Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=2.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Reactant: Cn1c(=O)c(N)c(N)c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2cccnc21
Temperature: 0 °C
Yield: 12.2 %

Procedure:
3-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.277 g, 1.0 mmol), TEA (0.10 g, 1.0 mmol), and HOBt (0.135 g, 1.0 mmol) were added sequentially to a stirred solution of 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (0.19 g, 1.0 mmol) in DMF (8 mL) at room temperature. The solution was cooled to 0° C. and EDCI (0.19 g, 1.0 mmol) was added. The resulting solution was allowed to stir, with warming to room temperature, for 17 h. The mixture was diluted with water (5 mL) and extracted with CH2Cl2, dried with MgSO4, and concentrated. The residue was purified by flash chromatography eluting with 5% MeOH in CH2Cl2 to give [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-[1,8]naphthyridin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (55 mg, 12% yield), and 60 mg (32%) of unreacted diamine. 1H-NMR (CDCl3): δ 8.59 (m, 1H), 8.21 (m, 1H), 7.91 (m, 1H), 7.33 (m, 6H), 7.20 (dd, 1H, J=8.0, 4.8), 5.51 (m, 2H), 5.12 (m, 2H), 4.76 (m, 1H), 4.10 (m, 1H), 3.81 (s, 3H), 2.60 (m, 1H), 2.33 (m, 1H), 1.93-2.05 (m, 3H), 1.73 (m, 2H), 1.45 (m, 2H). MS: calculated for C24H27N5O4+H 450.2; found: 450.5.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[CH:12]1([NH:18][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.1 %

Procedure:
A mixture of 15.09 g (78 mmol) 2,4-dichloronitrobenzen, 7.7 g (78 mmol) cyclohexylamine, 7.9 g (78 mmol) triethylamine and 100 ml dimethylformamide was stirred at 80° C. for 3 h. After cooling to 25° C. the mixture was evaporated, dissolved in 200 ml ether and filtered. The ether solution was washed with water and evaporated to the half volume. The precipitate was filtered off to give 3.8 g (19%) N-cyclohexyl-2-nitro-5-chloraniline. M.p. 124.5° C. 1H-NMR (CDCl3): 8.2 (2H, m), 6.8 (1H, d), 6.5 (1H, dd), 3.5 (1H, broad s), 2.4-0.8 (10H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.O.[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OOS([O-])=O.[K+]>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]3[NH:9][C:4]4[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=4[N:8]=3)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-1,2-benzenediamine (214 mg, 1.145 mmol) in N,N-dimethylformamide (12 mL) containing water (0.4 mL) was treated with the product of Example 147A (400 mg, 1.145 mmol) and OXONE (458 mg, 0.7443 mmol), and the reaction stirred at room temperature for 30 minutes. Water (40 mL) was then added and the reaction stirred for 10 minutes. The mixture was vacuum filtered and the solid washed with water, then dried under vacuum. Purification by silica gel chromatography using a gradient of 3% to 4% ethyl acetate/methylene chloride as eluent provided the title compound as a yellow solid (305 mg, 51%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(CC)CC.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[C:35]([O:34][C:33]([NH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (162.8 mg, 0.445 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (111.6 mg, 0.521 mmol) and Et3N (0.1 mL, 0.717 mmol) in THF (6 mL) and DMF (6.00 mL) was stirred at 60° C. for 12 h. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), were dried over anhydrous Na2SO4, and filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a yellow solid (182.2 mg, 75%). 1H-NMR (CDCl3) δ ppm 1.42-1.67 (m, 15H), 1.84-1.91 (m, 2H), 3.07 (s, 3H), 3.95-3.97 (m, 4H), 4.16-4.17 (m, 1H), 4.77 (s, 1H), 6.24 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.61 (m, 1H), 7.77-7.78 (m, 1H), 8.41 (s, 1H), 10.99 (s, 1H), 1H not detected.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:32])[NH:22][C:23]3[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=3)=[CH:17][C:16]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[S:24][C:25]([C:28]([CH3:30])([CH3:31])[CH3:29])=[N:26][N:27]=3)=[O:32])=[CH:17][C:16]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:45])[CH3:46])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 225d (212 mg, 0.323 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (9 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 1.42 (s, 9 H), 3.21-3.36 (m, 1 H), 6.79-6.87 (m, 2 H), 6.94 (d, J=8.82 Hz, 3 H), 7.86 (d, J=8.46 Hz, 1 H), 8.15 (dd, J=8.82, 2.21 Hz, 1 H), 8.28 (d, J=2.21 Hz, 1 H), 8.88 (s, 1 H), 8.99 (d, J=8.46 Hz, 1 H); MS (ESI+) m/z 555 (M+TFA+H)+; (ESI−) m/z 553 (M+TFA−H)−.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]2[O:21][CH2:20]2)=[CH:17][CH:16]=1.O.[B:25]([OH:28])(O)[OH:26]>C1(C)C=CC=CC=1>[OH:26][B:25]1[O:21][CH2:20][CH:19]([C:18]2[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=2)[N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]([C:18]2[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH2:20][O:28]1
Reactant: CCCCCCCCCCCCN
Reactant: Cc1ccc(C2CO2)cc1
Reactant: OB(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCN1C(c2ccc(C)cc2)COB(O)OCC1c1ccc(C)cc1
Temperature: 25 °C

