Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5])=[N+]=[N-]>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(N)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reaction time: 48 h

Procedure:
A mixture of N-(trans-4-(2-azidopropan-2-yl)cyclohexyl)-3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-amine (90 mg, 0.22 mmol) and Pd/C (30 mg) in MeOH (5 mL) and CH2Cl2 (5 mL) was hydrogenated under 50 psi of H2 at room temperature for 48 h. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-79 (4 mg, 5%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[Li].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:8]1[C:7](=[O:12])[CH:6]2[CH2:13][O:14][CH2:15][CH2:16][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: [Li]
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x38 using 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 500 mg, 2.078 mmol), 1M lithium bis(trimethylsiylyamide) in hexanes (2.493 mL, 2.493 mmol) and (bromomethyl)benzene (0.271 mL, 2.286 mmol) in DMF (10 mL) at 0° C. for 18 hours. 1H NMR (400 MHz, DMSO-d6) δ 2.94-3.06 (m, 1 H), 3.50-3.61 (m, 1 H), 3.62-3.72 (m, 1 H), 3.90-3.99 (m, 1 H), 4.17-4.32 (m, 2 H), 4.56-4.67 (m, 1 H), 5.02-5.22 (m, 2 H), 7.29 (s, 5 H), 7.72 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C16H15ClN4O2, 331.09; found 331.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=2)=[C:4]([O:22]C)[CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=2)=[C:4]([OH:22])[CH:3]=1
Reactant: COc1ccc(C(=O)Nc2cc(OC)c(Cl)cc2OC)cc1F
Solvent: ClCCl
Product: O=C(Nc1cc(O)c(Cl)cc1O)c1ccc(O)c(F)c1
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Boron trifluoride dimethyl sulfide complex (70 mL) was added into a mixture of N-(4 -chloro-2,5-dimethoxyphenyl)-3-fluoro-4-methoxybenzamide (1.75 g, 5.15 mmol) and CH2Cl2 (35 mL). After stirring for 20 h, the solvent and the excess reagent were evaporated under a nitrogen stream in the hood. The residue was taken in a mixture of ice and HCl (1N) and extracted with EtOAc. The organic layer was washed with HCl (1N) and dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/EtOAc 5/3/2, and AcOH 10 mL per 1 liter of the eluting solvent) gave a white solid (1.4 g, 91% yield, m.p. 254–256° C.); MS m/e 296 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cc(Cl)cc(Br)c1
Product: N#CCC(O)c1cc(Cl)cc(Br)c1

Procedure:
Alkylation of 5-bromo-3-chlorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(5-bromo-3-chlorophenyl)-3-hydroxypropanenitrile as a clear oil. Yield (3.21 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=2.0 Hz, 1H), 7.58-7.57 (m, 1H), 7.49-4.48 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 4.93-4.90 (m, 1H), 2.93 (ABd, J=16.8, 5.2 Hz, 1H), 2.86 (ABd, J=17.2, 6.8 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[C@H:10]([O:39]COC)[CH2:9]1)=O)(C)(C)C.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[ClH:43].[CH2:35]([C:19]1[N:18]=[N:17][C:16]([O:15][CH2:14][C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[OH:39])=[CH:21][C:20]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@H]2CCNC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.03 mmol, 0.60 g) in DCM (5 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred for 2 hours. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-3-ol dihydrochloride (0.50 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([O:25]CC)=[O:24].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
6.9 g (17.51 mmol) of ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate from Example 145A were dissolved in 374 ml of THF/methanol (5/1), 87.5 ml (87.5 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 5 hours. After cooling, the mixture was acidified, with ice-cooling, with 6 N aqueous hydrochloric acid, and the organic solvent was then removed on a rotary evaporator. The solid formed was filtered off with suction, washed with water and then dried under high vacuum. This gave 6.7 g of the target compound (108% of theory).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.OO.S([O-])([O-])=[O:27].[Na+].[Na+]>O.CO>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][S:18](=[O:27])[CH2:19][CH2:20]2)=[O:11])=[CH:21][CH:22]=1)(=[O:3])=[O:4]
Reactant: O=S([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCS(=O)CC2)cc1
Temperature: 0 °C

