Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[N:19]=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[C:21]=1[F:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc(NC(=O)C2CC2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc(NC(=O)C2CC2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-4-yl]carbamate (4, 0.89 g, 2.25 mmol) in dichloromethane (20 mL), trifluoroacetic acid (20 mL, 2.25 mmol) was added at 0° C. and stirred the reaction mass at room temperature for 16 h. After completion the reaction, trifluoroacetic acid was distilled and the crude compound was basified with liquid ammonia. The solid precipitated out was filtered and dried to afford N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide (5) as off white solid. Yield: 0.4 g, 90%; MS (ESI) m/z 197.06 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.99 (s, 1H), 7.16 (s, 2H), 7.04 (s, 1H), 2.06 (m, 1H), 0.82-0.78 (m, 4H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@H:41]([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:2]([NH:1][C:42](=[O:43])[C@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[CH3:45])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 100.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (279 mg) were used, whereby tert-butyl (2R)-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate (832 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (460 mg) was yielded.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]([O:19][CH3:18])=[O:21])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1

Procedure:
The procedure described in Example 3 is followed. Starting from 1.5 g (4.88 mmol) of 5-bromo-2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine, obtained according to the protocol described in Examples 1.3 or 2.3, 1.05 mg (5.83 mmol) of 3-methoxycarbonylphenylboronic acid, 4.6 g (14.61 mmol) of caesium carbonate, 0.400 g (0.49 mmol) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and 20 ml of a THF/water (9/1) mixture and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (9/1), 1.6 g (90%) of the expected product are obtained in the form of a yellow-white powder.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccccc4)cc3)nc2c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 2-(4-benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide (Example 3, 18 mg, 0.05 mmol) in anhydrous methanol (2.0 mL) was added sodium borohydride (2.0 mg, 0.05 mmol) in one portion. The reaction mixture was stirred under N2 for 1 h. The solvent was removed under reduced pressure, and the residue was re-dissolved in 1:1 ethyl acetate/H2O (40 mL). The solution was washed with H2O (20 mL) then brine (20 mL) and dried (Na2SO4). Solvent was removed under reduced pressure, and purification by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 15 mg (83%) of the title compound. TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.13. HPLC (Method A): Rt=6.36. MS (ESI+): mass calculated for C21H17N3O2, 343.1; m/z found, 344.1 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.17 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.82-7.80 (dd, J=8.4, 1.4 Hz, 1H), 7.63 (br d, J=6.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.42-7.40 (dd, J=8.5, 1.4 Hz, 2H), 7.32 (t, =J=7.5 Hz, 2H), 7.26-7.22 (m, 1H), 5.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5].CN(C)C=O.[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]([N:6]([C:23](=[O:24])[CH2:22][Cl:21])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5])=[O:15]
Reactant: COC(=O)C(C)Nc1c(Cl)cccc1Cl
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: COC(=O)C(C)N(C(=O)CCl)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
18.4 g of α-(2,6-dichloroanilino)-propionic acid methyl ester, 1 ml of dimethylformamide and 100 ml of chlorobenzene are heated to 100° (internal temperature). An addition is made dropwise at this temperature, with stirring, of 8 ml of chloroacetyl chloride. After the evolution of HCl has ceased, stirring is maintained for 1 hour at 130°-140° bath temperature. The reaction mixture is allowed to cool to room temperature, the solvent is removed in a rotary evaporator, and the yellow oil remaining as residue is crystallised from diisopropyl ether. There is obtained 16 g of final product having a melting point of 82°-85° (Compound No. 10).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[K+].Cl>CC(N(C)C)=O.CO>[N+:18]([C:14]1[CH:13]=[C:12]([NH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=2)=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Yield: 96 %

Procedure:
Into a 10 l flask fitted with an inlet tube for nitrogen, a mechanical stirrer, a dropping funnel, and a thermometer were introduced at room temperature 500 g (1.66 moles) of methyl-4-(m-nitrophenylcarbamoyl)benzoate in 4 l of dimethylacetamide. To the yellow solution there was added dropwise with stirring and cooling a solution of 231 g (85%) of KOH (3.5 moles) in 1 l of methanol. Subsequently, the orange solution was stirred for another hour at 60° C. Next, the reaction mixture was acidified with a dilute solution of hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried in vacuo. Obtained were 457 g of the envisaged product with a melting point of 319° C. (DSC) in a yield of 96%.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:32]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To dry dimethylformamide (DMF) (15 ml) was added 0.84 g (21 mmol) of sodium hydride (60% oil dispersion), and then 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate was added portionwise thereto under ice-cooling. After stirring at room temperature for 10 minutes, 6.65 g (24 mmol) of bromotetradecane was added dropwise under ice-cooling. The mixture was stirred for 3.5 hours at room temperature, and then 30 ml of water was added thereto. The resulting mixture was extracted with 70 ml of ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent, the remaining oil was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20-1/10) to obtain 6.33 g (89.0% yield) of ethyl 1-tetradecylpyrrole-3-carboxylate as white crystals, m.p. 32°-33° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]3[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[CH2:17][N:16]1[C:15]2[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=2[N:9]=[C:8]1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c(=O)c2c(nc(-c3cccc(N)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2nc3c(c(=O)n(C)c(=O)n3C)n2Cc2c(F)cccc2Cl)c1
Reaction time: 1.5 h
Yield: 14.6 %

