Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc(F)cc3)cc2F)C1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol) in dioxane (1.5 mL) was treated with (4-fluorophenyl)boronic acid (0.269 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.733 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 10 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound as an off-white solid (61%). MS(ES)+ m/e 425.0 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4C=CC=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.OC[C:31]1N=C[N:33](C)[N:32]=1>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[N:24]=[CH:25][N:32]([CH3:31])[N:33]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: FCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Reactant: Cn1cnc(CO)n1
Product: Cn1cnc(COc2nn3c(-c4cc(CF)on4)nnc3c3ccccc23)n1
Yield: 52 %

Procedure:
Prepared from the product of Example 66 part c (85 mg, 0.28 mmol) and 3-hydroxymethyl-1-methyl-1,2,4-triazole using the method of Example 1 to yield a pale yellow solid (56 mg, 52%), 1H NMR (360 MHz, CDCl3) 67 3.96 (3H, s), 5.58 (2H, d, J=44 Hz), 5.73 (2H, s), 7.51 (1H, s), 7.81 (1H, t, J=7 Hz), 7.96 (1H, t, J=7 Hz), 8.08 (1H, s), 8.30 (1H, d, J=7 Hz), 8.72 (1H, d, J=7 Hz); MS (ES30) m/e 381 [MH]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.[OH-].[K+]>CS(C)=O>[CH:11]1([CH2:14][O:15][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)cn1
Temperature: 80 °C
Yield: 34 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (1.50 g, 9.46 mmol) in dry dimethylsulfoxide (5 ml) was treated at 25° C. with cyclopropyl-methanol (1.02 g, 14.1 mmol) and powdered potassium hydroxide (2.12 g, 37.4 mmol). The mixture was heated in a microwave oven at 80° C. for 90 minutes. For the workup, the reaction mixture was quenched with an aqueous solution of citric acid (10%), then extracted with ethyl acetate (5×30 ml), followed by the extraction with a 4:1-mixture of dichloromethane and methanol. The combined organic layers were washed with brine (200 ml), dried and evaporated at reduced pressure. After lyophilization the 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (34% yield) was obtained as a white solid. MS (ISP): m/z=195.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9]O)=[CH:6][CH:5]=1)([O-])=O>[Ni].CO>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(N)cc1
Reaction time: 3 h
Yield: 44.2 %

Procedure:
An autoclave was then charged with the p-nitrobenzaldoxime obtained above, 5 grams of Raney nickel catalyst, and 500 ml of methanol. Reducing reaction was continued with a vigorous stirring at 25°-30° C., under hydrogen pressure of 30-50 Kg/cm2G for 3 hours. After the end of the reaction, the resultant mixture was filtered to remove the catalyst and distilled to obtain 18.9 grams of a light yellow oily fraction having a boiling point of 129.5°-130° C./5-6 mmHg. The p-Aminobenzylamine, thus obtained, is in the total yield of 44.2%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[I:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>CCO>[I:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:1][CH2:2][CH2:3][OH:4])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: NCCO
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCNC1CCC(n2cc(I)cn2)CC1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
2-Amino-ethanol (0.30 mL; 4.96 mmol; 1.4 eq.) was added in one portion to a solution of 4-(4-Iodo-pyrazol-1-yl)-cyclohexanone (intermediate 20; 1.00 g; 3.45 mmol; 1.0 eq.) in EtOH. After 1 h the reaction solution was cooled to 0° C. and NaBH4 (290 mg; 7.67 mmol; 2.2 eq.) added portionwise over 1 min. After a further 1 h the reaction suspension was poured into 1 N NaOH solution and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification using a SCX-2 cartridge afforded the title compound as a white solid (1.00 g; 84%). 1H NMR (300 MHz, DMSO) δ 7.94 (s, 1H), 7.49 (s, 1H), 4.47 (brs, 1H), 4.12 (m, 1H), 3.45 (m, 2H), 2.60 (t, J=5.8 Hz, 2H), 2.41 (m, 1H), 2.95 (m, 4H), 1.72 (m, 2H), 1.13 (m, 2H).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]>>[CH3:1][CH:2]1[NH:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC=O
Product: CC1NC(C(=O)O)CS1