Procedure:
To 50 ml of methanol add 1.0 g (2.93 mmole) of 4-[(methylsulfonyl)amino]-N-[2-(thiomorpholin-4-yl)ethyl]benzamide. Add dropwise 3.08 ml (3.08 mmole) of 1.0N hydrochloric acid. Cool the solution to 0° C. Slowly add 0.70 ml (6.16 mmole) of 30% w/v hydrogen peroxide. Stir the reaction at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (methanol:1M NaCl; 95:5). Upon the completion of the reaction, add 25 ml of 10% sodium sulfite to the stirring solution. Filter the resulting solid. Evaporate the filtrate in vacuo to yield a solid. Stir this solid in H2O overnight, then filter the solid and recrystallize it from methanol to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: OB(O)c1ccncc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.33 g, 1.0 mmol) and commercially available 4-pyridineboronic acid (0.184 g, 1.5 mmol) according to the general procedure IVb. Obtained as a light red solid (0.034 g, 9%). MS (ISP) 370.0 [(M+H)+]; mp 153.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:6]([NH2:8])[CH:7]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:55]=O)(C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])=[N:55][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1cc(Br)ccc1CS(=O)(=O)c1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccc(F)cc1)c1n[nH]c2cc(Br)ccc12

Procedure:
To a suspension of (5-bromo-2-{[(4-fluorophenyl)sulfonyl]methyl}phenyl)amine (Intermediate 68) (0.42 g) in chloroform (10 ml) was added potassium acetate (0.135 g) and acetic anhydride (0.24 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.64 g) and tert-butylnitrite (0.435 ml) were added and the mixture was stirred at reflux for a further 42 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethylacetate (4:1) to give the title compound (0.16 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1ccc(-c2ccnc(-n3cnc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3nccc(-c4ccc(Cl)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-pyrimidine (example E.15) (0.27 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.083 g, 30%). MS (ISP) 349.3 [(M+H)+]; mp 188-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:22]=[C:23]([CH:35]=O)[NH:24][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:23]4[NH:24][C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[C:21]([CH3:20])[CH:22]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C=O)[nH]c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 4-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.6 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 89.1 mg (72%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.13 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.27 (s, 1H), 7.75 (dd, J=2.7 & 6.5 Hz, 1H), 7.71 (s, 1H), 7.52 (m, 1H), 7.38 (t, J=8.85 Hz, 1H), 6.74 (s, 1H), 3.52 (m, 4H, 2×CH2), 2.37 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11]C1C=CC=CC=1.[Br:19]Br>C(Cl)Cl>[Br:19][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:18]
Reactant: O=C(Cc1ccccc1)c1cc(F)c(F)cc1F
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 2′,4′,5′-trifluorophenylacetophenone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at ambient temperature. Ice water was added to the reaction flask and the mixture was stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method d) Rt=2.20 min; MS m/z 251.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (53 mg, 35%) as a yellow solid. NMR (500 MHz, DMSO-d6) δ 10.50 (d, J=8.0 Hz, 1H), 8.96 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.72 (s, 2H), 4.14-4.06 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.23-2.15 (m, 2H), 2.18 (s, 6H), 2.15-2.10 (m, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.61-1.43 (m, 3H), 1.17-1.01 (m, 5H). ESI MS m/z 500 [C27H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.70 min.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[C:1]([CH:9]=[CH:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C=CC(=O)c1ccccc1

