Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.O.C([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([Br:20])=[CH:18][CH:19]=2)[C:10]1=[O:22])(=O)C>ClCCl>[Br:20][C:17]1[N:16]=[C:15]([CH3:21])[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([OH:8])[C:10]2=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)OC1CCN(c2ccc(Br)nc2C)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc(Br)ccc1N1CC[C@@H](O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
To a jacketed 5.0 liter glass reactor was added 2.150 liter of acetonitrile and 250 mL of water (10%, 27.78 moles, ˜87 molar equivalent to acetate). The temperature was set to 25° C. Then, to the same reactor was added 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (50 g, 0.160 moles, 20 g/L), followed by 100 mL of acetonitrile The reaction mixture was stirred for 10 min at 90 rpm until complete dissolution. To the reaction mixture added 12.5 g of Novozym 435 (Enzyme to substrate 1:4) with continuous stirring under same reaction conditions. The temperature of the reaction was maintained at 25° C. during the course of the reaction. The reaction was stopped after 28 h, and the Novozym 435 was filtered. The reaction mixture was concentrated to dryness 30° C. to yield a viscous brownish liquid. The reaction mixture was taken out in 75 ml dichloromethane and stirred it at room temperature for 1 h. To the reaction mixture was added 100 g of silica gel, and slurry was then allowed to dry under pressure. A Column was packed with ˜400 g of silica gel in heptanes and slurry was loaded into column with heptane. The column was run using 50% ethyl acetate-heptane until all the undesired chiral acetate was recovered. After the removal of acetate, the column was eluted with pure ethyl acetate and the (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one containing fractions were combined. The mixture was concentrated down to 50 mL under pressure at 20° C., stirred for 30 min, filtered, and washed with heptane. 16.042 g of (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one was obtained, as off-white solid, AP 99.4, ee 99.9% in 37% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18]([C:15]1[N:13]2[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:3][CH2:4]3)[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]2=[N:17][CH:16]=1)=[O:19]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5C (40 mg, 0.057 mmol) in CH2Cl2 (1 mL) was added DIEA (0.043 mL, 0.248 mmol) and methyl 2-bromoacetate (9.68 mg, 0.063 mmol). The solution was heated to 50° C. overnight. The volatiles were removed via a stream of nitrogen. The resulting dark brown oil was taken up in TFA (0.75 mL) and heated to 65° C. for 2 h, and then cooled to room temperature. The volatiles were removed under a stream of nitrogen and the crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 60 min at 25 mL/min, monitoring at 220 nm, and a total run time of 70 min. (Rt of desired=46.365 min) Appropriate fractions were concentrated and lyophilized overnight to afford methyl N-(trans-4-((3-((3-fluoro-4-pyridinyl)carbamoyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate (23 mg, 0.030 mmol, 52.5% yield). HPLC Rt=3.335 minutes. (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA. [M+H]=534.1.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[C:32]([O:36][C:37](ON1C(=O)CCC1=O)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[CH2:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:2]([NH:1][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyl 2-amino-6-benzyloxycarbonylamino-hexanoate (1.0 g, 2.68 mmol) was dissolved in N,N-dimethylformamide (50 mL) and then triethylamine (5.35 mmol, 0.75 mL) followed by N-(tert-butoxycarbonyloxy)succinimide (0.72 g, 3.35 mmol) was added to the solution. The mixture was stirred overnight and then concentrated. The product was purified from the residue by silica gel chromatography (20% MeOH/chloroform) to give tert-butyl 6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoate. The tri-protected product was reduced on a Parr hydrogenator (50 psi) to remove the benzyloxycarbonyl protecting group. The solvents were removed to give tert-butyl 6-amino-2-tert-butoxycarbonylamino-hexanoate (0.65 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]3([C:17]4[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]5[C:18]=4[CH:19]=[CH:20][N:21]5C(OC(C)(C)C)=O)[CH2:12][CH:11]3[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C3(C4C(OC)=CC(C)=C5C=4C=CN5C(OC(C)(C)C)=O)CC3C(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl[Sn](Cl)(Cl)Cl>ClCCl>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[NH:7][C:8]([C:10]3([C:17]4[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]5[C:18]=4[CH:19]=[CH:20][NH:21]5)[CH2:12][CH:11]3[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C1CC1(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)C1CC1(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1CC1(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(methoxy