Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]([C:7]1[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])=O.C1C=CC=CC=1.FC(F)(F)C(O)=O>>[C:10]([N:9]1[C:8]2[C:7](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:6])[CH:4]1[S:2][CH3:1])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)CC(=O)c1ccccc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CSC1C(=O)c2ccccc2N1C(=O)c1ccccc1
Yield: 68.4 %

Procedure:
2'-[(methylsulfinyl)-acetyl]benzanilide (7 g) is refluxed in benzene containing 1 equivalent of trifluoroacetic acid for 1 hour. The solvents are removed under reduced pressure to give an oil which crystallizes on standing. Recrystallization from ethyl acetate gives 1-benzoyl-2-(methylthio)-3-indolinone (4.5 g 67%) m.p. 126°-128° C.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH2:7][CH2:6][S:5]1)#[N:2].[OH-].[NH4+]>ClCCl>[C:1]([N:3]=[C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: COc1ccc(CN2CCSC2=NC#N)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CN=C1SCCN1Cc1ccc(O)cc1
Reaction time: 12 h
Yield: 0 %

Procedure:
0.49 g (2 moles) of 2-cyanimino-3-(4-methoxybenzyl)-thiazolidine are dissolved in 12 ml of dichloromethane and a solution of 3.01 g (1.14 ml, 13 mmoles) of borotribromide in 5 ml of dichloromethane is added in an argon atmosphere, dropwise. The mixture is stirred for 12 hours and is then alkalized with an aqueous ammonium hydroxide solution, under stirring and cooling. The phases are separated and the organic phase is evaporated. 0.22 g of 2-cyanimino-3-(4-hydroxy-benzyl)-thiazolidine are obtained in a white crystalline form, melting at 175° to 177° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(C)Oc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 94.4 %

Procedure:
Following a similar procedure to that described in Example (1a), 850 mg of 3-nitrophenyl 4-isopropoxyphenyl ketone, 936 mg of 1-(3,5-difluorophenyl)ethylamine, 1.66 ml of triethylamine, 0.39 ml of titanium tetrachloride, 788 mg of sodium cyanoborohydride and 0.26 ml of acetic acid were reacted, to obtain 1.20 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[F:25]C1C=NC=C(F)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: Fc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)ccn1
Temperature: 120 °C

Procedure:
In a 5 ml microwave reaction vessel were dissolved 70 mg (0.29 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (Example 5) and 266 mg (2.31 mmol, 8.0 equiv.) of 3,5-difluoropyridine in 1.5 ml of DMF. Cesium carbonate (376 mg, 1.16 mmol, 4.0 equiv.) was added and the suspension was sonicated under argon for 10 min. The mixture was heated for 72 h at 120° C. in an oil bath and then 1 h at 160° C. under microwave irradiation. The dark brown suspension was filtered over Dicalite which was washed with ethyl acetate. The filtrate was evaporated to dryness in vaccuo, and the residue dissolved in 200 ml of ethyl acetate, which was washed once with brine. After drying over magnesium sulfate and concentration in vaccuo, the residue (90 mg) was purified by flash chromatography (gradient heptane/ethyl acetate 1:1 to 0:1 ) to yield the title compound, light yellow solid, (23 mg, 24%). MS (ISP): m/e=338.1 (M+H+).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH3:15])[O:8][C:7]2[CH:9]=[C:10]([NH2:14])[C:11]([NH2:13])=[CH:12][C:6]=2[O:5]1.[OH-].[K+].C(O[C:21]([S-])=[S:22])C.[K+].C(O)(=O)C>C(O)(C)C.O>[CH3:3][C:4]1([CH3:15])[O:5][C:6]2=[CH:12][C:11]3[NH:13][C:21]([SH:22])=[N:14][C:10]=3[CH:9]=[C:7]2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CC1(C)Oc2cc(N)c(N)cc2O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Yield: 78.1 %

