Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]([C:20]([OH:22])=O)[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[OH:42].O>CN(C)C=O>[OH:42][CH:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[NH:36][C:20]([C@H:11]1[CH2:12][C@H:13]2[C@H:8]([CH2:7][C:6]3[C:19]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[N:9]([CH3:23])[CH2:10]1)=[O:22]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@H](C(=O)NC3CCCC3O)CN(C)[C@H]1C2
Reaction time: 4 h

Procedure:
To a suspension of 6.24 g of 1-isopropyl-6-methylergoline-8-carboxylic acid in 120 ml of dimethylformamide under a nitrogen atmosphere were added 3.2 g of 1,1'-carbonyldiimidazole. After stirring for approximately four hours, a solution of 2.02 g of trans-2-aminocyclopentanol in 40 ml of dimethylformamide was added with stirring. After stirring at room temperature overnight, the mixture was added to water. The resulting precipitate was extracted three times into methylene chloride. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was purified by preparative high pressure liquid chromatography over silica gel eluting with methylene chloride/methanol/ammonium hydroxide (100:10:1). The appropriate fractions containing the more mobile diastereomer were combined, concentrated to dryness, and crystallized from methanol to provide 1.15 g of the desired title isomer, m.p. 260-263° C. NMR, MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][OH:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cl
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Yield: 91 %

Procedure:
A solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, 5.00 g), hydroxylamine hydrochloride (1.30 g) and concentrated hydrochloric acid (1 mL, 1.05 g) in MeOH (37.5 mL) was stirred at 70° C. for 4 h. After cooling, the mixture was evaporated from all volatiles and partitioned between MTBE and water. The organic layer was separated and dried. Chromatography over silica gel yielded the title compound (4.70 g, 91%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>CCOC(C)=O>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([CH2:32][N:7]2[C:6]([CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:10][N:9]=[CH:8]2)=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Trityl-imidazole-4-propionic acid methyl ester (2.15 g, 5.42 mmol) and 4-bromomethyl-2-fluoro-benzonitrile, as described above in Step D, (1.16 g, 5.42 mmol) were dissolved in EtOAc (20 mL) and heated at 60° C. for 3 h. The precipitated solid was filtered off, and the filtrate was concentrated to 10 mL then heating at 60° C. was continued overnight. The precipitate was collected and combined with the first solid and heated at reflux in CH3OH (20 mL) for 5 h. The reaction mixture was concentrated to dryness and triturated with hexane to remove triphenylmethane. The residue was dissolved in THF (10 mL)-H2O (5 mL), treated with 1 N NaOH (5 mL) and stirred at ambient temperature for 16 h. The reaction mixture was neutralized with 1N HCl (5 mL), concentrated to remove the THF, then lyophilized to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@H:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C@H:14]1[C:35]([OH:37])=[O:36].[OH-].[Li+].[CH3:40]COC(C)=O.CCCCCC>>[CH3:40][O:36][C:35]([C@H:14]1[C@H:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][OH:1])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@@H:15]1[C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)=[O:37]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2

Procedure:
This intermediate was isolated by flash column chromatography (SiO2, EtOAc/Hexane=30/70) of a sample of the crude reaction mixture from the preparation of (1S, 2R, 3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylic acid described above prior to the saponification with lithium hydroxide.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.CC(=O)OCC>CN1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: Fc1cc2[nH]nc(Br)c2cc1F
Reactant: O=C([O-])[O-]
Agent: CN1CCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1nc(Br)c2cc(F)c(F)cc21