carbonyl)cyclopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-(methoxy carbonyl)cyclopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 142-B) (680 mg, 1.078 mmol) in dichloromethane (10.0 mL) at 0° C. was added a 1.0M solution of SnCl4 in dichloromethane (10.78 mL, 10.78 mmol). This mixture was stirred for 30 min at 0° C. followed by 60 min at room temperature. The reaction was partitioned between EtOAc and a saturated aqueous sodium bicarbonate solution. The layers were filtered through Celite® to remove emulsion formed and then the layers were separated. The organic phase was brine washed, dried over Na2SO4 and concentrated in vacuo to afford the crude product. This material was purified using FCC eluting with ethyl acetate/heptane (30-100%) to afford the title compound. MS (ESI+) m/z 401.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[C:30]1([NH:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:22]=[CH:21][C:11]4[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(-c3cccc(NC(=O)Nc4ccccc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A suspension of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea (0.062 g, 0.20 mmol), triethylamine (0.083 mL, 0.60 mmol, 3.0 eq), and phenyl isocyanate (0.055 mL, 0.50 mmol, 2.5 eq) in 2 mL toluene was stirred at room temperature for about 1 hour. The white precipitation was filtered off, washed with Et2O and MeOH, and dried under vacuum to give the desired compound 0.038 g (44%). LC/MS 431.8 (M+1); LC retention time 3.49 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3)ccc21
Yield: 35 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 4-chlorophenyl boronic acid. The title compound was obtained as a pale yellow solid, (yield=35%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[C:33]([CH:35]=1)[NH2:34].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:34][C:33]1[CH:35]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=1[CH3:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(F)cc1N
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
6.9 g of sodium triacetoxyborohydride (32.5 mmol) was added to a solution of 5.08 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (27.1 mmol), 5 g of 5-fluoro-2-methylaniline (27.1 mmol) and 1.55 ml of acetic acid (27.1 mmol) in methylene chloride (270 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=8/1) to obtain 5.68 g of the title compound (yield: 71%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:13]1([O-:22])[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:19]([C:16]2[CH:15]=[CH:14][N+:13]([O-:22])=[CH:18][CH:17]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc[n+]([O-])cc1
Reaction time: 0.75 h

Procedure:
1,1'-Carbonyldiimidazole (3.829 g, 23.6 mmol) was added to a suspension of 4-pyridinecarboxylic acid-1-oxide (2.986 g, 21.5 mmol) in dry dimethylformamide (50 ml) and the resulting solution was stirred for 45 minutes and treated with a solution of 4-chlorobenzenamine (3.012 g, 23.6 mmol) in dry dimethylformamide (20 ml). After 18 hours, the solution was evaporated in vacuo to give an oil which slowly solidified. The solid was recrystallised from ethyl acetate-cyclohexane and suspended in saturated aqueous sodium bicarbonate solution. The mixture was stirred vigorously for 20 minutes, filtered, and the crystals washed with water (3×10 ml) and ethanol (3×10 ml) and dried in vacuo to give the title compound as a quarter hydrate (1.614 g), m.p. 247°-249°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:43][C:38]4[N:39]=[CH:40][CH:41]=[CH:42][N:37]=4)(=[O:21])=[O:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (15.0 g, 25.24 mmol) and pyrimidin-2-amine (4.8 g, 50.48 mmol, Alfa Aesar) in THF (300 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 50.5 mL, 50.5 mmol, Aldrich) at 78° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 1.5 N HCl (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with 1.5N HCl (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product which was purified by column chromatography (Silica gel; 60-120 mesh, eluent: 3-5% Methanol in DCM) to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-N-2-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide (9.6 g, 75.3%) as off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.56-8.42 (m, 3H), 8.26 (d, J=9.6 Hz, 1H), 7.95 (dd, J=8.9, 2.1 Hz, 1H), 7.66 (d, J=6.2 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.05 (s, 1H), 6.79 (dd, J=16.1, 9.3 Hz, 2H), 3.68 (s, 3H); LCMS (ESI) m/z 505.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24])#[N:17]>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.COCCOC.O>[NH2:14][C:13]1[C:8]2[N:9]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[N:6][C:7]=2[C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([CH:19]=2)[C:16]#[N:17])[CH:10]=[CH:11][N:12]=1
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1F

Procedure:
