Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[F:24])[CH3:17])=[O:15])[C@:11]([CH2:31][OH:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1.C(O)(=O)C.[CH3:37][C:38]([CH3:40])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N:21]([CH:38]([CH3:40])[CH3:37])[CH2:20][C@H:19]2[F:24])[CH3:17])=[O:15])[C@:11]([CH2:31][OH:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1
Reactant: CC(C)=O
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CCNC[C@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CC[C@H](N(C)C(=O)N2CC(c3cc(F)ccc3F)=C[C@@]2(CO)c2ccccc2)[C@H](F)C1
Reaction time: 8 h

Procedure:
To a solution of 38 mg (0.085 mmol) of 10-2 in 1 mL of 1,2-dichloroethane was added 20 μL (0.34 mmol) of acetic acid, 25 μL (0.34 mmol) of acetone, and 27 mg (0.13 mmol) of Na(OAc)3BH. After stirring overnight, the reaction was partitioned between EtOAc and saturated aqueous NaHCO3, the organic phase was washed again with NaHCO3, H2O, brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by reverse phase chromatography with 95:5 to 5:95 H2O/CH3CN (both with 0.1% TFA). The fractions were basified with NaHCO3 to provide 11-1 as a colorless film. Data for 11-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.3 (m, 1H), 4.95-4.8 (m, 2H), 4.6 (m, 1H), 4.45 (m, 1H), 4.1-4.0 (m, 2H), 3.2 (m, 1H), 3.15 (s, 3H), 3.0 (m, 1H), 2.8 (m, 1H), 2.45-2.25 (m, 3H), 1.75 (m, 1H), 1.1-1.0 (m, 6H) ppm. HRMS (ES) calc'd M+H for C27H32F3N3O2: 488.2519. Found: 488.2517.
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11].[C:14]1([C-:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+]>CCOCC>[CH3:12][Si:2]([CH3:13])([CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21]1)[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: c1ccc(-[c-]2ccc3ccccc32)cc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3ccccc32)C(C)=C1C
Reaction time: 23 h

Procedure:
To a solution of chlorodimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silane (5.00 g, 23.3 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium(1-phenylindenide) (4.85 g, 24.5 mmol, 1.05 eq.). The reaction was stirred for 23 hours, and the volatiles were then removed under vacuum. The residue was extracted with pentane (40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 7.07 g (82%). 1H NMR(C6D6): δ 7.74 (d, 1H), 7.65 (d, 2H), 7.48 (d, 1H), 7.25 (m, 5H), 6.60 (s, 1H), 3.69, (s, 1H), 2.92 (br s, 1H), 1.93 (s, 3H), 1.90 (s, 3H), 1.82 (s, 3H), 1.821 (s, 3H), −0.09 (s, 3H), −0.39 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:9][CH:8]2[C:10]([OH:12])=O)=[CH:3][CH:2]=1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:13][N:14]([C:10]([CH:8]1[CH2:9][CH:7]1[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:12])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1CC1c1ccncc1
Product: CN(C(=O)C1CC1c1ccncc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(pyridin-4-yl)cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 404.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:7][C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:29]=3)[O:16][C:17]3[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=3)=[CH:10][CH:9]=2)=[N:5][CH2:4]1)[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C@@H:3]1[O:7][C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:29]=[C:28]([CH:27]=[C:15]([O:16][C:17]4[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=4)[CH:14]=3)[O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])=[CH:10][CH:9]=2)=[N:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CN=C(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)O1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1CN=C(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-(3-{5-[(5S)-5-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulfonyl)pyrazine (860 mg, 1.72 mmol) synthesized in Example (1060 was dissolved in methylene chloride (20 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 2.50 mL, 2.50 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 2 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-4%) to afford the desired compound (764 mg, yield 91%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]([F:15])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][N:12]2[CH:16]2[CH2:18][CH2:17]2)=[CH:7][C:6]=1[F:23])(=[O:3])N.S(=O)(=O)(O)[OH:25].N([O-])=O.[Na+]>>[CH:16]1([N:12]2[C:13]3[C:8](=[CH:7][C:6]([F:23])=[C:5]([CH2:4][C:1]([OH:25])=[O:3])[C:14]=3[F:15])[C:9](=[O:22])[C:10]([C:19]([OH:21])=[O:20])=[CH:11]2)[CH2:18][CH2:17]1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Reaction time: 1 h

