Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46][CH2:45]4)=[CH:40][CH:39]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][O:29]CC6C=CC=CC=6)[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([C:8]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:45][CH2:46][CH2:47]4)=[CH:40][CH:39]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@@H](COCc7ccccc7)C6)c5)nc43)cc2)CCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@@H](CO)C6)c5)nc43)cc2)CCC1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 18.8 %

Procedure:
10% Pd/C (30 mg) was added to a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-(3-{(2R)-2-[(benzyloxy)methyl]morpholin-4-yl}phenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (31.5 mg, 0.0427 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 14 hours and 7.5 hours at 50° C. under hydrogen atmosphere. The catalyst was removed by filtration through a Celite pad and washed with MeOH. The combined filtrate and washings were concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired compound (5.2 mg, 18.8%) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH2:43])[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>C1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH:43][C:19]([NH:18][C:14]3[CH:13]=[C:12]([N:6]4[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:25])=[C:5]4[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][CH:15]=3)=[S:20])[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCC(c3cccc(OC)c3)CC2)c1
Yield: 94.8 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (500 mg, 1.4 mmol) was refluxed with 4-(3-methoxyphenyl)-piperidine-1-propanamine (380 mg, 1.5 mmol) in 8 mL of benzene for 2 hours. Chromatographic purification (on silica gel, 100% methylene chloride first, followed by 10% (v/v) methanol in methylene chloride) of the residue after concentration in vacuo gave the title compound as a yellow foam (807 mg, 95%); 1H-NMR (CDCl3) δ 7.61 (br, 1H), 7.20 (t, 1H, J=7.9 Hz), 7.12 (t, 1H, J=8.1 Hz), 6.88 (br, 1H), 6.60 (m, 3H), 6.57 (dd, 1H, J=8.3, 2.1 Hz), 6.47 (br, 1H), 3.78 (s, 3H), 3.73 (s, 6H), 3.60-3.80 (m, 2H), 2.94 (m, 2H), 2.37 (s, 6H), 2.25-2.50 (m, 3H), 2.03 (m, 2H), 1.60-1.85 (m, 4H), 1.40-1.60 (m, 2H); 13C-NMR (CDCl3) δ 166.0, 159.6, 152.5, 149.2, 147.7, 130.2, 129.5, 119.5, 115.8, 113.1, 112.2, 111.1, 109.7, 108.8, 63.6, 55.2, 54.2, 51.8, 42.5, 32.8, 25.4, and 18.0.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH2:16]>>[F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]([C:11]([OH:10])=[O:12])[C:7]=1[C:8]([OH:16])=[O:9]
Reactant: O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
After mixing 10 g (0.945 mol) of tetrafluorophthalic anhydride obtained in the above step with 60 ml of water, the mixture was stirred for 3 hours at room temperature. Then, the product was extracted twice with 300 ml of ether and the ether layer thus obtained was dried with anhydrous magnesium sulfate and concentrated by distillation to provide 9.7 g (yield 90%) of tetrafluorophthalic acid as white crystals. By recrystalizing the crystals from an aqueous 6N hydrochloric acid solution, crystals having higher purity (99.5%) were obtained.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: N#CC(C#N)=NNc1ccccc1
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(-c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
1-phenyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 200 mg (1.2 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and phenylhydrazine (767 mg, 7.1 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 77 mg (23%) of the compound as an orange coloured solid.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17](OC)[C:4]=1C([C@@]([C@H](C(O)=O)O)(O)C(O)=O)=O.C[Si](C)(C)OC1CCCCC=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=[O:40].Cl>C(#N)CC.O1CCCC1>[OH:40][CH:39]([C@H:4]1[CH2:17][CH2:18][CH2:19][CH2:20][C:3]1=[O:2])[C:38]1[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH3:34])[CH:37]=1
Reactant: COc1cccc(OC)c1C(=O)[C@@](O)(C(=O)O)[C@@H](O)C(=O)O
Reactant: COc1cccc(C=O)c1
Agent: C[Si](C)(C)OC1=CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCC#N
Product: COc1cccc(C(O)[C@H]2CCCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 149.5 %

