Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:14][CH2:13][C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: OB(O)c1ccccc1
Reactant: O=c1oc(CO)c(Br)c2ccccc12
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: [Cs+]
Product: O=c1oc(CO)c(-c2ccccc2)c2ccccc12
Yield: 26.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, starting from 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.8 g, 3.14 mmol), phenylboronic acid (0.467 g, 3.83 mmol), Pd(PPh3)4 (0.181 g, 0.379 mmol) and Cs2CO3 (3.29 g, 10.11 mmol) to afford the title compound (210 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:33])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 1-fluoro-4-isocyanatobenzene (13 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 90 minutes before it was concentrated and directly purified by column chromatography on silica, eluting with 3:1 EtOAc/hexanes to yield the final product as a solid (30 mg, 84% yield). MS (apci) m/z=453.2 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:18]=[C:17]([CH3:28])[N:16]=2.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:29][C:30]([OH:32])([CH3:31])[CH3:33])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:23][CH2:24][N:25]([C:2]([O:4][CH3:5])=[O:3])[CH2:26][CH2:27]1)[N:18]=[C:17]([CH3:28])[N:16]=2
Reactant: COC(=O)Cl
Reactant: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3CC(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Add methyl chloroformate (0.29 g, 0.0031 mol) to a solution of 1-[8-(2-chlorophenyl)-2-methyl-6-piperazin-1-yl-purin-9-yl]-2-methyl-propan-2-ol (0.001 mol, 0.5 g) and pyridine (2.0 mL) in dry dichloromethane (3 mL) at 0° C. and stir for 2 h at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using methanol:dichloromethane (3:97) as eluent to give Methyl 4-[8-(2-chlorophenyl)-9-(2-hydroxy-2-methyl-propyl)-2-methyl-purin-6-yl]piperazine-1-carboxylate (0.3 g). ES/MS m/z 459 (M+1).
Reaction SMILES: O1CCOCC1.[OH-].[K+].C(N(CC)[C:12](=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([N:24]1[C:28]([I:29])=[CH:27][N:26]=[CH:25]1)[C:20]([OH:23])([CH3:22])[CH3:21])C.Cl>C(OCC)(=O)C>[I:29][C:28]1[N:24]([CH:19]2[C:14]3[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:30])[O:23][C:20]2([CH3:22])[CH3:21])[CH:25]=[N:26][CH:27]=1
Reactant: CCN(CC)C(=O)c1ccccc1C(n1cncc1I)C(C)(C)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Temperature: 60 °C
Reaction time: 13.5 h

Procedure:
Dioxane (22 mL) and 1M aqueous KOH (22 mL, 22 mmol) are added to N,N-diethyl-2-[2-hydroxy-1-(5-iodo-imidazol-1-yl)-2-methyl-propyl]-benzamide (1.65 g) and the mixture is heated to 60° C. After 13.5 h, the mixture is cooled to 0° C. and acidified to pH=1 with conc. HCl. The mixture is heated to 60° C. After 24 h, the mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gave an orange solid, which is purified by silica gel flash chromatography (methylene chloride-methanol, 49:1) to give a crystalline yellow solid; MS (ESI) m/z 369.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (s, 3 H), 1.57 (s, 3 H), 5.39 (s, 1 H), 7.19 (s, 1 H), 7.28 (br. d, J=7.6 Hz, 1 H), 7.39 (s, 1 H), 7.59 (td, J=7.6, 1.3 Hz, 1 H), 7.66 (td, J=7.6, 1.3 Hz, 1H), 8.27 (dd, J=7.6, 1.4 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.C(OC(=O)[NH:23][CH:24]([CH2:27][C:28]([F:31])([CH3:30])[CH3:29])[CH2:25][OH:26])(C)(C)C>>[F:31][C:28]([CH3:30])([CH3:29])[CH2:27][CH:24]([NH2:23])[CH2:25][O:26][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1
Reactant: CC1Oc2cc(Cl)ccc2-c2ccncc21
Reactant: CC(C)(F)CC(CO)NC(=O)OC(C)(C)C
Product: CC1Oc2cc(OCC(N)CC(C)(C)F)ccc2-c2ccncc21
Yield: 53.2 %