Procedure:
3.0 g of the compound from Example 10 are warmed to 90°-100° C. in 17 ml of 30% strength sulphuric acid. At this temperature, 6 ml of 2.5 molar sodium nitrite solution are added dropwise. The mixture is stirred for one hour more at 100° and then cooled. The precipitated solid is isolated, washed and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[C:28]([F:30])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([C:19]3[N:24]=[C:23]([NH2:25])[C:22]([O:26][CH3:27])=[CH:21][N:20]=3)=[N:10]2)=[C:6]([F:31])[CH:5]=1)[CH3:2].Cl.F[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:31])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([C:19]3[N:24]=[C:23]([NH:25][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[C:22]([O:26][CH3:27])=[CH:21][N:20]=3)=[N:10]2)=[C:28]([F:30])[CH:29]=1)[CH3:2]
Reactant: Fc1ccncc1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3c(C)cccc32)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3c(C)cccc32)c(F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine (1-4-6, 0.236 mmol, 1.0 eq.) and 94.2 mg 4-Fluoropyridin hydrochloride (0.705 mmol, 3.0 eq.) were dissolved in 1.1 ml of dry N,N-dimethylformamide. 113 mg sodium hydride (60%, 2.82 mmol, 12 eq.) were added. The reaction mixture was stirred at 90° C. for 2 h. Water and ethyl acetate were added and the aqueous layer was washed with ethyl acetate twice. The combined organic layers were dried over a silicone filter and concentrated in vacuum. The residue was purified by HPLC to yield 46 mg (0.09 mmol, 38%) of the analytically pure target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of methyl 3-bromo-5-iodobenzoate (4.5 g, 13.2 mmol) in N,N-dimethylformamide (36 mL) was treated with zinc cyanide (1.7 g, 14.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 1.5 g, 1.3 mmol). The reaction mixture was heated, under an argon atmosphere, for 1 hour at 80° C. After cooling the mixture was diluted with ethyl acetate. The resulting organic solution was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using a gradient of hexane to 10% ethyl acetate in hexane afforded 1.9 g (61%) of methyl 3-bromo-5-cyanobenzoate.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:11]=[N:10][C:5]3[O:6][CH2:7][CH2:8][NH:9][C:4]=3[CH:3]=2)[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1cnc2c(c1)NCCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cnc3c(c2)NCCO3)c1
Reaction time: 6 h
Yield: 76.4 %

Procedure:
By the same method as in the step b) of Example 45, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (99 mg, 0.46 mmol), 3-nitrophenyl boronic acid (115 mg, 0.69 mmol), palladium triphenylphosphine (26 mg, 0.023 mol) and potassium carbonate (127 mg, 0.92 mmol) were dissolved in tetrahydrofuran/water (2.4 ml/0.4 ml) and then stirred at 80□ for 6 hours to obtain 7-(3-nitro-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (90.4 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][C:14]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C2CCCC2)cc1
Reactant: Clc1cc(I)ccn1
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: O
Solvent: COCCOC
Product: Clc1cc(-c2ccc(C3CCCC3)cc2)ccn1
Yield: 67.9 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (6.43 g, 26.3 mmol), (4-cyclopentylphenyl)boronic acid (5.0 g, 26.3 mmol), Pd(Ph3P)4 (0.0.91 g 0.79 mmol), sodium carbonate (8.37 g, 79 mmol), DME (257 mL) and water (64 mL) was degassed with nitrogen and then refluxed overnight. The reaction mixture was concentrated and extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using dichloromethane in hexanes and then vacuum distilled to give 2-Chloro-4-(4-cyclopentylphenyl)pyridine (4.6 g, 68% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[OH-].[K+].C1(C)C=CC=CC=1.[F:22][C:23](=[CH2:26])[CH2:24]Br>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:12][O:11][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:26][C:23]([F:22])=[CH2:24])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)NCC(OC)OC
Reactant: C=C(F)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(F)CN(CC(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.6 g (65.5 mmol) of ethyl N-(2,2-dimethoxyethyl)-carbamate, 15 g of powdered potassium hydroxide and 0.25 g of triethylbenzylammonium chloride are initially introduced into 65 ml of toluene and 10 g (72 mmol) of 2-fluoroallyl bromide are added dropwise at room temperature. The mixture is stirred overnight at room temperature, 100 ml of water are added, and the aqueous phase is separated off and extracted using 30 ml of toluene. The organic solutions are dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: B#B.[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH2:5][OH:6]
Reactant: CC(Cc1ccc(Br)cc1)C(=O)O
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 102 %