Procedure:
To a solution of (R,R)-mono(2,6-dimethoxybenzoyl)tartaric acid (314 mg) in propionitrile (5 ml) was added 1M BH3 solution (1.0 ml) in tetrahydrofuran at 0° C. under N2. The reaction mixture was stirred for 1 hour at 0° C., and then the solution was cooled to -78° C. To this were added 1-(trimethylsilyl-oxy)cyclohexene (1.0 g) and 3-methoxybenzaldehyde (680 mg) successively. After stirring for 2 hours, the solution was poured into 1N-hydrochloric acid and the product was extracted with ether. The solvent was evaporated, and the residue was treated with 1N-hydrochloric acid-tetrahydrofuran solution (2 ml, 1:1). Usual chromatographic separation gave (2R)-2-(1-hydroxy-1-(3-methoxyphenyl)methyl]cyclohexanone (350 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[CH3:12][C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:14]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:17]1[C:13]([CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:16]1)=[O:11])[CH3:8]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.7 %

Procedure:
Potassium carbonate (0.19 g, 1.5 mmol) and ethyl isocyanate (0.09 g, 1.3 mmol) were added to a solution of 5-methyl-3-(4-nitrophenyloxy)pyrazole (0.29 g, 1.3 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/20), to give a white solid of N-ethyl-5-methyl-3-(4-nitrophenyloxy)pyrazole-1-carboxamide (0.38 g, yield: 99.2%). mp: 105-107° C., 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.64 (d, J=0.7 Hz, 3H), 3.40 (dq, J=5.9 and 7.2 Hz, 2H), 5.83 (q, J=0.7 Hz, 1H), 6.75 (m, 1H), 7.20-7.30 (m, 2H), 8.26 (dd, J=2.2 and 7.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:23]N1C(=O)CCC1=O>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[C:21]=1[I:23])[CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2ncccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)c1nc2cccnn2c1I
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-b]pyridazin-2-yl-ethyl)-carbamic acid benzyl ester (2.5 g, 8.44 mmol) in acetonitrile (30 mL) was added N-iodosuccinimide (2.3 g, 10.13 mmol) at rt and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-b]pyridazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2cncc(F)c2)nc2ncccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (165 mg, 0.774 mmol), 5-fluoropyridine-3-boronic acid (109 mg, 0.774 mmol), sodium carbonate (144 mg, 1.75 mmol) and Pd(PPh3)4 (89 mg, 0.077 mmol). Purification by column chromatography (hexanes:EtOAc, 1:0 to 1:1 as eluant) gave 4-chloro-2-(5-fluoropyridin-3-yl)-3-methyl-1,8-naphthyridine. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:23][C:22]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1N
Temperature: 0 °C
Yield: 28.2 %

