Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:24][CH2:25][C:26](=[O:27])[C:9]2=3)=[CH:4][CH:3]=1.O.[CH3:29][N:30](C)C=O>[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>[F:23][CH:21]([F:22])[C:17]1[CH:16]=[C:15]([N:11]2[C:10]3[CH2:24][CH2:25][C:26](=[O:27])[C:9]=3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=3)[NH:13][C:12]2=[O:14])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: O=C1CCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)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: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromophenyl)-1-(3-(difluoromethyl)-phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 6, 159 mg, 367 μmol), zinc cyanide (73 mg, 620 μmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. for 3 h and then cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The residue is purified by flash chromatography on silica (gradient cyclo-hexane/ethyl acetate 7:3 to ethyl acetate). Yield: 82 mg; ESI mass spectrum: [M+H]+=380; Retention time HPLC: 0.49 min (X012_S01).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH:39]([CH3:41])[CH3:40]>C(#N)C>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC(C)C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 74 °C
Reaction time: 12 h
Yield: 34.2 %

Procedure:
To a stirred solution of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) (0.25 g, 0.76 mmol) in acetonitrile (6 mL) under nitrogen was added cesium carbonate (0.13 g, 0.40 mmol), potassium carbonate (0.055 g, 0.40 mmol) and 1-iodo-2-methylpropane (0.30 mL, 0.48 g, 2.6 mmol). The mixture was stirred at 74° C. for 12 h. The solvent was then evaporated, and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The product was purified via Biotage Horizon® (SiO2, gradient from 4% EtOAc/hexane to 38% EtOAc/hexane) to yield 0.10 g (35%) of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-isobutyl-3,4-dihydroquinoxalin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[C:11]([CH2:18][CH3:19])[CH:10]=2)=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[C:24]2[C:26]([O:28][S:29](=[O:31])(=[O:30])[C:23]2=[CH:22][CH:21]=1)=[O:27]>ClCCl>[CH2:18]([C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([C:24]3[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=3[S:29]([OH:31])(=[O:30])=[O:28])=[O:27])=[CH:7][CH:6]=2)[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=1)[CH3:19]
Reactant: CCc1cc(Nc2ccc(N)cc2)n2nccc2n1
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1cc(Nc2ccc(NC(=O)c3ccccc3S(=O)(=O)O)cc2)n2nccc2n1
Temperature: 25 °C

Procedure:
1.3 g (5.1 mmol) of the amine from Example 14, Step B and 940 mg (5.1 mmol) of 2-sulfobenzoic acid cyclic anhydride were dissolved in 20 ml dichloromethane. A solid material precipitated immediately from the clear solution, and the mixture was stirred at room temperature over night. The pale yellow crystals of the title compound were filtered by suction, heated with ethanol, filtered again after cooling to room temperature, and dried in vacuo, m.p.>320° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]([C:22]2([C:25]3[CH:35]=[CH:34][C:28]4[O:29][C:30]([F:33])([F:32])[O:31][C:27]=4[CH:26]=3)[CH2:24][CH2:23]2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:36]>COCCOC.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>[F:33][C:30]1([F:32])[O:29][C:28]2[CH:34]=[CH:35][C:25]([C:22]3([C:20]([NH:19][C:17]4[CH:16]=[CH:15][C:14]([CH3:36])=[C:13]([C:6]5[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=5)[N:18]=4)=[O:21])[CH2:24][CH2:23]3)=[CH:26][C:27]=2[O:31]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Temperature: 120 °C
Yield: 63.6 %

