Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:28].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C([C@H](O)C(OC)=O)C=1C>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C@H:19]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:28]
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Agent: COC(=O)[C@@H](O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br

Procedure:
(S)-2-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (150B) was prepared in a similar manner to 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 124, except using (S)-methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate, giving the title compound (parent form). 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI− (m/z): [M—CO2—H]− calcd for C22H21BrClO: 415.2; Found: 415.0.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(-c2onc(O)c2C(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: Cc1ccc(-c2onc(OCCNC(=O)OC(C)(C)C)c2C(C)C)cc1
Yield: 81.4 %

Procedure:
3-Hydroxy-4-isopropyl-5-(4-methylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1 (a) to obtain the title compound (0.27 g, 82%) as a colorless powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][O:14]2)=[CH:9][C:8]=1[F:22])(=O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:50]=[C:51]([F:57])[C:52]=1[C:53]([F:56])([F:55])[F:54])[O:29][C:30]([F:49])([F:48])[C:31]1[C:36]([F:37])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[F:47].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:25][C:26]1[CH:27]=[C:28]([CH:50]=[C:51]([F:57])[C:52]=1[C:53]([F:54])([F:56])[F:55])[O:29][C:30]([F:48])([F:49])[C:31]1[C:32]([F:47])=[CH:33][C:34]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][O:14]3)=[CH:9][C:8]=2[F:22])=[CH:35][C:36]=1[F:37]
Reactant: CC1(C)OB(c2cc(F)c(C(F)(F)Oc3cc(F)c(C(F)(F)F)c(F)c3)c(F)c2)OC1(C)C
Reactant: CCC[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)OC1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)OC1

Procedure:
A mixture of 10.0 g (27.0 mmol) of 2-fluoro-4-(trans-5-propyltetrahydropyran-2-yl)phenyl trifluoromethanesulfonate and 14.3 g (29.4 mmol) of 2-{4-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-3,5-difluorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, 1.50 g (1.30 mmol) of tetrakis(triphenylphosphine)palladium(0) and 30 ml of 2 N sodium carbonate solution in 100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=7:3). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-{4′-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-2,3′,5′-trifluorobiphenyl-4-yl}-5-propyltetrahydropyran as a colourless solid (m.p. 95° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][Mg]Br>C1COCC1.CN1C(=O)CCC1>[Cl:16][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:2]([CH3:17])[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1
Reactant: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 0.25 h

Procedure:
tert-butyl (2,6-dichloropyridin-4-yl)carbamate (460 mg, 1.75 mmol) from Step 1 of this example, ferric acetylacetonate (309 mg, 0.87 mmol) was added in THF:NMP (1:1, 17.4 mL), methyl magnesium bromide (3 mL [3M], 8.9 mmol) was added drop-wise and stirred for 15 min. The reaction was quenched with ice-cold ammonia chloride saturated solution (100 mL), extracted with ethyl acetate (100 mL), second wash with brine (50 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel (1 inch deep), concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compounds as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:56]=[CH:55][CH:54]=[CH:53][C:24]=1[O:25][C:26]1[CH2:30]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:28](=[O:52])[CH:27]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:30][C:26]([O:25][C:24]2[CH:53]=[CH:54][CH:55]=[CH:56][C:23]=2[Cl:22])=[CH:27][C:28]1=[O:52])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a small pressure bottle was placed a mixture of 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (147 mg, 0.86 mmol), acetonitrile (6 mL) and N,N-diisopropylethylamine (220 μL, 1.03 mmol) which was heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 276 mg, 0.86 mmol) and the tube sealed and heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 16% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (108 mg, 35%) as an amber oil: HR-ES-MS m/z calculated for C19H22NO4Cl [M+H]+ 364.1310, observed 364.1310.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25](O)[CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:28])=[C:23]([CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Reactant: Cc1ccc(F)cc1O
Product: Cc1ccc(F)cc1OC1CCN(C(=O)CNc2ccnn(C)c2=O)CC1
Yield: 15 %

