Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NC1CCC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclobutylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21]C(C)(C)C)=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([OH:21])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(=Cc2cnn3c(Nc4cccc(C(=O)O)c4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Tert-butyl 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (97 mg, 0.2 mmol) was dissolved in 2 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour. Excess solvent and TFA were removed by evaporation under a stream of nitrogen. The residue was diluted with water then the mixture was filtered. The product, 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoic acid, was collected as a solid in 85% yield. LCMS (M+1=490)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:17])[CH2:9][CH:10]2[S:14][C:13](=[NH:15])[NH:12][C:11]2=[O:16])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[CH2:23]Br.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH:25]([CH2:23][C:3]1[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([NH:7][C:8](=[O:17])[CH2:9][CH:10]2[S:14][C:13](=[NH:15])[NH:12][C:11]2=[O:16])[S:6][C:2]=1[Br:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(NC(=O)CC2SC(=N)NC2=O)sc(Br)c1CBr
Product: CCOC(=O)c1c(NC(=O)CC2SC(=N)NC2=O)sc(Br)c1CNc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To ethyl 5-bromo-4-(bromomethyl)-2-{[(2-imino-4-oxo-1,3-thiazolidin-5-yl) acetyl]amino}thiophene-3-carboxylate (25 mg, 0.05 mmol) in N,N dimethyl formaide (1 mL) was added aniline (10 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was concentrated and purified by reverse phase column to yield ethyl 4-(anilinomethyl)-5-bromo-2-{[(2-imino-4-oxo-1,3-thiazolidin-5-yl)acetyl]amino}thiophene-3-carboxylate (5.0 mg, 20% yield).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([C:13]#N)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-:17].[K+]>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:13](=[O:17])[C:4]=2[CH:3]=1
Reactant: N#Cc1ncccc1Oc1ccc(Br)cc1
Reactant: [OH-]
Agent: [K+]
Product: O=c1c2cc(Br)ccc2oc2cccnc12
Temperature: 190 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(4-bromophenoxy)picolinonitrile (57 g, 207 mmol) and 300 g of PPA was stirred at 190° C. for 2 h, followed by 180° C. overnight. After cooling to RT, the reaction mixture was poured into 500 g of ice water. After the PH was adjusted to 7 with KOH, the suspension was filtered. The solid was washed with large excess of water, followed by washing with methanol and acetone. The resulting solid was air dried to give 8-bromo-10H-chromeno[3,2-b]pyridin-10-one as a tan solid with >90% purity. The material was carried on to the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.CCCCCCC.CCOCC.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[O:17][CH2:16][CH2:15][O:6]1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCCCCCC
Product: COc1ccc(C2(CCCCl)OCCO2)cc1
Temperature: 25 °C

Procedure:
A solution of 20.0 g (94.0 mmol) of 4-chloro-1-(4-methoxyphenyl)-1-butanone (origin: Acros), 19 ml of ethylene glycol and ca. 1 g of p-toluenesulfonic acid in 120 ml of toluene was heated under reflux with azeotropic removal of water for 16 h. After cooling down to room temperature, ether was added and the organic phase extracted with a saturated solution of NaHCO3 (2×), washed with water (2×), dried (Na2SO4) and concentrated in vacuo to give 24.6 g (99%) of the crude compound, which was used for further functionalization. Column chromatography of 2 g (SiO2, heptane/ether 9:1) afforded 1.15 g of a slightly yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:75]=[CH:74][C:67]([O:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=1>>[CH3:73][O:72][C:70](=[O:71])[CH2:69][O:68][C:67]1[CH:74]=[CH:75][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 58.8 %

Procedure:
In a manner similar to the method described in Example 5, rac-(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 trifluoroacetic acid prepared in Example 4 (80 mg, 0.138 mmol), was reacted with diisopropylethylamine (89 mg, 0.69 mmol), diphenylphosphinic chloride (80 mg, 0.34 mmol), then reacted with methyl 2-(4-aminophenoxy)acetate (Aldrich, 27 mg, 0.153 mmol) to give rac-(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}-phenoxy)-acetic acid methyl ester (51 mg, 59%). MS (ES+) m/z [(M+H)30]: 628
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=4)[CH2:24][CH2:23]3)=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=4)[CH2:24][CH2:23]3)=[S:51])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2CCN(CCCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=S)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