Into a 10 mL microwave vessel were added 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (100 mg, 0.0003 mol), 3-cyano-4-fluorophenylboronic acid (0.068 g, 0.00041 mol) potassium carbonate (88 mg, 0.00063 mol), Pd(PPh3)4 (40 my, 0.00003 mol), DME/Water (5:1) (5:1, DME:H2O, 1 mL) and the vessel was degassed 3× with N2. The reaction was microwaved on 300 watts, 100° C. for 45 min. The reaction vessel was resubjected to the microwave heating under the same conditions as before for 45 min. Purification by prep TLC using 4% MeOH in DCM eluting twice afforded 54 mg of the title compound as a yellow solid. MS (ES+): m/z 308.11 (100)[MH+]. HPLC: tR=2.14 min (Open Lynx polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2NN.C([O-])(O)=O.[Na+]>O.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[CH:5]2
Reactant: NNc1cnnc2ccc(Br)cc12
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Brc1ccc2nnccc2c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A solution of Example 34E (3.5 g, 14 mmol) in water (50 mL) was heated to reflux, treated dropwise with a solution of CuSO4 (2.8 g, 17.5 mmol) in water (20 mL), refluxed for 2 hours, cooled to room temperature, adjusted to pH 7 with saturated NaHCO3 (aq), and extracted with ethyl acetate (2×25 mL). The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.7 g, 24%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:15]1=[O:26].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:22][CH2:21][CH:20]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:14]([NH:13][C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:15]3=[O:26])[CH2:25][CH2:24]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (prepared according to the method of Example 45) (0.35 g, 0.862 mmol), 2-chloro-5-ethylpyrimidine (0.123 g, 0.862 mmol) and DIEA (0.334 g, 2.59 mmol) were dissolved in DMF (5 mL) and The reaction was stirred at 100° C. overnight. The reaction was cooled to ambient temperature and concentrated. The residue was purified over silica gel (50-100% EtOAc in hexanes) to afford (S)-1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.142 g, 0.299 mmol, 34.6% yield) as a yellow solid. Mass spectrum (apci) m/z=476.2 (M+H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)=[C:20]([F:27])[CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1F
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2F)cc1
Yield: 57 %

Procedure:
In accordance with Example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, and (4-bromo-2-fluorophenyl)boronic acid instead of (4-bromophenyl)boronic acid, the title compound (yield 57%) was afforded as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[C:7](Br)=[C:6]([O:15][CH2:16][O:17][CH3:18])[CH:5]=1.[F-].[Cs+].[CH3:22][C:23](=[CH2:38])[CH2:24][Sn](CCCC)(CCCC)CCCC>CN(C=O)C.[Cu]I.Cl[Pd]Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[C:7]([CH2:24][C:23]([CH3:38])=[CH2:22])=[C:6]([O:15][CH2:16][O:17][CH3:18])[CH:5]=1
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Reactant: COCOc1cc(C(=O)OC)cc(OCOC)c1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(OCOC)cc(C(=O)OC)cc1OCOC
Temperature: 45 °C
Yield: 125.4 %

Procedure:
To a solution of 4-bromo-3,5-bis-methoxymethoxy-benzoic acid methyl ester (3h) (3.10 g, 9.25 mmol) in DMF (20 mL) was added CsF (2.80 g, 18.4 mmol), CuI (200 mg, 1.05 mmol), PdCl2 (200 mg, 1.12 mmol), 2-methylallyltributyltin (3.80, 11.0 mmol) and PtBu3 (220 mg, 1.09 mmol). The reaction mixture was degassed and heated to 45° C. overnight. The mixture was filtered through Celite, quenched with H2O (100 mL), extracted with EtOAc (2×100 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give the desired product as brown oil (3.6 g) which contained tin impurities. 1H NMR (400 MHz, CDCl3) δ 7.44-7.46 (m, 2 H) 5.22 (s, 4 H) 4.61-4.76 (m, 1 H) 4.38-4.55 (m, 1 H) 3.90 (s, 3 H) 3.47 (s, 6 H) 3.42-3.45 (m, 2 H) 1.80 (s, 3 H); LCMS for C16H22O6 m/z 311.10 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[CH:25][CH:26]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)benzoate (515 mg) in N,N-dimethylformamide (10.0 mL) was added 55% sodium hydride (65.0 mg) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Under ice-cooling, tert-butyl bromoacetate (0.300 mL) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-(2-{[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}ethyl)benzoate (473 mg).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]#[N:34]>C1COCC1>[NH2:34][C:33]1[C:28]2[C:27](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Reactant: N#Cc1ccccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cccnc3[nH]2)c(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20 minutes, a solution of 2-aminobenzenecarbonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 3 hours, and then refluxed overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. A precipitate formed, was filtered off, and was washed repeatedly with ether to yield the desired compound as a light brown solid. LC/MS m/z 278.2 (MH+), Rt 1.82 minutes.