Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: Sc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1F
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.578 g) was added to a deoxygenated mixture of 2-fluoro-4-iodoaniline (2.37 g), thiophenol (1.07 ml) and sodium methoxide (1.13 g) in ethanol (80 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, cooled and filtered. The filter was washed with ether (3×20 ml) and the filtrates were combined and volatile material was removed by evaporation. The residue was treated with dichloromethane (50 ml), filtered and reconcentrated. This crude product was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50-70% dichloromethane/hexane to give the title compound (1.851 g) as a solid. M.p. 48-49° C.; NMR: 5.5 (s, 2H), 6.8 (t, 1H), 7.0-7.1 (m, 5H), 7.25 (t, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([OH:21])[CH2:19][CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C>CCO>[OH:21][CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[C:3]1=[O:22])[CH2:19][CH3:20]
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A solution of (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (47.6 mg, 0.153 mmol) in EtOH (3 mL) was charged with 4-chloro-6-(trifluoromethyl)quinazoline (46.3 mg, 0.2 mmol) and triethylamine (0.064 mL, 0.46 mmol). The mixture was heated for 30 min at 100° C. in the microwave oven. Solvent was evaporated off, and the residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH-MeOH—CH2Cl2 to afford the titled compound 1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (47.3 mg) as a solid. MS found: (M+H)+=508.3
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[CH:70]=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[C:68](Br)=[CH:67][C:66]=3[F:77])=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1.O.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:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[C:66]([F:77])=[CH:67][C:68]([C:30]4[CH:31]=[CH:32][C:27]([C:25]5[N:26]=[C:22]([C@@H:18]6[CH2:19][CH2:20][CH2:21][N:17]6[C:15](=[O:16])[C@@H:11]([NH:10][C:9]([O:8][CH3:7])=[O:42])[CH:12]([CH3:14])[CH3:13])[NH:23][CH:24]=5)=[CH:28][CH:29]=4)=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[CH:70]=3)=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (340 mg, 0.68 mmol) and (2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol; Preparation 49) dissolved in toluene (2.5 mL) and water (0.73 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce (2S,5R)-4-[5-(5-fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CCO.C1COCC1>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 41.6 mg (0.091 mmol) ethyl 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 40) in 2.0 ml EtOH and 2.0 ml of THF was added 40.0 mg NaOH (1.00 mmol, 1.0 ml of a 1 M aqueous solution). After stirring at room temperature for overnight, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a pale-yellow solid. 1H NMR (d6-acetone): δ 9.84 (1H, s), 7.94-7.83 (3H, m), 7.64 (1H, dd, J=2.0 Hz), 7.53 (2H, d, J=8.1 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz), 2.38 (2H, d, J=4.7 Hz), 2.36 (3H, s), 1.35 (6H, s).
Reaction SMILES: Cl[CH:2]1[CH2:8][N:7]2[C:9](=[O:23])[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:6]2[C:5]2[S:24][CH:25]=[CH:26][C:4]=2[S:3]1.N12CCCC1=NCCC2>CS(C)=O>[O:23]=[C:9]1[N:7]2[CH:8]=[CH:2][S:3][C:4]3[CH:26]=[CH:25][S:24][C:5]=3[C:6]2=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[C:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC(Cl)C2
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC=C2
Temperature: 25 °C

Procedure:
(ba) 6.05 g of methyl 5-chloro-5,6-dihydro-8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-11-carboxylate were suspended in 60 ml of dimethyl sulfoxide. 3.6 ml of 1,5-diazabicyclo[4.3.0]non-5-ene were added, whereupon the mixture was heated to 70°-75° in order to complete the reaction. The mixture was then cooled to room temperature, whereby crystals separated. The mixture was poured into 300 ml of water, and the crystals were removed by filtration and washed with water. The still moist crystals were dissolved in chloroform. The solution was dried over sodium sulfate, filtered and evaporated in vacuo. After chromatography on silica gel, there was obtained methyl 8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-11-carboxylate as yellow crystals which were recrystallized from toluene. The product then has a m.p. of 207°-210°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[NH2:30]>C(N(CC)CC)C>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[NH:30][C:12](=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: Cc1csc(N)c1-c1nc2ccccc2s1
Reactant: O=C(O)Cc1cccc2cnccc12
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Cc2cccc3cnccc23)c1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and 3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-amine using Protocol B except that triethylamine was also added. MS (ESI) 416.0 [M+H], Retention time=2.86 min; 1H-NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 8.57 (d, J=6.04 Hz, 1H), 8.10-8.07 (m, 2H), 8.0 (d, J=6.6 Hz, 1H), 7.90-7.88 (m, 1H), 7.83-7.77 (m, 1H), 7.71-7.68 (m, 1H), 7.55-7.51 (m, 1H), 7.42-7.37 (m, 1H), 6.56 (s, 1H), 4.39 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[C:11]1[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[F:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of dibenzyl-(2,4-difluoro-phenyl)-amine (17.5 g, 0.056 mol) in THF (140 mL), under nitrogen atmosphere, cooled at −78° C., n-butyllithium (1.6 M in hexane, 38 mL, 0.06 mol) was slowly added. The reaction was stirred for 1 hour, and then quickly added via a cannula to a solution of benzyl chloroformate (11.78 mL, 0.084 mol) in THF (140 mL) previously cooled at −78° C. The reaction was then allowed to warm to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane grading to 10% acetate (quant.).
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)[CH3:3]>C(Cl)(Cl)Cl>[CH3:3][C:2]1[NH:4][N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[N:1]=1
Reactant: COC(=O)c1cccc(C(=O)NNC(C)=N)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-c2n[nH]c(C)n2)c1