Procedure:
Acetaldehyde (0.27 g) and L-cysteine (0.75 g) were reacted in aqueous solution 10 ml at room temperature for 1.5 hours, followed by solvent evaporation evaporated in vacuo. The resulting product was recrystallized from methanol to yield the title compound. Melting Point: 161°-163° centigrade Optical Rotation [α]26D:-148°.
Reaction SMILES: [F:1][C:2]1([F:64])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:43][CH:44]5[CH2:49][O:48]C(C)(C)[O:46][CH2:45]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:52]([F:63])[C:53]2[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCOCC1>[F:64][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:43][CH:44]([CH2:49][OH:48])[CH2:45][OH:46])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:52]([F:63])[C:53]2[CH:58]=[CH:57][C:56]([C:59]([F:60])([F:62])[F:61])=[CH:55][CH:54]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of 8.42 g (9.39 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-2-(1-{5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 21, in 75 ml of 1,4-dioxane, 15 ml of 6 N hydrochloric acid was added, and the reaction mixture was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction solution was poured into a mixed solution of saturated sodium hydrogencarbonate aqueous solution and 2 N sodium hydroxide aqueous solution and extracted with ethyl acetate three times. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=60/40-30/70 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 5.72 g of the title compound as a white solid (yield: 83%).
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:24]2)=[O:22])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C>CO.C1COCC1>[OH:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C@H:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: CC(=O)O[C@@H](c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
) NaOH 1N (1 ml) was added dropwise to a stirred solution of (S)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl acetate (0.001 mol) in methanol (20 ml) and THF (20 ml) and the reaction mixture was stirred for one hour at RT. The solvent was evaporated under reduced pressure. The white solid residue was taken up into methanol. The precipitate was filtered off, washed with methanol and diethyl ether, then dried, yielding 0.2 g (92%) of (S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 57).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.I[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:22][N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[C:2]([CH3:1])[C:11]1=2
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1NCCO2
Reactant: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1N(C)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
An ice cold mixture of 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (65.0 mg, 0.236 mmol) in N,N-dimethylformamide (DMF) (0.5 mL) was treated with iodomethane (0.044 mL, 0.709 mmol) and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (hexanes/ethyl acetate) to afford a pale yellow residue (40 mg, 59%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (d, J=8.2 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.20-4.14 (m, 2 H), 3.12-3.03 (m, 2 H), 2.66 (s, 3 H), 2.49 (s, 3 H), 1.31 (s, 12 H); LC/MS (m/z) ES+=290 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:10][NH:11][C:12]=1[CH:13]([OH:15])[CH3:14].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:13]([C:12]1[NH:11][N:10]=[C:9]([O:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:15])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C(C)O)c2-c2ccccc2F)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To toluene-4-sulfonic acid 4-(2-fluorophenyl)-5-(1-hydroxyethyl)-1H-pyrazol-3-yl ester (16.4 g, 43.6 mmol) in dichloromethane (500 ml) was added pyridinium dichromate (19.7 g, 52.3 mmol) and the resulting slurry was stirred at room temperature for 1 h. The mixture was poured directly onto a column of silica gel, and the product was eluted off with ethyl acetate, yielding toluene-4-sulfonic acid 5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester as a yellow solid (8.64 g). 1H NMR (400 MHz, CDCl3) δ 2.16 (3H, s), 2.43 (3H, s), 7.09 (1H, m), 7.22 (3H, m), 7.34 (1H, m), 7.41 (1H, m), 7.65 (2H, d, J=6.8 Hz); MS (ES+) m/e 375 [MH]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].[Br-:14].[Li+]>CC(C)=O>[Br:14][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12]
Reactant: Cc1c(F)cccc1CC(=O)CCl
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: Cc1c(F)cccc1CC(=O)CBr
Reaction time: 8 h
Yield: 93.6 %

Procedure:
The compound of step 1 (3.20 g, 15.95 mmol) was dissolved in acetone (70 ml), and lithium bromide (11.08 g, 127.59 mmol) was added. The mixture was stirred overnight. The solvent was evaporated, the resulting solid was dissolved in EA and the solution washed twice with water followed by a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. 3.66 g of the title compound were obtained as a white powder.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[CH3:23][S-:24].[Na+]>CO>[CH3:22][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([CH2:2][S:24][CH3:23])[CH:4]=1)[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: C[S-]
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=Cc2cc(C)cc(CSC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (4 mL) and cooled to 0° C. (ice bath). Sodium thiomethoxide (0.04 g, 0.52 mmole) was added dropwise and stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.16 g, 98%). No further purification was performed: GCMS m/z 346.00 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])C([O-])=[O:5].[K+].C(=O)([O-])[O-].[K+].[K+].ClCl>O>[OH2:5].[F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])=[O:7]
Reactant: O=C([O-])C(O)(C(F)(F)F)C(F)(F)F
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C(F)(F)F)C(F)(F)F
Temperature: 40 °C

