Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=[O:29])[N:27]([CH2:30][CH2:31][CH3:32])[N:26]=[N:25]2)=[CH:20][CH:19]=1.[I-].[K+].C1(O)CCCCC1.C(=O)([O-])O.[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:17]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[C:28](=[O:29])[N:27]([CH2:30][CH2:31][CH3:32])[N:26]=[N:25]4)=[CH:22][CH:23]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: CCCn1nnn(-c2ccc(N)cc2)c1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: OC1CCCCC1
Solvent: O
Product: CCCn1nnn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Yield: 39 %

Procedure:
A mixture of 25 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 25.5 parts of 1-(4-aminophenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one monohydrochloride, 2 parts of potassium iodide and 200 parts of cyclohexanol was stirred and refluxed for 5 hours using a water-separator. The reaction mixture was cooled and neutralized with a sodium hydrogen carbonate solution. The product was filtered off and crystallized from 1-butanol, yielding 15.5 parts (39%) of 1,4-dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-4-propyl-5H-tetrazol-5-one; mp. 189.7 ° C. (int. 33).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](OCC)=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[BH4-].CC[O:22]CC>>[C:1]([N:8]1[CH2:11][CH:10]([CH:12]([OH:22])[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOCC
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Product: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 132 (0.96 g, 3.9 mmol) in ether (20 mL) at ambient temperature was treated with LiBH4 (0.34 g, 15.8 mmol) then heated to 55° C. After 45 min at 55° C., the cooled reaction was quenched with 5% KHSO4 (10 mL) and then diluted with EtOAc. The organic phase was washed with 5% KHSO4 and brine, dried (MgSO4), and concentrated to give 133 (0.79 g) as a colorless oil. Rf 0.46 (silica, EtOAc). 1H NMR (300 MHz, CDCl3) δ 4.04 (m, 2H), 3.70-3.50 (m, 4H), 2.63 (m, 1H), 1.83 (m, 2H), 1.44 (s, 9H). ##STR58##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[NH2:23][OH:24]>C(O)C>[OH:24][N:23]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1)[NH2:2]
Reactant: COCC(c1ccc(C#N)cc1)N(C)CC(=O)OC(C)(C)C
Reactant: NO
Solvent: CCO
Product: COCC(c1ccc(C(N)=NO)cc1)N(C)CC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
A solution of tert-butyl 2-((1-(4-cyanophenyl)-2-methoxyethyl)(methyl)amino)acetate (0.136 g; 0.45 mmol) and 50% aqueous hydroxylamine (0.137 mL; 2.24 mmol) in ethanol (2 mL) was heated at 80° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.141 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J=8.4 Hz, 2H), 7.59-7.57 (m, 2H), 6.70 (br s, 1H), 4.84 (br s, 2H), 4.05-4.02 (m, 1H), 3.71-3.67 (m, 1H), 3.63-3.60 (m, 1H), 3.40-3.35 (m, 1H), 3.34 (s, 3H), 3.21-3.16 (m, 1H), 2.40 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:23])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)CCCC(C)CCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 4-(3,7-dimethyl-1-octyloxy)benzoic acid was dissolved in anhydrous chloroform (25 ml), and after ice-cooling, thionyl chloride (6.72 ml, 92.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give the title compound as an oil. The present compound was directly used for the next step.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[CH3:7][N:5]1[CH:6]=[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:32])([F:31])[F:20])[C:3]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])=[N:4]1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cn1cc(Br)c(NC(=O)c2cnn3cccnc23)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2ccccc2C(F)(F)F)c(NC(=O)c2cnn3cccnc23)n1
Yield: 3.9 %

Procedure:
To a stir-bar equipped microwave vial was added: N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (101 mg, 0.313 mmol, 1 eq), 2-trifluoromethylphenyl boronic acid (126.6 mg, 0.6666 mmol, 2.13 eq), bis(triphenylphosphine)palladium(II) chloride (26.8 mg, 0.0382 mmol, 0.12 eq), sodium carbonate (1.0 mL of a 2.0 M aqueous solution, 2 mmol, 6 eq), and 3 mL acetonitrile. The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 4.7 mg (4%) of N-(1-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=387.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 9.32 (d, 1H), 8.74 (d, 1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.74 (d, 1H), 7.60 (t, 1H), 7.49 (m, 2H), 7.28 (d of d, 1H), 3.87 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:22]([BH3-])#N.[Na+].C=O.CC(O)=O.C([O-])(O)=O.[Na+]>CO>[CH3:22][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