Procedure:
Twenty grams of (4-methoxyphenyl)hydrazine hydrochloride, 18.6 g of ethyl (ethoxymethylene)cyanoacetate and 15.2 g of potassium carbonate were combined with 200 ml of ethanol and refluxed for 20 hours. The mixture was cooled and poured into ice water. The precipitated solid was collected by filtration, dried and recrystallized from ethanol to afford 8.1 g of 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 28%. mp=209°-211° C.
Reaction SMILES: CN(C)[C:3](=[O:32])[NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)[CH2:6]1.[C:34]1([C@@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O.[ClH:50]>CN1C(=O)CCC1.CC#N>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:13]2[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@@H:5]([NH:4][C:3]([NH:42][C@H:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:41])=[O:32])[CH2:6]3)[N:12]=2)=[CH:22][CH:23]=1.[ClH:50]
Reactant: COCCOc1ccc(Nc2nc(N3CCC[C@@H](NC(=O)N(C)C)C3)cnc2C(N)=O)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COCCOc1ccc(Nc2nc(N3CCC[C@@H](NC(=O)N[C@@H](C)c4ccccc4)C3)cnc2C(N)=O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(2-methoxyethoxyl)phenylamino)pyrazine-2-carboxamide (235) (14 mg, 0.03 mmol) in 1 mL NMP in a sealed tube added (S)-(−)-1-phenylethylamine (50 μL). The mixture was stirred in 100° C. bath for overnight. It was acidified with 0.5 mL TFA, and subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and neat MeCN to isolate the title compound, 3-(4-(2-methoxyethoxyl)phenylamino)-5-((R)-3-(3-((S)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide (506) as HCl salt (9.5 mg). LC-MS (ESI): m/z (M+1) 534.2. UV: λ=268, 276, 304, 339, 375 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=3)[C:31]#[N:32])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=[O:36].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([S:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=3)[C:31]([NH2:32])=[O:36])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(F)c(C#N)c2)n1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(F)c(C(N)=O)c2)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-2-fluorobenzonitrile (270 mg, 0.527 mmol) in TFA/H2SO4 (6 mL, 4:1, v/v) was heated at 65° C. for 8 h. The reaction mixture was cooled to room temperature, and the residue was partitioned into DCM and water. The separated organic layer was washed with satd NaHCO3, dried over MgSO4, filtered through Celite™, and concentrated. Purification by flash chromatography (DCM/EtOAc, 1:1) gave the title product (217 mg, 77%) as a white foam. 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 6H) 4.13 (s, 2H), 6.04 (br s, 1H), 6.36 (m, 2H), 6.65 (br s, 1H), 6.81 (m, 3H), 6.96 (s, 1H), 7.06 (m, 1H), 7.27 (m, 2H), 7.40 (m, 1H), 7.91 (m, 1H); MS (EI) m/z 532 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:5])[CH:6]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A round-bottomed flask was charged with 2-fluoro-5-bromobenzaldehyde (1.01 g) and tetrahydrofuran (50 mL), placed under a nitrogen atmosphere then cooled to −78° C. To this solution was added a 1M solution of phenylmagnesium bromide (5 mL). The reaction was stirred for 15 min then removed from the cold bath and allowed to warm to 0° C. Quenching was achieved by the addition of water and diethyl ether. The organic layer was collected, dried over magnesium sulfate then concentrated to an oil. Purification using silica gel chromatography provided (5-bromo-2-fluorophenyl)(phenyl)methanol as a colorless oil. H1 NMR (d6-dmso): 7.68 (dd, 1H), 7.46 (m, 1H), 7.32 (m, 4H), 7.23 (m, 1H), 7.12 (dd, 1H), 6.16 (d, 1H), 5.89 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[C:11](#[N:16])[CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH4+].[OH-]>O1CCOCC1>[CH2:12]([C:11]1[NH:16][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCC#N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1nc2ccsc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 3.14 g (0.02 mol) of methyl 3-amino-thiophene-2-carboxylate in 30 ml of dioxane was added 1.83 g (0.022 mol) of valeronitrile. Dry HCl was added over a period of 5 hours and the reaction mixture was then heated to 70° C. for 3 hours. The mixture was allowed to stand overnight at room temperature. The reaction mixture was diluted with 200 ml of ice water, made basic by addition of NH4OH and after standing for 30 minutes was filtered, and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with 50% EtOAc/hexanes after applying a suspension of the product in CH2Cl2 to the column. 1H-NMR (CDCl3): 0.96 (t, 3H, J=7.4 Hz), 1.44 (m, 2H), 1.62 (bs, 1H), 1.82 (m, 2H), 2.79 (3 line m, 2H, J=7.8 Hz), 7.33 (d, 1H, J=5.3 Hz), 7.81 (d, 1H, J=5.3 Hz).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[N:22][CH:23]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O>CO>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[N:22][CH:23]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(C(C)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Agent: O=C=O
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@@H](C)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1

Procedure:
The racemic 5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (prepared as in Example 146) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 75% CO2: 25% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as a white foam with Tr of 10.25 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([F:20])[CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1CCCNC1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[CH2:36].C([O-])(=O)C.[Na+]>CN1CCCC1=O.[Pd](Cl)Cl>[F:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:36]=[CH:35]/[C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[F:32])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:15]1
Reactant: C=Cc1ccccc1F
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccccc1CN1CCCC(F)C1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: FC1CCCNC1
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccc(/C=C/c2ccccc2F)cc1)c1ccccc1CN1CCCC(F)C1
Temperature: 130 °C