Procedure:
8.10 g (34.4 mmol) methyl 3-[N′-(1-imino-ethyl)-hydrazinocarbonyl]-benzoate are heated to 180° C. for 30 minutes. 80 mL chloroform are added to the solid obtained after cooling. The suspension is filtered and the product is dried. White solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH:20]=[O:21])[S:13][C:12]=1[C:23]([NH2:25])=[O:24].[NH4+].[Cl-]>C1COCC1>[NH2:10][C:11]1[C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH:20]([OH:21])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:13][C:12]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1cc(C=O)c2c(N)c(C(N)=O)sc2n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)Cc2ccccc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 344 mg CeCl3 in 3 mL dry THF at −78° was added 0.70 mL 2 M benzylmagnesium chloride and the reaction was stirred 1.5 h under Ar. Then, 41 mg of 3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 16) was added and the reaction was stirred 3.5 h in the cold and then allowed to warm to room temperature over 0.5 h. Aqueous NH4Cl was added and the reaction was filtered through diatomaceous earth, washing with EtOAc, and the aqueous phase was separated and extracted 3 times more with EtOAc. The combined organics were dried, concentrated in vacuo, and re-dissolved in EtOAc with a trace MeOH and washed 3 times with aqueous NaHSO3. This was dried, concentrated in vacuo, and the product was purified on a prep plate developed with 5% MeOH—CH2Cl2. The product was re-dissolved in MeOH—CH2Cl2, filtered, concentrated and dried in vacuo at 60° C. providing 16.3 mg of the title compound as an orange solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: COC1(c2cccc(Cl)c2F)CCNC1
Yield: 64.6 %

Procedure:
Preparation according to Example 1. (−)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.82 g, 2.56 mmol), 1,2-dichloroethane (10 ml), 1-chloroethyl chloroformate (1.12 ml, 10.25 mmol) refluxed for 2 h, and methanol (20 ml) reflux 1 h. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.38 g, 65%). [a]D=−7.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 183-185° C. MS m/z (rel. intensity, 70 eV) 229 (M+, 1), 199 (87), 187 (bp), 157 (55), 133 (51).
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[Br-].[NH4+].C(O)(=[O:19])C>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C1CCCCC1>[CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10](=[O:11])[CH3:12])[C:6]([CH3:14])([CH3:13])[CH2:5][C:4](=[O:19])[CH:3]=1
Reactant: CC(=O)O
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Solvent: C1CCCCC1
Product: CC(=O)/C=C/C1C(C)=CC(=O)CC1(C)C

Procedure:
Items 1-6 given in Table 1 hereinafter are carried out following the procedure of Example 1 substituting therein 5 g of 92% α-ionone for the 40 g of 98% α-ionone, 1.3 g (20 mol percent) of cobalt acetate tetrahydrate for the 10.4 g, and 0.7 g, (27 mol percent) of ammonium bromide for the 4.0 g. The amount of solvent substituting for glacial acetic acid and cyclohexane is represented in Table 1 and amounts to 60 ml. The yields of 3,5,5-trimethyl-4-[(E)-3-oxo-1-butenyl]-2-cyclohexen-1-one (3-oxo-α-ionone) are determined by gas chromatography (GC). It will be observed that the sum of all products appearing in the gas chromatogram only amounts to a maximum of about 60% of the total weight. The remainder probably consists of oligomeric by-products. The oxidation conditions are not optimized.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-])=O.[Cl-].N.C(O)C>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][C:12]([F:13])([F:14])[F:15])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(OC(F)(F)F)c1
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 74.6 %

