Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.I[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[N:36][C:37]=2[NH2:39])[N:32]([C@H:40]2[CH2:45][CH2:44][C@@H:43]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)[CH2:42][CH2:41]2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]2[N:32]([C@H:40]3[CH2:45][CH2:44][C@@H:43]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)[CH2:42][CH2:41]3)[N:31]=[C:30]([C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:3]([O:2][CH3:1])[CH:8]=3)[C:38]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]carbamate (2.00 g, 0.0052 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.92 g, 0.0044 mol), tetrakis-(triphenylphosphine)palladium (0.300 g, 0.00026 mol) and sodium carbonate (1.35 g, 0.0109 mol) was heated in a mixture of ethylene glycol dimethyl ether (70 mL) and water (35 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (180 mL), the organic layer separated and the aqueous layer further extracted twice with ethyl acetate (250 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate as a white solid (1.88 g, 0.0023 mol). Cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate (0.206 g, 0.00036 mol) was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.126 g, 0.00108 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}-carbamate dimaleate as a white solid (0.224 g, 0.00028 mol):
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccnc1
Reaction time: 4 h
Yield: 17 %

Procedure:
5.0 g (73.4 mmol) of imidazole and 3.36 ml(29.4 mmol) of ethyl bromoacetate were dissolved in 50 ml of dimethylformamide and stirred for 4 hours. Dimethylformamide was removed in vacuo. Then, 100 ml of ethyl acetate was added to the residue and it was washed with saturated sodium chloride solution. Removal of the organic solvent under reduced pressure provided 0.77 g(Yield: 17%) of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])(=[O:7])[NH2:6]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:12]([O:3][CH2:2][CH2:1][O:4][C:12](=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6])(=[O:13])/[CH:11]=[CH:10]\[C:9](=[O:14])[NH:8][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: OCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)OCCOC(=O)/C=C\C(=O)NC(N)=O
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of 3 g of ethylene glycol (0.048 moles), 12 g of N-carbamylmaleimide (0.086 moles) and 0.3 g of zinc chloride (0.0022 moles) in 70 mL of acetonitrile was heated to reflux. After 3 hours, a lot of solid material had been produced from the mixture. The mixture was filtered and the solids washed with acetonitrile and dried to afford 11.7 g of ethylene glycol bismaleurate. M.P.: 158°-60° C.; 1H NMR (DMSO-d6): δ 10.5 (s, 2 H), 7.2-7.8 (m, 4 H), 6.2-6.4 (m, 4 H), 4.3 (s, 4 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:27]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Clc1ccccc1CC1CCNC1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.4 mg). Calcd for C22H21ClN2O2: 380.1292, found 380.1300.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24](=O)([O:27]C)[O:25][CH3:26]>O1CCCC1>[CH3:26][O:25][C:24](=[O:27])[CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 1,1-dimethylethyl 7-acetyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.34 g, 4.60 mmol) in tetrahydrofuran (5 mL) was added to a suspension of sodium hydride (60% oil suspension, 0.80 g, 13.3 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for 5 minutes. Dimethyl carbonate (5 mL) was added and the resulting mixture was stirred at 65° C. for twenty minutes. Then the reaction mixture was cooled, quenched with ice (20 g) and aqueous ammonium chloride (20 mL) then extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water, then brine solution (80 mL each), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (25% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-[3-(methyloxy)-3-oxopropanoyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.94 g, 59% yield). MS (EI) for C18H23NO6: 350 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxynaphthaldehyde (1.24 g, 7.2 mmol) in DMSO (8 mL) was added 2-chloro-5-cyanopyridine (1.0 g, 7.2 mmol) and K2CO3 (2.0 g, 14.5 mmol). The reaction was heated at 80° C. for 4 h. The reaction was cooled to rt and poured into water (100 mL). The resulting solid was filtered, washed with water, ether and air dried to give the title compound: RT=3.54 min; m/z (ES+)=275.0 [M+H]+.
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:26])[O:18][C:19]([CH:23]4[CH2:25][CH2:24]4)([CH:20]4[CH2:22][CH2:21]4)[CH:13]3[CH2:12]2)=O)C=CC=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([CH2:32][N:33]=[C:34]=[O:35])=[CH:30][CH:29]=1>C(O)C.[C].[Pd]>[CH:23]1([C:19]2([CH:20]3[CH2:22][CH2:21]3)[CH:13]3[CH2:12][N:11]([C:34]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:37][CH:36]=4)=[O:35])[CH2:16][CH2:15][N:14]3[C:17](=[O:26])[O:18]2)[CH2:25][CH2:24]1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Reactant: O=C=NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(C3CC3)(C3CC3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
(Phenylmethyl)1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.18 g, 0.50 mmol) was dissolved in ethanol (10 mL). 10% Palladium carbon (17 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite, the Celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting 1,1-dicyclopropyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one was dissolved in tetrahydrofuran (10 mL). (4-Fluoro)benzyl isocyanate (0.25 mL, 2.0 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:4) to obtain the title compound (0.16 g, 87% yield from (phenylmethyl) 1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[C:36]([CH2:35][O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1)([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OCC)CC2c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a slurry of sodium hydride (5 mg, 0.21 mmol) in dimethylformamide (0.5 ml) was added (1RS,3RS )-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.058 g, 0.14 mmol) at ice-bath temperature under argon. After stirring for 15 min, ethyl bromoacetate (50 μl, 0.2 mmol) was added and the solution stirred for 1 h at room temperature. The product was partitioned between ethyl acetate and 3M aq HCl. The organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous) filtration and evaporation followed by chromatography gave (1RS,3RS)-3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.041 g). The product was dissolved in hot ethanol (10 ml) and 1M aq. NaOH added (1 ml). The mixture was refluxed for 1 h then cooled, acidified with 6M-aqueous HCl and extracted with ethyl acetate. After evaporation the residue was crystallized from ethyl acetate/hexane to give the title compound (0.035 g, 93%). m.p. 177°-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Cl:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[C:23](Cl)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:25])[CH3:24])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][Cl:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(N)c(Cl)cc2n1-c1ccc(CCCl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH2:12][C:13]#[N:14])=[CH:3]1.[O:15]([C:17]#[N:18])[K]>>[C:13]([CH2:12][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:17]([NH2:18])=[O:15])[CH:6]=2)[N:2]([CH3:1])[CH:3]=1)#[N:14]
Reactant: Cn1cc(CC#N)c2cc(N)ccc21
Reactant: N#CO[K]
Product: Cn1cc(CC#N)c2cc(NC(N)=O)ccc21
Yield: 80 %

