Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CCCCCC.C([O:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])C>C(OCC)C.C1CCCCC1.C(OCC)C>[F:28][C:27]([F:30])([F:29])[C:26]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[CH:4]=1)=[O:25]
Reactant: C[Si](C)(C)c1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: C[Si](C)(C)c1cccc(C(=O)C(F)(F)F)c1
Temperature: -78 °C
Yield: 52.7 %

Procedure:
To a solution of 3-trimethylsilyl-bromobenzene (7.62 g, 33.3 mmol) in diethyl ether (35 ml) was added at 0° C. 1.5M n-butyllithium in hexane (22.2 ml, 33.3 mmol) over 10 min. Then the mixture was allowed to react 15 min at room temperature, cooled to -78° C. and ethyltrifluoroacetate (14.2 g, 100 mmol) was added over 5 min. Then the mixture was allowed to react 15 min at -78° C., the cooling bath was removed and when the temperature rose to 0° C. 3N HCl (35 ml) was added dropwise. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. Chromatography (silica gel, cyclohexane/diethyl ether: 90/10) followed by distillation under reduced pressure afforded the expected compound as a colorless oil (4.32 g, 53% yield), b.p. 120° C., Rf: 0.28 (cyclohexane/diethyl ether: 95/5).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.N(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) CuI in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:34])[CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.O.C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([N:15]([CH3:34])[CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a suspension of tert-butyl 9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (330 mg, 0.67 mmol) in dichloromethane (15 mL) was added the solution of HCl in EtOAc (3 mL, 12 mmol). The reaction mixture was stirred at rt for 2 h and then adjust to pH=8-9 with the solution of saturated NaHCO3. The resulting mixture was diluted with 20 mL of H2O and exacted with a mixture of DCM and MeOH (10/1, 10 mL×3). The combine organic layers were washed with brine (20 mL×1), then over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=10/1 to 5/1) to give the title compound as a yellow solid (170 mg, 64.8%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([OH:37])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:26]=[C:27]([O:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:30]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(Oc2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 40 %

Procedure:
A mixture of N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamide (E2) (52 mg, 0.1 mmol), benzeneboronic acid (25 mg, 0.2 mmol), cupric acetate (18 mg, 0.1 mmol) and powdered 4 A molecular sieves in dichloromethane (1 ml) were treated with triethylamine (0.070 ml, 0.5 mmol). After stirring for 40 hrs at room temperature, the mixture was partitioned between ethyl acetate and 2N HCl and the product was extracted into ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and concentrated. Chromatography on silica gel (elution with ethyl acetate) gave E11 as a white solid (24 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([O:13][C:4]=2[CH:3]=1)=[C:11]([NH2:14])[N:10]([CH3:15])[N:9]=3.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([O:13][C:4]=2[CH:3]=1)=[C:11]([NH:14][C:16](=[O:18])[CH3:17])[N:10]([CH3:15])[N:9]=3
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc2c(oc3cc(Cl)ccc32)c1N
Product: CC(=O)Nc1c2oc3cc(Cl)ccc3c2nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (6.0 g, 27.1 mmol, described in Example 6) and acetic anhydride (60 mL) was stirred at room temperature for 2 hr. The precipitate was collected and washed with diethyl ether to give the title compound (7.0 g), mp 290°-300° C. Crystallization from ethanol gave title compound having mp 293°-298° C.: IR (mineral oil) 3220, 3170, 1665 and 1540 cm-1 ; UV max (MeOH) 297 nm (ε=7755), 274 (22760) and 229 (21360); NMR (DMSO-d6) δ2.13 (3H, s), 3.82 (3H, s), 7.33 (1H, 2d), 7.76 (1H, d) and 7.82 (1H, d); and Anal. Calcd for C12H10ClN3O2 : C, 54.66% H, 3.82% N, 15.94% and Found: C, 54.52% H, 3.86% N, 15.86%.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A stirred mixture of 2.91 g (20 mmol) of 4-vinylbenzoic acid, 5.84 g (22 mmol) of 1-octadecanol, 0.17 g (1 mmol) of 4-toluenesulfonic acid, and 75 ml of toluene was heated at reflux with water separated azeotropically using a Dean-Stark trap. After 16 hours, the mixture was cooled to ambient temperature and filtered through a short column of basic alumina, eluting with tetrahydrofuran. The filtrate was concentrated to deposit a solid product, which was purified by chromatography on silica gel (a heptane/dichloromethane eluate), followed by recrystallization from acetonitrile. A white solid was obtained, mass 3.98 g (51% yield).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd]>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1cnc(Br)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1

