Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:11][C:12]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([NH:11][CH2:12][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(Nc1nccc2ccccc12)C1(c2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2(CNc3nccc4ccccc34)CCCCC2)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A solution of 1-phenyl-cyclohexanecarboxylic acid isoquinolin-1-ylamide (0.117 g; 0.35 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with lithium aluminum hydride (0.040 g; 1.05 mmol). The reaction mixture was allowed to slowly warm to room temperature. After 18 h at room temperature additional lithium aluminum hydride was added (0.04 g; 1.05 mmol) and the reaction mixture was heated at 40° C. for 2 h. The reaction mixture was cooled back to 0° C. and carefully quenched by the dropwise addition of water. The tetrahydrofuran was removed by evaporation and the crude residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated. Column chromatography on silicia gel using 7:3 hexane:ethyl acetate as the eluent gave 0.042 g of isoquinolin-1-yl-(1-phenyl-cyclohexylmethyl)-amine as a light yellow oil. LCMS m/z=317.2 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ (ppm) 7.96 (1H, d, J=6.0 Hz), 7.54–7.26 (9H, m), 6.61 (1H, d, J=6.0 Hz), 4.80 (1H, broad S), 3.76 (2H, d, J=5.4 hz), 2.26–2.20 (2H, m), 1.84–1.77 (2H, m), 1.66–1.61 (2H, m), 1.55–1.43 (4H, m); 13C NMR (CDCl3, 75 MHz) 155.4, 144.9, 141.4, 137.1, 129.5, 128.9 (two carbons), 127.1, 127.0 (two carbons), 126.4, 125.8, 121.0, 118.1, 110.5, 52.2, 42.6, 34.3 (two carbons), 26.6, 22.2 (two carbons).
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][CH:2]1[CH:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C(F)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 0.287 mol) in anhydrous methylene chloride (630 mL) was treated with triethylamine (60 mL, 0.43 μmol) followed by methane sulfonyl chloride (26.7 mL, 0.345 mol) at 0° C. under N2 atmosphere. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride (2×500 mL). The combined organic phases were washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 20-30% EtOAc/Hexane to provide the tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g, 91%). 1HNMR (CDCl3, 400 MHz): δ 4.98-4.86 (m, 1H), 4.80-4.74 (m, 0.5H), 4.67-4.63 (m, 0.5H), 3.92-3.45 (m, 3H), 3.44-3.25 (m, 1H), 3.08 (s, 3H), 2.20-2.07 (m, 1H), 1.93-1.80 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1.[BH4-].[Na+]>CS(C)=O>[F:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2cc(F)ccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(COc2cc(F)ccn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
To an acetic acid (1.7 mL) and dimethyl sulfoxide (29 mL) solution of 4-fluoro-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (1.72 g, 6.27 mmol) described in Manufacturing Example 59-1-3 was added sodium borohydride (380 mg, 10 mmol) at room temperature while cooling appropriately. This mixture was stirred for 5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (960 mg, 55%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[N:23]=4)=[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]4[N:14]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][C:20]1[N:15]2[N:14]=[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:12]=3)[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[N:23]=3)=[C:16]2[CH:17]=[CH:18][CH:19]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3ccccc23)n1
Agent: [Li]CCCC
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3c(Cl)cccc23)n1

Procedure:
In a similar manner as described in Example 17 from N-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine (155 mg, 0.375 mmol), n-butyllithium (700 μL 1.6 M in hexanes, 1.12 mmol), and carbon tetrachloride (145 μL, 1.50 mmol) was formed 4-{7-chloro-2-[2-(cyclopentylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-isopropyl-2-pyrimidinamine. Flash chromatography (1:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate) provided sample (65 mg, 39%). Rf 0.20 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.14–8.11 (m, 2H), 7.27 (m, 1H), 7.07 (d, 1H), 6.82 (d, 1H), 6.66 (s, 1H), 6.46 (d, 1H), 5.11 (d, 1H), 4.79 (d, 1H), 4.21 (m, 1H), 3.98 (m, 1H), 1.98 (m, 2H), 1.74–1.44 (m, 6H), 1.30 (d, 6H); MS