Procedure:
A solution of 8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (25 mg, 0.06 mmol) in 255 μL CH2Cl2 was treated with acetic anhydride (6.6 μL, 0.07 mmol). The reaction was stirred for 1.5 hr and then blown dry under nitrogen. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (3:1) to give 4 mg (15% yield) of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) 7.67-7.61 (m, 2H), 7.36-7.26 (m, 2H), 7.21-7.15 (m, 1H), 7.13-7.01 (m, 2H), 6.84-6.75 (m, 1H), 5.86 (s, 2H), 3.62 (s, 3H), 3.38 (s, 3H), 2.97 (s, 3H); MS (ESP+) m/e 456 (MH+); TLC (EtOAc:hexanes/3:1) Rf=0.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(O)[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=[CH2:14].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C.O>[CH3:10][O:11][CH:12]1[CH2:13][CH2:14][C:6]2[C:16](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:15]1
Reactant: COc1cccc(O)c1
Reactant: C=CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)OC(OC)CC2
Reaction time: 3 h
Yield: 34.5 %

Procedure:
A 500-milliliter flask fitted with a dropping funnel was charged with 12.4 g of 3-methoxyphenol, 0.2 g of p-toluenesulfonic acid monohydrate and 100 ml of diethyl ether for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 14.3 g of acrolein dimethyl acetal under room temperature. After the dropwise addition, the solution was stirred for 3 hours while being cooled with ice. The reaction solution was alkalized with the addition of 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water. Subsequently, 200 ml of diethyl ether was added thereto for extraction. Thus obtained organic layer was washed with 30 ml of water, the diethyl ether was removed by distillation in vacuo therefrom, and the resulting residue was purified by distillation to obtain 6.7 g of a colorless liquid (yield 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]#[N:17])([CH2:14][CH3:15])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O.[OH-].[Na+]>C(O)(=O)C>[CH3:15][CH2:14][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:16](=[O:18])[NH:17][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: CCC(C#N)(CCC(=O)O)c1ccc(N)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@]1(c2ccc(N)cc2)CCC(=O)NC1=O
Temperature: 60 °C
Yield: 97 %

Procedure:
4-(4-Aminophenyl)-4-cyanohexanoic acid (Example 9; 1.8 g, 7.7 mmol), enriched in the (R)-enantiomer, was dissolved in glacial acetic acid (6.0 ml) contained in a 25 ml round-bottomed flask. The resulting mixture was heated to 60° C. with the aid of an oil bath followed by dropwise addition of conc. H2SO4 (3.0 ml). The solution was then heated to 100° C. and maintained there for 30 minutes before pouring onto ice (100 g). The pH is adjusted to 6 using 5M NaOH followed by extraction with dichloromethane (3×200 ml). The extracts were pooled, dried (over MgSO4) and concentrated under reduced pressure, giving (R)-aminoglutethimide (1.75 g, 97%) as a brown oil. Chiral HPLC analysis (Chiralcel OJ column; mobile phase 1:1 n-heptane-isopropanol) indicated an ee of 78%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=O.C([BH3-])#N.[Na+].Cl>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]3[CH3:33])[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: CC1CCCCC1=O
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCC1N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)C1
Yield: 157.5 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclohexanone (0.12 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded, after treatment with HCl, 82 mg (80%) of the title compound as the hydrochloride salt.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(OP([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:31](O)[CH2:32][O:33][C:28]=2[CH:27]=1.O>C1COCC1>[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH:31]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:32][O:33][C:28]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2OCC1O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)OC(C)(C)C
Yield: 106.6 %

