Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])[C:15]([CH3:31])=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[OH:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:24][CH2:25]2)=[O:19])[C:15]([CH3:31])=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCOCc2ccccc2)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCO)nc1C(=O)N1CCC(N2CCCC2)CC1
Yield: 76.4 %

Procedure:
A solution of 0.14 g (0.25 mmol) of [6-(2-benzyloxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 14) in 6.0 ml of MeOH was treated at RT with 0.49 ml (0.49 mmol) of hydrochloric acid (1.0 molar in MeOH), followed by 0.026 g (0.025 mmol) of Pd—C (10%). The reaction mixture was vigorously stirred in an atmosphere of hydrogen for 3 hours. After filtration through dicalite, the solvent was removed by evaporation, then the residue was dissolved in H2O/Na2CO3 and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.091 g (77%) of the title compound as yellow amorphous solid. MS: 477.3 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=[O:14])C.Cl([O-])=O.[Na+]>>[O:14]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCOC(=O)C(=O)C(=O)OCC

Procedure:
A reaction was performed similarly to Example 1 using 0.25 g (0.0016 mole) diethyl malonate, 0.95 mL (0.0166 mole) acetic acid, 1.71 g (0.0047 mole) of 25% sodium chlorite aqueous solution, and GC analysis was performed to give 88.1% GC total area value of diethyl ketomalonate.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:35]=[CH:36][C:37]([OH:43])=[C:38]([CH:42]=1)[C:39]([OH:41])=[O:40])(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[CH:36][C:37]([OH:43])=[C:38]([CH:42]=3)[C:39]([OH:41])=[O:40])(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Product: O=C(O)c1cc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)ccc1O

Procedure:
The title compound was prepared from of 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 5-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 171-173° C.; MS m/e 575 (M-H)+;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH:14]([CH3:16])[CH3:15])=[N:9]2)[CH:5]=[N:6][CH:7]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH:13][C:18](=[O:19])[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]([CH:14]([CH3:16])[CH3:15])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1cc(N)n(-c2cncc(F)c2)n1
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Yield: 35 %