Procedure:
To a mixture of 2-methoxypyrimidin-5-ylboronic acid (92 mg, 0.60 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (180 mg, 0.50 mmol) in DME (3 mL) and 2 M Na2CO3 (1 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The mixture was heated in a microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxypyrimidin-5-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (140 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.6, 2.1 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 3.98 (s, 3H), 2.26 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.12 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 441.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 49.6 g of N-(4-chloro-2-fluorophenyl)phthalimide and 180 ml of concentrated sulfuric acid was cooled in an ice bath, and a mixed acid consisting of 22.7 g of 60% nitric acid and 18 ml of concentrated sulfuric acid was slowly added dropwise under stirring (reaction temperature<10° C.). After the dropwise addition, the stirring was continued under cooling in an ice bath for 1 hour and then at room temperature for 1 hour. The reaction mixture was poured into ice-water, and the precipitated solid was collected by filtration. The resulting solid was washed successively with water and methanol and dried under reduced pressure to give 57.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.7 %

Procedure:
A solution of tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.30 g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) was hydrogenated at room temperature for 72 h using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3×100 mL). The combined organic filtrates were concentrated in vacuo to afford tert-butyl 4-[5-amino-2-methoxyphenyl]-1-piperidinecarboxylate (1.00 g, 84%): ESMS m/e: 307.2 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:21][CH:22]=[CH2:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C=O)C.O>[CH2:43]([N:24]([CH:20]([CH2:21][CH:22]=[CH2:23])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH:42]=[CH2:41]
Reactant: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of N-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4-methylbenzenesulfonamide (D9) (13 g, 26.33 mmol) in DMF (80 ml), Cs2CO3 (12.86 g, 39.49 mmol) and allyl bromide (1.8 ml, 21.06 mmol) were added and the mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with water (40 ml) and extracted with EtOAc (3×60 ml). The combined organic phases were evaporated and the resulting residue was was purified by Biotage SNAP-Si (100 g) cartridge eluting with a mixture cycloexane/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D10) (10.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][NH2:38]>>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:41]=1)[CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:30])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=672.88 (M+H+); retention time=1.11 minutes.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[NH2:37][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (3.00 g, 9.22 mmol) in dichloromethane (60 mL) at rt was added m-CPBA (2.89 g, 9.22 mmol). After 1 h, concentrated ammonium hydroxide (60 mL) was added and the mixture was cooled in an ice bath. To the mixture was added TsCl (1.85 g, 9.68 mmol). The reaction was stirred rapidly overnight at rt. Additional TsCl (0.21 g) was added in the morning and the mixture was stirred 45 min. Water (75 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated. The resulting foam was treated with acetonitrile and a white solid formed. The solid was recrystallized from acetonitrile and dried under vacuum to yield 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol as fine tan crystals (1.57 g, 50%), mp 156.5-158.0° C. 1H NMR (300 MHz, d6-DMSO) δ 8.27 (dm, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.2 Hz, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 6.54 (br s, 2H), 4.89 (br s, 2H), 4.82 (br s, 2H), 4.78 (s, 1H), 3.52 (q, J=7.0 Hz, 2H), 1.75-1.43 (m, 8H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI) m/z 341 (M+H+). Anal. calcd for C19H24N4O2: C, 67.04; H, 7.11; N, 16.46. Found: C, 67.12; H, 6.94; N, 16.36.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])[C@H:4]([O:6][Si](C)(C)C)[CH3:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=1[F:19])([OH:11])[CH:4]([OH:6])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.7 g (3.6 mmol) of (R)-1-chloro-3-(trimethylsilyloxy)butan-2-one in 5 mL of THF was cooled to −20° C., and 5.4 mL (3.8 mmol) of a 0.7 M solution of 2,4-difluorophenylmagnesium bromide prepared by a method as that in Example 3 was added dropwise thereto over a period of 10 minutes. After the completion of the dropwise addition, stirring was continued for another 5 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). As a result, the yield was determined to be 79% ((2S,3R)/(2R,3R)=43/57).
Reaction SMILES: [ClH:1].[C:2]([C:6]1ON=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(OC(N1CCC(OC2C=CN=C(C(O)=O)C=2)CC1)=O)(C)(C)C.Cl.NC1C=CC(NC(NC2[O:76][N:75]=C(C(C)(C)C)C=2)=O)=CC=1.NC1C=CC(NC(NC2C=C(C(C)(C)C)ON=2)=O)=CC=1>>[ClH:1].[C:2]([C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[O:76][N:75]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)on1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)O)c2)CC1
Agent: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Agent: Cl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)on1

