Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(CCCO)c1cncc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.9 %

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-4-hydroxy-butan-1-one (1) (5.0 g, 20.5 mmole) in 90 mL of CH2Cl2 at 25° C., is added a solution of Dess-Martin periodinane (9.6 g, 22.5 mmole) in 70 mL of CH2Cl2 slowly. After stirring at 25° C. for 20 minutes, the reaction mixture is diluted with 200 mL of ether (a lot of white precipitates came out of the solution) and cooled by dry-ice-acetone bath. The solid is filtered out and discarded. The filtrate is concentrated. The residue is diluted with 100 mL of ether and cooled by dry-ice-acetone bath and precipitates was removed by filtration. The filtrate is concentrated to give 6.2 g of 4-(5-Bromo-pyridin-3-yl)-4-oxo-butyraldehyde (2) as a pale brown oil which turned to a pale brown solid after cooled to 0° C., without further purification for next step reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:25]=[C:26]([CH2:28]Br)[CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([CH2:28][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1
Reactant: Clc1ccccc1-c1cc(Br)cc(CBr)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(Br)cc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 91, 109 mg (0.36 mmol) of the compound from Example 5A were reacted with 128 mg (0.36 mmol) of the compound from Example 117A. This gave 148 mg (68% of theory) of the target compound.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C@H:23]3[CH2:25][C@H:24]3[CH2:26][CH2:27][O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[C:31]([F:44])[CH:30]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C@H:23]3[CH2:25][C@H:24]3[CH2:26][CH2:27][O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([CH2:36][C:37]([OH:39])=[O:38])=[C:31]([F:44])[CH:30]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:9]
Reactant: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC(C)(C)C)c(F)c3)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A solution of 4 M HCl in dioxane (16.2 mL, 64.7 mmol) was added to a solution of tert-butyl 2-(4-(2-((1S,2R)-2-(1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)-2,6-difluorophenyl)acetate (3.35 g, 6.47 mmol) in DCM (16 mL). This mixture was stirred at 35° C. for 4 hrs. The mixture was concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 462 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]([NH2:14])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClC(Cl)C>[CH:1]1[C:13]([NH:14][C:18](=[O:20])[CH3:19])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Yield: 22 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine (0.10 g, 0.44 mmol), acetic anhydride (0.042 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-ylacetamide (26 mg). MS (ESI) m/z 269; HPLC purity 99.4% at 210-370 nm, 9.1 min.; 98.4% at 248 nm, 9.1 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C17H20N2O+H+, 269.16484; found (ESI, [M+H]+), 269.1646.
Reaction SMILES: CO.S([O:8][CH3:9])(OC)(=O)=O.[CH3:10][C@@:11]12[C:27](=[O:28])[CH2:26][CH2:25][C@H:24]1[C@H:23]1[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:29])=[CH:19][C:20]=3[CH2:21][CH2:22]1)[CH2:13][CH2:12]2.[OH-].[K+]>O>[CH3:10][O:8][CH3:9].[CH3:10][C@@:11]12[C:27](=[O:28])[CH2:26][CH2:25][C@H:24]1[C@H:23]1[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:29])=[CH:19][C:20]=3[CH2:21][CH2:22]1)[CH2:13][CH2:12]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC
Reaction time: 2 h

Procedure:
Into a mixture of 20 ml of methanol and 4 ml of dimethyl sulfate, 1.0 g of estrone was suspended and the mixture was cooled in an ice bath and stirred while 16 ml of 30% aqueous solution of potassium hydroxide was added over a period of 1 hour. Stirring was continued for 2 hours. Water was added to the reaction mixture, and the precipitated crystals were filtered, washed with water and dried to obtain 1.017 g of the 96.0% purity methyl ether of estrone in a 96.7% yield.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26][CH:25]=1.[BH4-].[Na+]>CS(C)=O>[F:19][C:13]([F:18])([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:20]=[CH:21][CH:22]=[N:23][C:2]=2[NH:1][CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][N:26]=2)=[CH:8][CH:9]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: Nc1ncccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=Cc1ccncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1NCc1ccncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TSOH (40 mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml) were stirred at 60 C for 6 h. Treated with NaBH4 (200 mg) and stirred for 2 h at RT. MS (ES+): 566.3 (M+H)+; Calc'd for C26H28F5N7O2−565.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH2:10]([N:12]=[C:13]=[S:14])[CH3:11]>C(#N)C>[CH2:10]([NH:12][C:13]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[S:14])[CH3:11]
Reactant: CCN=C=S
Reactant: c1nc2c([nH]1)CCNC2
Solvent: CC#N
Product: CCNC(=S)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1.85 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2 g of ethyl isothiocyanate in 15 ml of acetonitrile are refluxed for 7 h. The solution is cooled and filtered: 2.5 g of 5-[N-ethyl-thiocarbamoyl]-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 185°, are collected.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(Br)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C)nc1Br
Yield: 88.3 %

