Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:23]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]3)[CH3:24])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cnc(-c2ccc(S(C)(=O)=O)cc2)cn1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound (0.463 g, 58%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 0.43 g, 1.72 mmol), (±)-1,1-dimethylethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.74 g, 2.41 mmol) and K2CO3 (0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 150, Step 3. The crude product was purified by chromatography on a silica gel column eluted with 1:2 EtOAc/hexanes then 40% EtOAc/hexanes to give the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.24 (s, 1H), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.3 Hz), 5.15-5.05 (m, 1H), 4.20-4.10 (m, 2H), 3.07 (s, 3H), 2.75-2.60 (m, 2H), 1.85-1.55 (m, 3H), 1.44 (s, 9H), 1.40-1.20 (m, 5H); LRMS (ESI), m/z 462 (M+H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[N:19](COCC[Si](C)(C)C)[C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C1COCC1>O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([O:14][C:15]4[NH:19][C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:32][CH:33]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(C3CCCn4ccnc43)cc2)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2[nH]c(Oc3ccc(C4CCCn5ccnc54)cc3)nc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
2-[4-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyridin-8-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.19 g), 1.0 M tetrabutylammonium fluoride-THF solution (1.7 ml) and THF (3 ml) were stirred under microwave irradiation at 100° C. for 3 hr. The reaction mixture was stirred at 80° C. overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from methanol/ethyl acetate to give the title compound (0.071 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[C:20](N=C(N(C)C)N(C)C)([CH3:23])([CH3:22])[CH3:21].BrCC(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([N:8]([CH2:21][CH:20]([CH3:23])[CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(Cl)cnc1NS(=O)(=O)c1ccc(F)cc1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-4-fluorobenzenesulfonamide (502 mg, 1.67 mmol) was dissolved in acetonitrile (3.5 mL) and to this solution was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (350 μL, 1.67 mmol). The solution was left to stir for 15 minutes then 1-bromo-2-methylpropane (363 μL, 3.34 mmol) was added. The reaction vessel was sealed and heated by microwaves to 150° C. for 1 hour. After cooling, additional 0.5 eq of 2-(tert-butyl)-1,1,3,3-tetramethylguanidine was added, along with 1 eq of 1-bromo-2-methylpropane. The reaction vessel was sealed and heated by microwaves to 150° C. for an additional 1 hour. The solution was concentrated in vacuo and the crude product extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The relevant fractions were combined and evaporated to give the title compound (396 mg). LCMS (2 min, formic) Rt 1.38 min, m/z (ES+) 357 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][C:18]([OH:22])([CH3:21])[CH2:17][CH2:16]1)[C:4]1[C:5]([CH3:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[H-].[Na+].[CH3:25]I>C1COCC1>[CH2:1]([N:3]([CH:15]1[CH2:16][CH2:17][C:18]([O:22][CH3:25])([CH3:21])[CH2:19][CH2:20]1)[C:4]1[C:5]([CH3:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a cooled solution of methyl 3-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (300 mg, 0.98 mmol) in THF (5 ml), was added sodium hydride (235 mg, 5.89 mmol) portion-wise followed by methyl iodide (0.61 ml, 9.8 mmol). The mixture was stirred at room temperature for 1 h, cooled to 0° C. quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 300 mg of the crude title compound.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:24])[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:26])([CH3:28])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:24])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Temperature: 60 °C
Yield: 75 %