m/z 448 (M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12])[CH3:19]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2nc[nH]c2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzimidazole-5-carboxylic acid (Aldrich, 10 g, 61.7 mmol) in EtOH (200 mL) was added dropwise conc. H2SO4 (8 mL), and the solution was heated to reflux. After 1 h the solution was cooled to 60° C. and stirred for 16 h. The solution was then concentrated in vacuo and the residue was partitioned between EtOAc and saturated Na2CO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford the title compound as a brown solid:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:19](=[O:48])[NH:20][CH:21]([C:26](=[O:47])[N:27]([CH:29]([CH:44]([CH3:46])[CH3:45])[CH:30]=[C:31]([CH3:43])[C:32]([C:34]1[N:35](COCC)[CH:36]=[CH:37][N:38]=1)=[O:33])[CH3:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:35]1[CH:36]=[CH:37][N:38]=[C:34]1[C:32](=[O:33])/[C:31](/[CH3:43])=[CH:30]/[C@@H:29]([N:27]([CH3:28])[C:26](=[O:47])[C@@H:21]([NH:20][C:19](=[O:48])[C@@H:9]([NH:7][CH3:6])[C:10]([CH3:11])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:18])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:44]([CH3:46])[CH3:45]
Reactant: CCOCn1ccnc1C(=O)C(C)=CC(C(C)C)N(C)C(=O)C(NC(=O)C(N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)c1ncc[nH]1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
[1-(1-{[4-(-Ethoxymethyl-1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxo-but-2-enyl]-methyl-carbamoyl}-2,2-dimethyl-propylcarbamoyl)-2-methyl-2-phenyl-propyl]-methyl-carbamic acid tert-butyl ester (45 mg, 0.066 mmole) is treated with 2 ml trifluoroacetic acid in 2 ml dichloromethane at room temperature for 2 hours. The solvent is evaporated and pumped in oven overnight to give 8 mg white solid product, (2S)-N-[(1S,2E)-4-(1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxobut-2-enyl]-N,3,3-trimethyl-2-{[(2S)-3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanamide: 8 mg (16%). MS (ES+): (M+H)=524.4
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=[CH:25][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7].C(N(CC)CC)C.Cl.C(OCC)(=O)C>CS(C)=O>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]2[CH:2]=[CH:3][C:4]3[C:5](=[CH:25][CH:26]=[C:27]([O:35][CH3:36])[C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6]2=[O:7])=[CH:16][CH:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc(OCc3ccccc3)cc2)c1CCO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(OCc4ccccc4)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
2-(2-Hydroxyethyl)-4-methoxy-3-pentyloxy-N-[2-(4-benzyloxyphenyl)-ethyl]benzamide (1.33 g, 2.7 mmol, 1.0 eq) was dissolved in DMSO (26 ml), and triethylamine (3.49 ml, 24.3 mmol, 9 eq) and sulfur trioxide-pyridine complex (1.29 g, 8.1 mmol, 3 eq) were successively added under ice-cooling. The mixture was stirred at room temperature for 2 hours. 3N Hydrochloric acid (35 ml) was added to this reaction mixture. The mixture was stirred at room temperature for 30 minutes and e xacted twice with ethyl acetate (40 ml). The organic layers were combined, washed with a saturated aqueous sodium carbonate solution (40 ml) and saturated brine (100 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-[2-(4-benzyloxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (1.275 g, 100%) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[S:20][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1)=O.[CH3:21][NH2:22]>[Ni].O1CCCC1>[CH3:21][NH:22][CH2:1][C:3]1[S:20][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: CN
Reactant: COc1ccc(C2CN(C)Cc3sc(C=O)cc32)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CNCc1cc2c(s1)CN(C)CC2c1ccc(OC)cc1

Procedure:
