Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].ClS([N:13]=[C:14]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>C(#N)C>[C:14]([C:5]1[CH:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1)#[N:13]
Reactant: Cn1cccc1C=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1cc(C#N)cc1C=O
Temperature: -45 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
1-Methylpyrrole-2-carbaldehyde (10 g, 91.6 mmol) was dissolved in acetonitrile (100 ml) and cooled to −45° C. Chlorosulfonyl isocyanate (38.9 g, 274.9 mmol) in acetonitrile (40 ml) was added dropwise in the course of 40 minutes. The mixture was subsequently stirred for 12 hours at room temperature. After dropwise addition of dimethylformamide (35 ml), the mixture was warmed to 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice (200 ml) and 2N sodium hydroxide solution (286 ml). The precipitate formed was filtered off with suction. The filtrate was extracted with diethyl ether. The combined ether phases were washed until neutral with dilute sodium hydrogen carbonate solution and water and dried over sodium sulfate. The solvent was distilled out in a water pump vacuum and the residue was combined with the precipitate previously obtained. Recrystallization from petroleum ether gave 4-cyano-1-methylpyrrole-2-carbaldehyde (4.3 g) (see, for example, C. E. Loader et al. Can. J. Chem. (1981), 59, 2673-6) 1-H [sic] NMR (CDCl3) δ=4.0 (s, 3H); 7.2 (s, 1H); 7.3 (s, 1H); 9.6 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]([O:15][CH:16](OCC)OCC)[CH3:14]>C(OC(=O)C)(=O)C>[CH2:13]([O:15]/[CH:16]=[C:4](/[C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F

Procedure:
To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (20 g, 108.63 mmol) in acetic anhydride (39 mL) was added triethylorthoformate (54.2 mL, 325.89 mmol) and the reaction heated to reflux for 18 hours. The reaction was cooled, concentrated in vacuo and used directly in the next step.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[NH2:33][C@H:3]1[C@H:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[N:18]=2)[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@@H]1NS(C)(=O)=O
Yield: 13 %

Procedure:
Method 5 was followed using (+/−)-tert-butyl (1R,2R,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate and methanesulfonyl chloride to give N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 13% yield; N-(4-((1S,3S,4S,5R)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=534.2 (MH+), Rt=0.58 min.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.Cl[C:17]([O:19][CH3:20])=[O:18]>ClCCl.O>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]1)#[CH:2]
Reactant: C#CC1CCCNC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC1CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 10A (500 mg, 4.58 mmol) in dichloromethane (10 mL) was added triethylamine (2.55 mL, 18.32 mmol) followed by methyl chloroformate (0.532 mL, 6.87 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and dichloromethane and the organic layer was separated and washed with water and brine. After drying over sodium sulfate, filtration, and concentration, the residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to afford the title compound. LCMS: 168.3 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:22])[F:23])[CH2:7]1
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.70 g, 3.83 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 8.70 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 1.00 g (crude) of 4-(4-[[(3R)-3-methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl)morpholine as yellow oil. LCMS (ESI, m/z): 344 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:17]=[C:16]2[CH2:27][CH2:28][CH2:29][C:15]=12>CO.ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]3[CH2:27][CH2:28][CH2:29][C:15]3=[C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 86.4 %

Procedure:
An 18-mL vial was charged with methyl 4-aminobenzoate (20 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent to give the desired product methyl 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate (21.6 mg, 86% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:6][N:5]2[CH:22]=1.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:22]=[C:2]([C:23]#[N:24])[CH:3]=2)[CH2:6]3)=[CH:15][CH:16]=1
Reactant: COc1ccc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3)cc1
Temperature: 160 °C
Yield: 58 %