Procedure:
To a light brown suspension of 3-bromo-5,6-difluoro-1H-indazole (1.0 g, 4.29 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in N-methylpyrrolidine (20 mL) was added iodomethane (0.81 mL, 12.9 mmol) at room temperature. The resulting dark brown solution was stirred for 15 h at room temperature under nitrogen atmosphere by which time the TLC (2:1, Hex:EA, Rf=0.6, major and 0.4, minor) indicated the presence of the desired compound. The reaction was diluted with water (˜100 mL), the organic compound was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine solution. After drying over MgSO4, the filtrate was concentrated to obtain the crude light brown solid which was purified by chromatography using an ISCO (80 g) column eluting with hexanes (1 min), 0-15% EA in hexanes (2 min), 15-40% EA in hexanes (15 min) to obtain 746 mg (70%) of 3-bromo-5,6-difluoro-1-methyl-1H-indazole as a white solid and 186 mg (18%) of 3-bromo-5,6-difluoro-2-methyl-2H-indazole as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:36]4[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and 1-methanesulfonyl-piperazine (72 mg, 0.436 mmol) gave 7-cyclopentyl-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (97 mg, 46%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/DCM].
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]
Reactant: Cc1nc(Cc2ccccc2)c(=O)n(CCO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cc2ccccc2)c(=O)n(CCCl)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml), and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K2CO3, the resulting aqueous layer being twice extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain compound 613 (1.00 g, yield: 87.5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[C:52](=[O:53])[N:25]2[C:26]([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]12.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([NH:22][C@@H:23]2[C:52](=[O:53])[N:25]3[C:26]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]23)=[O:17])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)C=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=CC(C)C)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoic acid (1.56 g), diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g), and N-methylmorpholine (2.0 ml) in dichloromethane (50 ml) is added diphenylphosphoryl chloride (1.27 g) at -30° C. After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed, dried, and purified by chromatography give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g). Yield: 73%.
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.O1CCCC1>[OH:28][CH2:27][CH2:29][NH:30][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 53.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with ethanolamine (0.094 g) and the mixture was refluxed for 48 hours. The solvents were removed by evaporation and the residue was purified by HPLC (ethyl acetate-methanoltriethylamine; 95:5:2) followed by crystallization from tetrahydrofuran-ethyl alcohol to give 0.29 g of N-(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][C:13]([OH:15])=[O:14].[CH2:20]([Mg]Br)[CH2:21]CCCC>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Reactant: CCCCCC[Mg]Br
Product: CCCCCCC(CC(=O)O)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 42a, but using hexylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](#N)[CH3:10]>>[CH2:5]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:9][CH3:10]
Reactant: Nc1ccccc1N
Reactant: CC#N
Product: CCCCCCCCNc1ccccc1N

Procedure:
Into 500 ml of acetonitrile was suspended 50.9 g (0.1 mol) of the phenylenediamine derivative obtained in the foregoing process (2) in an atmosphere of nitrogen. The suspension was cooled with ice to 5° C. or lower where it was then kept. To the suspension was then added 55.8 ml (0.4 mol) of triethylamine. To the reaction mixture was then added dropwise 11.5 g (0.1 mol) of thiophosgene while the temperature of the reaction system was being controlled to lower than 10° C. After completion of the dropwise addition, the temperature of the reaction solution was gradually returned to room temperature. The reaction solution was then allowed to undergo at the same temperature for 2 hours. To the reaction solution was then added a mixture of ethyl acetate and water. The reaction solution was then subjected to separation. The organic phase thus extracted was dried, and then concentrated to obtain 29.4 g of a crude reaction product in the form of oil. The crude reaction product was then purified through a column filled with a 1/5 mixture of ethyl acetate and hexane to obtain 12.6 g (0.048 mol) of the desired benzimidazole (yield: 48%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3C=CC=CC=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCCBr>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][CH2:21][NH:27][C:15]=3[CH:14]=2)=[O:30])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
Steps 5 and 6. A solution of 4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester (26 g, 63 mmol) in DMF (2644 mL) was treated with 10% palladium on carbon (5.3 g). The reaction vessel was evacuated and filled with hydrogen. The mixture was stirred at room temperature for 4 hours, then the catalyst was filtered, washing with a small quantity of dimethylformamide. The resulting solution, containing crude 4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester, was concentrated to a volume of 300 mL, and treated with K2CO3 (34.1 g, 247 mmol) and 1,2-dibromoethane (46.4 g, 247 mmol). The resulting mixture was warmed at 70° C. and stirred for 18 hours. The mixture was then concentrated to a volume of 100 mL and diluted with ethyl acetate and water. The organic phase was separated, washed three times with water, dried over sodium sulfate and evaporated. The residue was taken up in methanol and sonicated. The white solid was filtered, yielding pure 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (8.6 g). The filtrate was evaporated and the residue purified by flash chromatography (toluene/acetonitrile gradient) providing further 2 g of material. 4-[(3,4-Dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester was thus obtained as a white solid, 10.6 g (52%), MS (ISP): m/e=327.0 (M+H+.); δH (300 MHz; d6-DMSO) 10.27 (1H, s), 7.92 (4H, s), 7.16-7.19 (2H, m), 6.75 (1H, d), 6.04 (1H, s), 4.29 (2H, q), 4.19 (2H, s), 3.32 (2H, s), 1.32 (3H, t).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:35]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:37]([NH:36][C:34]1[CH:35]=[C:30]([NH:29][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)[CH:31]=[CH:32][C:33]=1[O:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cc(N)ccc1OCCN1CCCC1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cc(Nc2ncc(C(N)=O)c(NCc3cccc(F)c3)n2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (57 mg, 0.15 mmol) in NMP (0.6 mL) was added N-(5-amino-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (47 mg, 0.18 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamido-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (46 mg). MS found for C26H30FN7O3 as (M+H)+ 508.5. λ 248.5.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=3)[CH2:38][CH2:37]2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 34 %

