Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH3:9].[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(N)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NO)nc1C(N)=O
Product: N
Temperature: 45 °C
Yield: 107.1 %

Procedure:
A solution of 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxamide (Preparation 74) (133 mg, 0.31 mmol) in ethanol (6 ml) was treated with 5% palladium on barium sulphate (80 mg) and ammonium formate (196 mg, 3.10 mmol) and the mixture was heated at 45° C. for 2.5 hours. The solution was filtered through Arbocel® and the solvent removed from the filtrate under reduced pressure. The residue was azeotroped from dichloromethane (×3) then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0.2 to 90:10:1) to afford the title compound as a white solid (56 mg).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:3][CH:2]=1.[CH2:29](C1C=CC(N=C=O)=CC=1)C>>[CH2:28]([C:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:5][CH:6]=1)[CH3:29]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Reaction time: 2.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 2.5 h. The title compound is obtained as a white solid: ES-MS: 403.0 [M+H]+; single peak at tR=9.72 min (System 2).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:12]1(C)[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)C.Cl>[CH:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[C:2]1[C:16]3[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=3[N:18]=[C:1]12
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: C1=C2C(=Nc3ccccc32)c2ccccc21

Procedure:
A mixture of 1-indanone (30.6 g, 232 mmol) and p-tolylhydrazine hydrochloride (37.0 g, 233 mmol) in ethanol (350 mL) and aqueous HCl (12 N, 18 mL) are heated to reflux for 90 minutes. The mixture is cooled and filtered, and the solid is washed with ethanol (600 mL) followed by 20% aqueous ethanol (400 mL) and finally hexanes (200 mL). The off-white solid is dried under vacuum (36.5 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][O:21][C:22](=[O:24])[CH3:23].[H][H]>CO>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][O:21][C:22](=[O:24])[CH3:23]
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1COC(C)=O)NC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1COC(C)=O)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylic acid methyl ester (1.9 g, 4.2 mmol) in anhydrous methanol under nitrogen atmosphere was added 1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclootadiene)rhodium (I) trifluoromethanesulfonate (50 mg) and stirred on a Parr shaker at 50 psi of hydrogen atmosphere for 18 h. The solvent was evaporated and the desired product was crystallized from ethyl acetate-hexane in 90% yield. MS (ESI) 458 (M+H); Rf=1.81.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].N1(CC([C:15]2[C:28]3[NH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[C:29](=[S:31])[NH2:30])C)CCCCCC1.S>C(O)C>[N:4]1([CH2:17][CH:18]([N:27]2[C:28]3[CH:15]=[C:16]([C:29](=[S:31])[NH:30][CH2:22][CH2:21][CH3:26])[CH:17]=[CH:18][C:19]=3[S:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:19])[CH2:28][CH2:15][CH2:16][CH2:3][CH2:2][CH2:1]1
Reactant: CC(CN1CCCCCC1)c1c(C(N)=S)ccc2c1Nc1ccccc1S2
Reactant: CCCN
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
n-Propylamine (3.3 cc) is added to a solution of -[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.2 g) in absolute ethanol (80 cc). The mixture is saturated with hydrogen sulphide and then brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is diluted with ethyl 5 acetate (150 cc), washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) before being purified by chromatography on a column (height: 32 cm; diameter: 4 cm) of silica gel (0.06-0.2 mm), eluting with a 60:40 (by volume) mixture (1,000 cc) of cyclohexane and ethyl acetate, collecting 60-cc fractions. Fractions 3 to 11 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinethiocarboxamide (2.5 g) in the form of a clear orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH3:15][S:16]([N:19]=[C:20](SC)[S:21][CH3:22])(=[O:18])=[O:17]>C(OCC)(=O)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:20]([S:21][CH3:22])=[N:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:7][CH:8]=1)[CH3:14]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: CCOC(C)=O
Product: CSC(=NS(C)(=O)=O)NCCSCc1ccc(CN(C)C)o1
Yield: 79 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-furanmethanamine (2.97 g) and methylsulphonylcarbonimidodithioic acid, dimethyl ester (4.0 g) in ethyl acetate (250 ml) was refluxed for 18 hours. The mixture was washed with acetic acid (0.126 ml) in water (20 ml) three times, the aqueous extracts combined and the pH adjusted to 9 with 8% aqueous potassium carbonate. The oily suspension was extracted with ethyl acetate (3×125 ml), the combined extracts dried (magnesium sulphate) and evaporated to dryness to give the title compound (4 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][C:12]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH3:24])([CH3:16])[CH3:15]>O1CCOCC1.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:27][C:26]([F:29])([F:28])[C:12]([CH2:11][C:10]1[NH:1][C:2]2[C:3]([CH:9]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[F:8])([OH:25])[CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH3:24])([CH3:15])[CH3:16]
Reactant: Cc1ccc(F)cc1C(C)(C)CC(O)(CC#Cc1cccc(F)c1N)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cccc(F)c2[nH]1)C(F)(F)F
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of 1-(2-amino-3-fluorophenyl)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (900 mg, 2.2 mmol) in 10 mL of anhydrous dioxane was treated with dichlorobis(triphenylphosphine)palladium (II) (250 mg, 0.36 mmol) and the mixture was heated at 100° C. for 60 hours. The crude reaction mixture was purified on SiO2 (20% dichloromethane in hexanes) to afford 700 mg of the title product as a yellow oil (78% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.N12[CH2:22][CH2:21]CN=C1CCCCC2.[OH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:23][CH2:21][CH3:22])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 5-bromo-2-chloro-3-nitropyridine (100 mg, 0.42 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (315 uL, 2.11 mmol) in ethanol (1 mL) was heated to 50° C. for 50 min and then cooled to rt. Water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with 1 N HCl, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 90% hexanes:10% ethyl acetate) to provide 5-bromo-2-ethoxy-3-nitropyridine (52.2 mg, 0.211 mmol, 50% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, 1H), 8.36 (d, 1H), 4.55 (q, 2H), 1.45 (t, 3H); MS (EI) for C7H7BrN2O3: 246, 248 (M).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[C:12]=2[CH3:27])[CH:7]=[N:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:28])=[O:2])=[C:12]([CH3:27])[N:13]2[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cncc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Sc2cncc(C(=O)O)c2)c2ccc(Cl)cc2n1-c1cnn(C)c1

Procedure:
5-[6-Chloro-2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-ylsulfanyl]-nicotinic acid methyl ester (from the previous step) was dissolved in THF:MeOH (1:1, 4 mL) and LiOH (1 M aq., 2 mL) was added. After 15 minutes the reaction mixture was concentrated to dryness then purified via preparatory HPLC (10-100% ACN in H2O, 15 minute run, r.t.=8.21 minutes) to provide the desired product. Mass spectrometric data: [M−H]=397.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][NH:40][CH2:41][CH2:42][C:43]#[N:44])[CH:36]=[N:37][CH:38]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.CO>[C:43]([CH2:42][CH2:41][NH:40][CH2:39][C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:38]=[N:37][CH:36]=1)#[N:44]
Reactant: CC1(C)OB(c2cncc(CNCCC#N)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCC#N)c4)cc23)CC1
Yield: 17.4 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.072 mmol) was added 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile (24.8 mg, 0.086 mmol). To this mixture was added dioxane (0.75 mL), followed by a solution of potassium carbonate (60 mg, 0.434 mmol) in water (0.25 mL) and SK-0002-A (4.4 mg, 0.007 mmol). The vials were capped and reacted in a CEM microwave at 150° C. for 30 min. The reaction was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was purified on the Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru a 5 g CHQAX cartridge primed with 4 mL of methanol and 4 mL of water. The solvents were evaporated under a stream of N2 at 65° C. to give 6.2 mg of the title compound (17.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([N:30]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:49](=[O:56])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[NH2:50].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[C:52]([O:51][C:49](=[O:56])[NH:50][C:2]1[N:7]=[CH:6][C:5]2[C:8]([N:30]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(N)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(NC(=O)OC(C)(C)C)ncc23)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
Under inert atmosphere, to a solution of 6-chloro-N,N-bis(4-methoxybenzyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (0.5 g, 0.77 mmol) in anhydrous 1,4-dioxane (10.0 mL) was added tert-Butyl carbamate (0.26 g, 2.3 mmol), brettphos pre catalyst (0.03 g, 0.004 mmol), Cs2CO3 (0.75 g, 2.3 mmol) and the contents were heated in a sealed tube at 100° C. After 6 h, the reaction mixture was brought back to ambient temperature and the volatiles were removed under reduced pressure. The residue thus obtained was purified by a flash column chromatography to afford the title compound (0.4 g, 71% yield). MS ES calc'd. for C46H45N5O4 [M+H]+ 732. Found 732.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([CH3:9])[C:7](=[O:10])OC1=O)(=[O:3])[CH3:2].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([C@@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=1.Cl>C(OCC)(=O)C>[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:7](=[O:10])[C@H:8]([CH3:9])[NH:4][C:1](=[O:3])[CH3:2])[CH3:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
(S)-3-Acetyl-4-methyl-2,5-oxazolidinedione (N-acetyl-L-alanine-NCA)(424 mg, 2.7 mmol) was dissolved in ethyl acetate (10 mL), followed by the addition of (S)-1-(p-tolyl)ethylamine (406 mg, 3 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting white solid was washed with hexane-ethyl acetate to afford the title compound (380 mg, 57%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CC(O)=O.CC(O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cc(C2CCNCC2)ccc1N
Reaction time: 72 h
Yield: 12 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]pyridine (Example 137, step A) (4.6 g, 20 mmol) in HOAc (20 mL) is added platinum oxide (460 mg, 2 mmol). The reaction was evacuated then refilled with 60 psi H2 gas. The reaction was stirred under a H2 atmosphere for 3 days. The reaction was evacuated and the atmosphere replaced with N2. The solvent was removed under vacuum, and the residue taken up in DCM/MeOH. Silica was added, and the solvent removed under vacuum. Silica gel chromatography provided material which contained product and other impurities. This material was dissolved in iPrOH and allowed to stand overnight. The crystals which formed were collected by decanting off the solvent and rinsing with iPrOH. Obtained the title compound of step A (500 mg, 2.4 mmol, 12%) slightly wet with iPrOH as colorless crystals. 1H NMR (400 MHz, DMSO-d6) δ 6.68-6.60 (m, 3H), 3.83 (s, 3H), 3.71 (br s, 2H), 3.38-3.31 (m, 2H), 2.85-2.75 (m, 2H), 2.59-2.49 (m, 1H), 1.91-1.75 (m, 5H).
Reaction SMILES: CO[CH:3]1[C:11]2[C:6](=[C:7]([CH2:14][CH2:15][C:16]3(O)[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH:4]1[CH3:26].C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH2:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH2:15][CH2:14][C:7]1[C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=[C:11]2[C:6]=1[CH2:5][C:4]([CH3:26])=[CH:3]2
Reactant: COC1c2cc(C)c(C)c(CCC3(O)Cc4ccccc4C3)c2CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(C)c(C)c(CCC3=Cc4ccccc4C3)c2C1

Procedure:
To a hot (110° C.) solution of 6.0 g (18.61 mmol) of 2-[2-(1-methoxy-2,5,6-trimethyl-2,3-dihydro-1H-inden-4-yl)ethyl]indan-2-ol in 130 ml of toluene 0.708 g (3.72 mmol) of TsOH*H2O was added. This mixture was refluxed with a Dean-Stark trap for 30 min, and then passed through short column with Silica Gel 60 (40-63 um, d 80 mm, l 60 mm). The column was additionally washed with 300 ml of toluene. The combined elute was evaporated to dryness. The product was isolated by flash chromatography using a short column with Silica Gel 60 (40-63 um, d 60 mm, l 70 mm; eluent: hexanes/ether=50/1). Yield 4.58 g (82%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:22]=[CH:23][CH:24]=1>>[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[N:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(-n2nccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 393.13 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:15]([O:14][CH3:13])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Br)cc1F
Reactant: CNOC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(Br)cc1F

Procedure:
A solution of crude 5-bromo-3-fluoropyridine-2-carboxylic acid (40.65 g, 184.8 mmol), O,N-dimethylhydroxylamine hydrochloride (21.63 g, 221.7 mmol), 1-ethyl-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride (70.85 g, 369.6 mmol), 1-hydroxy-7-azabenzotriazole (2.497 g, 18.48 mmol), and triethylamine (16.48 mL, 118.3 mmol) in 200 mL DMF was stirred at room temperature overnight. The solution was partially concentrated in vacuo and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate. The aqueous layer was extracted 4× with ethyl acetate, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 5-bromo-3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 263.01 for M+H+(79Br).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1.[OH-:29].[Na+].OO>CO>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([NH2:24])=[O:29])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCOc1ncc(Cc2cnc(C(N)=O)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 5-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile (Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH (0.78 mL, 0.78 mmol), followed by hydrogen peroxide (0.78 mL, 0.79 mmol) The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated, and the precipitate filtered and washed with water to obtain the title compound as a white solid (70 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91-7.84 (m, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H), 7.44-7.02 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=402.26.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-fluoro-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: FC(F)(F)C1C=CC(NC2N=C3C=CC=C([C:18]4[CH:19]=[CH:20][C:21]5[N:25]=[C:24]([C:26]#[N:27])[NH:23][C:22]=5[CH:28]=4)N3N=2)=CC=1>N>[NH:23]1[C:22]2[CH:28]=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]=[C:24]1[C:26]#[N:27]
Reactant: N#Cc1nc2ccc(-c3cccc4nc(Nc5ccc(C(F)(F)F)cc5)nn34)cc2[nH]1
Agent: N
Product: N#Cc1nc2ccccc2[nH]1
Yield: 96.1 %

Procedure:
6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazole-2-carbonitrile. A solution of 5-(2-(trichloromethyl)-1H-benzo[d]imidazol-6-yl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyridin-2-amine (380 mg, 0.745 mmol) in methanolic ammonia solution (20 mL) was stirred at 0° C. to room temperature for 2 h. The solvent was removed under reduced pressure to give crude 64244-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)-1H-benzo[d]imidazole-2-carbonitrile (300 mg, 96.1% yield). MS (ESI): m/z 420.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1cccc(OC(F)(F)F)c1
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.