Procedure:
In a 50-ml three-necked flask were placed 7.85 g (17.8 mmol) of the 56.8% aqueous potassium 3,3,3-trifluoro-2-trifluoromethyl-2-hydroxypropionate solution prepared in Reference Example 1 and 2.46 g (17.8 mmol) of potassium carbonate. 16 g of water was added to dissolve the mixture. The pH was 13. The reaction was performed by blowing chlorine gas at 20 ml/min for 37 minutes (33 mmol, 1.85 eq.) while stirring the solution under heat at 40° C. in a water bath. The pH when the reaction was complete was 6.6. Hexafluoroacetone hydrate was obtained at a starting material conversion of 99.7% with a selectivity of at least 99%.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])[CH2:10][CH:5]2[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:30]1([C:15](=[O:16])[CH2:14][NH:13][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:5]3[CH2:10]2)=[O:12])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(O)CNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]glycine (0.15 g, 0.38 mmol) was dissolved in N,N-dimethylformamide (3 mL). Morpholine (0.14 g, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.76 mmol) and 1-hydroxybenzotriazole (0.11 g, 0.77 mmol) were added thereto, and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and water and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:methanol=95:5) and powder was formed from hexane to obtain the title compound (90 mg, yield 51%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]=[CH:9]1.OO.[OH-].[Na+].[O:18](C1CC(=O)C(SCCCCCCCC)=C1)[Si](C(C)(C)C)(C)C>CO>[O:13]1[CH:12]2[CH:11]1[C:10](=[O:18])[CH2:9][CH:8]2[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C1C=CC(OC2CCCCO2)C1
Reactant: CCCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(OC2CCCCO2)C2OC12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
One gram of 4-(2-tetrahydropyranyloxy)cyclopent-2-en-1-one was dissolved in 20 ml of methanol, and 10 ml of 30% hydrogen peroxide was added at room temperature. Then, with ice cooling, 3 ml of a 2 N aqueous solution of sodium hydroxide was added slowly. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was post-treated in the same way as in Example 1, (1). The resulting crude product was chromatographed on a thin layer plate with cyclohexane/ethyl acetate (=7/3) to afford 730 mg of 2,3-epoxy-4-(2-tetrahydropyranyloxy)cyclopentan-1-one in a yield of 84%. The product had the following spectral data.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:7]([O:6][C:4](=[O:5])[C@@H:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:13][CH2:14][OH:15])[CH2:2]1)[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (R)-enantiomer of ethyl nipecotate (100 g, 0.64 mole) (Akkerman, A. M. et al., Gazz.Chim.Ital., 102 (1972) 189) was mixed in dry acetone (300 ml) with 2-bromoethanol (85 g, 0.68 mole), dried, powdered potassium carbonate (188 g, 1.28 mole) and potassium iodide (21.6 g, 0.13 mole). The reaction mixture was stirred at room temperature for 18 h and at reflux for 24 h. Filtration of the reaction mixture and evaporation of the resultant filtrate gave (R)-1-(2-hydroxyethyl)nipecotic acid ethyl ester as an oil, which was purified by distillation in vacuo (110-115C, 0.1 mmHg), yield (72.2 g, 56%). TLC: rf=0.20 (SiO2; dichloromethane/methanol=19:1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[OH:10].OS(O)(=O)=O.[O-][Mn](=O)(=O)=O.[K+].[OH-].[Na+].Cl.[CH2:25]([O:27]CC)C>[C-]#N.[Zn+2].[C-]#N>[OH:9][C:5]1[CH:4]=[C:3]([OH:10])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[CH:25]=[O:27]
Reactant: Cc1cc(O)cc(O)c1C
Reactant: CCOCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1c(O)cc(O)c(C=O)c1C
Temperature: 25 °C

Procedure:
4.450 g (32 mmol) of 2,3-dimethyl-5-hydroxyphenol are dissolved in 100 ml of anhydrous ethyl ether in a round-bottomed flask equipped with a gas inlet, a thermometer and a condenser (the outflow gases being trapped by 3 successive bubblers: H2SO4, saturated KMnO4 solution, 3N NaOH). After 5.635 g (48 mmol) of zinc cyanide have been added, a stream of gaseous hydrochloric acid is passed through for 2 hours with stirring at room temperature. A copious precipitate appears, increasing with the passage of time. At the end of the operation, a powerful stream of nitrogen is passed through the reaction medium. The insoluble matter is separated by filtration and dissolved in boiling water. After cooling, the aldehyde precipitates. After filtration, the crystals are washed with water and dried.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:17][C@H:18]([C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1)[CH3:19]>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:17][C@H:18]([C:20]1[CH:21]=[C:22]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:30][CH2:31]3)[CH:23]=[CH:24][CH:25]=1)[CH3:19])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[C@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Product: C[C@H](NC(=O)c1c(O)c(=O)n(C)c2ccccc12)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1

Procedure:
Following the same procedure as described for Example 3, Example 205 was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride and (S)-benzyl 4-(3-(1-aminoethyl)phenyl)piperazine-1-carboxylate (Intermediate 34). LC-MS (ESI) m/z 541 (M+H), RT=2.00 min (Method B). Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=8.9 min, 93%}; Xbridge {RT=8.5 min, 92%}.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C(N(CC)CC)C.CS([Cl:22])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Cl)cccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1CCl
Reaction time: 3 h
Yield: 69 %

Procedure:
910 mg of 3-chloro-2-methylbenzylalcohol was dissolved in 10 mL of methylene chloride, 1.21 mL of triethylamine and 495 μL of methanesulfonyl chloride were added thereto at room temperature, followed by stirring for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 700 mg (yield 69%) of a title compound as a white solid.