Procedure:
A stirred mixture of 2-bromo-3-hydroxy-6-methyl-pyridine (7.89 g, 42.0 mmol), potassium carbonate (11.60 g, 83.9 mmol) and iodomethane (8.93 g, 62.9 mmol, 3.92 mL) in acetone (100 mL) was heated under reflux overnight. The mixture was filtered, evaporated and purified on silica gel (hexane:ethyl acetate, 95:5 to 9:1) to give the desired product as a white solid (7.49 g, 88.3%). 1H NMR (500 MHz, CDCl3): δ2.46 (s, 3H), 3.87 (s, 3H), 7.04 (s, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:26]([O:29][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:25]([O:30][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:24]([CH2:31][O:32][CH2:22][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=2)[O:23]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200 %

Procedure:
To a solution of tetraol (13, 8.4 g, 18 mmol) from Step 2 in N,N-dimethylformamide (100 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in mineral oil, 10.1 g, 252 mmol), and the mixture was stirred for 30 min at the same temperature. Then benzyl bromide (19.5 mL, 162 mmol) was added dropwise, and the mixture was stirred with gradual warming to ambient temperature over 5 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (100 mL). The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (19, 14.8 g, 18 mmol, 100%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80](O)=[O:81])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7])=[O:81])=[O:75])([CH3:72])([CH3:70])[CH3:71]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)O
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCN)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)c2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a solution of methyl 5-(4-amino-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.2; 5.52 mmol) in dichloro methane (5 mL) was added DIPEA (18.7 mmol) and HBTU (5.63 mmol). The mixture was stirred for 5 min at rt. 2((Tert-butoxycarbonylamino)methyl)-5-fluorobenzoic acid (4.69 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was washed with a 1M Na2CO3 solution. The aqueous phase was extracted with dichloro methane, dried and was concentrated. The crude product was purified by SiO2 column chromatography (5:1 to 1:1 hexanes:ethyl acetate) to give the target compound in 49% yield.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1F
Yield: 29.4 %

Procedure:
The title compound (42.7 mg) was prepared as in Example 177, Steps C and D, using 205.2 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 224.9 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C19H23F2N3, 331.40; found, m/z 332.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.44 (m, 1H), 7.34-7.28 (m, 1H), 7.17-7.13 (m, 1H), 3.91-3.84 (m, 1H), 3.42-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.78 (m, 6H), 1.70-1.64 (m, 1H), 1.32-1.19 (m, 3H).
Reaction SMILES: [NH:1]1[C:51](=[O:52])[C@H:50]2[CH2:53][CH2:54][CH2:55][CH2:56][N:49]2[C:47](=[O:48])[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][C:36](=[O:37])[C@H:31]([CH2:32][C:33](=[O:35])[OH:34])[NH:30][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O>C(O)(C(F)(F)F)=O.ClCCl.C1(S)C=CC=CC=1>[NH:1]1[C:51](=[O:52])[C@H:50]2[CH2:53][CH2:54][CH2:55][CH2:56][N:49]2[C:47](=[O:48])[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][C:36](=[O:37])[C@H:31]([CH2:32][C:33](=[O:34])[OH:35])[NH:30][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:23]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H]3CCCCN3C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC2=O)c(C)c1C
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@@H]1NC(=O)[C@H]2CCCCN2C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
Reaction time: 4 h