Procedure:
A solution of 104 g of 2,5-dibromopyrimidine, 100 g of 4-benzoxyphenylboronic acid, 4.75 g of Pd (10% on activated charcoal), 4.5 g of triphenylphosphene and 93 g of sodium carbonate in 1 l of toluene, 0.5 l of ethanol and 0.3 l of water is heated at 80° C. for 24 hours. After filtration, the organic phase is separated off and evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile: 83 g of solids of melting point 153°-155° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:15][C:11]([S:10][C:7]1[S:8][CH:9]=[C:5]([CH2:4][C:1]([N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:3])[N:6]=1)([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: CNc1ccccc1
Product: CN(C(=O)Cc1csc(SC(C)(C)C(=O)O)n1)c1ccccc1

Procedure:
The title yellow resin (2.0 g) was obtained using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and N-methylaniline (0.52 ml) as starting materials and by an operation similar to that of Example 461-5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:23]O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=NO
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
1-Hydroxyimino-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.00 g, 3.09 mmol) obtained in Step 1 was dissolved in methanol (100 mL), and 10%-palladium (583 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 786 mg of the titled compound (yield: 82%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:25][CH2:24][CH2:23][N:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[CH:22]=[C:14]4[C:13]=3[CH:26]=2)O1.Br[C:29]1[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]2[O:36][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=2[CH:48]=1>CN(C=O)C.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:26]1[C:13]2[C:14]3[N:15]([CH2:23][CH2:24][O:25][C:12]=2[CH:11]=[CH:10][C:9]=1[C:29]1[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]2[O:36][C:35]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=2[CH:48]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[CH:22]=3
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CC1(C)OB(c2ccc3c(c2)-c2cc4ccccc4n2CCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3cc5ccccc5n3CCO4)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A mixture of compound 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole (72 mg, 0.2 mmol), 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (91 mg, 0.2 mmol), K3PO4-3H2O (160 mg, 0.6 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in 2 mL of DMF was stirred at 90° C. for 8 h under N2, then the mixture was purified using prep-HPLC to provide Compound 42 (30 mg, yield: 24.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.92˜7.97 (m, 3H), 7.81 (s, 1H), 7.63˜7.65 (m, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.12˜7.25 (m, 5H), 6.97 (s, 1H), 6.00 (d, J=4.0 Hz, 1H), 4.62 (t, J=4.2 Hz, 2H), 4.54 (t, J=4.2 Hz, 2H), 3.18 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 610.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>CC#N>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc2c(Br)cccn2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-pyrazolo[1,5-a]pyridin-2-ylamine (Intermediate 3) (259 mg, 1.22 mmol) was dissolved in dry CH3CN (10 mL) at 5° C. and Et3N (425 μL, 3.05 mmol) was added followed by the cyclopropane carbonyl chloride (278 μL, 3.05 mmol). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash column chromatography (2:1 petroleum ether 40-60:EtOAc) yielded cyclopropanecarboxylic acid (4-bromo-pyrazolo[1,5-a]pyridin-2-yl)-amide (Intermediate 4).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1)=[O:5].[C:25]([O:29][C:30]([N:32]1[C@@:36]([CH3:40])([C:37](O)=[O:38])[CH2:35][O:34][C:33]1([CH3:42])[CH3:41])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:41][C:33]1([CH3:42])[N:32]([C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C@@:36]([CH3:40])([C:37](=[O:38])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([C:21]([F:22])([F:23])[F:24])[CH:7]=2)=[O:5])[CH2:35][O:34]1
Reactant: CCCCCCCCOc1ccc(C(=O)CN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: Cl
Product: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
Synthesis of phenyl-thiazoles is described in Scheme 4. Reaction of benzyl or allyl alcohol with substituted 4-fluorobenzoic acid 1 afforded the substituted ether-benzoate 2. The substituted ether-benzoate 2 was then coupled with hydrazine to afford benzohydrazide 3. Reaction of benzohydrazide 3 with orthogonally protected amino acid 4 under HATU conditions followed by cyclization and deprotection (or vis versa) provided phenol 6 in good yield. Mitsunobu reaction of phenol 6 with desired alcohol followed by deprotection afforded the desired final compound 8. Reaction of the alcohol 8 with diethyl chlorophosphate followed by deprotection with TMSBr gave the corresponding phosphate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][N:7]([CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:45])[CH2:32][CH2:33][NH:34][C:35]([C:37]2[C:38]([CH3:44])=[N:39][CH:40]=[N:41][C:42]=2[CH3:43])=[O:36])[CH2:27][CH2:26]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C(C2C(C)=NC=NC=2C)=O)=[CH:10][CH:9]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH:25]1[CH2:26][CH2:27][N:28]([CH:31]([CH3:45])[CH2:32][CH2:33][NH:34][C:35]([C:37]2[C:42]([CH3:43])=[N:41][CH:40]=[N:39][C:38]=2[CH3:44])=[O:36])[CH2:29][CH2:30]1)#[N:2]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OC(=O)c3c(C)ncnc3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Temperature: 40 °C
Yield: 56.1 %