Procedure:
To 18.8 g of 2,2-dimethyl-1,3-benzodioxole-5,6-diamine dihydrochloride in 250 ml of isopropanol were added first a solution of 8.6 g of potassium hydroxide in 25 ml of water and then 13.7 g of potassium ethylxanthate, and the mixture was left to boil at reflux overnight. The mixture was diluted with 250 ml of water, neutralized with glacial acetic acid and suction filtered. There were obtained 12.9 g (78.2% of theory) of 2,2-dimethyl-5H-1,3-dioxolo(4,5-f)benzimidazole-6-thiol with a melting point above 300° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]([O:22]C)=[O:21])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of methyl 4-(4-(trifluoromethoxy)phenylamino)thieno[2,3-d]pyrimidine-6-carboxylate (152 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) was dissolved in THF (4 ml) and H2O (1 mL). The mixture was stirred at 60° C. for 3 h. Acidified with acetic acid resulted brown solid which was collected by filtration. It was then dried in vacuo and used for the next step without any further purification (115 mg, 75% Yield). MS m/z 356.1 (M+1)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3-chlorophenyl)ethylamine (0.63 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.88 g (63%) of the title product:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([I:19])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=O)c(I)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a mixture of 4-benzyloxy-3-methoxybenzaldehyde (10 g), silver trifluoroacetate (11.4 g) and methylene chloride (105 mL) was added iodine (13.1 g) at room temperature. After stirring for 2 hours, the mixture was passed through a layer of Celite (registered mark). The filtrate was washed with an aqueous solution of sodium hydrogen sulfite and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol: water=4:1 to give the title compound (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:42](=[O:43])[NH:41][CH:38]3[CH2:40][CH2:39]3)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: O=C=NC1CC1
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: O=C(NC1CC1)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 48.5 %

Procedure:
Using 7-(2-chloro-4-fluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.18 mmol) obtained in step 5 and cyclopropylisocyanate (0.046 g, 0.549 mmol) instead of ethylisocyanate, and in the same manner as in Example 7, the title compound (0.055 g, 47%) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[O:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])[CH:2]=[CH2:3].[Cl:22]C1C=CC(CO)=CC=1>>[CH2:1]([O:4][C:5]([NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[O:10][CH:9]1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccccc1
Reactant: OCc1ccc(Cl)cc1
Product: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccc(Cl)cc1

Procedure:
was synthesized from allyloxycarbonylamino-β-tert-butyl aspartate by the methods employed by Chapman (Bioorg. & Med. Chem. Lett., 2, pp.6.15-6.18 (1992)) to prepare (3S,2RS)3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran using 4-chlorobenzyl alcohol instead of benzyl alcohol to afford 1.84 g of 2101a as a crystalline solid.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH:14]=[O:15])=[CH:11][C:12]=1[CH3:13])=[O:7])C>CO.O>[CH:14]([C:10]1[NH:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[CH:11]=1)=[O:15]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C=O)[nH]c1C(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
Lithium hydroxide (8.73 g, 36.44 mmol) was added to the 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.32 g, 7.27 mmol) in methanol (27 mL) and water (9 mL). The mixture was stirred at room temperature for over the weekend. The reaction was diluted with water (10 mL), evaporated most of the methanol and washed with ether. The aqueous layer was acidified with 1N HCl (37 mL) to pH=2, extracted with ethyl acetate. Washed with brine, dried and concentrated. The residue was washed with dichloromethane and filtered to give 0.98 g (88%) of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid as a tan solid. 1H NMR (360 MHz, DMSO-d6) δ 12.87 (br s, 1H, COOH), 12.41 (br s, 1H, NH), 9.63 (s, 1H, CHO), 6.74 (s, 1H), 2.26 (s, 3H, CH3).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][S:6]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[Cl:16])(=[O:8])=[O:7])#[N:2].O.[NH2:20][NH2:21]>C(O)C>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([NH:5][S:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])(=[O:8])=[O:7])[N:3]=1
Reactant: NN
Reactant: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Solvent: CCO
Solvent: O
Product: Nc1nc(NS(=O)(=O)c2cc(Cl)ccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.2 %

