Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].N([O-])=O.[Na+].[C:16]([CH:19](C(=O)C)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])[CH3:17].[N:29]1C=CC=CC=1>O.C(O)C.Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][N:29]=[C:19]([C:16](=[O:18])[CH3:17])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([CH3:11])[CH:4]=1)([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=NNc1ccc(C(=O)O)cc1C)C(C)=O
Reaction time: 24 h

Procedure:
A mixture of 3 g (19.8 mmol) of 4-amino-3-methylbenzoic acid in 50 ml of water and 50 ml of ethanol and 3.56 ml of concentrated hydrochloric acid was cooled in an ice bath and then 1.5 g of NaNO2 (21.8 mmol) in 10 ml of water was added portionwise. The mixture was allowed to come to room temperature and then added to a solution of 4.06 g (21.8 mmol) of ethyl 3-acetyl-4-oxopentanoate and 8 ml of pyridine in 25 ml of ethanol. The reaction mixture was left for 24 hr at room temperature with stirring. The mixture was acidified with concentrated hydrochloric acid and the mixture diluted with 20 ml of water. The resulting solid was collected and washed with water and pentane to yield 5.2 g of ethyl 3-(4-carboxy-2-methylphenylhydrazono)-4-oxopentanoate with m.p. 161°-162.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[O:29]>CN(C)C=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:26][CH2:27][C:28]([NH:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)=[O:29])=[O:10]
Reactant: O=C(O)CN1CCCC1=O
Reactant: NCC(=O)Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1=O)NCC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
40.9 g of (2-oxo-1-pyrrolidinyl)acetic acid was dissolved in 300 ml of dimethylformamide and the solution was cooled to 0° C. Then, a solution of 78.7 g of dicylohexylcarbodiimide dissolved in 80 ml of dimethylformamide was added thereto while maintaining the temperature at -2° C. to +1° C. After stirring for 5 minutes, 28.8 g of 4-(glycylamino)pyridine dissolved in 50 ml of dimethylformamide was added while maintaining the temperature at 0° to 3° C. and then the reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The liquid was cooled with ice and 200 ml of ice water was added dropwise thereto. The precipitated dicyclohexylurea was filtered off and the solvent was distilled off under reduced pressure. 200 ml of ethanol was added to the residue and stirred and the insoluble matter was filtered off. This insoluble matter was dissolved in 130 ml of water and 50 ml of methanol with warming and then the solution was concentraterd to about 60 ml. After 300 ml of ethanol was added, again the solution was concentrated to about 100 ml and allowed to stand overnight to form the precipitate, which was filtered off to obtain the titled compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][C:34]([N:36]5[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]5)=O)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][N:36]5[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]5)=[CH:31][C:24]=3[S:23]4)=[CH:18][CH:19]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN1CCN(C(=O)CCc2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Solvent: C1CCOC1
Solvent: CSC
Product: CCN1CCN(CCCc2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)-3-oxo-propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea from Example 12A (0.17 g, 0.28 mmol) in THF (10 mL) at room temperature was added 2.0 M solution of BH3/Me2S in THF (1 mL). The mixture was heated to reflux for 4 hours. The reaction was quenched by dropwise addition of 10% HCl solution and stirred at room temperature for 15 min. The mixture was basified with saturated NaHCO3 solution and was extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by Flash chromatography with silica gel using a 30-100% hexane/ethyl acetate gradient followed by a 0-20% methanol/ethyl acetate gradient. The appropriate fractions were collected, combined, and concentrated to give free base, N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea. The free base was dissolved in dichloromethane (about 1 mL) and methanol (a few drops). To this solution was added dropwise a 1.0 M solution of HCl/ether (1.3 equivalents) and a precipitate was formed. After evaporation of the solvents, the residue was taken up in ether, filtered, and washed with ether to give the product as a white solid (0.011 g, 6%). 1H NMR (DMSO-d6) δ 9.6 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 7.92 (m, 2H), 7.78 (d, 2H), 7.54 (d, 2H), 7.48 (d, 1H), 6.53 (s, 1H), 3.50 (4H, overlapping with solvent), 3.22 (m, 6H), 2.75 (m, 4H), 2.10 (m, 2H), 1.30 (s, 9H), 1.24 (t, 3H); LC-MS: ESI 586 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.O1CCCC1.O>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([N:1]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(c1cc(C#Cc2cncc(C#N)c2)ccc1F)S(C)(=O)=O
Temperature: 50 °C
Yield: 36.2 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous pyridine. Add a solution of methanesulfonyl chloride (0.2 g, 1.9 mmol) in tetrahydrofuran to the reaction and heat at 50° C. for 16 h. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate), to give the title compound as a white solid (114 mg, 36%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.0 g), DMAP (1.55 g) and triethylamine (2.34 g) in DCM (80 mL) was cooled to 0° C. A solution of acetic anhydride (2.35 g) in DCM (20 mL) was added dropwise over 20 minutes and the reaction mixture was stirred at room temperature for 1 hour. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ether and washed with 10% aqueous citric acid solution and brine, dried (MgSO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl 3-acetoxyazetidine-1-carboxylate (2.34 g) as a clear oil.
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:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=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: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 12.4 %