Procedure:
A 1 M solution of LiHMDS (23.0 mL, 23.0 mmol) in THF was a added dropwise to a solution of ethyl 2-(diethoxyphosphoryl)acetate (4.57 mL, 23.0 mmol) in THF (30 mL) at 0° C. under nitrogen and the resulting mixture was stirred for 10 min where after tert-butyl 7-chloro-3-hydroxy-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 17, 3.29 g, 11.5 mmol) dissolved in THF (30 mL) was added dropwise at 0° C. The reaction mixture was stirred under nitrogen at rt for 1 h where after water (100 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried by passage through a phase separator and concentrated giving crude the title compound (4.36 g, 106%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[N:11]2)=[CH:5][CH:4]=1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH:28][C:38]([NH:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])=[CH:26][CH:25]=3)=[N:11]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(N)cc3)n2)cc1
Product: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(NC(=O)Nc4ccccc4)cc3)n2)cc1

Procedure:
Following the procedure described in Example 1 with crude 4-[1-{[4-(methyloxy)phenyl]methyl}-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and phenyl isocyanate provided the title product. ESMS [M+H]+: 515.4
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](/C=C/C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](CCC(=O)OC(C)(C)C)CC2)cc1

Procedure:
0.150 g of ethyl trans-4-[4-((E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoate (0.42 mmol, 1 eq.) is dissolved in 15 mL of ethanol in a Parr bottle. 0.044 g of 10% palladium-on-charcoal (0.04 mmol, 0.1 eq.) is added and the medium is subjected to 50 psi of hydrogen for 5 hours. The medium is filtered through Whatman paper, washed with ethanol and evaporated to give 0.19 g of ethyl trans-4-[4-(2-tert-butoxycarbonylethyl)cyclohexyl]benzoate.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[CH2:11]>>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:11]=[CH:10]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C=Cc1ccccn1
Product: Nc1ncc(Cl)cc1/C=C/c1ccccn1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and 2-vinylpyridine. Purification by column chromatography on silica gel eluting with methylene chloride—methanol (95:5) and repeated using hexane—EtOAc (70:30 to 50:50) as eluant gave a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[CH:26][C:27](O)=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[CH:26]/[C:27]3[NH:1][C:2]4[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=4[N:8]=3)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCCO4)nc2n(CC)c1=O
Yield: 50.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.85 g (14.4 mmol) of 5,6-diamino-1,3diethyluracil and 2.70 g (13.1 mmol) of 3-(1,4-benzodioxan-6-yl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.45 g (yield 51%) of Compound 80 as a pale yellow powder.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23]([O:25]C)=[N:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23](=[O:25])[NH:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]c(=O)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)-2-methylpentanoate, intermediate 19, (171 mg, 0.38 mmol) in dioxane (6 mL) is added 4 M HCl in dioxane (0.25 mL, 1.00 mmol). The crude is stirred at room temperature for 5 hrs. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3-dihydrothiazole-5-carboxamido)pentanoate (57 mg). HPLC retention time=1.80 minutes (condition A), MS 439.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=7.1 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.67 (ddd, J=14.0, 10.0, 3.5 Hz, 1H), 1.85-2.03 (m, 1H), 2.51-2.69 (m, 1H), 2.77-2.91 (m, 1H), 2.93-3.05 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.26-4.42 (m, 1H), 5.97 (d, J=8.1 Hz, 1H), 7.17-7.29 (m, 2H) 7.29-7.37 (m, 1H) 7.42 (t, J=7.6 Hz, 2H) 7.53 (d, J=7.8 Hz, 2H) 7.57 (d, J=8.1 Hz, 2H) 9.46 (br. s., 1H).
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:20]O>>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([O:13][CH3:20])=[O:12])([O-:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 99 %

Procedure:
SOCl2 (3.4 ml, 5.61 g, 47.1 mmol, 5 eq) was added dropwise to a stirred solution of 3,5-dinitrobenzoic acid (2.0 g, 9.43 mmol, 1 eq, Aldrich) in 20 ml anhydrous MeOH at 0° C. under Ar. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 2.12 g (9.38 mmol, 99% yield) of methyl 3,5-dinitrobenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14](Cl)(=[O:16])=[O:15].Cl.[CH3:19][O:20][C:21](=[O:34])[C@@H:22]([NH2:33])[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26]>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C@@H:22]([NH:33][S:14]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:2]=1[CH3:1])(=[O:16])=[O:15])[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Reactant: Cc1c(-c2cccnc2)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(-c2cccnc2)c1C
Reaction time: 16 h

Procedure:
Intermediate 75 (0.85 g, 3.17 mmol) was dissolved in 10 ml DCM and TEA (1.55 ml, 11.11 mmol). Intermediate 76 (876 mg, 3.33 mmol) in 10 ml DCM was slowly added at 0° C. and the reaction was stirred for 16 h. After that the solution was evaporated to dryness and purified by silica gel chromatography (cyclohexane/AcOEt from 0% to 100% AcOEt). Yield: 589 mg, 38%