Procedure:
The boramid compound, 1-hydroxy-4,6-dicresyl-5-dodecyl-5-aza-1-bora-2,8-dioxacyclooctane is prepared by adding 61.7 grams of dodecylamine, 89.3 grams of para methylstyrene oxide and 250 ml of toluene to a single necked one liter round-bottomed flask. The toluene acts as a solvent and as an azeotrope for water produced during the reaction. The mixture thus formed is heated until it begins to reflux. Next, the mantle heat is adjusted to give a moderate reflux rate. The reaction mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature and 21 grams of boric acid are added to the flask. Next, the flask is equipped with a Dean-Stark trap topped with a water-cooled condenser and the reaction mixture is refluxed until water stops collecting in the trap (12 ml). Toluene is distilled from the reaction product. The reaction produces 160 grams of product.
Reaction SMILES: N1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]4[C:31]5[C:26](=[C:27]([C:32]#[N:33])[CH:28]=[CH:29][CH:30]=5)[O:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)C=NN=N1.C(C1C2C(=C(C#N)C=CC=2)OCC1)=O.O=C(N1CCNCC1)CC1C=CC2[C:55](=[O:58])[O:56][CH2:57]C=2C=1>>[O:58]=[C:55]1[C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]4[C:31]5[C:26](=[C:27]([C:32]#[N:33])[CH:28]=[CH:29][CH:30]=5)[O:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH2:57][O:56]1
Reactant: O=C1OCc2cc(CC(=O)N3CCNCC3)ccc21
Reactant: N#Cc1cccc2c1OCCC2CN1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Agent: N#Cc1cccc2c1OCCC2C=O
Product: N#Cc1cccc2c1OCCC2CN1CCN(C(=O)Cc2ccc3c(c2)COC3=O)CC1