Procedure:
The title compound (17.2 mg) was prepared as in Example 177, Steps C and D, using 206.5 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 193.2 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C19H24FN3, 313.41; found, m/z 314.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.28 (m, 4H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.32-3.27 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.79 (m, 6H), 1.69-1.63 (m, 1H), 1.30-1.19 (m, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
tert-butyldimethylsilyl chloride (3.7 g, 1.5 eq) was added portionwise to a solution of 3-hydroxybenzaldehyde (2.0 g, 16 mmol), triethylamine (3.4 mL, 1.5 eq) and dimethylaminopyridine (50 mg, 0.025 eq) in DCM (100 mL). After stirring for 2 h at rt, water was added. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and concentrated in vacuo to afford 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (3.6 g, 16 mmol, 100%).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:7])=[CH:4][CH2:5][NH2:6].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:8]([O:12][C:3]([CH3:7])([CH2:4][CH2:5][NH2:6])[CH3:2])([OH:11])(=[O:10])=[O:9]
Reactant: CC(C)=CCN
Reactant: O=S(=O)(O)O
Agent: Cl
Product: CC(C)(CCN)OS(=O)(=O)O
Temperature: 90 °C
Yield: 85 %

Procedure:
3-Methyl-2-butene-1-amine hydrochloride (2.86 g, 0.02 mmoles) was dissolved in 5% aqueous sulfuric acid (25 ml) and heated to 90° C. for 18 h. The solvent was removed under reduced pressure yielding 4-amino-2-methyl-butan-2-ol sulfate as a yellow oil (4.73 g, 85%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:18]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([C:24]1[CH:29]=[CH:28][C:27]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=1)=[O:31])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Dimethyl malonate (4.24 g, 32.1 mmol), K3PO4 (18.57 g, 88.0 mmol), and tert-butyl-4-bromobenzoate (7.50 g, 29.2 mmol) were placed in a dry 500 mL flask under N2. Bis(tri-t-butylphosphine)palladium(0) (745 mg, 1.46 mmol) and toluene (100 mL) were added, and the slurry was degassed with N2 for 20 minutes. The reaction was subsequently stirred at 80° C. overnight. The slurry was cooled, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-25% EtOAc/hexanes) afforded dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.96 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.68 (s, 1H), 3.73 (s, 6H), 1.56 (s, 9H). MS: cal'd 331 (MNa+), exp 331 (MNa+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH:40]([C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[C:53](=[O:54])[CH2:52][N:51]([C@@H:55]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C:56](O)=[O:57])[C:50]2=[O:63])[N:47]=1)([CH3:42])[CH3:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:56](=[O:57])[C@@H:55]([N:51]1[CH2:52][C:53](=[O:54])[N:49]([CH2:48][C:46]2[N:47]=[C:43]([CH:40]([CH3:42])[CH3:41])[S:44][CH:45]=2)[C:50]1=[O:63])[CH:59]([CH3:62])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2csc(C(C)C)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2csc(C(C)C)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution containing the product from Example 2C (0.030 g, 0.056 mmol) in THF (0.5 mL) was treated with the product from Example 56E (0.026 g, 0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.033 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.66 (d, J=6.62 Hz, 3 H), 0.73 (t, J=7.35 Hz, 3 H), 0.88 (m, 12 H), 1.26 (s, 3 H), 1.29 (s, 3 H), 1.50 (m, 2 H), 1.73 (m, 1 H), 2.69 (m, 4 H), 3.10 (d, J=18.38 Hz, 1 H), 3.50 (s, 3 H), 3.78 (m, 3 H) 4.17 (m, 3 H), 4.66 (m, 3 H), 6.67 (d, J=9.93 Hz, 1 H), 6.99 (m, 3 H), 7.07 (m, 2 H), 7.23 (m, 3 H), 7.31 (m, 1 H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]2[CH2:33][CH:21]3[N:22](C(OC(C)(C)C)=O)C(=O)[O:24][CH:20]3[CH2:19][CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:34].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:22][CH:21]1[CH:20]([OH:24])[CH2:19][CH2:18][CH:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:34])=[C:2]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][C:38]=3[F:42])[N:7]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3NC(=O)c3ccc(F)c(Br)n3)CC21
Reactant: OB(O)c1c(F)cccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC1CC(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)CCC1O