Procedure:
3-Benzoylacrylic acid (3 g.) was refluxed for 2 hours with 100 ml. of methylene chloride and 10 ml. thionyl chloride. Concentration to dryness gave 3-benzoylacrylyl chloride. Methanol (15 ml.) was added and the resulting solution stirred for 0.5 hour. Ether (35 ml.) was added. The resulting organic mixture was washed in sequence with 15 ml. of water, 15 ml. of 1N sodium hydroxide and twice with 15 ml. of water, concentrated to an oil, the oil triturated with 25 ml. of hot hexane, decanted from insolubles and the hexane concentrated to yield methyl 3-benzoylacrylate (1.9 g., oil, m/e 190).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=4[F:30])[N:20]=[C:19]4[NH:31][N:32]=[C:33]([CH3:34])[C:18]=34)[C:10]([CH3:36])([CH3:35])[CH2:9]2)[CH2:4][O:3]1>O1CCOCC1.O>[F:30][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[C:21]1[N:20]=[C:19]2[NH:31][N:32]=[C:33]([CH3:34])[C:18]2=[C:17]([CH2:16][N:11]2[C:10]([CH3:35])([CH3:36])[CH2:9][N:8]([CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])[C:13]([CH3:15])([CH3:14])[CH2:12]2)[CH:22]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(C[C@H]4COC(C)(C)O4)CC3(C)C)c12
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(C[C@H](O)CO)CC3(C)C)c12
Yield: 31.3 %

Procedure:
208 mg 4-{4-[4-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-2,2,5,5-tetramethyl-piperazin-1-ylmethyl]-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}-3-fluoro-phenol were dissolved in 2 ml of dioxane and 0.3 ml of water. 2 ml of hydrorchloric acid (4M in dioxane) were added. After 1.5 h at rt the volatiles were removed in vacuo and the residue was purified by HPLC. 60 mg of the title compound ewre obtained.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[N:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][N:29]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)N3CCN(CCO)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-piperazin-1-yl ethanol.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH3:16])[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1.[Br:17]Br.O>C(Cl)(Cl)Cl>[Br:17][C:7]1[C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH3:16])[CH:8]=1
Reactant: CC1(CF)C=Cc2cc([N+](=O)[O-])ccc2O1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(CF)C=C(Br)c2cc([N+](=O)[O-])ccc2O1

Procedure:
To 8.24 g of 2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran dissolved in 100 ml of chloroform was added dropwise 2.7 ml of bromine with stirring under cooling with water, and the mixture was stirred for 20 hours at room temperature. After the solvent was removed, 100 ml of dioxane and 2N NaOH solution were added to the residue and stirred at room temperature for 16 hours. When ice-water was added to the reaction mixture, crystals were separated out. The crystals were collected by filtration, washed with water and dissolved in methylene chloride. It was washed with water and dried. The solvent was evaporated off to obtain 11.01 g of 4-bromo-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran with a melting point of 116°-117° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)[CH2:2][CH3:3].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH3:3])[CH:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCC(=O)c1cccnc1
Solvent: CCO
Product: CCC(=NNC(=O)c1ccccc1)c1cccnc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 6.76 gm (0.05 mole) of 3-propionylpyridine, 6.81 gm (0.05 mole) of benzhydrazide and 100 ml of absolute ethanol is refluxed 8.5 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled. The crystals that separate are collected and dried to yield 10.18 gm (80%) of the title compound having a melting point of 169.4° C.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][N:32]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCNCC3)ccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCN(S(C)(=O)=O)CC3)ccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (92) (15.6 mg, 0.032 mmol) and Et3N (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (0.0074 mL, 0.095 mmol) and stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F49). MS (m/z) 571.1 (M+1)+.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: COc1cnccc1N
Product: CCc1cc2c(C(=O)Nc3ccncc3OC)cnc(OC)c2o1
Yield: 86.1 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (170 mg) and 4-amino-3-methoxypyridine (120 mg). Purification by column chromatography on silica eluting with ethyl acetate gave the title compound (0.14 g) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2[O:8][N:7]=[C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: ON=C(Cl)c1ccc(Cl)nc1
Reactant: C#Cc1cccc(Cl)c1
Agent: N
Product: Clc1cccc(-c2cc(-c3ccc(Cl)nc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 95B (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, CDCl3) δ6.88 (s, 1H), 7.43-7.52 (m, 3H), 7.69-7.78 (m, 1H), 7.81-7.89 (m, 1H), 8.18 (dd, J=8.3, 2.4 Hz, 1H), 8.84 (d, J=2.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.