Procedure:
A solution of 7.0 g (0.038 mole) of 1-methyl-5-aminoindole-3-acetonitrile was treated with KOCN as in Example 1 to give a beige solid which was filtered off, washed with cold water and triturated with 50% aq. EtOH to give 6.95 g (80%) of a beige solid: m.p. 250° (dec); nmr (d6 -DMSO) δ(TMS) 8.41 (1, s), 7.65 (1, s), 7.42-7.08 (3, m), 5.73 (2, s, --NH2 --), 4.00 (2, s, --CH2 --) and 3.73 ppm (3H, S, N--CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:15]2[CH2:16][C@@H:17]3[C@@H:13]([CH2:12][N:11]([CH3:10])[CH2:18]3)[CH2:14]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Solvent: CCO
Product: CN1C[C@@H]2CN(c3cc(Cl)nc(N)n3)C[C@@H]2C1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
2-Amino-4,6-dichloropyrimidine (1.64 g, 10 mmol) was added portionwise to a stirred solution (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (1.6 g, 12.5 mmol) in absolute EtOH (10 mL) followed by TEA (1.8 mL, 12.5 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) and resulted in the gradual formation of a tan coloured precipitate. The mixture was refluxed for a total of 3 hours. The mixture was allowed to cool, EtOH (30 mL) was added to the mixture and heated to give a solution and was left to cool to ambient temperature. The resulting solid was collected by filtration, washed with cold EtOH (50 mL) and dried under suction to yield the title compound as a solid (2.07 g, 82%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH2:24][CH2:25]Cl)(=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19]>CN1C(=O)CCC1>[C:4]([O:6][CH2:25][CH2:24][O:23][C:15](=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)OCCCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)/C=C/C(=O)OC
Yield: 17 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.22 g, 1.7 mmol) in NMP (4 mL) was reacted with CsHCO3 (0.38 g, 1.9 mmol) and chloroethyl methyl (2E)but-2-ene-1,4-dioate (0.27 g, 1.4 mmol) to afford 0.068 g (17% yield) of the title compound (45) after purification by silica gel flash chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:3). 1H NMR (CDCl3, 400 MHz): δ 7.03 (q, J=5.2 Hz, 1H), 6.90 (d, J=16.0 Hz, 1H), 6.82 (d, J=16.0 Hz, 1H), 3.82 (s, 3H), 1.60 (d, J=5.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=12.[F:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:2]([C:25]3[CH:24]=[CH:23][N:22]=[C:21]([F:20])[CH:26]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]3[N:4]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COc1cccc2c(Br)c(-c3ccc(F)cc3)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c(-c3ccnc(F)c3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of 3-bromo-2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridine (from Example 27,180 mg, 0.560 mmol), 2-fluoropyridin-4-ylboronic acid (from Example 33, 112 mg, 0.800 mmol) and dichlorobis(triphenylphosphine)palladium (40.0 mg, 0.056 mmol) in N,N-dimethylformamide (6.00 mL) was placed in a pre-heated oil bath at 110° C. To the reaction was added, in a dropwise manner, 2M sodium carbonate (0.840 mL, 1.68 mmol). The reaction was allowed to stir for three hours before cooling to room temperature and filtering through a Celite 545 pad. The Celite filter was washed with ethyl acetate and the filtrate was concentrated to dryness at 50° C. under vacuum. The residue was dissolved in methylene chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to yield the title compound (110 mg, 0.326 mmol, 58%). 1H NMR (CDCl3): δ 8.14(d, 1H, J=5.5 Hz), 7.53(dd, 2H, J=6.0, 8.0 Hz), 7.24–7.32(m, 2H), 7.00–7.10(m, 3H), 6.89(s, 1H), 6.23(dd, 1H, J=2.0, 6.0 Hz), 4.2(s, 3H). MS (ES+ve): 338.1 (40, M+), 323.1 (100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C