A mixture of 2.87 gm (0.01 mol) of 2-formyl-4-(p-methoxy-phenyl)-6-methyl-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridine (prepared analogous to Example 5; light yellow oil), 70 ml of tetrahydrofuran, an excess of methylamine, and Raney nickel was kept at a temperature of 60° C. for several hours under a hydrogen pressure of 5 bar. After the catalyst had been removed by suction filtration, the title compound was precipitated in the form of the dimaleate by the addition of ethanolic maleic acid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]([O:20]CC)=[O:19])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:17][C:18]([OH:20])=[O:19])([OH:16])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A 2.0 M solution of sodium hydroxide in water (28 mL) was added to a solution of A1 (11.31 g) in methanol (40 mL). The reaction mixture was stirred for 1 h at RT. The organic solvent was removed under a vacuum and the remaining aqueous reaction mixture was repeatedly extracted with ether. The aqueous phase was acidified with 2.0 M hydrochloric acid solution in water and repeatedly extracted with DCM. The combined DCM organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. 7.9 g of the desired product 4-carboxymethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (A2) were obtained and further reacted without purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([N:18]3[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]3)[C:12]([O:14]CC=C)=[CH:13][C:8]=2[O:7][N:6]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+]>CCO.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>[CH2:1]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([N:18]3[S:22](=[O:23])(=[O:24])[NH:21][C:20](=[O:25])[CH2:19]3)[C:12]([OH:14])=[CH:13][C:8]=2[O:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc2onc(OCC=C)c2cc1N1CC(=O)NS1(=O)=O
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: [K+]
Solvent: CCO
Product: C=CCOc1noc2cc(O)c(N3CC(=O)NS3(=O)=O)cc12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5-(3,6-bis-allyloxybenzo[d]isoxazol-5-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.055 g, 0.15 mmol) in EtOH (4 mL) is added tetrakis(triphenylphosphine)palladium(0) (0.005 g, 0.004 mmol). The mixture is stirred for 5 min at room temperature, at which point potassium carbonate (0.056 g, 0.405 mmol) is added. The mixture is stirred at room temperature for 5.5 h. The solvent is removed under reduced pressure and the crude product is purified by chromatography on a Biotage purification system eluting with a gradient of water/CH3CN to afford 5-(3-allyloxy-6-hydroxybenzo[d]isoxazol-5-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a solid: (M−H)−=324.0.
Reaction SMILES: [CH3:1][N:2]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)C.[C].[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:2]([CH:13]([CH2:14][OH:15])[CH2:16][OH:17])[CH3:1])=[CH:5][CH:6]=1
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(CO)CO
Agent: [Pd]
Solvent: CCO
Product: CN(Cc1ccc(N)cc1)C(CO)CO
Yield: 23.6 %

Procedure:
In ethanol (50 ml) was dissolved 2-(N-methyl-N-(4-nitrobenzyl)amino)-1,3-propanediol (2.9 g), and catalytic reduction was carried out with 5% palladium carbon (0.15 g) at room temperature for 2 hours. The catalyst was filtered off, and the solvent of the filtrate was evaporated. The residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give 2-(N-(4-aminobenzyl)-N-methylamino)-1,3-propanediol (0.6 g) as pale yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:23]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH:40]1(B(O)O)[CH2:42][CH2:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:40]1([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([C:23]4[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]5[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=5[N:24]=4)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=3)[CH:5]=[CH:4][N:3]=2)[CH2:42][CH2:41]1
Reactant: OB(O)C1CC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(C3CC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 100 °C
Reaction time: 9 h

Procedure:
100 mg of 6-(2-chloropyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one, 29.2 mg of cyclopropylboronic acid and 138 mg of potassium phosphate are dissolved in 1 ml of toluene and 0.05 ml of water and, under an argon atmosphere, 17 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1:1 complex with CH2Cl2) are added. The mixture is stirred at 100° C. for 9 h. After cooling to room temperature, it is diluted with 15 ml of water and extracted several times with ethyl acetate, and the combined organic phases are extracted once more with saturated sodium chloride solution and dried using a Varian Chem Elut CE 1005 cartridge. The crude product is purified by RP HPLC (acetonitrile (+0.05% HCOOH)/water (+0.05% HCOOH)).