3-(Piperidin-4-yl)-2-phenyl-1H-indole (200 mg, 0.7 mmol), sodium cyanoborohydride (51 mg, 0.8 mmol), formaldehyde (60 μl, 40% in H2O, 0.8 mmol) and AcOH (97 μl, 1.7 mmol) were stirred in MeOH (5 ml) at 0° C. for 1 h, then room temperature for 2 h. The solution was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried, and evaporated in vacuo to give white crystals (49 mg, 23%), mp 245-246° C. (from EtOH); δH (360 MHz, d6-DMSO) 1.88 (2H, d, J 13, NCH2CHAHB), 2.60-2.80 (2H, m, NCH2CHAHB), 2.76 (3H, s, CH3), 3.00-3.20 (3H, m, CH2CH and NCHAHB), 3.44 (2H, d, J 12, NCHAHB), 6.99 (1H, t, J 7, indole-H), 7.09 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.98 (1H, d, J 7, ArH), 11.20 (1H, br s, indole NH); m/z (ES+) 291 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 65 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To the solution of 2-bromo-5-fluoro-3-nitrobenzoic acid (35 g) in MeOH (400 mL) was added SOCl2 (40 mL) drop-wise at 10-15° C. The reaction was then stirred at 65° C. for 1 h. After cooling to room temperature, the solvent was evaporated in vacuum to afford a residue, which was chromatographed on silica gel using gradient eluant of 0-100% EtOAc in hexane to provide methyl 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:18].[CH:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[C:37]([CH3:38])=[C:36](Cl)[N:35]=[CH:34][N:33]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])[CH3:20].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[C:37]([CH3:38])=[C:36]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH2:12][CH2:13][O:14][CH:15]([CH3:16])[CH3:17])=[CH:4][C:3]=3[F:18])[N:35]=[CH:34][N:33]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])[CH3:20]
Reactant: CC(C)OCCNS(=O)(=O)c1ccc(N)c(F)c1
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(S(=O)(=O)NCCOC(C)C)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 4-amino-3-fluoro-N-(2-isopropoxy-ethyl)-benzenesulfonamide (116 mg, 0.42 mmol), 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (100 mg, 0.3 mmol), palladium acetate (3 mg, 0.017 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (7.1 mg, 0.034 mmol), and sodium t-butoxide (87 mg, 0.90 mmol) in dioxane (2 mL) was heated under microwave irradiation for 60 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A106 as a brown solid (50 mg, 22%). 1H NMR (CDCl3, 400 MHz) δ 1.04 (d, 6H), 1.19 (d, 6H), 1.67-1.78 (m, 2H), 1.89-1.99 (m, 5H), 3.05 (t, 2H), 3.30-3.40 (m, 4H), 3.42-3.52 (m, 1H), 3.66-3.76 (m, 1H), 4.87 (h, 1H), 5.19-5.38 (m, 2H), 7.58 (t, 3H), 7.90-7.98 (s broad, 1H), 8.24 (t, 1H), 8.35 (s, 1H). Exact mass calculated for C23H36FN5O6S 553.65, found 554.6 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1>Br.CCO>[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: COC(=O)Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Agent: Br
Solvent: CCO
Product: COC(=O)Cc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-Methyl 2-(2-(4-(dimethylamino)-4-phenylcyclohex-1-enyl)-1H-indol-3-yl)acetate (936 mg, 2.4 mmol) was dissolved in HBr/glacial acetic acid (33% HBr, 30 ml). Sn powder (2.88 g, 24 mmol) was then added to the mixture in portions at RT in the course of 1 h. When the addition had ended, the reaction mixture was stirred at RT for a further 16 h.—For working up, the mixture was diluted with EtOH (10 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 2 N NaOH (100 ml). The aqueous mixture obtained was extracted with methylene chloride (4×40 ml). The combined organic phases were dried over Na2SO4 and then concentrated. The crude product obtained (900 mg) was purified by column chromatography [silica gel 60 (100 g); MeOH (1,000 ml)] Methyl 2-(2-(4-(dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)acetate (less polar diastereomer) was obtained in a yield of 290 mg (31%), and the polar diastereomer was obtained in a yield of 200 mg (21%). Both products were colourless oils.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:14])=[N:6][N:5]2[C:15]=1[C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=2)=[CH:19][C:20]=1[CH3:21].[CH3:29][CH2:30]OCC.C([Mg]Br)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([OH:13])([CH2:29][CH3:30])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:14])=[N:6][N:5]2[C:15]=1[C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=2)=[CH:19][C:20]=1[CH3:21]