Procedure:
7-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (100 mg, 0.28 mmol), zinc cyanide (50 mg, 0.42 mmol) and palladium(0) tetrakistriphenylphosphine (32 mg, 0.03 mmol) were suspended in dry DMF (3 mL) in a microwave vial flushed with argon. The mixture was heated in the microwave reactor at 160° C. for 20 minutes. A saturated aqueous solution of NaHCO3 (50 mL) was added and the mixture extracted with CH2Cl2 containing 20% of isopropyl alcohol. The organic layers were dried (MgSO4), filtrated and concentrated in vacuo. The resulting residue was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-5% methanol in CH2Cl2) to give 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (50 mg, yield 58%) ESI-MI m/z [M+H]+ 308.9. Used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)[CH:27]=[N:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:27]=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(-c3cncc(N[C@@H]4CCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)pyrrolidine-1-carboxylate (280 mg, 0.486 mmol) in DCM was added TFA (0.5 ml, 6.49 mmol). The reaction was stirred at RT for 2 h, and then TFA was removed. The residue was purified with RP-HPLC to give (R)-6-(5-(2,6-difluorophenyl)-1H-indazol-3-yl)-N-(pyrrolidin-3-yl)pyrazin-2-amine as an orange solid. MS (ESI, pos. ion) m/z: 393 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1 H, s), 8.47 (1 H, s), 7.87 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.41-7.55 (2 H, m), 7.18-7.31 (3 H, m), 4.22-4.36 (1 H, m), 2.88-3.05 (2 H, m), 2.61-2.82 (2 H, m), 1.97-2.12 (1 H, m), 1.57-1.73 (1 H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I>O1CCCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([I:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: II
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nccc2ccc(I)cc12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Into a 50 mL round-bottom flask, was placed 7-bromo-1-chloroisoquinoline (as prepared in the previous step, 520 mg, 2.15 mmol, 1.00 equiv) and tetrahydrofuran (10 mL). This was followed by the addition of n-BuLi (0.85 mL, 1.25 equiv) dropwise with stirring at −78° C. in 2 min. The resulting solution was allowed to react, with stirring, for an additional 40 min at −80° C. To this was added a solution of I2 (541 mg, 2.14 mmol, 1.25 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −78° C. in 1 min. The reaction mixture was allowed to react, with stirring, overnight at 25° C. The reaction was then quenched by the addition of 1 mL of water. The residue was diluted with 40 mL of DCM, washed with 3×15 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/hexane (1:50). The title compound was obtained as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH2:32]([N:34]([CH3:35])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[CH3:33]
Reactant: CCNC
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: CCN(C)CCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and N-ethyl methyl amine as starting materials. MS: m/z (MH+)=463.2
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O.O>[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:17][CH:16]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
tert-Butyldimethylchlorosilane (8.7 g) and imidazole (3.9 g) were added to a solution of 3-(4-bromophenoxy)propan-1-ol in N,N-dimethylformamide (193 mL) under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was ice-cooled and water and a saturated ammonium chloride solution were added, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1). Pyrrolidine (4.82 mL) and triethylamine (8.86 mL) were added to a solution of the resulting crude product in tetrahydrofuran (145 mL) under ice-cooling, and the mixture was stirred at room temperature for 27 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution was added, followed by extraction with a mixture of hexane-chloroform (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→80:1) to give the title compound (7.88 g, 79% (two steps)).
Reaction SMILES: O=C[C@H]([C@H]([C@H](CO)O)O)O.[OH:11][CH2:12][C:13]([C@H:15]([C@H:17]([C@@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])=[O:14]>>[O:11]=[CH:12][C@@H:13]([C@H:15]([C@H:17]([C@@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])[OH:14]
Reactant: C[C@@H](O)[C@H](O)[C@H](O)C(=O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O

Procedure:
6-Deoxy D-talose was produced by allowing L-ribose isomerase to react with 6-deoxy D-tagatose produced from D-fucose.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Product: COc1ccc(-c2cc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccn2)cc1