Reaction SMILES: Br[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[O:5][C:6]=1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C([Li])(C)(C)C.CON(C)[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33].O>CCOCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:6]1[O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[C:2]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[CH3:10]
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: CCOC(OCC)c1oc2ccccc2c1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1oc2ccccc2c1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
To a solution of 3 g of 3-bromo-2-(diethoxymethyl)-benzo[b]furan in 80 ml of dry ether under nitrogen at -100° C was added 17.4 ml of a 1.7 M solution of tert-butyllithium in hexanes. The solution was stirred at the low temperature for 2 h then a solution of 2.76 g of N-methoxy-N-methyl-2-fluorobenzamide in 20 ml of dry ether was added and the solution stirred at the low tempertature for 10 min. The solution was then allowed to slowly warm to 0° C., water was added and the organic layer was separated, washed with water and dried over sodium sulfate and evaporated. Gravity chromatography eluting 0 to 50% toluene in heptane afforded 0.91 g of 2-(diethoxymethyl)-3-(2-fluorobenzoyl)-benzo[b]furan as an oil, 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[C:24]([Cl:30])[CH:23]=1>C1COCC1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]3)[C:8]2=[O:12])=[C:24]([Cl:30])[CH:23]=1
Reactant: O=C1CCCN1C1CC=CCC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CC=CCC1
Temperature: -78 °C
Yield: 55.1 %

Procedure:
Dissolve 1-cyclohex-3-enyl-pyrrolidin-2-one (Preparation 66) (300 mg, 1.82 mmol) in anhydrous THF (8 mL), cool to −78° C. and add LDA (2M in THF, 1.36 mL, 2.72 mmol) dropwise. After 10 minutes add 4-bromo-1-bromomethyl-2-chloro-benzene (512 mg, 1.82 mmol) and allow the mixture to warm to room temperature over 16 h. Quench with saturated aqueous ammonium chloride, extract with dichloromethane, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0 to 50% ethyl acetate in hexane) to give the title compound as a clear oil (370 mg, 56%): MS (EI) m/z=367,369 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:27]1
Reactant: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.0341 g, 0.0981 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0151 g, 0.103 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}piperidine-1-carboxylate (0.0446 g, 96%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=2)[C:50]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:68])[C:51]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)=[N:52]2
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.35 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.09 g, 0.30 mmol) Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.071 g, 0.74 mmol) in toluene (2.7 mL) at 120° C. for 10 days. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1H, d, J=4.9 Hz), 7.95 (1H, d, J=2.2 Hz), 7.81 (1H, d, J=2.2 Hz), 7.65-7.62 (2H, m), 7.20 (1H, m), 6.98-7.07 (2H, m), 6.62 (2H, app t, J=4.5 Hz), 3.86 (4H, t, J=1.9 Hz), 3.20 (4H, t, J=1.9 Hz), 2.48 (3H, s), 2.15 (3H, s). Mass Spectrum (ESI) m/e=448.1 (M+1).
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.C(O)(C)C.CC(C)([O-])C.[K+].[Cl:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]([CH3:49])[CH3:48])[CH:42]=1)=[O:40]>C(O)(C)C>[Cl:37][CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]([CH3:49])[CH3:48])[CH:42]=1)[OH:40]
Reactant: CN(C)c1cccc(C(=O)CCl)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Product: CN(C)c1cccc(C(O)CCl)c1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of di-μ-chlorodichlorobis(pentamethylcyclopentadienyl)dirhodium (III) (1.5 mg, 0.0025 mmol) and (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (3.7 mg, 0.01 mmol) in isopropyl alcohol (4.75 ml) was heated at 80° C. for 20 minutes while stirring. After cooling the solution to room temperature, a 0.1 M potassium tert-butoxide isopropyl alcohol solution (0.25 ml, 0.025 mmol) and 2-chloro-3′-(dimethylamino)acetophenone (98.8 mg, 0.5 mmol) as a reaction substrate were added thereto, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to give a desired compound, (+)-2-chloro-1-(3′-dimethylaminophenyl)ethanol (95.3 mg; yield: 95.3%; optical purity: 98.8% ee).