Procedure:
Prepared in analogy to example 1 (b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example A27) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a brown solid (yield 34%). MS (m/e): 473.4 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])C.CO.Cl>[OH-].[Na+].CCOC(C)=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[C:12]([Cl:18])[CH:13]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a 250 mL round bottom flask was added 1-(4-Bromo-2-chloro-phenyl)-2-(2-chlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (3.60 g, 8.18 mmol), MeOH (65 mL), and IN aq NaOH (41 mL). The reaction solution was allowed to stir at 50° C. for 2 hr. The reaction solution was diluted with EtOAc (200 mL), neutralized by the addition of aq 1 N HCl, and poured into a separatory funnel. The organic phase was partitioned, and the aqueous phase was and extracted with EtOAc (150 mL×2). The combined organic phases were dried over Na2SO4, filtered into a round bottom flask and concentrated on the Rotavapor. The crude residue was reprecipitated in an EtOAc/hexane solution and the solid precipitate was filtered under vacuum to afford 2.98 g (88% yield) of title product. MS (ESI) 410.3, 412.3, 414.3 [M+H]+.
Reaction SMILES: [NH2:1]C1C=CN=CC=1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[C:16](=[O:17])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of 4-aminopyridine (2.00 g, 21.2 mmol) in CH2Cl2 (30 mL) at 0° C. was added triethylamine (3.50 mL, 25.0 mmol) and benzyl chloroformate (3.10 mL, 22.0 mmol). The ice bath was removed and the resulting mixture was allowed to warm to rt overnight before being poured into saturated aqueous NaHCO3. The product was extracted with CH2Cl2, dried (Na2SO4) and concentrated. The crude product was recrystallized from EtOAc to give 2.90 g (60% yield) of pure benzyl carbamate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
A mixture of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 2.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was treated with lithium hydroxide monohydrate (0.12 g, 2.85 mmol). The reaction was stirred at 25° C. for 2.5 h. At this time, the reaction was diluted with water (75 mL) and extracted with diethyl ether (1×75 mL). The aqueous layer was acidified with a 2N aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo to afford (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 90%) as a light orange solid: HR-ES-MS m/z calculated for C16H17NO4FCl [M+H]+ 342.0903, observed 342.0904; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 1.35-1.56 (m, 1H), 1.56-1.70 (m, 1H), 1.72-1.86 (m, 1H), 4.19 (d, J=18.2 Hz, 1H), 4.29 (d, J=18.2 Hz, 1H), 4.63 (dd, J=11.5, 4.3 Hz, 1H), 5.05 (s, 1H), 7.33 (td, J=8.3, 1.4 Hz, 1H), 7.49-7.55 (m, 1H), 7.57 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 12.92 (br. s., 1H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=[O:12].[N-]=C=O>C1C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[O:12])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1I
Agent: [N-]=C=O
Solvent: c1ccccc1
Product: Cc1cc(NC(=O)Nc2cccc(C(F)(F)F)c2)ccc1I
Temperature: 90 °C

Procedure:
To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group discussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification.