Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]4)[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(=[O:38])C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][CH:27]([OH:29])[CH:28]4[OH:38])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3C=CC(O)C3)c2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Reaction time: 3 h

Procedure:
To a solution of the product of step d) (0.78 g), pyridine (0.43 ml) and 4-dimethylaminopyridine (1 mg) in dichloromethane (15 ml) was added acetyl chloride (0.16 ml). The solution was stirred for 3 hours and then concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate:hexane 1:1 as eluant) to afford the sub-title compound (0.75 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=O)[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: Cc1c(C(=O)c2ccccc2C(=O)O)cc(F)c2c1CCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2C(=O)O)cc(F)c2c1CCCO2

Procedure:
A mixture of 2-(8-fluoro-5-methylchroman-6-carbonyl)benzoic acid (673 mg, 2.141 mmol) in acetic Acid (15 mL) was treated with Pd/C (60.0 mg) and the mixture was stirred under 50 psi of hydrogen at 65° C. until the reaction was judged complete by LCMS. The mixture was filtered over Celite and the filtrate was concentrated to give the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.05 (m, 5 H), 2.63 (t, J=6.44 Hz, 2 H), 3.95-4.15 (m, 2 H), 4.24 (s, 2 H), 6.57 (d, J=12.29 Hz, 1 H), 6.95 (d, J=7.61 Hz, 1 H), 7.21-7.34 (m, 1 H), 7.42 (td, J=7.56, 1.27 Hz, 1 H), 7.81 (dd, J=7.71, 1.07 Hz, 1 H), 12.92 (br. s., 1H); LC/MS (m/z) ES+=301 (M+1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cnc3c([N+](=O)[O-])cccc32)cc1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred suspension of sodium hydride (665 mg, 16.64 mmol) in DMF (90 mL) at rt was added 4-nitro-1H-benzimidazole (2714 mg, 16.64 mmol) in several portions. After stirring for 1 h, 4-fluorobenzonitrile (1350 mg, 11.146 mmol) was added and the mixture was stirred for 15 h at 130° C. After cooling, water was added, the precipitate was filtered off, washed with water and dried to yield 4-(4-nitro-benzoimidazol-1-yl)-benzonitrile (2.47 g, 47.76%).
Reaction SMILES: CN(C=O)C.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>C(N(CC)CC)C>[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CN
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
In a DMF solution containing a mixed anhydride prepared from 2.0 g oi Boc-Phe-OH, 1.15 ml of triethylamine and 1.08 ml of isobutyl chloroformate, 1.50 ml of isobutylamine was added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.91 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1Cl
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 36.4 %

Procedure:
A mixture of 391 mg of 2-benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 152 mg of (3R)-3-ethynyl-3-quinuclidinol, 105 mg of tetrakis(triphenylphosphine)palladium(0), 9 mg of cuprous iodide, 0.38 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring for 4 hours at 75° C. in a nitrogen atmosphere, followed by removing the solvent. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1) and then crystallized from hexane/ethyl acetate, to give 150 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(#N)C>[S:25]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 3,4,5-trimethoxy-benzyl alcohol (9.0 g, 45.4 mmol), diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and them a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=3)[C:12]([Cl:29])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (42 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 32 mg of 5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 528.4 (MH+), retention time=0.53 min.; 1H NMR (400 MHz, DMSO-d6) d ppm 1.09-1.34 (m, 4H) 1.35-1.54 (m, 2H) 1.55-1.69 (m, 2H) 1.73-1.89 (m, 1H) 1.94-2.17 (m, 4H) 3.04-3.15 (m, 1H) 3.14-3.20 (m, 2H) 3.20-3.30 (m, 2H) 3.30-3.47 (m, 2H) 3.55-3.72 (m, 1H) 3.84 (dd, J=11.15, 2.54 Hz, 2H) 4.35 (t, J=4.70 Hz, 2H) 6.65 (s, 1H) 6.67-6.83 (m, 2H) 7.05 (br. s., 0H) 7.46-7.68 (m, 0H) 8.06 (s, 0H) 8.82 (d, J=3.52 Hz, 2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]=1.FC1C=CC=CC=1C1CCC(=O)C=C1.[H][H]>[Pd].C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1
Reactant: O=C1CC=C(c2ccccc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1C=CC(c2ccccc2F)CC1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccccc2F)CC1