Procedure:
By following a procedure analogous to Example 27 starting from the 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 25 and 4-methoxyphenylboronic acid, 2-(4-methoxyphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige solid (yield=53%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]([CH3:29])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([Cl:28])[CH:22]=1)=O>>[Cl:28][C:23]1[CH:22]=[C:21]([C:19]2[N:16]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:12][CH:11]=3)[S:15][C:18]=2[CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Reactant: Cc1ccc(C(=O)C(C)Br)cc1Cl
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccc(C)c(Cl)c4)c(C)s3)cc2)cn1
Yield: 67.7 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (example 72c)) and 124 mg (0.47 mmol) 2-bromo-3′-chloro-4′-methylpropiophenone. 115 mg (68%) of the product was isolated as a colorless solid. MS ISP (m/e): 395.1 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.50 (s, 1H), 9.47 (s, 1H), 7.95 (s, 1H), 7.87 (d, 2H), 7.70-7.60 (m, 3H), 7.52 (d, 2H), 2.45 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].CCOCC>C1(C)C=CC=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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]12([NH:11][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A mixture of Pd(dba)2 (0.259 g, 0.450 mmol) and (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (0.417 g, 0.670 mmol) in toluene (40 mL) was stirred for 30 min at room temperature before adding 1-adamantylamine (2.269 g, 15.0 mmol), bromobenzene (1.60 mL, 15.2 mmol) and sodium tert-butoxide (2.02 g, 21.0 mmol). The reaction solution was stirred for 24 h at 100° C. After cooling the reaction mixture to room temperature, Et2O (50 mL) was added. The reaction mixture was filtered through a pad of celite and was concentrated. Flash column chromatography (silicagel, 7:1 hexanes/EtOAc) afforded the desired product (2.239 g, 65.7%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=7.6 Hz, 2H), 6.83 (m, 3H), 3.26 (br. s, 1H), 2.14 (m, 3H), 1.91 (m, 6H), 1.71 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 146.3, 129.0, 119.4, 119.3, 52.5, 43.8, 36.8, 30.0. HRMS-ESI (m/z): [M+H]+ calcd for C16H21N, 228.1747. found, 228.1756.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:27]#[C:28]Br>C(O)C>[NH2:27][C:28]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3([OH:26])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:18])[N:10]3[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Reactant: N#CBr
Solvent: CCO
Product: Nc1nc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc2[nH]1
Yield: 1.6 %

Procedure:
A solution of 3-(3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (613 mg, 1.77 mmol) and cyanogen bromide (188 mg, 1.77 mmol) in anhydrous ethanol (10 mL) was heated to 60° C. for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC. To the combined fractions were added 6N aqueous hydrochloric acid (10 mL) and heated for 10 mins, at which time saturated aqueous sodium bicarbonate was added until pH reached 7. To the aqueous layer was added ethyl acetate (300 mL) and then separated. The organic layer was washed with brine and dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 3-(2-amino-1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (10.3 mg). 1H NMR (400 MHz, d6-DMSO): 7.76 (d, 1H), 7.59-7.52 (m, 2H), 7.26-7.18 (m, 3H), 7.12-7.09 (m, 5H), 7.03-7.01 (m, 1H), 4.43 (d, 1H), 4.21 (d, 1H), 3.48-3.39 (m, 1H); MS (EI) for C22H18N4O2: 371 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 52.1 g (197 mmol) of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Example 1, Step A) and methyl acrylate (19.5 ml, 216 mmol) in 360 mL of THF was added 20 mL of a 1M solution of potassium tert-butoxide in THF slowly at 0° C. over a period of 20 min (reaction solution temp kept <10° C.). The reaction was allowed to warm to ambient temperature. After being stirred at rt for 1 h, the reaction was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 15% EtOAc/hexanes) provided the title compound as a colorless liquid. R is CH3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:53][NH2:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:54][CH3:53])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 72 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.25, 0.43 mmol), MCPBA (0.081 g, 0.47 mmol) and 2 M methylamine in THF (1 mL) were combined to provide 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (0.17 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J=2.0 Hz, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.83-7.78 (m, 1H), 7.65 (s, 1H), 7.54-7.47 (m, 4H), 7.43-7.38 (m, 1H), 7.11 (d, J=12.0 Hz, 1H), 6.34 (s, 1H), 3.59 (s, 3H), 2.90 (d, J=4.4 Hz, 1H), 2.05 (s, 3H), 1.23 (s, 9H); MS (ESI) m/z; 555.2 (M+H+).