Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:34]([O:36][C:37]([C@@:39]1([NH2:44])[CH2:41][C@H:40]1[CH:42]=[CH2:43])=[O:38])[CH3:35].[C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](O)=[O:55])([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>ClCCl>[C:48]([O:47][C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](=[O:55])[NH:44][C@@:39]1([C:37]([O:36][CH2:34][CH3:35])=[O:38])[CH2:41][C@@H:40]1[CH:42]=[CH2:43])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
A solution of HATU (6 g), diisopropylethylamine (6.8 mL), (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.5 g) and BOC-L-hydroxyproline (1.6 g) in dichloromethane was stirred for 1 hrs. The mixture was extracted with DCM-NaHCO3 (aq) dried and concentrated. HPLC purity ca 90% M+H+ 369.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:4].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:35](=[O:36])[CH2:34][C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:32])(=[O:33])[N:30]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
(1R,2S)-2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (106 mg, 0.42 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in U.S. Pat. No. 7,939,524 B2, 140 mg, 0.42 mmol) were dissolved in a 1:1 mixture of dichloromethane and N,N′-dimethylformamide (6 mL). A 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.46 mL, 0.46 mmol) was added. The reaction was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-85% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (127 mg, 0.22 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.80-2.22 (6H, m), 3.07 (3H, s), 3.24 (1H, dd, J1=18.8 Hz, J2=8.0 Hz), 3.32 (1H, dd, J1=15.6 Hz, J2=8.0 Hz), 3.69 (1H, s), 4.63 (2H, d, J=4.8 Hz), 4.67-4.74 (1H, m), 4.82-4.89 (1H, m), 6.99-7.14 (5H, m), 7.51-7.64 (2H, m). LC-MS (ESI) calcd for C24H27FN4O7S2 566.62. found 567.1 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1C=C(O)C=CC=1C.[CH3:21][CH:22]([CH3:39])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]3[S:36][CH:35]=[N:34][C:30]3=[CH:31][CH:32]=2)[C:27](=[O:37])[C:26]1=[O:38].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:37][C:27]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:28]2[C:33](=[CH:32][CH:31]=[C:30]3[N:34]=[CH:35][S:36][C:29]3=2)[N:25]([CH2:24][CH2:23][CH:22]([CH3:21])[CH3:39])[C:26]1=[O:38]
Reactant: CC(C)CCN1C(=O)C(=O)c2c1ccc1ncsc21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: CC(C)CCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3,4-dimethylphenol, and 6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one was obtained (46%): 1H NMR (300 MHz, CDCl3) δ9.00 (s, 1H), 8.80 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 4.15 (s, 4H), 3.81-3.59 (m, 2H), 1.79-1.55 (m, 1H), 1.56-1.42 (m, 2H), 0.93 (d, J=6.6 Hz, 6H); MS (ES+) m/z 427.0 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>ClCCl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:17][CH2:16]1
Reactant: C=CC(=O)Cl
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Acryloyl chloride (10.6 mL, 11.8 g, 0.13 mol) was added dropwise to a stirred, cooled (0° C.) mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (15 g, 66 mmol) and triethylamine (27.3 g, 19.8 g, 0.20 mol) in dichloromethane and the mixture was stirred at room temperature for 2 h. The mixture was poured into hydrochloric acid (1M) and extracted with dichloromethane. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (saturated), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (40:60 increasing to 20:80), to give the title compound as a pale yellow oil (3.6 g, 22%). 1H NMR (360 MHz, CDCl3) δ 7.04 (1H, m), 6.95-6.84 (3H, m), 6.61 (1H, dd, J 16.8, 10.6 Hz), 6.32 (1H, dd, J 16.8, 1.8 Hz), 5.72 (1H, dd, J 10.6, 1.8 Hz), 3.94-3.84 (2H, m), 3.89 (3H, s), 3.74 (2H, m), and 3.06 (4H, m). m/z (ES+) 247 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:48])([OH:47])[CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([OH:47])([CH3:48])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)/C=C/CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SC/C=C/C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.2 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (33.5 mg, 0.0577 mmol), (E)-5-bromo-2-methyl-3-penten-2-ol (41.2 mg, 0.230 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate=5:1, developed twice) to give 26.2 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from (E)-5-bromo-2-methyl-3-penten-2-ol.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=[N:28][OH:29])[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Yield: 93 %

Procedure:
To a solution of 2.00 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol of Example 4 in 100 ml of 95% ethanol is added a solution of 1.2 g of sodium acetate in 10 ml of H2O and a solution of 1.0 g of hydroxylamine hydrochloride in 4 ml of H2O and the mixture is refluxed for 90 minutes. The solvents are removed under reduced pressure and the product is crystallized from ethanol-H2O (20 ml-100 ml) and dried (P2O5 --40°) in vacuo to provide 1.96 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol oxime, m.p. 137°-138° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl[C:12]1[N:17]2[N:18]=[CH:19][CH:20]=[C:16]2[N:15]=[C:14]([S:21][CH3:22])[N:13]=1.O>O1CCOCC1>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([S:21][CH3:22])[N:13]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CSc1nc(Cl)n2nccc2n1
Reactant: CCOc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(Nc2nc(SC)nc3ccnn23)cc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
p-Phenetidine (3.09 g, 22.51 mmol) was added to a mixture of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (300 mg, 1.5 mmol) from 1d in 1,4-dioxane (6 mL). The mixture was heated to 100° C. for ½ hour. Water (15 mL) was then added to the reaction mixture and the resulting precipitate was collected by vacuum filtration, washed with cold water and hexane, and then air dried to give 360 mg (80%) of N-(4-ethoxyphenyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].CO[C:19]1C(OC)=C[C:22]2[NH:23][C:24](CCCNC)=N[C:21]=2[CH:20]=1>>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[C:8]2[N:14]=[C:19]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(O[Si](C)(C)C(C)(C)C)cccc2[nH]1