Procedure:
N-(4-(3-(3-tert-Butylisoxazol-5-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride was prepared as a yellow solid (500 mg) using procedures analogous to those described in Steps 3-4 of Example 1, substituting 541-(tert-butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Example 6 for 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)picolinic acid, and 1-(4-aminophenyl)-3-(3-tert-butylisoxazol-5-yl)urea hydrochloride from Step 1 of this example for 1-(4-aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea used in Example 1. LC-MS (ESI) m/z 479 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>S1C=CC=C1.[Pd]>[C:14]1([CH2:13][CH:4]2[CH2:3][CH:2]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:7][CH2:6][N:5]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCC(=O)CC1Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCC(NCc2ccccc2)CC1Cc1ccccc1

Procedure:
A mixture of (±)-ethyl 4-oxo-2-(phenylmethyl)-1-piperidinecarboxylate (10 g) and benzylamine (4 g) was hydrogenated at 50° C. in thiophene (4% solution; 1 ml) and methanol (150 ml) with palladium on activated carbon (10%; 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated, yielding (±)-ethyl 2-(phenylmethyl)-4-[(phenylmethyl)amino]-1-piperidine-carboxylate (interm. 22).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl(1RS,2RS,3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:49]([Si](C)(C)C)([F:52])([F:51])[F:50]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([OH:19])[C:49]([F:52])([F:51])[F:50])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C(F)(F)F)O[C@@H]2S1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of the aldehyde (95) (3.0 g, 7 mmol) (Prepared according to the synthesis of Example 149 step 3) TBAF (1.06 g, 3 mmol) and 4 Å molecular sieves (2.0 g) in THF (60 mL) was stirred for 30 min followed by the addition of CF3SiMe3 (5.8 g, 40 mmol) at −30° C. The mixture was kept overnight at room temperature, additional TBAF (20 g, 63 mmol) was added. After stirred additional 1 hour, the reaction was quenched by brine (40 mL) and extracted with ethyl acetate (3×50 mL). The organic layers combined, washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 5%-25% ethyl acetate in petroleum ether to afford 110 as a light yellow syrup (1.7 g, 49%). (ES, m/z): [M+H]+ 497.7; 1H NMR (300 MHz, CDCl3) δ 7.31-7.40 (m, 10H), 6.29 (d, J=6.6 Hz, 1H), 4.57-4.78 (m, 4H), 4.30-4.43 (m, 2H), 3.80-4.17 (m, 4H), 3.01 (s, 6H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9])[CH3:5]>C(O)CCC>[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8]([NH:2][NH2:3])=[O:9])[CH3:5]
Reactant: CCc1c(C(=O)OC)ccc(O)c1C
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CCc1c(C(=O)NN)ccc(O)c1C
Yield: 68 %

Procedure:
1 ml of butanol and 4.5 ml of hydrazine hydrate are added to 1.88 g of methyl 2-ethyl-4-hydroxy-3-methylbenzoate in a screw-lid vial, and the mixture is stirred at 100° C. until the hydrazide formation is complete. The cooled reaction mixture is poured onto water, the precipitate is filtered off with suction and dried. Purification by recrystallisation from water/1 -propanol gives 1.28 g of 2-ethyl-4-hydroxy-3-methylbenzohydrazide as colourless crystals (68%); MS-FAB (M+H+)=1.95.1; Rf (polar method): 0.99 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of (4-bromo-2-methylphenyl)methanol (1 g, 5 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 4-bromo-2-methyl-1-(phenoxymethyl)benzene (640 mg, 46%).