Procedure:
Diborane (192 ml of a 1.0M solution in THF) was added dropwise over 25 minutes to a solution of 2-methyl-3-(4-bromophenyl)propanoic acid (38.9 g) in THF (240 ml) at 0° C. The reaction mixture was stirred for 45 minutes at 0C and then allowed to warm to ambient temperature over 2 hours. Water (120 ml) was added followed by solid potassium carbonate (144 g) and then more water (80 ml). The reaction mixture was extracted with diethyl ether (3×250 ml), the combined organic layers were dried (MgSO4) and the solvent was evaporated to give 2-methyl-3-(4-bromophenyl)propanol as a yellow oil (37.4 g), mass spectrum (+ve CI): 248 (M+NH4)+.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].O>CN(C=O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([S:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:33]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)(=[O:35])=[O:34])(=[O:10])=[O:9])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(S(=O)(=O)c1ccc(OC)c(OC)c1)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a stiffing solution of N-hexyl-3,4-dimethoxybenzenesulfonamide (0.250 g, 0.830 mmol) in 3.30 mL of DMF, NaH (0.037 g, 0.913 mmol; 60% in oil dispersion) was added. After 30 mins, 3,4-dimethoxybenzenesulfonyl chloride (0.222 g, 0.937 mmol) was added. After a further 1 hr, the reaction solution was poured over water (15 mL) forming a white solid. The solid was filtered and recrystallized from methanol to afford 0.103 g (25%) of N-(3,4-dimethoxyphenylsulfonyl)-N-hexyl-3,4-dimethoxybenzenesulfonamide as a white solid. 1H NMR (acetone-d6, 400 MHz) δ 7.62 (dd, J=2.9, 8.2 Hz, 2H), 7.57 (d, J=2.3 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 3.95 (s, 12H), 3.60 (m, 2H), 1.63 (m, 2H), 1.21 (m, 6H), 0.85 (t, J=6.8 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 150.05, 144.99, 131.10, 121.34, 115.05, 115.00, 49.00, 31.65, 26.38, 22.45, 13.51.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[N:10][O:11][C:12]([CH3:13])=[C:6]2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4]1)[CH3:2]>[Pd].C(O)C>[C:12]([C:6]1[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[C:7]=1[NH2:10])(=[O:11])[CH3:13]
Reactant: CCn1nc(-c2ccccc2)c2c(C)onc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(N)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A mixture of 6-ethyl-3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) (2.0 g , 7.83 mmol) and, 10% palladium on charcoal (400 mg) in ethanol (400 ml) was shaken under hydrogen at room temperature and 2 bar for 3 h. The catalyst was filtered off and the solvent was removed under reduced pressure to yield the title compound (1.97 g, 98% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:14]=[N:13][C:12]=1[C:27](O)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:14]=[N:13][C:12]=1[C:27]([NH:36][CH:34]1[CH2:35][CH2:33]1)=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCOCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.2 %

Procedure:
5-[2-(Benzyloxy)ethyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (375 mg, 0.951 mmol) obtained in Example 107b), HOBt (64.9 mg, 0.475 mmol, 0.5 eq.) and cyclopropylamine (0.088 ml, 1.24 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 4.5 ml), WSC (223 mg, 1.14 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate-hexane (4:1, 50 ml), washed twice with 2% aqueous sodium carbonate solution and with 10% aqueous sodium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:2-3:2) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (1:1-3:2) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (262 mg, 0.604 mmol, 79.4%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.4 %

Procedure:
To a pre-stirred solution of 4-bromo-2-trifluoromethoxybenzaldehyde (1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. The reaction mixture was then allowed to warm to ambient temperature and stirred for an additional 14 h. The reaction was quenched by the addition of water (30 mL) and extracted into ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.6 g, 84%) that was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): 7.47 (d, J=8.2 Hz, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.39-7.35 (m, 1H), 3.46 (s, 2H), 2.42-2.32 (m, 4H), 1.64-1.51 (m, 4H), 1.48-1.37 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:32].O.[OH-].[Na+]>CC(O)=O>[Br:32][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of {3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol from Step 1 (1.0 eq.) in AcOH (0.3M) was added HBr (48%; 9.5 eq.). The mixture was stirred at 80° C. for 12 h, cooled to rt, poured in cold water containing 10 eq. of NaOH and extracted with EtOAc. The organic extract was washed with saturated aqueous NaHCO3 (3×), brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:23][N:22]([CH3:24])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 142.7 %

Procedure:
To 1-tert-Butyloxycarbonyl-4-[(4-dimethylaminophenyloxy)methyl]piperidine (0.1 g) obtained in Example 13 was added trifluoroacetic acid (0.5 ml) followed by stirring at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with methylene chloride (100 ml) and washed with aqueous saturated solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with fumaric acid and the resulting fumarate was recrystallized from methanol to obtain 4-[(4-dimethylaminophenyloxy)methyl]piperidine 1/2 fumarate (0.1 g) as pale yellow crystals, m.p. 210°-213° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:19]#[N:20])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NCc1cc(C#N)cc(Cl)c1F
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (3 g, 8.86 mmol) in DMF (45 mL) was added zinc cyanide (1.04 g, 8.86 mmol) and Pd(Ph3P)4 (1.02 g, 0.886 mmol). The reaction mixture was stirred at 120° C. for 15 min in a microwave apparatus (Personal Chemistry, Biotage). After cooling to RT, the mixture was filtered through Celite and rinsed down with EtOAc. The filtrate was washed with saturated aqueous NH4Cl solution (4×75 mL), dried (Na2SO4) and evaporated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 9:1 to 3:1) afforded the title compound as white solid. TLC Rf (c-hexane/EtOAc 3:1)=0.35; tR (HPLC conditions c): 5.28 min.