Procedure:
Compound 14 is prepared from intermediate 5b and from 5-fluoro-2-methyl-phenol following synthesis method 3 (yield: 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.C(#N)C>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=3)=[CH:4][C:3]=2[C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1noc(=O)[nH]1
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(F)cc(F)c1)Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of dry toluene was 5 g of 3-(4-amino-4′-trifluoromethyl-biphenyl-3-yl)-4H-[1,2,4]oxadiazol-5-one suspended and 2.5 g of 3,5-difluorophenyl isocyanate was added, the reaction mixture was stirred at room temperature overnight, 1.3 g of 3,5-difluorophenyl isocyanate was added and stirring was continued overnight. 3,5-Difluorophenyl isocyanate (1.3 g) and 100 ml of acetonitrile was added, the reaction mixture was stirred at room temperature for 90 min. and evaporated to dryness. The residue was dissolved in 100 ml of boiling acetone, then cooled to 0° C. and filtrated. The precipitate was recrystallized from 200 ml of ethanol, after filtration while hot, the solution was added 400 ml of water. The product was isolated by filtration. Yield 4 g (54%) mp.>150° C. decomp.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:27]([C:26]([F:25])([F:41])[F:40])[CH:28]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3,5-bis-trifluoromethyl-phenyl boronic acid to give the title compound as colorless solid. MS: 529.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=O)[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:32][NH2:33]>C(O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[N:32][NH2:33])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CCO
Product: COc1cc(C(C)=NN)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 381.4 %

Procedure:
A stirred mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydrazine (0.8 g, 2.5 mmol), and ethanol (40 ml) was refluxed for 16 hours. The cooled solution was concentrated to yield an oily residue. The residue was triturated with water and the resultant solid was collected to afford 4.2 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrazone as a yellow solid. The compound was recrystallized from isopropanol and then from toluene to afford 1.7 g (39%), m.p.=106°-108° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:16][C:15]([N:17](C)[C:18](=O)OC(C)(C)C)=[N:14][CH:13]=1)=[O:11])[CH2:2]2.[ClH:26].O1CCOCC1>CO>[ClH:26].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH3:18])=[N:14][CH:13]=1)=[O:11])[CH2:2]2
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(C(=O)N[C@H]2CN3CCC2CC3)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNc1ncc(C(=O)N[C@H]2CN3CCC2CC3)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63 %

Procedure:
A flask is charged with tert-butyl 5-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,3-thiazol-2-yl(methyl)carbamate (72 mg, 0.18 mmol) in MeOH (5 mL). To this suspension is added a solution of 4.0N HCl/dioxane (10 mL) and the reaction mixture is stirred at room temperature for 3.5 hours. The solvents are removed in vacuo and the residue crystallized from IPA/ether. Yield 63%. MS (ESI) for C12H18N4OS m/z 267.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][CH3:18]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([N:17]([CH3:18])[CH3:16])[N:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CN(C)c1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 2 h

Procedure:
A red to brown solution of 2,6-dichloro-isonicotinic acid tert.-butyl ester (1.49 g, 6.0 mmol) in 2 M dimethylamine in THF (20 mL) is stirred at 65° C. for 2 h, then at 80° C. for 2 h and finally at 110° C. for 12 h in an autoclave. The mixture is concentrated to give crude 2-chloro-6-dimethylamino-isonicotinic acid tert-butyl ester (2.0 g) as a brown residue; LC-MS: tR=1.08 min; [M+H]+=257.32; 1H NMR (D6-DMSO): δ 1.54 (s, 9H), 3.06 (s, 6H), 6.85 (s, 1H), 6.92 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35]O[CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5].[CH3:40][N:41]1CCNCC1>>[CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:41]([CH3:40])[CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCOCC5)nc4)cc3)cc2C1=O
Reactant: CN1CCNCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C)CC5)nc4)cc3)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 218 was prepared analogous to compound of example 212 by reaction of compound of example 211 with N-methyl piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:28][C:19]1[C:18]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1
Reactant: Cc1cc2c(cc1Br)OCCO2
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1ccc(N)nc1)OCCO2
Temperature: 85 °C
Yield: 25.8 %