Procedure:
Prepared as described in Example 8, Part D using 8-chloro-5-methyl-5H-chromeno[3,4-c]pyridine (0.100 g, 0.432 mmol) and tert-butyl(4-fluoro-1-hydroxy-4-methylpentan-2-yl)carbamate (0.168 g, 0.712 mmol) to afford 4-fluoro-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-amine (80 mg, 0.23 mmol, 99% yield) as a yellow oil. 1H NMR (400 MHz, MeOD) δ 8.66 (d, J=6.4 Hz, 1 H), 8.64 (s, 1 H), 8.24 (d, J=6.4 Hz, 1 H), 8.08 (d, J=8.8 Hz, 1 H), 6.94 (dd, J=2.4 Hz, 8.8 Hz, 1 H), 6.78 (d, J=2.8 Hz, 1 H), 5.57 (q, J=6.4 Hz, 1 H), 4.38 (dd, J=6.4 Hz, J=10.8 Hz,1 H), 4.22 (dd, J=6.4 Hz, 10.8 Hz, 1 H), 3.99 (m, 1 H), 2.16 (m, 2 H), 1.75 (d, J=6.8 Hz, 3 H), 1.55 (s, 3 H), 1.50 (s, 3 H); LCMS (ESI) m/e 331.2 [(M+H)+, calcd for C19H24FN2O2331.2] LC/MS retention time (method D): tR=0.97 min; HPLC retention time (method B): tR=8.04 min.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([O:29]CC)=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([OH:29])=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was neutralized with 2N-hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.Br>[CH3:12][O:11][C:9](=[O:10])[CH:8]([Br:13])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) are dissolved in CCl4 (80 mL). HBr (64 ul, 0.56 mmol) is added and the mixture is stirred under reflux overnight. The mixture is cooled at RT, diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated obtaining intermediate I144 as a yellow oil (2.68 g, 96% yield).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: CC(=O)C(CC=Cc1ccccc1C)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C=CCC(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
A sodium hydroxide solution (5.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (14.06 g., 0.1 mole) and 3-phenyl-6-(o-methylphenyl)-5-hexen-2-one (26.4 g., 0.1 mole) in ethanol (260 ml.) with stirring. The yellowish solid that separates on continued stirring is filtered and air-dried, yield 22.5 g., m.p. 60°-76°C. Recrystallization from hexane gives material with m.p. 79°-82°C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cc(Br)ccc12
Temperature: 5 °C
Reaction time: 50 h

Procedure:
0.24 cm3 of butyryl chloride is added to 500 mg of 6-bromo-1H-indazole-3-amine described previously in Example 12, in 15 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 50 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of dichloromethane and filtered to give after drying (90 Pa; 50° C.), 356 mg of N-[6-bromo-1H-indazol-3-yl]butanamide in the form of an off-white solid melting at 202° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH2:22]O)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])(C(C)(C)C)(C)C.[CH3:41][C@@H:42]1[NH:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]1>>[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[C:24]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:38])[N:12]([CH2:11][C:10]([CH3:39])([CH3:40])[CH2:9][OH:8])[CH:21]=[C:20]4[CH2:22][N:47]3[CH2:46][CH2:45][NH:44][CH2:43][C@@H:42]3[CH3:41])[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=2)[CH2:32][CH2:31]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@@H]3C)c2c1
Yield: 14.1 %

Procedure:
The title compound was synthesised by a similar method to Example 26 h using 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (0.54 g), and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.191 g). Purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.072 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)Nc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A mixture of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (706 mg, 2 mmol), aniline (0.22 mL, 2.4 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3 mmol) in dichloromethane (6 mL) and triethyl-amine (0.7 mL, 5 mmol). The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (800 mg, 93%) as a brown oil which was used for next step without further purification: MS (ESI) M+1=429.2.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:1])=[CH2:29])[CH:23]=1)[CH3:20]
Reactant: CC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Methyl triphenylphosphonium bromide (2.33 g; 6.52 mmol) was suspended in tetrahydrofuran (15 ml). While the suspension was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.68 M: 4.6 ml; 7.82 mmol) was added dropwise. After the reaction mixture turned deep red, the mixture was cooled in an ice bath, and Compound 1 (1.54 g; 5.43 mmol) in tetrahydrofuran (15 ml) was added dropwise thereto. After completion of the addition, the mixture was removed from the ice bath, and stirred for 30 minutes at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.69 g of the target compound (yield: 45.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].Cl[CH2:12][C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:10][CH2:14][C:13](=[CH2:12])[CH3:15])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: C=C(C)CCl
Reactant: Cc1cc(O)cc(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C)c(C)c(C)c1

