Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:13][OH:14]>>[OH:14][CH2:13][CH2:4][CH2:3][CH2:2][C:1]([O:6][CH3:5])=[O:7]
Reactant: O=C1CCCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCO

Procedure:
reaction of valerolactone with methyl alcohol in the presence of sulphuric acid to produce methyl 5-hydroxypentanoate,
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:30]([O:32]C)=[O:31])=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1([C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:30]([OH:32])=[O:31])=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: COC(=O)c1c(F)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)C1(N)CC1)c1ccc(-c2cccc(F)c2C(=O)O)cc1

Procedure:
A solution of methyl 4′-{(1R)-1-[({1-[(tert-butoxycarbonyl)amino]-cyclopropyl}carbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (466 mg, 1.0 mmol) in DCM (15 mL) and TFA (15 mL) was stirred under N2 for 20 minutes at ambient temperature, then the organic solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL), 4N NaOH (10 mL) and water (10 mL). This mixture was heated at reflux for 4 hours and then neutralized with 6N HCl. Purification was achieved by preparative HPLC on a delta-pack C18 column, 300 Å, pore size 15 μM with 0.05% HCl acid-aqueous acetonitrile solvent systems using various linear gradients. Fractions containing product of 99% purity as measured by HPLC were combined and lyophilized to give 4′-((1R)-1-{[(1-aminocyclopropyl)-carbonyl]amino}ethyl)-3-fluoro-1,1′-biphenyl-2-carboxylic acid as a white solid.
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[C:10]4[CH:11]=[CH:12][N:13]=[CH:14][C:15]=4[CH:16]=[CH:17][CH:18]=2)[CH2:3]3)=[CH:22][CH:21]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cc(NC2CC3CCC2N3)c2ccncc2c1
Product: Cc1ccc(CN2C3CCC2C(Nc2cccc4cnccc24)C3)cc1

Procedure:
Reaction of Intermediate 29 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [CH2:1]([CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].Br[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:1]([CH:3]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCCC(CC)Nc1ccccc1
Reactant: CCCCBr
Product: CCCCC(CC)N(CCCC)c1ccccc1

Procedure:
N-(1-ethylpentyl)-N-butylaniline was prepared from N-(1-ethyl-pentyl)aniline and bromobutane using the same method as Example 2ii).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[CH:11][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccc(N)n1
Product: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Temperature: 25 °C
Yield: 84.7 %

Procedure:
20 g (92.5 mmol) of 2-ethoxymethylene-malonic acid diethyl ester and 10 g (92.5 mmol) of 2-amino-6-methylpyridine were heated neat at 110° C. for 2 h. The reaction was allowed to cool to room temperature and the product was recrystallized from dichloromethane and hexane to afford 21.8 g of 2-[(6-Methyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester as a white solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=O)=O.CS(O)(=O)=O.[Cl:11][C:12]1[CH:13]=[CH:14]C2S[C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH2:18][CH:17]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[C:16]=2[CH:37]=1.OO.[OH-].[NH4+]>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:1]2[S:2](=[O:5])[C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH2:18][CH:17]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[C:16]=2[CH:37]=1
Reactant: CS(=O)(=O)O
Reactant: COc1cc2c(cc1OC)Sc1ccc(Cl)cc1C(N1CCN(C)CC1)C2
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)c1ccc(Cl)cc1C(N1CCN(C)CC1)C2
Reaction time: 20 h

Procedure:
A solution of 8-chloro-2,3-dimethoxy-10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine dimethanesulfonate (8.5 g) (see Example 4) in water (50 ml) was treated with 30% hydrogen peroxide (16 ml) and the mixture allowed to stand for 20 hours at room temperature. Addition of ammonium hydroxide liberated the base which was extracted with benzene. The extract affords an oily residue which crystallized from a mixture of benzene-light petroleum, m.p. 178°-179° C., yield 3.70 g of the desired base.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.CCOC(C)=O>C1COCC1>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-thiol (1.14 g, 10 mmol) in THF (50 ml) under argon at 0° C. was treated with NaH (303 mg, 11.98 mmol). The mixture was warmed to rt. A solution of 2-chloro-1-fluoro-4-nitro-benzene (1.76 g, 10 mmol) in THF (50 ml) was added, and the mixture was stirred at 70° C. for 4 h, cooled to rt. Treated with EtOAc (100 ml), the mixture was washed with H2O (2×25 ml), 1N KOH (30 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave a yellow solid. Recrystalization of the solid in CH2Cl2/hexanes gave 426A (2.31 g, 86%) as a slight yellowish solid. It has a retention time of 3.99 min (standard LC1 method, 8 min run). MS Found: (M+H)+=270.1
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:30][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Product: COc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-phenyl-methylamine (CA [2538-34-3]).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH:10]([OH:11])[C:30]([F:32])([F:31])[F:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CC(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 97A, 300 mg (0.78 mmol) were dissolved in 5 ml of THF, cooled to 0° C., and admixed with 183 μl (1.17 mmol) of (trifluoromethyl)trimethylsilane and then with 39 μl (39 μmol) of a 1M solution of tetra-n-butylammonium fluoride in THF. The cooling bath was removed and the mixture was stirred at RT overnight. Following addition of 2 ml of 1N hydrochloric acid, it was stirred for a further 30 min. The THF was removed on a rotary evaporator and the product was purified by preparative chromatography (Method 10). This gave 168 mg (47% of theory) of the title compound as a diastereomer mixture (ratio about 3:2)
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28]1([S:34][CH2:35][C:36](Cl)=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34][CH2:35][C:36]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(Cl)CSc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
To a stirred mixture of 5.89 g of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (see U.S. Pat. No. 3,534,019) and 2.8 ml of triethylamine in 50 ml of cold (ca. 0° ) dichloromethane was slowly added 3.8 g of the title product of Example 1. The mixture was then stirred for twenty hours at room temperature. The solution was then washed three times with 50-ml portions of water, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound, m.p. 172°-175°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>ClCCl>[N:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: O=C(Cn1ccnc1)OCc1ccccc1
Yield: 89.6 %