Procedure:
Following the procedure for Example 282A Step 2, 1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-amine was treated with phenyl chloroformate. Purification using silica gel chromatography eluting with MeOH/DCM (0-10%) afforded phenyl 1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (235 mg, 35% yield) for steps B and C. 1H NMR (300 MHz, DMSO d6) δ 1.25 (s, 6H), 2.93 (m, 1H), 6.40 (s, 1H), 7.15 (bs, 2H), 7.29 (m, 2H), 7.42 (m, 3H), 8.00 (m, 1H), 8.65 (s, 1H), 8.72 (s, 1H), 10.32 (s, 1H); LC-MS (ESI) m/z 341 (M+H)+
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[CH3:12][O:13][C:14](=[O:29])[C:15]1[CH:27]=[C:26](I)[CH:25]=[C:17]([C:18]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[O:19])[CH:16]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:13][C:14](=[O:29])[C:15]1[CH:27]=[C:26]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[CH:25]=[C:17]([C:18]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[O:19])[CH:16]=1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: Cn1ccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2nccn2C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add n-butyl lithium (2.0 M in pentane, 0.78 mL, 1.55 mmol) dropwise over 30 min to a previously nitrogen-flushed, flame-dried vessel containing 1-methyl-1H-imidazole (0.12 mL, 1.5 mmol) in THF (10 mL) at −78° C., and stir for 30 min at the same temperature. Warm the solution to 0° C. and add dropwise zinc (II) chloride (1.0 M in diethyl ether, 4.5 mL, 4.5 mmol) over 10 min. Stir the mixture at the same temperature for 1 h and at room temperature for 30 min. Add 5-iodo-N-methyl-N-propyl-isophthalamic acid methyl ester (361 mg, 1.0 mmol) and tetrakis(triphenylphosphine)palladium (0) (12 mg) under nitrogen before heating the reaction to reflux for 20 min. Cool to room temperature, concentrate and purify (silica gel chromatography, eluting with 0:100 to 8:92 methanol:dichloromethane) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24]CC4C=CC=CC=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCO)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a mixture of 0.434 g (0.795 mmole) of 2-[6-(4-benzyloxy-butyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41c) and 5 mL of acetonitrile at 0 degrees was added dropwise 0.836 mL (0.795 mmole) of boron trifluoride-dimethyl sulfide complex. The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. Saturated sodium bicarbonate was added to the residue and the mixture was extracted three times with 15 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-3:97) to give 0.266 g of 4-(3-chloro-phenyl)-2-[6-(4-hydroxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41d) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9]C2C=C(C(F)(F)F)C3C(=CC=C(O[C@H]4CC[C@H](C(C)(C)C)CC4)C=3)N=2)[CH2:6]1)=[O:4].[C:35]([C@H:39]1[CH2:44][CH2:43][C@H:42]([O:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[C:51](C=O)[CH:52]=3)[N:47]=2)[CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][CH:50]=2)[N:47]=[C:46]([O:45][C@H:42]2[CH2:41][CH2:40][C@H:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:44][CH2:43]2)[CH:55]=[CH:54]3)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Product: COC(=O)C1CN(Cc2ccc3nc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 2-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline-6-carbaldehyde as starting material. ESI-MS(M+H+): 411.30.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[CH:27][C:28]=1[Cl:29].C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[Cl:29][C:28]1[CH:27]=[N:26][N:25]([CH3:30])[C:24](=[O:31])[C:23]=1[NH:14][C@H:12]([C:10]1[N:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[N:11]=1)[CH3:13]
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1c(Cl)cnn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Reaction time: 20 h
Yield: 6.4 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1.0 g, 3.05 mmol), 4,5-dichloro-2-methyl-2H-pyridazin-3-one (J. Org. Chem. 2473-76, 46, 1981) (0.546 g, 3.05 mmol) and diisopropylethylamine (2.1 mL, 12.8 mmol) in isopropanol (5 mL) was heated to reflux for 4.25 h then at 75° C. for 20 h. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with 1M sodium carbonate (10 mL). The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM then gradient 20-100% EtOAc in DCM). Fractions containing the less polar product were evaporated and freeze dried to give 323 as a yellow solid, (78 mg, 6.4%). LCMS (Method C): RT 4.80 min [M+H]+ 398.00. 1H NMR δ (ppm) (DMSO-d): 7.77 (1H, dd, J=8.82, 4.85 Hz), 7.56-7.55 (6H, m), 7.14 (1H, ddd, J=9.9, 8.9, 2.50 Hz), 6.89 (1H, dd, J=8.91, 2.51 Hz), 6.61 (1H, d, J=9.09 Hz), 5.94 (1H, t, J=7.66 Hz), 3.56 (3H, s), 1.51 (3H, d, J=6.65 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2C=CC=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.C1(CO)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Agent: OCC1CC1
Product: Fc1cc2nc(-c3cccnc3OCC3CC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and cyclopropyl-methanol (CAS Reg. No. 2516-33-8). Colorless powder (20%). MS (Turbo Spray): m/z=426.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1>C(N(CC)CC)C.[Pd].CN(C)C=O>[CH3:16][C:14]1[CH:15]=[C:6]2[NH:5][C:4]3[CH:3]=[CH:2][N:11]=[CH:10][C:9]=3[C:8](=[O:12])[N:7]2[N:13]=1
Reactant: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc2[nH]c3ccncc3c(=O)n2n1

