10 minutes. To the mixture was added 7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine (0.3 g), and the mixture was stirred, under nitrogen atmosphere, at 90° C. for 3 hours. To the mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-sulfonylchloride (0.36 g) as pale yellow crystals.
Reaction SMILES: [Na+].[I-:2].[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10]OCC1C=CC=CC=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O>[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10][I:2])[C:6]#[N:7]
Reactant: [I-]
Reactant: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Chlorotrimethylsilyl (22 g) is added dropwise over 20 minutes to a suspension of NaI (30 g) in CH3CN (300 ml) cooled to 0° C. Stirring is continued for 30 minutes at room temperature. 2-Fluoromethyl2-phthalimido-5-benzyloxypentanenitrile (25 g) in CH3CN (50 ml) is added, and the mixture is stirred overnight at room temperature. This mixture is then poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is taken up in THF (200 l) and triethylamine (7 g) is added. After stirring for 1 hour, the mixture is poured into water and extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue, a mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile and 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is taken up in CH3CN (50 ml) and added to a solution of iodotrimethylsilyl prepared as described above from TMS Cl (22 g) and NaI (30 g) in CH3CH (300 ml). The mixture is stirred overnight at room temperature. Then it is poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The residue obtained after concentration of the organic layer in vacuo is filtered on a florisil column (30 g). Elution with diethyl ether and removal of the solvent under reduced pressure gives 22 g of 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile as an oil.