Procedure:
A solution of 1.4 g (21 mmol) of imidazole and 1.0 ml (6.3 mmol) of benzyl 2-bromoacetate in 40 ml of dichloromethane was stirred at ambient temperature for 16 h. The resulting solution was washed with water, dried over Na2SO4, and concentrated in vacuo. Silica gel chromotography of the residue using 5% methanol in chloroform provided 1.22 g (89%) of the desired compound as an oil. 1H NMR (CDCl3) δ 4.73 (s, 2H), 5.21 (s, 2 H), 6.96 (t, J=1 Hz, 1H), 7.11 (t, J=1 Hz, 1H), 7.36 (m, 5H), 7.51 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]([CH3:43])[CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (240 mg, 56%).
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3]1.[I:12]I.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N>[I:12][C:5]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][NH:2][CH:6]=1
Reactant: CCOC(=O)c1ccn(C)n1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 80 °C
Reaction time: 1 h
Yield: 166 %

Procedure:
To a stirred solution of ethyl 1-methyl-1H-pyrazole-3-carboxylate (5 g, 32.4 mmol) in CH3CN (200 mL) under Ar was added I2 (4.94 g, 19.46 mmol) and after 5 min CAN (10.67 g, 19.46 mmol). The reaction mixture was stirred for 1 hr at 80° C., concentrated, quenched with a 10% aq. Na2S2O3 solution, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 25-45%) to afford the title product (9.04 g, 32.3 mmol, 100% yield) as a white solid. tR: 3.78 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 281 [M+H]+ (LC-MS 2); Rf=0.45 (hexane/EtOAc 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29](O)=[O:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1ccnc(Cl)c1
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3ccnc(Cl)c3)cc1-2

Procedure:
This material was prepared from Example 244 (8-amino-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide) and 2-chloroisonicotinic acid by the method described for Example 246 step 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:43]3[CH2:45][CH2:44]3)=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:43]3[CH2:44][CH2:45]3)=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (318 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6](Cl)=[O:7])#[N:2].O[NH:18][C:19](=[NH:39])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[C:25]2[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:18]=[C:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:39]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)#[N:2]
Reactant: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(C#N)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
A solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D25; 54.2 mg, 0.23 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 68.9 mg, 0.219 mmol) and triethylamine (0.048 ml, 0.345 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (40 ml) and ethyl acetate (3×25 ml), and the combined organic layers washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil which was purified by flash chromatography on silica gel, eluting with 0-40% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (36 mg)
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][C:41]1[CH:42]=[C:43]([N:48]=C=O)[CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[CH:42]=[C:43]([NH:48][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1cc(C)cc(C)c1
Yield: 2.4 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio} methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 3,5-dimethylphenyl isocyanate as described in Example 16 in a 2.4% yield; ESMS, (M+1)+474.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>CCOC(C)=O>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Cl)CC1
Reactant: NCc1ccccc1OC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Cl)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The above {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (97 mg, 0.26 mmol) was dissolved in 2-trifluoromethoxy-benzylamine (2.5 mL) and the mixture was heated to 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl solution. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured into 10% NaHCO3 and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 97 mg (87%) of the title compound, m/z 430.5 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH2:34]([NH2:36])[CH3:35]>O>[CH2:34]([NH:36][C:31]([CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:20][CH:19]=2)[CH2:25]1)=[O:33])[CH3:35]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: CCN
Solvent: O
Product: CCNC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Yield: 63 %

Procedure:
As described for example 8b, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted, using ethylamine (1 M in DMF) instead of methylamine, to the title compound (47 mg, 63%) which was obtained as an off white solid after trituration with water. MS: m/e=478.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].[C:12]([O:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:23](O)[CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:26]2[CH:27]=[C:21]([O:20][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:23][CH:25]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(CCOc2cccc(OC(=O)c3ccccc3)c2)nc1
Reaction time: 1 h

Procedure:
To a solution of 2-(5-ethyl-pyridin-2-yl)-ethanol (480 mg, 3.17 mmol, example 69) in THF (10 mL) is added resorcinol monobenzoate (630 mg, 2.94 mmol), triphenylphosphine (850 mg, 3.24 mmol) and diethyl azodicarboxylate (510 μL, 3.24 mmol). The resulting mixture is stirred for 1 h then concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate in hexane) to give the title compound as a yellow oil. MS (ESI) 348 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)(=[O:26])=[O:25])[C:20]=1[O:21][CH3:22])[C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7].F[C:38](F)(F)[C:39]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:38]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])[C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:39]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3,4-Dimethoxy-5-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[3,4-dimethoxy-5-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: O=Cc1cccnc1
Product: Clc1cc2c(NC3CCN(Cc4cccnc4)CC3)ncnc2s1

Procedure:
The title compound was prepared (338 mg, 94%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (341 mg, 1.0 mmol) and 3-pyridinecarboxaldehyde (107 mg, 1.0 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (dd, 1H), 8.43 (s, 1H), 7.68-7.65 (m, 1H), 7.29 (d, 1H), 7.02 (s, 1H), 5.14 (d, 1H), 4.21-4.17 (m, 1H), 3.54 (s, 2H), 2.88 (d, 2H), 2.43 (t, 2H), 2.10-2.07 (m, 2H), 1.62-1.52 (m, 2H); MS (ESI) m/z: Calculated: 359.88; Observed: 360.2 (M++1).