Procedure:
To a suspension of palladium on carbon (1.1 g) in 100 mL ethylacetate was added the mixture of 4-(2-Fluoro-phenyl)-cyclohex-3-enone and 4-(2-Fluorophenyl)-cyclohex-2-enone (5.1 g) under argon. The suspension was placed under 50 psi hydrogen for 36 h, filtered through celite, concentrated in vacuo, and passed through silica (10% ethylacetate, hexane) to give 4-(2-fluorophenyl)-cyclohexanone (3.5 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]2
Reactant: [H][H]
Reactant: COC(=O)c1cnc2ccc(OC)nc2c1Br
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnc2ccc(OC)nc2c1
Yield: 96.7 %

Procedure:
To a mixture of methyl 4-bromo-6-(methyloxy)-1,5-naphthyridine-3-carboxylate (1.67 g, 5.64 mmol)) and NaHCO3 (0.84 g, 10 mmol) in MeOH (20 ml) and 1,4-dioxane (15 ml) was added 10% Pd/C (0.75 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 3 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH. The filtrate was evaporated and stirred in 50 ml of water, the solid was then filtered off and dried in vacuo to give the desired product (1.19 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]2[O:13][C:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1

Procedure:
To a solution of 4-[2-(2-Methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile (500 mg, 1.56 mmol) in ethanol (15 mL) was added tin(II) chloride dihydrate (677 mg, 3 mmol). The reaction mixture was heated under reflux for 4 h. The mixture was then concentrated, saturated aqueous NaHCO3 was added and the resultant suspension was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated. The residue was alumina column chromatographed (dichloromethane/ethanol: 99/1). 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was obtained as pale yellow powder (172 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1Cl
Temperature: 10 °C

Procedure:
To a 500 mL, round-bottom, 3-necked flask equipped with dropping funnel and magnetic stirrer and set for reflux was prepared a solution of 2-chloro-3-(hydroxymethyl)-pyridine (25.0 g, 174 mmol) in DCM (250 mL) under positive nitrogen atmosphere. The solution was cooled to 10° C. and thionyl chloride (31.0 g) was added dropwise over 25 minutes (exothermic). The reaction was then heated to reflux for 90 minutes, at which point the reaction was deemed complete by HPLC. The reaction mixture was cooled below boiling point and the equipment set for distillation. A total of 110 mL of DCM was initially removed and replenished with fresh DCM (110 mL), followed by another 80 mL of DCM before cooling the solution to 5-10° C. The acidic mixture was treated with a saturated solution of sodium bicarbonate (3 volumes) to pH 10. The lower organic phase was separated and the aqueous phase extracted with DCM (2 volumes). The organic phases were gathered, dried on sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil in excellent purity and yield (24.8 g, 88%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.10 (1H, dd), 7.50 (1H, dd), 4.85 (2H, s). LCMS (ES)+ RT 3.00 min, m/e 162.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[CH:42][C:40]#[N:41])[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a stirred solution of 3-{3-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy}-5-methyl-benzaldehyde (533 mg, 1 mmol) and diethyl cyanomethyl-phosphonate (162 μl, 1 mmol) in THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (224 mg, 2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.19 was collected.) to afford 445 mg (80%) of a white foam. 1H NMR (300 MHz, CDCl3) δ 1.10 (6H, d, J=6.9 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.79 (3H, s), 4.31 (2H, d, J=5.5 Hz), 4.73 (2H, s), 5.02 (1H, t, J=5.5 Hz), 5.81 (1H, d, J=16.6 Hz), 5.85 (1H, s), 5.98 (1H, s), 6.64 (2H, s), 6.86-6.89 (2H, m), 6.98 (1H, s), 7.20-7.24 (3H, m), 8.98 (1H, s).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C.O1CCOCC1>[ClH:1].[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: NNc1ccc(Br)cc1
Reactant: CCC(=O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12