Procedure:
1-{2-[(4-Bromophenyl)sulfonyl]benzyl}-3-fluoropiperidine (prepared according to the methods of Example 75 Step 1 followed by Example 74 using 3-fluoropiperidine; 63 mg, 0.152 mmol), 2-fluorostyrene (36 μL, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and palladium(II) chloride (1 mg) were combined in 1-methyl-2-pyrrolidinone (0.5 mL) and heated for 2 hours at 130° C. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed further with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 30% ethyl acetate/isohexane, to give the title compound. δH (400 MHz, d6 DMSO): 8.19 (1H, d, J=6.3 Hz), 8.00–7.97 (2 H, m), 7.86–7.82 (2H, m), 7.77 (4H, s), 7.48–7.34 (3H, m), 7.23–7.19 (2H, m), 5.15 (1H, d, J=49 Hz), 4.72 (1H, d, J=13.4 Hz), 4.45–4.40 (1H, m), 3.79–3.73 (1H, m), 3.55–3.51 (1H, m), 3.45–3.32 (2H, m), 3.20–3.14 (1H, m), 1.99–1.93 (2H, m), 1.73 (1H, d, J=12.1 Hz). m/z (ES+) 454 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH2:11][CH2:12][CH3:13])=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[N:6][N:5]2[CH:17]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]1([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][CH2:11][CH2:12][CH3:13])=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[N:6][N:5]3[CH:17]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCNc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCNc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 92.5 °C
Yield: 80.6 %

Procedure:
Nitrogen was bubbled through a mixture of 6-bromo-4-(propylamino) pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 8, 20 mg, 0.067 mmol), phenylboronic acid (24.62 mg, 0.202 mmol), tetrakis(triphenylphosphine) palladium(0) (7.78 mg, 6.73 μmol) and potassium carbonate, 2M (0.135 mL, 0.269 mmol) in dimethoxyethane (0.6 mL) for ˜1 minute. The reaction mixture was then heated to 90-95° C. for 2 hr. The reaction mixture was partitioned between EtOAc (20 ml) and water (20 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and concentrated to a brown residue that was dissolved in MeOH and was subjected to preparative HPLC (Phenomenex 30×100 mm S-5 column; eluting with 45-90% aqueous MeOH+0.1% TFA over an 12 minute gradient, flow rate=1 mL/min, 220 wavelength detection). The product containing fraction was concentrated to afford the title compound (16 mg, 0.054 mmol, 80% yield) as a tan solid. HPLC (condition M): retention time=2.93 min.; LCMS (ES+) m/z: 295.14 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.12 (t, J=7.3 Hz, 3 H), 1.77-1.87 (m, 2 H), 3.83 (t, J=6.5 Hz, 2 H), 7.20-7.31 (m, 2 H), 7.32-7.44 (m, 2 H), 7.66 (d, J=7.5 Hz, 2 H), 7.91 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:16][CH:17]=1
Reactant: CSc1ccc(N=Cc2ccc(C)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(NC(C#N)c2ccc(C)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylbenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15]>N1C=CC=CC=1>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[N:1]1[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Aminobenzimidazole (13.3 g.) is dissolved in 50 ml. of pyridine, and 10.2 g. of phthaloyl chloride is added, causing immediate precipitation. On mixing and heating on the steam-bath, all dissolves. The solution is heated 2 hours on the steam-bath with occasional swirling. It is cooled to room temperature and quenched in 200 ml. of water. After 1 hour agitation, the mixture is filtered free of solids and the solids washed with water. The yield of N-(benzimidazol-2-yl)phthalimide is 11.6 g. Recrystallization from glacial acetic acid results in bright yellow crystals of N-(benzimidazol-2-yl)phthalimide which, after drying, melts at 266°-268° C., λmax. 295.0, E11%cm. 529.