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92C (102 mg, 0.250 mmol) and potassium hydroxide (84 mg, 1.50 mmol). Ethanol (1 mL) and water (0.25 mL) were added. The vial was heated to 60° C. and the reaction mixed for 24 hours. After cooling to room temperature, the pH was adjusted to ˜1 by addition of 1N hydrochloric acid. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated by rotary evaporator to afford a tan solid. The product was recrystallized from ethyl acetate/hexanes to afford 74 mg (75%) of the title compound. 1H NMR (DMSO-d6) δ ppm 0.63 (br s, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.23-1.38 (m, 8H), 1.57-1.68 (m, 12H), 1.76-1.87 (m, 1H), 2.00-2.11 (m, 1H), 2.65-2.84 (m, 4H), 8.7 (br s, 1H), 11.7 (br s, 1H). MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19]C)=[C:12](Cl)[N:11]=1>>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH3:19])=[C:12]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Sc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from 4-chlorobenzenethiol and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=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.CN(C=O)C.O1CCOCC1>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:4][CH:3]=2)[CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
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+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)c3ncnn23)ccn1
Yield: 46.6 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (80 mg, 0.206 mmol), 2-methoxypyridine-4-boronic acid (63 mg, 0.412 mmol), Pd(PPh3)4 (0.052 mmol) and 1.5N Na2CO3 (1.1 mL, 1.65 mmol) in 2:1 DMF/dioxane (2.2 mL). The crude product is purified by silica gel column chromatography using 96:4 DCM:NH3 (7M in MeOH) and the fractions containing the desired product are combined and evaporated to afford the title compound (40 mg, 47%). HPLC (254 nm): Rt 2.26 min (65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[C:31]([O:40][CH3:41])[C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>[F-].[K+].C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13]([C:29]3[CH:30]=[C:31]([O:40][CH3:41])[C:32]([CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[CH:14]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cnc(F)c(-c3cc(Cl)ncc3N)c2)OC1(C)C
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(OC)c1CN1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
A degassed mixture of 6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine (630 mg, 1.80 mmol), trifluoromethanesulfonic acid 3,5-dimethoxy-4-piperidin-1-ylmethylphenyl ester (1.06 g, 1.98 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 0.18 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM (50 mL) and brine (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (830 mg, 76%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.52-8.57 (m, 1H), 8.12-8.19 (m, 1H), 7.98 (s, 1H), 7.19 (s, 1H), 6.91 (s, 2H), 4.34 (s, 2H), 4.01 (s, 6H), 2.87-3.64 (ν br m, 4H), 1.63-2.02 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:18]F>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([F:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: FF
Solvent: CC#N
Product: CCOC(=O)C(=O)C(F)c1ccc([N+](=O)[O-])cc1

Procedure:
In the same manner as described in Example 1, ethyl 3-(4-nitrophenyl)pyruvate (11.86 g) is dissolved in acetonitrile (500 ml) and reacted with fluorine at -10° C. After the same work-up as above described, the residue is rectified to give syrupy ethyl 3-(4-nitrophenyl)-3-fluoropyruvate (3.83 g).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH2:27][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(OCCO)c(C)c2)c2c1CC(C)(C)CC2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)CCc2cc(C)c(OCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-propan-1-one (255 mg, 0.615 mmol) in THF (10 mL) and DIPEA (0.29 mL, 1.70 mmol) is added methane sulfonylchloride (0.09 mL, 1.15 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by 10% aq. citric acid solution, dried over Na2SO4 and evaporated to give methanesulfonic acid 2-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-ethyl ester (300 mg) as a brown resin; LC-MS: tR=1.18 min, [M+1]+=493.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH:18]=[O:19])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(OCC)(=O)C.C(O)CCC>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:21])=[O:19])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C=O)c12
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Reaction time: 0.08 h

Procedure:
To a suspension of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (25.0 mg, 0.098 mmol) in water (1 ml) was added sodium dihydrogen phosphate (82 mg, 0.68 mmol). After 5 minutes, n-butanol (5 ml), 2-methyl-2-butene (0.145 ml, 1.37 mmol), and sodium chlorite (79 mg, 0.88 mmol) were added. After 3 hours, LCMS indicated incomplete conversion to product. Sodium chlorite (44 mg, 0.49 mmol) and 2-methyl-2-butene (0.104 ml, 0.98 mmol) were added. After 16 hours, reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as white solids which were used without further purification. LRMS (ESI) calculated for C13H13N4O3 [M+H]+, 273.1 found 273.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Br)c2F)c1
Yield: 69 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.046 g, 0.158 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.032 g, 0.158 mmol) and DIEA (0.055 mL, 0.316 mmol) were combined in THF (3 mL) and treated with EDC (0.061 g, 0.316 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-bromo-N-({4-chloro-3-[(3-cyano-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.052 g, 0.109 mmol, 68.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ ppm 7.38-7.49 (m, 2H), 7.31 (t, J=7.90 Hz, 1H), 7.15 (m, 1H), 7.11 (s, 1H), 4.47 (s, 2H), 2.31 (s, 3H), 2.24 (s, 3 H). LC-MS (ES−) m/z 475.07, 477.03, 479.03 [M−1]. LC-MS (ES+) m/z 477.11, 479.09, 481.07 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([CH2:13][CH2:14][C:15](OCC)=[O:16])=[C:4]([CH3:20])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C(=O)=O.CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([CH2:13][CH2:14][CH:15]=[O:16])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(Cl)c2ccc(Cl)cc2c1CCC=O
Reaction time: 1 h
Yield: 51.6 %