Reactant: CCC(=O)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Reactant: CCOCC
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 37 %

Procedure:
To a −0° C. solution of 1-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-propan-1-one (0.040 g, 0.10 mmol) and Et2O (5 mL) is added 3.0 M ethyl magnesium bromide (0.68 mL, 2.05 mmol). The solution is warmed to ambient temperature, diluted with EtOAc (30 mL) washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (0.016 g, 0.038 mmol, 37%). 1H NMR (CDCl3), δ 0.89 (t, J=7.4 Hz, 6H), 1.92-2.01 (m, 4H), 2.14 (s, 3H), 2.46 (s, 3H), 2.53 (s, 3H), 3.57 (s, 3H), 6.39 (s, 1H), 6.66 (s, 1H), 7.01 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.57 (dd, J=7.9, 7.5 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4OS (M+H)+: 421.3; found: 421.3.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.C(O)C.[ClH:15].CN.[C:18]([BH3-])#[N:19].[Na+].[OH-].[K+]>CO>[ClH:15].[CH3:18][NH:19][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenylacetaldehyde (24.0 g, 0.20 mol), a 33% solution of methylamine in ethanol (42.35 g, 0.41 mol) and methylamine hydrochloride (10.13 g, 14.8 mmol) were dissolved in methanol (200 ml). Sodium cyanoborohydride (3.77 g, 60 mmol) was introduced and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated in vacuo to ca. 50 ml, concentrated hydrochloric acid (40 ml) was added and once the exotherm had subsided the reaction mixture was stirred for 2 h. Water (200 ml) was introduced followed by potassium hydroxide (27 g, 0.48 mol) and the cooled solution was extracted with dichloromethane (7×100 ml). The combined dichloromethane extracts were extracted with 2N hydrochloric acid solution (200 ml) and 0.2N hydrochloric acid solution (200 ml). The combined acidic extracts were washed with dichloromethane (2×50 ml) and the aqueous phase was basified with 4N sodium hydroxide solution before being extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and evaporated to a residue (9.2 g) which was dissolved in toluene (200 ml) with methanol (5 ml) present. Chlorotrimethylsilane (8.63 ml) dissolved in toluene (300 ml) was added and the hydrochloride salt of N-methyl-2-phenylethylamine precipitated. After cooling the suspension, the solid was collected by filtration and dried in vacuo; 1H NMR (DMSO-d6)γ2.54 (3H, s, --CH3), 2.92-3.07 (4H, m, --CH2CH2 --), 7.20-7.40 (5H, m, Ar-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:19]([F:22])([F:21])[F:20])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]2[C:15](O)=[O:16].CCN(CC)CC.Cl.[F:31][C:32]([F:51])([F:50])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)=[O:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:51][C:32]([F:50])([F:31])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][N:47]([C:15]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][C:19]([F:22])([F:20])[F:21])[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=3)=[O:16])[CH2:46][CH2:45]2)[CH:38]=1)=[O:34]
Reactant: O=C(NCc1ccc(F)c(C2CCNCC2)c1)C(F)(F)F
Reactant: COCCn1cc(C(=O)O)c2c(OC(F)(F)F)ccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)C(F)(F)F)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 8 (19.1 g, 59.6 mmol), Et3N (24.8 mL, 177.9 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride (11, 26.4 g, 77.5 mmol) (14), and EDCI (17.1 g, 89.3 mmol) in CH2Cl2 is stirred at rt overnight. Both TLC and LC/MS indicate that the reaction is completed. The mixture is partitioned between H2O and CH2Cl2. The two layers are separated, and the organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (40/60 to 0/100) as eluant to give 9 (36 g, 99%) as a white foam. 1H NMR (CDCl3) δ 7.37 (s, 1H), 7.20-7.10 (m, 2H), 7.10-6.85 (m, 4H), 4.95 (br s, 1H), 4.60-4.35 (m, 4H), 3.90 (br s, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.32 (s, 3H), 3.25-2.70 (m, 3H), 2.05-1.50 (m, 4H); 19F NMR (CDCl3) δ −57.54 (s, 3F), −75.39 (s, 3F), −119.31 (s, 1F), −134.96 (d, J=11.3 Hz, 1F); MS 608 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](Br)[CH:22]=2)[C:17]=1[F:27].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Li+].C[Si]([N-:46][Si](C)(C)C)(C)C.[ClH:51]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:27])=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:46])[CH:20]=[CH:19]2.