Procedure:
4-({4-[(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-8-carbonitrile was prepared in an analogous fashion to that described for the synthesis of 4-[(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)methyl]-3,4-dihydro-2H-chromene-8-carbonitrile above starting from 4-formyl-3,4-dihydro-2H-chromene-8-carbonitrile and 5-[2-oxo-2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.85 (d, J=7.8 Hz, 1H), 7.31˜7.38 (m, 4H), 6.8 (t, J=7.8 Hz, 1H), 5.24 (s, 2H), 4.15˜4.45 (m, 2H), 3.8 (s, 2H), 3.4˜3.73 (m, 4H), 2.88˜2.95 (m, 1H), 2.3˜2.52 (m, 6H), 1.97˜2.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=O)[N:8]3[CH2:9][C:10]=2[CH:11]=1.[OH2:17].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:26]O>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=[N:26][OH:17])[N:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: O
Reactant: NO
Reactant: O=C1c2ccc(Cl)cc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccc(Cl)cc2CN2C(=NO)CCC12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
A suspension of 9.00 g of 7-chloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (65 ml) was treated with a premixed solution prepared from 10.40 g of sodium acetate trihydrate in water (35 ml) and 5.31 g of hydroxylamine hydrochloride in water (35 ml). The suspension was heated to reflux and after 10 minutes a solution formed. After 1 hour of refluxing, a precipitate began to form and heating was continued for another 1.5 hours, after which time the mixture was allowed to cool to ambient temperature. The precipitate was isolated by vacuum filtration and dried under vacuum at 40° C. The solid was recrystallized form n-propanol (300 ml) to give 6.45 g of crystals, m.p. 249°-252° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.C(OC([NH:39][CH2:40][C:41]([NH:43][C@H:44]1[CH2:49][CH2:48][C@@H:47]([N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:51]([CH3:53])[CH3:52])[CH2:46][C@H:45]1[C:61]([O:63][CH:64]([CH3:66])[CH3:65])=[O:62])=[O:42])=O)C1C=CC=CC=1>C1COCC1.O>[C:57]([O:56][C:54]([N:50]([CH:51]([CH3:53])[CH3:52])[C@H:47]1[CH2:46][C@@H:45]([C:61]([O:63][CH:64]([CH3:66])[CH3:65])=[O:62])[C@@H:44]([NH:43][C:41](=[O:42])[CH2:40][NH:39][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)[CH2:49][CH2:48]1)=[O:55])([CH3:59])([CH3:58])[CH3:60]
Reactant: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
A solution of 3-Trifluoromethyl-benzoic acid (0.23 g, 0.0012 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine(0.13 g, 0.0013 mol) and then drop-wise with isobutyl chloroformate (0.16 g, 0.0012 mol). The resulting mixture was stirred for 5 min and then treated with a solution of isopropyl (1R,2S,5R)-2-(2-aminoacetamido)-5-(tert-butoxycarbonyl-isopropyl-amino)cyclohexanecarboxylate (0.45 g, 0.0011 mol; See Example 8b, Step 4) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 55% ethyl acetate/hexane) to give 0.4 g of isopropyl(1R,2S,5R)-5-(tert-butoxycarbonyl-isopropyl-amino)-2-(2-(3-trifluoromethyl-benzamido)acetamido)cyclohexanecarboxylate as a white solid, MS found: (M+H)+=572.4.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH:5][C:20](=[O:21])[O:22][CH2:23][CH3:24]
Reactant: CCCCC(C)C(C)(O)CCN
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC(C)C(C)(O)CCNC(=O)OCC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred suspension of 3-hydroxy-3,4-dimethyoctylamine (4.91 g; 28.38 mmole) and anhydrous sodium carbonate (5 g) in dry etanol (40 ml) was added ethyl chloroformate (3.65 g; 33.6 mmole) in dry ethanol (25 ml), over 30 min. The mixture was heated under reflux for 1 hr and then poured into water (200 ml). The product was extracted into diethyl ether (3×100 ml), and the combined organic layers washed with dilute hydrochloric acid (1×100 ml) and brine (1×100 ml) and dried. (Na2SO4). Evaporation in vacuo gave ethyl N-[3-hydroxy-3,4-dimethyloctyl]-carbamate (6.2 g; 891).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].ClC1C=C(C=CC=1Cl)CC1CCN(C[C@H](N)C(C)C)CC1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:55]=[CH:56][C:57]=1[Cl:58])[CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([NH2:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][CH2:43]1>>[Cl:37][C:38]1[CH:39]=[C:40]([CH:55]=[CH:56][C:57]=1[Cl:58])[CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([NH:54][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:15])[C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:47]1
Reactant: CC(C)(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: CC(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Product: COc1cc(NC(=O)N[C@@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)(C)C)cc(OC)c1OC

Procedure:
Proceeding as described in Example 13 above, but substituting 3-methoxyphenylisocyanate with 3,4,5-trimethoxyphenylisocyanate and 1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropylamine with 1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropylamine gave 1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>>[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:33]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1
Yield: 69 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (35.3 mg, 0.093 mmol) and 2-methyl-5-nitrobenzoic acid 20 mg, 0.11 mmol) were reacted as described in example 34 to give 4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (34 mg, 69%), HR—FAB—MS: obs. mass 530.2298. Calcd. mass 530.2291 (M+H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:15])O[C:12](=[O:13])[CH:11]=[CH:10]1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].C[N:29](C=O)C>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[C:9]([NH:29][C:12](=[O:13])[CH:11]=2)=[O:15])=[CH:3][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C=C(c2ccc(O)cc2)C(=O)N1
Temperature: 50 °C