Procedure:
Prepared from 3-(tert.-butyl-dimethyl-silanyloxy)-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)O1.Br[C:29]1[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][CH:34]=1.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>[N:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: OCc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
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
Solvent: O
Product: OCc1cccc(-c2ccc(N3CCOCC3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium (36 mg) and sodium carbonate (330 mg) were added to a mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (300 mg), (3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml), followed by stirring at 80° C. overnight, and then the reaction mixture was concentrated under reduced pressure. Water and CHCl3 were added to the obtained residue, and the organic layer was dried over MgSO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain [4′-(morpholin-4-yl)biphenyl-3-yl]methanol (242 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1Br.[CH2:18]([O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CO>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(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[C:31]1[C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Reactant: CC1(C)OB(c2cccnc2OCc2ccccc2)OC1(C)C
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: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 79.2 %

Procedure:
step 2—A microwave vial was charged with 64 (903 mg, 3.00 mmol), 2-benzyloxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (1.12 g, 3.60 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), Na2CO3 (950 mg, 9.00 mmol), MeOH (10 mL) and DCM (3 mL). The vial was sealed and irradiated at 115° C. for 30 min in microwave synthesizer. The reaction was quenched with H2O and extracted with DCM. The combined organics were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (10% to 20% EtOAc) to afford 964 mg (80%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid methyl ester (66) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([CH3:13])(O)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[FH:37].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([F:37])([CH3:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 42 °C
Reaction time: 15 h

Procedure:
To a solution of 5.5 g (13.5 mmole) of (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl) azetidin-3-yl]-2-methylpropan-2-ol in 25 mL of CH2Cl2 was added 15 mL of hydrogen fluoride-pyridine and the two-phase mixture was stirred for 15 h at 42° C. Then the reaction mixture was poured to 100 mL of 5N NaOH, 20 mL of aq NaHCO3, 150 mL of CH2Cl2 and 100 mL ice. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×1500 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.25 ( t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.30 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 10H); Mass Spectrum: m/e=410 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1)[NH2:5].[F:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[C:25]2[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:24]=2[F:23])=[O:30])[CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Into a solution containing 3.0 grams (9.0 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline prepared in Part B of Example I in 25 milliliters of toluene which solution was warmed to a temperature of 50° .C and placed under a nitrogen atmosphere was slowly added a solution containing 2.5 grams (13.5 mmol) of 2.6-difluorobenzoyl isocyanate in 5 milliters of toluene. After stirring for one hour at a temperature of 50° C. the reaction mixture was cooled to room temperature, placed in an ice bath. and filtered through a Buchner funnel. The collected solid was dried under a vacuum at a temperature of 50° C. to afford 2.89 grams of 1-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl)urea as a white powder havin a melting point of 187° C. Elemental analysis of the white powder indicated the following:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:15][C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:8]=[O:9])([CH3:17])[CH3:16]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Yield: 75.7 %

Procedure:
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH2Cl2 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2Cl2, washed with 1N HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH3:10][C:5]1[C:6]([S:8][CH3:9])=[N:7][C:2]([N:15]2[CH:16]=[CH:17][C:13]([C:12]([F:19])([F:18])[F:11])=[N:14]2)=[N:3][CH:4]=1
Reactant: CSc1nc(Cl)ncc1C
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1nc(-n2ccc(C(F)(F)F)n2)ncc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 350 %

Procedure:
A mixture of 2-chloro-5-methyl-4-methylthiopyrimidine (2.5 g, 14 mmol), 3-(trifluoromethyl)-1H-pyrazole (2.3 g, 2.5 mmol) and potassium carbonate (4.8 g, 35 mmol) in 25 mL of N,N-dimethylformamide was heated at 70° C. with stirring for 5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with water and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide a white solid which was suspended in hexane and filtered to provide 2.4 g of the title compound of Step B as a solid melting at 126-127° C. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.24 (s, 1H), 6.73 (d, 1H), 2.68 (s, 3H) 2.25 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH2:20]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH2:20]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-benzyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C25H26O5 [M+Na]+: 429.3.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 18.7 %

Procedure:
Using the general method of Example 146 Part B, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.50 g, 8.9 mmol) was reacted with phenyl isocyanate (1.78 mL, 16.4 mmol) to provide 0.67 g of N-[4(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)OCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 48 h

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (40 g) was dissolved in dichloromethane (1.4 L) and triethylamine (23.3 mL). 3-Isopropoxypropylamine (19.3 mL) was added dropwise. After 48 hours, the reaction mixture washed successively with water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (7-Bromo-3-nitroquinolin-4-yl)-(3-isopropoxypropyl)amine was isolated as a tan solid (51.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].CI.[C:28](O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:28])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 50.2 g of ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 300 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 3.6 g of sodium hydride in 100 ml of absolute 1,2-dimethoxyethane. The reaction mixture is stirred for 1 hour, treated with 21.3 g of methyl iodide and stirred for a further 2 hours. The mixture is subsequently rendered neutral with 0.5 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, the solution shaken three times with 250 ml of water, and the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of hot methylene chloride, seeded, and treated with diethyl ether. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d] pyrimidin-3-yl)-benzoate, m.p. 141°-143° C.