Procedure:
Ethyl 3-(4,7-dichloro-2-methylnaphthalen-1-yl)propanoate (1.583 g, 5.087 mmoles) was dissolved in dry toluene (25 ml) under nitrogen with syringe cap attached to flask. The soluton was cooled to -78° C. in dry ice-acetone bath and diisobutylaluminum hydride (3.62 ml of a 1.5M solution in toluene; 5.443 mmoles ) was added dropwise slowly by syringe. Stirring was continued at -78° C. for 1 hour. Then while still at -78° C., the reaction was poured quickly into an aqueous NH4Cl solution with stirring. This mixture was extracted two times with ether. The combined ether extracts were extracted successively with NH4Cl solution, water, brine, then dried (MgSO4), filitered, and the solvent evaporated to leave a solid. This solid was triturated with a little ether in hexane to give 0.701 g of pure solid product, mp 104°-106° C. The solvent was stripped from the mother liquor to give 0.681 g of impure product. This impure product was flash chromatographed on a 20×200 mm silica column eluting with 70% CH2Cl2 in hexane to give 0.45 g of pure solid product mp 103°-105° C. Combining the two samples of pure solid product gave 1.15 g of pure title, compound mp 104°-106° C. after drying;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:12]([N:9]1[C:8]2[CH:31]=[CH:32][C:5]([CH2:3][OH:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To an ice-cooled stirred suspension of the product of step b (3.61 g, 7.94 mmol) in THF (30 ml) was added dropwise a solution of lithium aluminium hydride (1.0M in THF, 10 ml, 10.0 mmol). The suspension was stirred at this temperature for 1 h and then was quenched with saturated aqueous ammonium chloride (100 ml). The aqueous solution was extracted thrice with ethyl acetate (100 ml) and the combined organic phases were washed with brine (200 ml). The organic phase was dried over magnesium sulfate and the filtrate was evaporated at reduced pressure and the residue recrystallised from ethyl acetate/hexane to afford the title compound (2.68 g, 79%). 1H NMR 7.89 (1H, s), 7.74 (1H, d, 8.4), 7.33-7.17 (17H, m), 6.44 (1H, d, 0.9), 4.45 (2H, d, 6), 1.37 (1H, t, 6).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CC(OC)(C)C.COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Agent: Cl[Pd+]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: NCCc1[c-]cccc1
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCCCC1
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (15 mg, 0.045 mmol, 1 eq.), cyclohexenylboronic acid (9 mg, 1.5 eq.), Sphos precatalyst (5 mg, 15%) and potassium phosphate (29 mg, 3 eq.), THF (0.2 mL) and water (0.2 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg). Analytical HPLC (Gemini, 2-98% ACN/H2O+0.05% TFA, 10 minutes run): tR (min)=7.06.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][CH2:12][C@H:4]13.Cl[CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].C(N(CC)CC)C.O1CCOCC1>C1(C)C=CC=CC=1>[CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:21])[CH2:13][CH2:12][C@H:4]13
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3)c1ccc(F)cc1
Yield: 64.7 %

Procedure:
A mixture of (±)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4.3-b]pyrrolo[3,2,1-hi]indole (2.8 g, 14 mmol), 4-chloro-4′-fluorobutyrophenone (4.21 g, 21 mmol), triethylamine (3 mL), KI (3.48 g, 21 mmol), dioxane (25 mL), and toluene (25 mL) was stirred and refluxed for 15 h under an atmosphere of nitrogen and then evaporated under reduced pressure to remove the volatiles. The residue was triturated with a small volume of dichloromethane and decanted from the insoluble material. The process was repeated two more times and the combined dichloromethane solution was added to 0.5N solution of hydrogen chloride in ether(200 mL). The salt that separated was filtered off, washed with ether, dissolved immediately in a minimum quantity of water and the solution extracted with ether. The ether extract was discarded and aqueous layer basified with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloro-methane (2×) and the extract dried over magnesium sulfate and stripped of the solvent under reduced pressure to yield the title compound (3.3 g, 65%) as a highly viscous light brown liquid. 1H NMR (CDCl3, 300 MHz) δ1.70-1.80 (m, 2H), 1.80-2.02 (m, 2H), 2.19 (t, J=10.9 Hz, 1H), 2.30-2.52 (m, 3H), 2.62-2.72 (m, 1H), 2.72-2.85 (m, 1H), 2.99 (t, J=7.0 Hz, 2H), 3.02-3.20 (m, 2H), 3.25-3.42 (m, 2H), 3.59-3.65 (m, 1H), 6.85 (s, 1H), 6.90 (s, 1H0, 7.01 (t, J=7.0 Hz, 2H), 7.98-8.03 (m, 2H) ppm. MS (CI): 365 (M+H+).