Procedure:
A solution of 0.28 g of cyclo-(Arg(Mtr)-Gly-Asp-DPhe-DhPro) [obtainable by cyclization according to Ex. 1] in 8.4 ml of TFA, 1.7 ml of dichloromethane and 0.9 ml of thiophenol is allowed to stand at room temperature for 4 hours, then concentrated, and the residue is diluted with water and then freeze-dried. Gel filtration on Sephadex G 10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under the conditions indicated give cyclo-(Arg-Gly-Asp-DPhe-DhPro); FAB-MS (M+H): 587.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:16][CH3:17])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[K+].S(=O)(=O)(O)O.O.[C:25]([O-])(O)=O.[Na+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:16][CH3:17])[C:13]([O:15][CH3:25])=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C([O-])O
Reactant: COC(C(=O)[O-])c1ccc(-n2cccn2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(OC)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a stirred solution of potassium 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (˜7.55 mmol) in dry MeOH under argon was added sulfuric acid (2.0 mL) dropwise. The mixture was heated at 80° C. for 17 hours. After cooling to room temperature, water was added then the mixture made basic with saturated aqueous NaHCO3 addition. The aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexanes) provided methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate as a colorless oil (0.88 g, 47% yield for two steps).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>O.[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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine) palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl) oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(tri isopropylsilyl) oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Reactant: Nc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
Reaction time: 0.17 h

Procedure:
4-Pyridazinamine (207 mg, 2.18 mmol), diisopropylethylamine (0.52 ml, 2.97 mmol) and HATU (904 mg, 2.38 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 636 mg, 1.98 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours, after 10 minutes a solid had crashed out of solution. The solid was filtered and washed with ethyl acetate (10 ml) to yield the title compound. 475 mg.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:18]1([C:24]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]2[N:25]([C:24]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=[N:27][N:28]=2)=[CH:41][CH:40]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 25 %

Procedure:
L-phenylalanine t-butyl ester hydrochloride (Bachem Bioscience, Inc.) (1.0 g, 3.9 mmol) was suspended in ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and the solvent removed in vacuo. This residue was dissolved in 20 mL of THF and 1.95 g (3.5 mmol) of 2'-(N-triphenylmethyl tetrazol-5-yl)-4-bromomethylbiphenyl (prepared as described in EP 0 324 377) and 0.54 mL (3.9 mmol) triethylamine were added. The reaction was stirred at room temperature for 5 days. The THF was removed in vacuo and the residue dissolved in ethyl acetate. This was extracted 3× with K2CO3 and 1× with brine, dried over (MgSO4), filtered, and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate-hexanes to yield 0.61 g (25%) of a white glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH3:23]>CN(C=O)C>[NH2:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][CH2:22][CH3:23]
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)OC)cc([N+](=O)[O-])c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of methyl 3,4-diamino-5-nitrobenzoate (D204) (1.5 g, 7.1 mmol, 1 equiv) in DMF (30 ml) at room temperature was added K2CO3 (2.2 g, 16.0 mmol, 2.25 equiv) then ethyl iodide (1.28 ml, 16.0 mmol, 2.25 equiv). The resulting suspension was stirred at 60° C. for 2 h then ethyl iodide (1 ml, 12.5 mmol, 1.8 equiv) was added and the resulting mixture stirred for another 6 h then cooled to room temperature and partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the organic phase washed with H2O, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give methyl 4-amino-3-(ethylamino)-5-nitrobenzoate (D205) (0.85 g, 50%) as a red solid which was used in the next step without further purification. [M+H]+=240.2, RT=2.95 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]([NH2:27])=[N:25][OH:26])[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]5[N:27]=[CH:29][O:26][N:25]=5)[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Solvent: O
Solvent: COC(OC)OC
Product: O=C(Cn1cc(-c2ncon2)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A mixture of 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 0.30 mmol) and p-TsOH.H2O (0.030 g, 0.15 mmol) in HC(OMe)3 (3 mL) was heated at 100° C. for 1.5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.055 g, 21%). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.65-8.50 (m, 3H), 7.44 (dd, J=8.4, 4.6 Hz, 2H), 7.17 (dd, J=9.2, 7.6 Hz, 2H), 5.27 (m, 2H), 3.85 (m, 2H), 2.85 (m, 2H), 2.14 (m, 2H); MS: (ES) m/z calculated for C19H16FN7O2 [M+H]+ 394.1, found 394.1.