4-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-butan-1-one (28 mg; 0.049 mmol, prepared in accordance with Example 90) is reacted with Lawesson's reagent (10 mg; 0.024 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (13 mg; 0.023 mmol). The structure was confirmed using Protocol I-B. Calculated mass=592; observed mass=592; HPLC retention time=4.811 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[N:23]1([CH2:22][CH2:21][N:20]([CH2:31][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[CH:7][CH:8]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1coc(-c2ccc(Cc3ccc(OCCNCCN4CCOCC4)cc3)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CN(CCOc2ccc(Cc3ccc(-c4ncco4)cc3)cc2)CCN2CCOCC2)cc1
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of N-[2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]-4-morpholineethanamine (0.25 g, 0.6 mmol) and methyl 4-formylbenzoate (0.11 g, 0.66 mmol) in dichloroethane (5 mL) was stirred as sodium triacetoxyborohydride (0.16 g, 0.74 mmol) was added and stirred for 17 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried and concentrated. Purification by chromatography on silica gel using a gradient of methanol in dichloromethane gave 0.28 g of methyl 4-[[[2-(4-morpholinyl)ethyl][2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]amino]-methyl]benzoate; 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 4H), 7.68 (s, 1H), 7.42 (d, 2H), 7.27 (d, 2H), 7.21 (s, 1H), 7.08 (d, 2H), 6.78 (d, 2H), 4.03 (t, 2H), 3.96 (s, 2H), 3.92 (s, 3H), 3.79 (s, 2H), 3.66 (m, 4H), 2.92 (t, 2H), 2.73 (t, 2H), 2.47 (m, 2H) 2.42 (m, 4H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9](=O)[CH:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[NH:17][N:16]=[CH:15]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](N=[N+]=[N-])(C)C>O1CCCC1>[C:25]([O:24][C:23](=[O:29])[NH:22][CH:10]([C:9]1[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[N:7][N:8]=1)[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[NH:17][N:16]=[CH:15]2)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)NNc2ccccn2)cc2cn[nH]c12
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nnc3ccccn23)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 1-{2-(pyridin-2-yl)hydrazinyl}-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-ylcarbamate (70 mg, 0.17 mmol), triphenylphosphine (54 mg, 0.2 mmol), and trimethylsilyl azide (25 μL, 0.19 mmol) were combined in dry tetrahydrofuran (2.0 mL) at 0° C. Diethylazodicarbaoxylate (33 μL, 0.2 mmol) was added to the reaction mixture to afford a brown solution which was stirred at room temperature for 2 h. The solvents were removed in vacuo and the crude mixture purified by column chromatography to afford 45.2 mg (71%). Mass spec.: 393.04 (MH)+.
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Br:28])[C:7]1=[O:36])=O)C.[OH-].[Na+].CO>>[Br:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:9]1[C:8]2([C:29]3[C:34](=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[NH:6][C:7]2=[O:36])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:12][C:11](=[O:21])[NH:10]1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccccc2Br)N1
Yield: 63.7 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′S,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 0.76 mmol) was reacted with NaOH in methanol (2N, 5 mL, 10 mmol) to give racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)=[CH:3][C:4]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 43.4 %

Procedure:
2-(4-bromo-2-nitrophenyl)isoindoline-1,3-dione (500 g, 1.4 mmol), tert-butyl piperazine-1-carboxylate (402 g, 2.2 mmol), Pd2(dba)3 (66.0 g, 0.07 mmol), Xantphos (83 g, 0.144 mmol) and Cs2CO3 (939 g, 2.9 mmol) were placed in reaction vial (microwave reaction vial 10-20 ml) and purged with nitrogen. Toluene (5.0 ml) was added and nitrogen was bubbled for 10 min. The reaction mixture was heated at 100° C. for 5 hours. Heating was stopped and cooled to rt. The reaction mixture was filtered through a pad of celite and filtrate was evaporated. The remaining material was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (275 mg, yield: 42%). 1H-NMR (400 MHz, CDCl3) δ 1.51 (s, 6H) 3.28-3.39 (m, 2H) 3.57-3.70 (m, 2H) 7.20-7.24 (m, 1H) 7.35 (d, 1H) 7.66 (d, 1H) 7.75-7.87 (m, 1H) 7.96 (dd, 1H)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:8]=1[C:9]1[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:25])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:14]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl.O.C(OCC)(=O)C>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[N:6][N:7]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:8]=1[C:9]1[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:25])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH:14]=1)([CH3:38])[CH3:2]
Reactant: CC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)c(=O)n(C(C)C)c1=O