[ClH:51]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3F)c2cc1OC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(6,7-dimethoxy-4-quinolyloxy)-6-bromo-1-fluoronaphthalene (Step b, 1.7 g, 4.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol, Aldrich) and P(t-Bu)3 (40 mg, 0.2 mmol, Aldrich) in a two-necked round-bottom flask was degassed under vacuum and refilled with N2. Under N2, dry toluene and LiHMDS (5 mL, 1M in THF, 5.0 mmol, Aldrich) was added to the mixture via syringe. The reaction was stirred at RT under N2 for 16 h. To the reaction was added 1N aqueous HCl (10 mL) and a yellow precipitate was collected by filtration. The solid was washed with 10 mL of water and dried in vacuo at 50° C. for 24 h to give title compound as HCl salt in the form of yellow solid. MS (ESI, pos. ion) m/z: 365 (M+1). Mass Calc'd for C21H17FN2O3: 364.12.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH:62]=[CH:61][N:60]=[C:59]1[C:63](O)=[O:64]>CN1C(=O)CCC1>[CH3:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:63]([C:59]4[N:58]([CH3:57])[CH:62]=[CH:61][N:60]=4)=[O:64])[CH2:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([CH3:23])[C:15]1=[O:22]
Reactant: Cn1ccnc1C(=O)O
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1ccnc1C(=O)NC1CC=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round bottom flask were added 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) (0.0010 g, 0.028 mmol), DIPEA (0.050 mL, 0.286 mmol), HATU (0.0013 g, 0.034 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (0.00467 g, 0.037 mmol), and NMP (1 mL). The reaction was stirred at room temperature overnight (˜14 hours), the reaction mixtures were then filtered & purified by reverse-phase chromatography (5-95% 0.1% TFA in H2O:acetonitrile) to give N-{4-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}-1-methyl-1H-imidazole-2-carboxamide (17-3). HRMS m/z (M+H): calculated=423.2503; observed=423.2507.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>CC(C)=O>[I:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:8]=2)[NH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cc(-c2cnc3[nH]ccc3n2)ccn1
Solvent: CC(C)=O
Product: Ic1c[nH]c2ncc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 22 (0.35 g) and acetone (20 mL) of acetone was added in one portion N-iodosuccinimide (0.44 g). The mixture was stirred at RT for 30 min and then concentrated to afford 0.8 g of crude material. The crude product was purified by SiO2 chromatography eluting with and EtOH/EtOAc gradient (1 to 15% over 15 minutes) to afford 0.36 g of pure 7-iodo-2-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (24).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[BH4-].[Na+].P(Br)(Br)[Br:16]>CCO>[Br:16][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=2[CH:7]=1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Compound 34 (160 mg, 0.89 mmol) was dissolved in EtOH (5 mL). NaBH4 (36 mg, 0.98 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The resulting crude alcohol residue was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (92 μL, 0.98 mmol) was added dropwise over 10 min. The mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 35 (128 mg, 57%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.48 (1H, d, J=2.05 Hz, ArH), 7.37 (1H, d, J=8.70, ArH), 7.25 (1H, dd, J=8.80 & 2.05 Hz ArH), 6.68 (1H, s, ArH), 4.55 (2H, s, 2-CH2).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:28]=[CH:27][C:26]([OH:29])=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[O:10])[CH:7]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CCCCCC.CN(C)C=O>[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:28]=[CH:27][C:26]([O:29][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=2)=[O:10])[CH:7]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
Sodium hydride (60%; 1.04 g, 26 mmol) was washed with n-hexane, and suspended in N,N-dimethylformamide (100 mL). A solution of N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (Compound No. 81; 8.15 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added dropwise under cooling with ice bath. After the addition was finished, the mixture was stirred at room temperature for 1 hour. A solution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice and water, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate/n-hexane) to give the title compound (5.38 g, 54.1%) as a white solid.