Procedure:
23.5 g. of 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 3 are hydrogenated at 80° in 200 ml. of dimethylformamide in the presence of 15 g. of triethylamine and 10% palladium on charcoal as catalyst. When the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered hot and the mother liquor evaporated in vacuo to dryness. The remaining 2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is recrystallized from dimethylformamide, yield: 18.5 g. (92%); m.p. >300°.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=O.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].[BH4-].[Na+].CO>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7][NH:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 3,4-bis(difluoromethoxy)benzaldehyde (10-2, 100 mg, 0.42 mmol, 1 equiv) in THF (840 uL) was added 2-methylpropane-2-sulfinamide (56 mg, 0.46 mmol, 1.1 equiv) and titanium ethoxide (440 uL, 2.10 mmol, 5.0 equiv), and the reaction mixture stirred at ambient temperature for 4.5 hours. The reaction mixture was then cooled to 0° C. and sodium borohydride (31.8 mg, 0.84 mmol, 2.0 equiv) was added portionwise and the reaction was stirred for an additional hour. Methanol (2 mL) was added slowly and the reaction mixture was partitioned between EtOAc (20 mL) and brine (20 mL) and filtered. The organic phase was dried over MgSO4 and concentrated to afford crude N-[3,4-bis(difluoromethoxy)benzyl]-2-methylpropane-2-sulfinamide, which was dissolved in methanol (2.2 mL). To the solution was added HCl (2 M in ether, 655 uL, 3 equiv), and the reaction mixture stirred for 30 minutes. It was then concentrated to afford the desired product (10-3) as a white solid. ESI+MS [M-NH2]+ C9H7F4O2: 223.0 found, 223.0 required.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:44]([C:46]1[CH:51]=[C:50]([N+:52]([O-])=O)[CH:49]=[CH:48][C:47]=1[CH3:55])=[O:45]>>[NH2:52][C:50]1[CH:49]=[CH:48][C:47]([CH3:55])=[C:46]([C:44]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)=[CH:35][C:30]=2[Cl:29])=[O:45])[CH:51]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc(N)cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 460 (2.13 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH2:24][CH2:25]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:24][CH:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCC=C(c1ccccc1)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Product: O=C(NC1CCN(CCC=C(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
Using the procedure of Example 77 over a period of 20 hours, 4-benzamidopiperidine (7.473 g.) was alkylated with 1,1-diphenyl-4-chlorobut-1-ene (8.879 g.). The title compound was filteredoff after addition of water and ether to the reaction mixture and a furthercrop was obtained from the ether washings. Conversion of the combined product to the hydrochloride using ethanolic hydrogen chloride gave 6.308 g. (38.2%). m.p. 220°-230° (dec.). C28H30N2O.HCl.1/4H2O requires C, 74.46; H, 7.03; N, 6.20. Found: C, 74.77; H,7.26; N, 6.14%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH:16]O.Br>CO>[C:11]([C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: OO
Agent: Br
Solvent: CO
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reaction time: 0.83 h
Yield: 97 %

Procedure:
A solution of 2,6-di-tert.butyl-phenol (11 g, 53.3 mmol), hydrogen peroxide at 60% (8 ml) and hydrogen bromide (5 g, 61.7 mmol) in methanol (150 ml) is refluxed for 25 minutes. On concentrating the solution, 2,6-di-tert.butyl-1,4-benzoquinone (10.5 g, 89.4%) crystallizes. This product is hydrogenated, in methanol (110 ml), in autoclave, with Pd/C at 5% (0.12 g), under a hydrogen pressure of 10 kg/cm2, for 50 minutes, at 20° C. After the catalyst being filtered off, and solvent evaporation, 2,6-di-tert.butyl-hydroquinone is obtained with a yield of 97%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([Si:15](C)([CH3:17])[CH3:16])C=C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:11][Si:15]([CH3:17])([CH3:16])[CH3:12])=[CH:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C=CC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CC=C(O[Si](C)(C)C)CC1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Into a two-necked flask were placed 4-tert-butylcyclohexanone (74.1 mg, 0.480 mmol), and toluene (5.0 ml) as a solvent, and the mixture was subjected to heating under reflux conditions under an argon atmosphere. After the start of the refluxing, allyltrimethylsilane (82.3 mg, 0.720 mmol) was added, and a solution (0.1 M) of triflic imide (1.35 mg, 4.80 μmol) in toluene was added dropwise. After 5 min, triethylamine (0.486 mg, 4.80 μmol) was added, and the mixture was reacted for 10 min. Thereafter, cooled aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with hexane and dried over sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to give the object product 4-tert-butyl-1-trimethylsilyloxy-1-cyclohexene (yield 88%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C@H:10]([CH3:23])[C:9]3=[CH2:24].[OH-].[Na+]>C(O)C>[F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C@@H:10]([CH3:23])[C:9]3=[CH2:24]
Reactant: C=C1[C@@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1[C@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Yield: 84.9 %