Procedure:
A solution of tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting cyclic carbamate and Boc groups were deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 443.2 (MH+); LC Rt=2.11 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CS(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: OCc1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
A solution of 2.6 g of 3-hydroxybenzyl alcohol in 10 ml of dry dimethylsulfoxide was added dropwise with stirring under ice cooling to a suspension of 0.88 g of 60% sodium hydride in 5 ml of dry dimethylsulfoxide. After the addition, the mixture was stirred at room temperature for 20 minutes, and 6 g of N-bromopropylphthalimide was added. The mixture was reacted at room temperature for 1 hour, and ice water was added. The mixture was extracted with ether, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized with ether to afford 2.6 g of N-[3-[3-(hydroxymethyl)phenoxy]propyl]phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Nc1cncc(Br)c1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.4 %

Procedure:
To a mixture of 2-[(5-bromopyridin-3-yl)amino]-2-methylpropanoic acid I-4b (2.0 g, 7.72 mmol), 2,2,2-trifluoroethylamine (1.214 mL, 15.44 mmol), HOBT (1.773 g, 11.58 mmol) and DIPEA (2.70 mL, 15.44 mmol) in DMF (20 mL) was added EDC (2.220 g, 11.58 mmol). The mixture was allowed to stir at RT for 18 hr. The reaction was quenched into water (100 mL) and ethyl acetate (100 mL) and aq. KHSO4 added to adjust the pH to 6.5. Organic layer removed, washed with aqueous NaHCO3 (50 mL) and then brine (50 mL). The aqueous extracts were washed with ethyl acetate (50 mL). Organics combined, dried over sodium sulfate, filtered thru a pad of silica and concentrated to give a solid 2.9 gms. Solid slurried in ether, sonicated and filtered to give 2.4 g, (91%) title compound, I-4, as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[OH:12][CH2:11][CH2:10][C@@H:8]1[CH2:9][C@@H:7]1[CH:4]1[CH2:5][CH2:6][N:1]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][N:15]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(O)c1cnc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 65 °C

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (810 mg, 4.79 mmol) and 2-(2-chloropyrimidin-5-yl)propan-2-ol (991 mg, 5.74 mmol) were dissolved in 12 mL of DMF, to which was added cesium carbonate (2.0 g, 6.20 mmol). The mixture was heated at 65° C. overnight. The mixture was cooled to rt, diluted with 20 mL of EtOAc and 20 mL of water. The layers were separated and the aqueous phase extracted with EtOAc (20 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 50 SNAP column, Biotage system) eluting with a range of 40-90% EtOAc/Hex over 12 CV to give the desired compound. LC/MS (m/z): 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30])[CH3:25].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:24]([O:26][C:27]([C:28]1[C:29](=[O:30])[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:5]2[C:6]([C:7]=1[OH:8])=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:32])[CH3:25]
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 42749.8 %

Procedure:
A solution of 9 (0.13 g, 0.38 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (54 μL, 63.0 mg, 0.421 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting precipitate was filtered to give 10 (63.0 g, 43%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C:16]1([OH:23])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=O)C.O.[OH-].[Li+].Cl>O>[OH:23][C:16]1([CH2:15][N:14]2[CH2:13][CH2:12][C:7]3[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=3[C:4]2=[O:3])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCC1(O)CCN(C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Temperature: 135 °C
Yield: 232.4 %

Procedure:
A stirred mixture of 2-{2-[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-amino]-ethyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.931 g, 18.36 mmol) in glycol (257 ml) was added with lithium hydroxide monohydrate (6.169 g, 147 mmol). The resulting mixture was heated to 135° C. for 4 hours. The mixture was added with cold water (250 ml), adjusted to pH from 14 to 12 with 2N hydrochloric acid in an ice-water bath. The mixture was extracted with a 10 to 1 solvent mixture of dichloromethane and methanol (200 ml×8). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography with dichloromethane: methanol:ammonia (600:45:2) as eluents to give 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (11.837 g) as a light brown oil which was used as such.