Procedure:
To a solution under dry N2 of 54.56 grams para aminophenol (0.5 mole) at 25 percent solids in DMF, add a solution of 49.03 grams maleic anhydride (0.5 mole) at 50 percent solids in DMF at a rate sufficient to keep the temperature below 70° C. Stir solution 15 minutes. Add 122.51 grams acetic anhydride (1 mole+20% molar excess) and 9.84 grams sodium acetate (0.1 mole+20% molar excess). Heating the resulting mixture to 50° C. and maintain for 1.5 hours. At this point, the whole mass yields a yellow precipitate. Filter the cool precipitate, wash well with water, dry in vacuum oven at 40° C. overnight. The product achieved has a melting point of 158°-162° C.
Reaction SMILES: [F-].[K+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:36](=[O:39])[CH2:37]Br)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]([F:48])=[C:43]([F:49])[C:42]=1[OH:50]>CN(C=O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:36](=[O:39])[CH2:37][O:50][C:42]1[C:43]([F:49])=[C:44]([F:48])[CH:45]=[C:46]([F:47])[C:41]=1[F:40])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])(=[O:30])[CH2:28][CH2:27][CH2:36][CH3:37]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)C(C)C)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Product: CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 371.5 %

Procedure:
Potassium fluoride (21.6 mg, 0.37 mmol) was added to a solution of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (86.1 mg, 0.149 mmol) and 2,3,5, 6-tetrafluorophenol (27.0 mg, 0.163 mmol) in DMF (2.0 ml). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. The residue was triturated with ether to give the titled product, N-(1-methyl-3-isobutyl-indole-2-carbonyl)-valinyl-3-amino-4-oxo-5-(2,3,5,6-tetral]uorophenyloxy)-pentanoic acid, tert-butyl ester as a white solid (43.8 mg, 44%). TLC (hexane/EtOAc, 50/50): Rf=0.50.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2.CI>C1COCC1>[CH3:9][O:10][C:11](=[O:25])[CH:12]([C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:2]
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of LDA (1.2 M in THF, 9.5 mL, 11.4 mmol) in dry THF (30 mL) at −78° C. was added a solution of (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester (2.12 g, 9.5 mmol) in THF (20 mL) dropwise. After 30 min, MeI (0.9 mL, 14.2 mmol) was added dropwise, and the reaction mixture was allowed to rise to 0° C. naturally. After 1 h, the reaction was quenched by saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 2.272 g (95%) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.93 (d, 1H), 8.39 (dd, 1H), 7.61 (dd, 1H), 7.41-7.46 (m, 1H), 4.29 (q, 1H), 3.73 (s, 3H), 1.62 (d, 3H). LCMS (method A): [MH]+=252, tR=5.09 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH:10]=[O:11])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[F:12][C:13](I)([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].C[Li].[Br-].[Li+]>C(OCC)C>[CH3:1][C:2]1([C:7]2([CH:10]([C:13]([F:24])([F:12])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[OH:11])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: CCOCC
Product: CC1(C2(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC2)OCCO1
Reaction time: 0.5 h

Procedure:
1.2 g of 97 and 3.92 ml of perfluorobutyl iodide in 40 ml of diethyl ether are introduced under argon and methyllithium/lithium bromide complex (1.5 M in diethyl ether) is added in drops at −78° C. After 30 minutes, it is quenched with sodium chloride solution and diluted with ethyl acetate. Extraction with ethyl acetate, washing of the combined organic phases with sodium chloride solution, drying on sodium sulfate, removal of the solvent and chromatography on silica gel with ethyl acetate/hexane yields 2.1 g of 1-(2-methyl-1,3-dioxolan-2-yl)-α-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)cyclopropanemethanol 98 as a colorless oil.