Procedure:
To a solution 20 g of 3,4,5-trimethylphenol in 150 ml of absolute acetone was added 22 ml of 3-chloro-2-methylpropene and 20.3 g of anhydrous potassium carbonate. After refluxing for 45 hours, the reaction mixture was filtered, washed with acetone, concentrated under reduced pressure and diluted with 200 ml of diethyl ether. The mixture was extracted three times with 50 ml of 2N hydrochloric acid and 50 ml of 20% aqueous solution of sodium hydroxide. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 27 g of methallyl 3,4,5-trimethylphenyl ether as yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: COCCN
Product: COCCNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and 2-methoxy-ethylamine. MS (ESI): 452.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]1([CH3:49])[CH2:43][O:42][CH:41]([CH2:44][CH2:45][CH2:46][CH:47]=O)[O:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:47][CH2:46][CH2:45][CH2:44][CH:41]3[O:40][CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][O:42]3)[CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CC1(C)COC(CCCC=O)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCN(CCCCC1OCC(C)(C)CO1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (68.2 mg, 0.129 mmol) in dichloroethane (2 mL) was added 4-(5,5-dimethyl-1,3-dioxan-2-yl)butanal (119 mg, 0.643 mmol) and NaBH(OAc)3 (136 mg, 0.643 mmol). The reaction was stirred at room temperature for 72 hours and then diluted with EtOAc (30 mL), quenched with saturated NH4Cl solution (10 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl](ethyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.62 (25% EtOAc/hexanes). LCMS=701.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ7.97 (s, 1H), 7.85 (s, 2H), 7.23-7.19 (m, 3H), 5.79 (d, J=8.1 Hz, 1H), 4.79 (d, J=16.0 Hz, 1H), 4.62 (d, J=16.0 Hz, 1H), 4.43 (t, J=4.9 Hz, 1H), 4.11-4.01 (m, 1H), 3.61 (d, J=1.1 Hz, 2H), 3.44 (d, J=10.8 Hz, 2H), 3.06-3.00 (m, 4H), 1.71-1.41 (m, 6H), 1.12 (s, 3H), 1.05-1.01 (t, J=7.0 Hz, 3H), 0.77 (s, 3H), 0.74 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)ncn1
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.32 g, 1.1 mmol), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (XLI) (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 min. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.40 g of 3-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLII).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C@@H:13]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:14]2[CH:19]=[CH:18][C:17](/[C:20](=[N:22]/[OH:23])/[NH2:21])=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[C:32]1([C:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47](Cl)=O)[O:40][N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(#N)C>[Si:25]([O:24][C@@H:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:47]([C:41]3[O:40][N:39]=[C:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:42]=3[C:43]([F:46])([F:44])[F:45])[O:23][N:22]=2)=[CH:18][CH:19]=1)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 1282 %

Procedure:
(S)-Ethyl-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (32.6 g, 72 5 mmol) was dissolved in acetonitrile (145 ml) (anhydrous) and cooled to ˜3° C. with ice-bath. 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl chloride (19.98 g, 72.5 mmol) was dissolved in 50 mL anhydrous acetonitrile and added dropwise. The internal temperature was kept below 10° C. during addition. After addition, the reaction mixture was allowed to warm to room temperature. At 30 minutes, HPLC showed completion of the first reaction step. The reaction mixture was re-cooled to below 10° C. DIEA (18.99 ml, 109 mmol) was added slowly. After the addition, the reaction mixture was heated up to 55° C. for 17 hrs. HPLC/LCMS showed completion of the reaction. The solvents were removed by ROTAVAPOR®. The residue was stirred in 250 mL 20% EtOAc/hexanes and the DIPEA HCl salt precipitated from solution and was removed via filtration. The filtrate was concentrated and purified using a silica gel cartridge (3×330 g silica, 0-50% EtOAc/hexanes gradient). (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (43g, 64.1 mmol, 88% yield) was obtained a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (2H, d), 7.68 (2H, d), 7.57 (5H, m), 4.85 (1H, m), 4.14 (2H, m), 2.95 (1H, m), 2.82 (1H, m), 2.64 (1H, dd), 2.51 (1H, m), 2.49 (1H, dd), 2.35 (1H, tt), 2.14 (1H, dt), 1.91 (1H, m), 1.66 (1H, dt), 1.57 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.92 (9H, s), 0.11 (3H, s), −0.05 (3H, s).