Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>C(#N)C>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1cccc(Br)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 1-bromo-3-fluorobenzene
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.ClCCl.[CH3:25][N:26](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C(OCC)(=O)C>[C:25]([C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)#[N:26]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(C#N)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.11 g, 0.38 mmol), zinc cyanide (45 mg, 0.38 mmol), zinc (5 mg, 0.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (14 mg, 0.019 mmol), and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. under argon for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (10 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 3-(6-cyanopyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (70 mg, 0.24 mmol, 63% yield) as a colorless solid. MS found: (M+H)+=295.27.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:20][C:19]([N:36]=[C:37]=[O:38])=[C:18]([F:39])[CH:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([F:39])[C:19]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N=C=O)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To ethyl 3-amino-4,4,4-trifluorocrotonate are added N,N-dimethylformamide and sodium hydride and the mixture is stirred at 0° C. Thereafter, to the reaction solution is added a mixture of 4-chloro-2-fluoro-5-{2-(ethoxycarbonylmethoxy)phenoxy}phenyl isocyanate [Intermediate compound A12-23] and N,N-dimethylformamide, and the mixture is stirred at room temperature. The reaction solution is poured into a mixture of hydrochloric acid and ice water, and the deposited crystal is collected by filtration to obtain ethyl [2-{2-chloro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-4-fluorophenoxy}phenoxy]acetate.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23]Br)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8](=[O:9])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:6][CH2:5]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CC(C)(C)OC(=O)NCCN1CCN(CC(=O)N2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (commercially available from CHESS GmbH) and (2-Bromo-ethyl)-carbamic acid tert-butyl ester analogously to the preparation of Intermediate 269.2 as a colorless oil; ES-MS: M+H=341.3: CtRet=4.08.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])C1C=CC=CC=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)cc1O
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a 500 mL parr shaker flask was charged with ethyl (2E)-3-[2,4-bis(benzyloxy)phenyl]prop-2-enoate (2.3 g, 5.92 mmol), ethyl acetate (10 mL) and methanol (10 mL). To the reaction mixture was added palladium hydroxide (20%) and kept for hydrogenation at 50 psi for 2 h. After completion of the reaction, the reaction mixture was filtered through celite, washed thoroughly with ethyl acetate (25 mL) and concentrated to distill off the solvent. The product was obtained as brown solid (1.2 g, yield: 96.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([C:20]2([C:23](O)=[O:24])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:20]2([C:23]([NH:12][C:8]3[C:7]([Cl:13])=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]4)=[O:24])[CH2:21][CH2:22]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(O)C1(C2CCCCC2)CC1
Product: O=C(Nc1c(Cl)ccc2nc(Cl)ccc12)C1(C2CCCCC2)CC1
Yield: 50.8 %

Procedure:
Prepared according to the method of example 1(a), using 2,6-dichloro-5-quinolinamine (prepared as described in Example 1(d)) (0.3 g) and 1-cyclohexyl cyclopropanecarboxylic acid (Example 26(a)) (0.28 g) at 100° C. for 15 hours. Purification by chromatography (SiO2, dichloromethane as eluant) afforded the sub-title compound (0.26 g).
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:13])[C:7]([OH:12])=[C:8]([CH:11]=1)C=O.OO>S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:3][C:4]1[CH:11]=[C:8]([OH:1])[C:7]([OH:12])=[C:6]([F:13])[CH:5]=1
Reactant: [OH-]
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Product: Oc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a 1 N aqueous solution of sodium hydroxide (230 mL, 0.23 mol), 5-bromo-3-fluoro-2-hydroxybenzaldehyde (45.0 g, 0.21 mol) was added at room temperature, and a 6% hydrogen peroxide solution (225 mL) was added dropwise over five minutes at room temperature. After the reaction mixture was stirred at room temperature for two hours, a saturated aqueous solution of sodium thiosulfate (150 mL) was added thereto at room temperature. The mixture was extracted three times with ethyl acetate (450 mL), the organic layer was washed sequentially with a 1 N aqueous solution of hydrochloric acid (150 mL) and saturated saline, dried over anhydrous magnesium sulfate, and filtered through silica gel. The solvent was distilled off from the resultant filtrate under reduced pressure to give 39.0 g of the title compound (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:14]1=[O:25].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:22]2[CH2:21][CH2:20][CH:19]([N:15]3[CH2:16][CH2:17][CH2:18][CH:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:25])[CH2:24][CH2:23]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(NC2CCCN(C3CCNCC3)C2=O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCCC(Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
3-(2-Fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.300 g, 0.812 mmol), 2-chloro-5-ethylpyrimidine (0.116 g, 0.812 mmol) and DIEA (0.210 g, 1.62 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to provide 1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.198 g, 0.416 mmol, 51.3% yield) as white solid. Mass spectrum (apci) m/z=476.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]1(C)C=CC=C[CH:17]=1>FC(F)(F)C(O)=O.CC(OC)(C)C>[CH2:8]([CH:9]1[CH2:10][CH2:5][CH:3]=[CH:2][O:1]1)[CH2:7][CH:6]=[CH:16][CH3:17]
Reactant: Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CC=CCCC1CCC=CO1
Temperature: 50 °C