Procedure:
The 2-aminopyridine-5-boronic acid pinacol ester (400 mg, 1.8 mmol) and 182 (550 mg, 2 mmol) was dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. The 4 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 2 min before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 70 mg, 0.1 mmol) was added. The reaction was heated at 85° C. for 2 h. The reaction mixture was worked-up with EtOAc extraction. The product was purified by flash column and afforded 183 (112.4 mg, 26%) as yellow oil. LC-MS: calcd. for C14H14N2O2: 243 (M+1).
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13].CC(N=NC(C#N)(C)C)(C#N)C>CC(N=NC(C#N)(C)C)(C#N)C.C(O)C>[CH3:11][CH:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][PH:2](=[O:4])[OH:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2][O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C[PH](=O)O)CC(C)(C)C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A 2 L 4-neck flask, equipped with thermocouple well, a dropping funnel, overhead stirrer and reflux condenser is charged with 199 grams (1.88 moles) of sodium hypophosphite monohydrate and 500 mL of 2B ethanol. Into the resultant stirred suspension is added via the dropping funnel, 52 mL (1.87 moles) of concentrated sulfuric acid. During the addition the reaction mixture temperature rises from 21° C. to 27° C. After approximately 15 minutes, 100 mL (0.624 moles) of 2,4,4-trimethyl-1-pentene is added, followed by 10.24 g (0.062 moles) of AIBN powder. The reaction mixture is heated at reflux under a nitrogen atmosphere for 20 hours. An additional 6.84 g (0.042 moles) of AIBN powder is added and the mixture is refluxed under nitrogen for another 20 hours. Solvent is removed under vacuum and the residue is partitioned between 400 mL heptane and 1 L of water. The heptane layer is concentrated under vacuum to give 98 grams (88% of theory) of 2,4,4-trimethylpentyl phosphinic acid as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11](OCC)=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccc(F)c2o1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2cccc(F)c2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a stirred solution of ethyl 7-fluorobenzofuran-2-carboxylate (3.70 g, 17.8 mmol) in tetrahydrofuran (70 mL) was added lithium aluminum hydride (6.7 mL, 2.0 M solution in tetrahydrofuran, 13.3 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h and solid sodium sulfate decahydrate (15.0 g) was added slowly in portions. The mixture was stirred at 0° C. for 10 min and at ambient temperature for 30 min. The solid was filtered off and washed with ethyl acetate (3×150 mL). The combined filtrate was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate, 7/1-4/1) to afford (7-fluorobenzofuran-2-yl)methanol (2.4 g, 81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.34-7.29 (m, 1H), 7.19-7.10 (m, 1H), 7.06-6.98 (m, 1H), 6.73-6.69 (m, 1H), 4.82-4.78 (m, 2H), 2.07-2.01 (m, 1H); MS (ES+) m/z 167.1 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:65][CH:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
A mixture of 0.042 g (0.0001 mole) of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-1), 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.026 mL (0.00015 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.038 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-2) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].I[CH3:22].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:22])[CH2:9][CH2:10]1)=[O:4]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-(tert-butoxycarbonylamino)cyclohexane carboxylic acid methyl ester (5 mmol, 1.3 g) in dimethylformamide (15 mL) is cooled to 0° C. and treated with of sodium hydride (60% in oil, 6 mmol, 240 mg) over 30 minutes. The mixture is stirred at room temperature for 1 hour, then cooled to 0° C. and treated with iodomethane (6 mmol, 0.38 mL). After stirring overnight at room temperature, the mixture is poured into a saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phase is washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue is purified by column chromatography on silica gel (eluent: n-hexane-ethyl acetate 10:1) to obtain 1.3 g (96%) of trans-4-[(tert-Butoxycarbonyl)(methyl)amino]cyclohexane carboxylic acid methyl ester as colorless oil. ESI-MS m/z: 272 [M+1]+, Retention time 3.57 min (condition B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH:20]=[N:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH:20]=[N:21][NH:22][C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2[nH]ncc2cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
A solution of (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (157 mg, 0.291 mmol) in DCM (0.8 mL) was treated with TFA (0.2 mL) and triethylsilane (0.1 mL). The mixture was stirred at room temperature for 1.5 h. Additional TFA (0.2 mL) and triethylsilane (0.1 mL) were added and the mixture was stirred for 1.5 h and then evaporated in vacuo to afford a residue, which was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to yield (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)urea (14 mg, 0.034 mmol, 12%). MS ESI calc'd. for C15H15FN5O [M+H]+ 300, found 300. 1H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.32 (dd, J=8.5, 5.6 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H), 7.07 (s, 1H), 6.78 (s, 1H), 4.79 (m, 1H), 1.35 (d, J=7.0 Hz, 3H).