Procedure:
To a solution of COMPOUND 136 (870 mg, 1.39 mmol) in MeOH (14 mL) was added 10N NaOH (1.4 mL, 14 mmol) and the mixture was heated at 40° C. overnight to afford 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide as a pink solid (400 mg, 53%) following an acidic work-up and purification.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH3:24]
Reactant: CCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using ethyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a light brown amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.15 (t, 3H), 1.70–2.01 (m, 3H), 2.65–2.70 (t, J=9.6 Hz, 3H), 2.70–2.95 (m,2H), 2.95–3.13 (m, 2H), 3.13–3.72 (m, 5H), 3.60–3.95 (m, 1H), 6.39 (d, J=8.0 Hz, 1H), 6.47 (d, J=7.4 Hz, 1H), 6.64 (t, J=7.3 Hz), 1H) ppm. MS (CI): 244 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([NH:11][C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([OH:23])[CH2:13]1)=O>CO.O>[NH2:11][C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([OH:23])[CH2:13]1
Reactant: COc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@H]2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)[C@H](N)C[C@H]2O
Reaction time: 72 h
Yield: 77.6 %

Procedure:
Potassium carbonate (16 mg, 0.116 mmol) was added to a solution of trans-2,2,2-trifluoro-N-(-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide (32 mg, 0.116 mmol) in methanol (2 mL) and water (1 mL). After stirring for 72 hours, the reaction mixture was diluted with methanol, filtered through a cotton plug, and concentrated in vacuo. The crude compound was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane with 0.1% NH4OH to give the title compound (17 mg, 0.09 mmol). MS (ESI) m/z (M+H+): 180.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[C:13]3([CH2:15][CH2:14]3)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[C:13]3([CH2:15][CH2:14]3)[CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C2(CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ccc(Cl)cc2)CCNCC12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A solution of tert-butyl 8-(4-chlorophenyl)-8-hydroxy-5-azaspiro[2.5]octane-5-carboxylate (1.81 g, 5.36 mmol) in dioxane (2 mL) was treated with 4.0 M HCl in dioxane (7 mL, 28.0 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was concentrated in-vacuo then concentrated 2× from methylene chloride to remove residual HCl. The residue was dissolved in water and washed 2× with diethyl ether. The aqueous phase was treated with sodium bicarbonate until the mixture was basic, then washed 2× with 10 mL diethyl ether. The aqueous phase was treated with solid sodium hydroxide until the pH was >13, and the mixture was extracted 5× with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated in vacuo to yield (±)-8-(4-chlorophenyl)-5-azaspiro[2.5]octan-8-ol as a colorless powder (1.1 g, 87% yield). MS (ESI+)=238.1, (M+H)+. The isomers were separated via chiral super critical fluid chromatography to yield 463 mg of isomer A and 522 mg of isomer B.
Reaction SMILES: [Cl:1]N1C2C=CC=CC=2N=N1.[F:11][C:12]([F:29])([F:28])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]3[N:25]=[CH:26][CH:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[CH:14]=1.C(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:27]1[CH:26]=[N:25][N:24]2[C:19]([C:15]3[CH:14]=[C:13]([C:12]([F:28])([F:11])[F:29])[CH:18]=[CH:17][CH:16]=3)=[CH:20][CH:21]=[N:22][C:23]=12
Reactant: Cln1nnc2ccccc21
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Temperature: 25 °C

Procedure:
A 3.3 g. portion of N-chlorobenzotriazole is added to a solution of 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of chloroform producing an exothermic reaction. The mixture is refluxed on a steam bath for 15 minutes, cooled to room temperature and then poured into an ice-cold solution of 2.5 N sodium hydroxide. The organic layer is separated, dried over socium sulfate and passed through a hydrous magnesium silicate column. The effluent is heated to reflux and hexane is added giving a solid. The solid is dissolved in methylene chloride re-processed through the column and precipitated from refluxing solution with hexane giving crystals of the desired product, m.p. 155°-157° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([NH:20][C:21]([O:23]C(C)(C)C)=O)=[C:9]([NH:12][C:13](OC(C)(C)C)=[O:14])[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH:1]1([C:7]2[C:8]3[NH:20][C:21](=[O:23])[C:13](=[O:14])[NH:12][C:9]=3[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1scc(C2CCCCC2)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2scc(C3CCCCC3)c2[nH]c1=O
Yield: 24 %

Procedure:
A mixture of di-t-butyl 4-cyclohexylthiophene-2,3-dicarbamate (400 mg, 1mmol), diethyl oxalate (5 ml, 37 mmol) and glacial acetic acid (5 ml) was refluxed for 16 h. The precipitate was filtered off and washed with glacial acetic acid to give 60 mg (24%) of the title compound. M.p.>270° C. 1H-NMR (DMSO-d6, δ): 1.1-1.9 (m, 10H), 2.75 (m, 1H), 6.7 (s, 1H), 11.9 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[CH:24]=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)n1
Temperature: 125 °C
Yield: 19.6 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (29.3 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 5.6 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 470.2 (M+H)+, Rt 0.83 min.