Procedure:
The cyclic vinyl ether (2 eq.) was added to a suspension of the hydroxy-acetophenone (10 mmol) in toluene (10 ml), followed by trifluoroacetic acid (2 or 3 drops, ˜0.01 eq.). The mixture was heated at 50° C. When the reaction was complete (TLC, 2-3 hours), it was diluted with MTBE and poured into aq. NaHCO3 (sat.). The aqueous phase was separated and extracted with MTBE, and the combined organic layers were washed with brine and dried over MgSO4. The crude, obtained after evaporation of the solvents, was purified by chromatography (SiO2, EtOAc/Hexane) to afford the desired product as a colorless to pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH:8]=[CH2:9].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:13][CH2:12]1)[CH:8]=[CH2:9]
Reactant: Nc1nc[nH]n1
Reactant: C=CCOC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCOC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (2.4 g) and 4-(prop-2-en-1-yloxy)cyclohexanone (5.3 g) in acetic acid was added sodium cyanoborohydride (9.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Br:26][C:27]1[CH:32]=[C:31]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccc(C(F)(F)F)cc2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.55) (1.6 g, 4.15 mmol) and commercially available 3-bromobenzeneboronic acid (0.751 g, 3.74 mmol) according to the general procedure Iba. Obtained as a light yellow oil (1.39 g, 85%). MS (ISP) 392.0 [(M+H)+] and 394.1 [(M+2+H)+].
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1.O>[CH3:30][C:8]1[N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:6]([Sn:35]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])[N:7]=1
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was added dropwise to a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (5.30 g, 11.8 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 8.49 g of impure 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole as a orange liquid. Method [7]Retention time 11.32 min by HPLC (MH+ 615).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: NCc1ccccc1N
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3N)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.O1CCOCC1>CO.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]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccsc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), thiophen-3-ylboronic acid (64 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 40-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (6.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 6.61 (d, 1H) 7.63 (d, J=8.34 Hz, 2H) 7.84 (dd, J=5.18, 2.91 Hz, 1H) 7.93 (dd, J=5.18, 1.14 Hz, 1H) 8.04 (d, J=8.34 Hz, 2H) 8.23-8.40 (m, 2H) 9.12 (dd, J=3.03, 1.26 Hz, 1H) 11.24 (s, 1H). ESI-MS: m/z 379.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(COCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
4-[(2-Hydroxyethoxy)methyl]benzonitrile (5.5 g, 30.5 mmol; see step (i) above) was dissolved in DCM (61 mL) and cooled to −10° C. Triethylamine (5 mL, 36.5 mmol) and methanesulfonyl chloride (3.84 g, 33.5 mmol) were added and the resulting mixture was stirred at below −5° C. for 1.5 h and then at RT overnight. Dichloromethane (200 mL) was added and the mixture was washed with water (2×100 mL) and then dried over Na2SO4. Evaporation of solvents gave 7.3 g (94%) of the title compound, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([NH2:11])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[N:22]=[C:23]=[O:24])[CH3:13]>C(OC(=O)C)C>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[NH:22][C:23]([NH:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1)=[O:24])[CH3:13]
Reactant: CCc1cccc(CC)c1N=C=O
Reactant: NC1(c2ccccc2)CCC1
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)NC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
To a solution of 1-phenylcyclobutyl amine (1.0, 0.0057 mole) in 30 ml of ethylacetate, 2,6-diethylphenylisocyanate (0.84 g, 0.0057 mole) is added and the reaction mixture is stirred at room temperature for 20 hours. Precipitated solid is filtered, washed with ethylacetate and dried yielding 1.46 gm of N-(2, 6-diethylphenyl)-N'-(1-phenylcyclobutyl)urea having a melting point of 227°-230° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)C>CN(C=O)C>[CH2:33]([N:38]([CH2:37][CH2:36][CH3:35])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH3:34]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCCNCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-ethylpropylamine (572 μL, 4.9 mmol) are added. The reaction stirred at room temperature 16 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[OH:9])[CH:2]=[C:18]1[NH:12][C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Reaction time: 0.5 h

Procedure:
Vanillin (3.04 g.) and hydantoin (2.0 g.) in water (20 ml) were heated on the steam-bath for a few minutes until dissolution occurred. Ethanolamine (0174 g.) was then added and the solution heated at 85°-90° (bath temperature) for 4.5 hours. The solution deposited crystals and solidified within 0.5 hours. Concentrated HCl (5 ml) was added, the mixture was refrigerated overnight (18 hours), filtered, water washed and dried. The title compound was obtained as a yellow solid (4.18 g; 93%), m.p. 266°-271° decomp.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:39]([F:49])[CH:38]=2)[CH2:33][CH2:32]1)=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37]6[CH:42]=[CH:41][C:40]([C:43]7[N:44]=[CH:45][CH:46]=[CH:47][N:48]=7)=[C:39]([F:49])[CH:38]=6)[CH2:33][CH2:32]5)=[O:30])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (12AB) (40 mg, 0.09 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (37 mg, 0.11 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (23 mg, 32 uL, 0.18 mmol, 2 equiv). The reaction content was stirred at room temperature overnight.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]1[S:22][C:21]([CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[S:22][C:21]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(CC(=O)O)s1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: Cc1ccc(CC(=O)Nn2nc(C(F)(F)F)c3ccccc3c2=O)s1

Procedure:
The product of Example 11B and 2-(5-methylthiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.85-11.96 (m, 1H), 8.43 (d, J=6.9 Hz, 1H), 8.10-8.17 (m, 1H), 8.01-8.08 (m, 2H), 6.81 (d, J=3.4 Hz, 1H), 6.66-6.68 (m, 1H), 3.84-3.85 (bs, 2H), 2.41 (d, J=0.8 Hz, 3H); MS (ESI+) M/Z 368 (M+H)+, 385 (M+NH4)+.