Procedure:
To a suspension of 4-bromophenylhydrazine hydrochloride (10.00 g, 42.95 mmol) in anhydrous ethanol (200 mL) is added 3-propionylpyridine (7.51 g, 42.95 mmol) and the mixture is stirred at reflux for 30 min. 4M HCl in 1,4-dioxane (42.9 mL) is added to the yellow solution and stirring is continued at reflux overnight. The reaction mixture is cooled with an ice-water bath and the yellow precipitate is filtered through a sintered funnel to give 5-bromo-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. The product is dissolved in methanol (100 mL) and treated with sodium methoxide to give the free base, which is used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:20](OCC)(=[O:22])C>CN(C)C=O>[CH:20]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:10]=2)[NH:6][CH:7]=1)=[O:22]
Reactant: CCOC(C)=O
Reactant: CC(=O)NCc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)NCc1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO2000/75139). N,N-Dimethylformamide (2.0 mL) cooled to 0° C. was added dropwise with phosphorus oxychloride (0.54 g, 3.5 mmol), and then the mixture was stirred for 15 minutes. Then, the mixture was added with a solution of N-[(1H-indol-5-yl)methyl]acetamide (0.60 g, 3.2 mmol) in N,N-dimethylformamide (4.0 mL), and then the mixture was stirred overnight at room temperature. The reaction mixture was added with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (90:10)) to obtain a solid containing the objective substance. This solid was washed with ethyl acetate to obtain N-[(3-formyl-1H-indol-5-yl)methyl]acetamide (0.12 g, 17%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:21])O[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][CH2:30][CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH2:18][CH2:17][CH:16]1[C:15](=[O:20])[N:32]([CH2:31][CH2:30][O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]2=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Reactant: NCCOCc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2,4-Dioxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 2, 1.02 g, 3.52 mmol) was dissolved in dioxane (5 mL), and 2-benzyloxyethylamine (0.50 g, 3.32 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour (hr). Then, acetic anhydride (0.62 mL, 6.64 mmol) was added, and the reaction was refluxed for 5 hours. Dioxane was evaporated, and flash chromatographic purification of the residue (20% EtOAc/hexanes) gave Compound 3 (1.26 g, 90%) as a pale yellow oil: Rf (50% EtOAc/hexanes): 0.80.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].C1([O-])C=CC=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 4-bromo-3-methoxyphenol (5.00 g, 24.6 mmol, Chontech) in THF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g, 60% dispersion in mineral oil, 27 mmol) in THF (100 ml) over 10 min while cooling in ice. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 60 min. Triisopropylsilyl chloride was added dropwise to the phenolate solution, and the reaction mixture was stirred at room temperature for 60 min. Water was added to the mixture while cooling in ice, and it was then extracted several times with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (mobile phase: 2-10% gradient of ethyl acetate in dichloromethane) afforded 8.67 g (98%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[C:9]([F:25])=[N:8]2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
A suspension of 1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (0.9 mmol, from Example 1)) and SelectFluor® (2 eq., Aldrich) in CH3CN (3 mL) was heated in a microwave reactor at 140° C. for 30 min. The solvent was evaporated and the residue was washed with DCM. The insoluble solid was discarded. The combined organic washings were concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-carbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:14]2[C:13]([Cl:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=2[F:20])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: Oc1c(F)ccc(F)c1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(F)c(OCCCc2ccc(Br)cc2)c1Cl
Temperature: 80 °C

Procedure:
3-(4-Bromophenyl)propan-1-ol from the previous step (1 eq.) and 2-chloro-3,6-difluorophenol (1 eq.) were taken up in freshly deoxygenated toluene (0.3 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→15:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.