Procedure:
A ethanol solution (10 ml) of 16α-fluoro-1β,6β-dimethyl-7-methylenandrost-4-ene-3,17-dione (344 mg), which contains 0.1N sodium hydroxide (1 ml), is heated to reflux for about 30 min. Then the ethanol is removed in vacuo and the residue taken up in benzene. The organic phase is washed to neutrality with water, dried and evaporated. The residue is submitted to chromatographic purification as described above to give the isomeric 16α-fluoro-1β,6α-dimethyl-7-methylenandrost-4-ene-3,17-dione (292 mg).
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1.[Na+].[Br-:21].N(OC(C)(C)C)=O>C(#N)C.O>[Br:21][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1
Reactant: [Br-]
Reactant: Nc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1csc(Br)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a suspension of 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione (4.13 g, 15 mmol), NaBr (3.10 g, 30 mmol) and CuBr (2.15 g, 15 mmol) in acetonitrile (150 mL) at 40° C. under nitrogen atmosphere was added tert-butyl nitrite (2.32 mL, 19.5 mmol) dropwise over 30-40 min. After the addition was complete, heating was maintained towards an internal temp of 60-70° C., and the suspension was stirred at this temperature for 2 h. After cooling down, the mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers (200 mL) were washed with aq HCl (1M, 50 mL), then with brine (50 mL) and dried (MgSO4). After concentration on the rotary evaporator, the residue was purified on silica gel to afford 2-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione [1.50 g, yield 28%; HPLC/MS: m/z=339 (M+H); log P(HCOOH)=2.39].
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][C:15]([OH:17])=O)=[CH:11][CH:10]=1.CC(C)(C)C(Cl)=O.[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([Li])CCC>CCOCC.C1COCC1.CCCCCC>[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:15](=[O:17])[CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(Cl)s1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)s1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
Triethylamine (7.32 mL, 52.5 mmol) was added to a solution of 5-chlorothiophene-2-acetic acid (8.83 g, 50.0 mmol) in ether (200 mL) at −78° C., followed by 2,2-dimethylpropanoyl chloride (6.46 mL, 52.5 mmol). The resulting mixture was stirred at 0° C. for 2 hours, and then re-cooled to −78° C. Meanwhile, a solution of (R)-4-benzyl-2-oxazolidinone (9.30 g, 52.5 mmol) in THF (100 mL) in a separated flask was cooled to −78° C. 2.5M of n-butyllithium in hexane (22.0 mL) was added dropwise. The resulting solution was stirred at −78° C. for 1 hour, and then added via cannula into the solution of the mixed anhydride. The reaction mixture was stirred at −78° C. for 15 minutes, at 0° C. for 30 minutes, then at room temperature overnight. Saturated NHCl (300 mL) was added to quench the reaction. The mixture was extracted with EtOAc (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane (0-25%) to give (R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43 g, 56%). 1H NMR (CDCl3, 400 MHz) δ 7.33-7.25 (m, 3H), 7.16-7.13 (m, 2H), 6.79-6.76 (m, 2H), 4.70-4.65 (m, 1H), 4.38 (q, J=17.2 Hz, 2H), 4.25-4.18 (m, 2H), 3.27 (dd, J=13.6 Hz, J=3.6 Hz, 1H), 2.77 (dd, J=13.6 Hz, J=3.6 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[CH2:18]([C:25]1[N:30]=[C:29]([CH2:31]O)[CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:31][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:30]=1)=[O:13]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: OCc1cccc(Cc2ccccc2)n1
Product: CC(C)C(C(=O)OCc1cccc(Cc2ccccc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1, the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid is reacted with (6-benzyl-2-pyridyl)methanol to yield (6-benzyl-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: [Cl:1][Pt-2:2](Cl)(Cl)[Cl:3].[K+].[K+].[CH3:8][C:9]([CH3:14])([CH2:12][NH2:13])[CH2:10][NH2:11]>O>[Pt:2]([Cl:3])[Cl:1].[CH3:8][C:9]([CH3:14])([CH2:12][NH2:13])[CH2:10][NH2:11]
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: CC(C)(CN)CN
Agent: [K+]
Solvent: O
Product: Cl[Pt]Cl
Reaction time: 8 h

Procedure:
To a solution of 12.45 g of potassium tetrachloroplatinate in 60 ml of water was added 3.06 g of 2,2-dimethyl-1,3-propanediamine. This mixture was allowed to stand overnight and then the solid was collected, giving 7.0 g of 2,2-dimethyl-1,3-propanediamine compound with platinum chloride (1:1).