Procedure:
A mixture of 8.51 g (26.2 mmol) of N'-cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea and 10 ml (10 g, 0.20 mol) of hydrazine monohydrate in 85 ml of ethanol was heated at reflux for 30 minutes. After cooling to room temperature, the solid which separated was collected and suspended in 170 ml of H2O and the suspension was acidified with concentrated aqueous HCl. After stirring the suspension for 4 hours the solid was collected and dried in vacuo to yield 5.10 g (57 percent) of the desired product as a hydrochloride salt, mp 306°-308° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=2)=[CH:11][C:10]=1[CH2:16][C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A mixture of 2-benzyloxy-5-bromophenylacetic acid (261 mg, 0.813 mmol), 4-(trifluoromethoxy)phenyl boronic acid (218 mg, 1.056 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43 mg, 0.057 mmol), potassium carbonate (169 mg, 1.22 mmol), dioxane (4 ml) and water (0.5 ml) was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the solution was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (160 mg, 48.9%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:20]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=2)=[C:19]([NH:18][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:24]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(CO)cc2)c(N)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(CO)cc3)ccnc2n1

Procedure:
The product from Example 2g as a 3.15M solution in ethanol (0.08 mL, 0.25 mmol) was reacted with the product from Example 115b (0.061 g, 0.25 mmol) for 18.5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0195 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.75-1.93 (m, 2H) 2.31-2.42 (s, 3H) 2.91-3.08 (m, 2H) 4.42 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 7.11-7.42 (m, 7H) 7.81 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.98 (d, J=8.82 Hz, 1H) 11.01 (s, 1H); MS (ESI+) m/z 416.2 (M+H)+, (ESI−) m/z 414.3 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:48]=[CH:47][C:43](C(O)=O)=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.C1(P([N:63]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:41]=[CH:42][C:43]([NH2:63])=[CH:47][CH:48]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.5 %

Procedure:
A mixture of 100 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}benzoic acid obtained in Example 48, 44 mg diphenyl phosphoryl azide, 23 mg potassium carbonate, and 4 mL N,N-dimethylformamide was stirred at 80° C. for 6 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed twice with water and then with brine, and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), to give 30 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
Under an atmosphere of nitrogen was added to a solution of {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in dichloromethane (30 mL) at ambient temperature trifluoroacetic acid (4.3 mL, 56 mmol) and stirred for 20 h at this temperature. The reaction mixture was added slowly onto an aqueous solution of sodium carbonate (1M, 60 mL). The organic layer was separated and washed with brine (50 mL). The aqueous layers were extracted with dichloromethane (30 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (1.79 g, 73%) as a light brown oil. MS m/e: 438.3 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][C:27]=4[O:36][CH3:37])=[O:24])[NH:12][C@H:11]3[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:5]2=[CH:4][CH:3]=1.CC[N:46]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23]([C@@H:13]2[NH:12][C@@H:11]([CH2:38][C:39]([CH3:42])([CH3:40])[CH3:41])[C@:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[C@H:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[C:27]([O:36][CH3:37])[CH:28]=1)(=[O:34])[NH2:46]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
To a solution of chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid (0.1 g, 0.17 mmol) prepared in Example 160 in anhydrous DMF (2 mL) were added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), NH4Cl (89 mg, 1.67 mmol), and triethylamine (34 mg, 0.33 mmol) sequentially. The reaction mixture was heated at 80° C. for 3 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoylmethyl-2-methoxy-phenyl)-amide as a off white solid (81 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(Cl)ccc1N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of Compound 35A (1 g) in methanol (30 mL) was added Raney-Ni (0.05 g) and the resulting mixture was cooled at 0-5° C.; 98% hydrazine hydrate (1.5 mL) was dropped in at the same temperature and the suspension stirred at room temperature for 2 h. The catalyst was filtered off and the solvents evaporated in vacuo. The crude was dissolved in dichloromethane (100 mL) and washed with water (60 mL); the organic layer was dried over sodium sulphate and evaporated to dryness affording 0.78 g (90%) of the title product as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 3-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=385.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:35])(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:39]3[CH:40]=[CH:41][C:36]([C:34]([OH:35])=[O:33])=[CH:37][CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1

Procedure:
The title compound was prepared from compound 2b and 4-(tert-butoxycarbonyl)phenylboronic acid pinacol ester using the methods described in Example 1, Step G, followed by the deprotection of the resulting product with TFA using the methods described in Example 6, Step B. Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H23N5O3: 478.2 [M+H]. found 478.1.