Procedure:
223 mg (1.0 mmol) of 4-nitro-2-trifluoromethoxyphenol, 224 mg (4.0 mmol) of reduced iron powder, and 321 mg (6.0 mmol) of ammonia chloride were successively added to a mixture of 20 mL of ethanol and 6.0 mL of water under argon atmosphere with mechanical stirring. The mixture was slowly heated to 50° C. and allowed to react at this temperature for 1.5 h until the solution turned brown. The reaction was stopped, naturally cooled, filtered under reduced pressure, and the filter cake was washed with 10 mL of ethyl acetate. 20 mL of water and 20 mL of ethyl acetate were added to the filtrate. The organic layer was isolated, and the water layer was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 50 mL of water and 50 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated to obtain 144 mg of a dark red solid. Yield 74.4%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
234 mg (0.440 mmol) of (2R*,4S*)-2-benzyl-1-benzoyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 67 mg (1.76 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR61## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.33, FD-MS: M+ =435.
Reaction SMILES: [BH4-].[Na+].C(OC(=O)[C:7]([CH:9]1[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH2:15]C)=[O:8])C.[Cl-].[NH4+].C(N(CC)CC)C>C(O)C>[O:14]1[CH:10]2[O:11][CH2:12][CH2:13][CH:9]2[CH:7]([OH:8])[CH2:15]1
Reactant: CCOC(=O)C(=O)C1CCOC1OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC1COC2OCCC12
Temperature: 55 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Dissolve sodium borohydride (35.5 g) in ethanol (400 ml) under nitrogen atmosphere. Ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (100 g) was dissolved in Ethanol (100 ml) and slowly added at 15-30° C. Reaction mass was then maintained at 50-60° C. for 8 hrs. Reaction mass was cooled to 20-30° C. and slowly added ammonium chloride solution (57.5 g in 100 ml water) and stirred for 1 hrs. Reaction mass was filtered and filtrate was distilled out under vacuum to residue. Dichloromethane (400 ml) was added to residue and cooled to −10° C. Hydrochloric acid (85 ml) was added slowly drop wise in 2 hours by maintaining temp 0 to −10° C. Reaction temp was maintained for 1 hr at 0 to −10° C. Triethyl amine (91.3 g) was added to the reaction mass at 0 to −10° C. and reaction mass was stirred for 1 hour at 0 to −10° C. Reaction mass was concentrated to residue. Residue was stripped out with Ethyl acetate (2×100 ml). Ethyl acetate (500 ml) was added to the residue and cooled to 10-15° C. Reaction mass was then filtered off and filtrate was concentrated to residue to get Hexahydrofuro[2,3-b]furan-3-ol (Yield 56 g).
Reaction SMILES: [CH2:1]([C:8]([OH:10])=[O:9])[C:2]([CH2:4][C:5]([OH:7])=O)=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([O:7][C:5]1[CH2:4][C:2](=[O:3])[O:1][C:8](=[O:9])[CH:10]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1=CC(=O)OC(=O)C1
Temperature: 35 °C
Reaction time: 24 h
Yield: 54.2 %

Procedure:
Acetone-1,3-dicarboxylic acid (30 g; 205 mmol) was added in portions to acetic anhydride (55 ml; 582 mmol) and the mixture was stirred at 35° C. for 24 h. The reaction mixture was diluted with toluene (200 ml) and kept at 4° C. for 3 h. A precipitate was isolated by filtration, washed with toluene and dried under reduced pressure to furnish 18.91 g (54%) of 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate as a light brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][CH:8]=1>I.CC(O)=O.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][CH:8]=1
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)nc1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)cn2)oc2ccccc12
Temperature: 25 °C
Yield: 36.2 %

Procedure:
2-(5-Methoxy-pyridin-2-yl)-chromen-4-one (790 mg, 3.12 mmol) in HI (10 mL) and AcOH (4 mL) was heated at reflux for 6 h. Reaction mixture was cooled to rt, diluted with water, neutralized and extracted with EtOAc to give crude product. This was purified by column chromatography using 5% MeOH in dichloromethane to give (270 mg, 36%) of 2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one. MS (ES) m/z: 240.09 (M+1).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C=O)cc2)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C(=O)O)cc2)CC1

Procedure:
4.0 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzaldehyde, 10 ml of Jones' reagent and 100 ml of acetone were reacted in an analogous manner to Example 2(b) to give 2.6 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzoic acid with m.p. 215° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O.O1CCOCC1>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: Fc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(F)cc3)[C@@H](CO)O2)cc1F
Temperature: 35 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
A 7.5 g quantity of potassium hydroxide was dissolved in a mixture of 300 ml of water and 80 ml of dioxane. To the solution were added 2.00 g of 2'-deoxy-5-fluorouridine and 4.9 ml of 4-fluorobenzyl chloride, and the resulting mixture was stirred at 35° C. for 2 days. After the reaction, the same subsequent procedure as in Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.57 g of the title compound in a yield of 20%.