Procedure:
A solution of 24 g of 2,3-dimethylpyridine in 100 ml of methylene chloride was treated while cooling with ice with a solution of 46.6 g of m-chloroperbenzoic acid in 100 ml of methylene chloride. The reaction mixture was heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue was chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ether there was obtained 2,3-dimethylpyridine 1-oxide of melting point 56°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(O)(O)[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.[F-].[Cs+]>O1CCCC1.C(OCC)C.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>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16]([C:43]2[C:44]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[CH:41][CH:42]=2)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
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: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(-c2cccc3ccccc23)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of (S)-2-[5-bromo-2-oxo-3-(4-trifluoromethylbenzoylamino)-2H-pyridin-1-yl]-3-phenylpropionic acid methyl ester from Step E (66.8 mg, 0.128 mmol), 1-naphthyleneboronic acid (44.0 mg, 0.256 mmol), cesium fluoride (97 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform complex (13.0 mg, 0.013 mmol) and bis(tri-t-butylphosphine)palladium(0) (16.0 mg, 0.031 mmol) in tetrahydrofuran (2.0 mL) was heated to reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (100 mL), washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated. Purification by medium pressure liquid chromatography on silica gel (1:5 ethyl acetate/hexanes) gave 59 mg (81%) of the title compound as a semisolid. MS 571.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([Cl:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Cl:12][C:7]1[C:8]([C:10]#[N:11])=[N:9][C:4]([C:1](=[O:3])[CH:2]=[CH:15][N:16]([CH3:18])[CH3:17])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)c(C#N)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccc(Cl)c(C#N)n1
Yield: 34.9 %

Procedure:
Compound 64 (633 mg, 2.7 mmol) and N,N-dimethylformamide dimethyl acetal (1.1 mL, 8.1 mmol) in toluene was heated to reflux for 5 h. After which time the solvent was evaporated and the crude product triturated with isoxane/diethylether to give compound 67 as an orange solid (222 mg, 35%); LCMS Rt=2.35 min (MeOH-FA method), m/z 236 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])[CH2:29][CH2:28]1
Reactant: O=C(O)c1nc2ccccc2s1
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)c2nc3ccccc3s2)CC1
Temperature: 50 °C

Procedure:
A solution of benzothiazole-2-carboxylic acid (359 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.525 mL, 3 mmol) were added and the mixture heated at 50° C. for 3 hours. The reaction mixture was cooled, and treated with 10% HCl (15 mL). The solution was extracted with ethyl acetate (15 mL). The ethyl acetate extract was then washed with 10% HCl (15 mL), water (15 mL), and brine (15 mL). Dilution of the remaining solution with ethyl acetate (50 mL) and cooling to −20° C. afforded 25 mg (5%) 412:
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([S:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCBr
Reactant: N#Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Combine 4-mercapto-benzonitrile (0.4 g, 2.96 mmol), bromoethane (1.4 mL, 8.88 mmol) and potassium carbonate (3.3 g, 23.7 mmol) in anhydrous DMF (7 mL) and heat at 60° C. for 17 h. Cool the reaction mixture to ambient temperature and partition between brine (20 mL) and EtOAc (20 mL). Separate the organic layer, dry over anhydrous Na2SO4 and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.4 g, 83%).