Reactant: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1c(=O)c(-c2c(C(C)(C)O)cnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of 4-(4-acetyl-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 136) (28.2 mg) in tetrahydrofuran (1.0 ml) was added under ice-cooling methyl magnesium chloride (3.0 M tetrahydrofuran solution, 27.8 μl) dropwise and the resulting mixture was stirred under ice-cooling for one hour. To the resulting mixture was water (1 mL) followed by an addition of ethyl acetate (50 ml), and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(2-hydroxypropan-2-yl)-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (4.3 mg) as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH2:56][N:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:51]3[CH2:55][CH2:54][CH2:53][C@H:52]3[CH2:56][N:57]3[CH2:61][CH2:60][CH2:59][CH2:58]3)=[O:16])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)s1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 57 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 8 mL 37% DMF/dichloromethane using 4-(5-methanesulfonyl-thiophen-2-yl)-benzoic acid, Lithium salt (92 mg, 0.32 mmol), EDC-HCl (92 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol), DIEA (0.14 mL, 0.8 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (45 mg, 0.29 mmol) to give the title compound (60 mg, 57% yield). MS (ES+) 419.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16](I)=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].O.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CN(C=O)C.CS(C)=O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16]([C:26]4[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=4)=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
To 4-hydroxy-3-(5-iodo-4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (200 mg, 0.48 mmol, Example 222) and MgO (58.0 mg, 1.44 mmol) in dioxane (1.25 ml) and DMF (1.25 ml) was added H2O (0.530 ml) and the mixture was stirred for 10 min and then degassed with N2 for 2 min. 4-hydroxyphenylboronic acid (86 mg, 0.62 mmol), Cs2CO3 (344 mg, 1.06 mmol) and Pd(PPh3)4 (28.0 mg, 0.024 mm were added, the vessel flushed with N2, and then stirred at 80° C. for 2 h. The reaction was cooled to rt and overwhelmed with MeOH, filtered and the filtrate was concentrated to give a brown oil. The residue was taken up in DMSO: MeOH (1:1) and purified by reverse phase HPLC to give the title compound (98 mg, 0.26 mmol, 53%) as a light yellow solid MS (ESI) m/z 381.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.51 (s, 3H), 7.28 (d, 1H), 6.83 (d, 1H), 6.79 (s, 1H), 4.09 (m, 1H), 2.22 (s, 1H) and 4-hydroxy-3-(4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (Example 217) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:21]1([C:19]([NH:18][C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[O:20])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]cyclobutyl}carbamate (Intermediate 69, 23.5 mg) in dry dichloromethane (3.5 ml), TFA (159 μl, 2.07 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 2 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (18 mg).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:19][O:20][C:21](=[O:42])[C@H:22]([CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)[NH:23][C:24](=[O:35])[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:26][CH3:27]>>[CH3:19][O:20][C:21](=[O:42])[C@H:22]([CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)[NH:23][C:24](=[O:35])[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:26]([C:16](=[O:18])[C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH3:27]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Reactant: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)C

Procedure:
N-Pivaloyl-L-phenylalanine and N-methyl-L-phenylalanyl-L-histidine methyl ester are treated in the same manner as described in Example 1 to give N-pivaloyl-L-phenylalanyl-N-methyl-L-phenylalanyl-L-histidine methyl ester.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].N#N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C.C(COC)OC>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: N#Cc1ccsc1I
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1ccsc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Degass a solution of 2-iodo-thiophene-3-carbonitrile (20 g, 85 mmol), 4-bromobenzeneboronic acid (18.8 g, 94 mmol), potassium carbonate (26 g, 187 mmol) and tetrakis(triphenylphosphine)-palladium (0) (10 g, 8.5 mmol) in a mixture of anhydrous dimethoxyethane (300 mL) and absolute ethanol (150 mL) with Ar or N2 for 15 min and stir for 12 hours at 80° C. Cool the reaction mixture to room temperature, add water (100 ml) and extract the crude product dichloromethane (3×150 mL). Purification by chromatography (hexane-ethyl acetate 10/1) yields 16.3 g (72%) as a white solid: 1H NMR (CDCl3): δ 7.32 (m, 2H), 7.62 (m, 4H).