Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:5]([O:7]C)=[O:6])=[N+:2]=[N-:3].[OH-].[Li+]>C1COCC1.O>[N:1]([CH:4]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(N=[N+]=[N-])c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NC(C(=O)O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in THF/H2O (2.6:1) cooled to 0° C. was added 1.7 eq. of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory funnel. The mixture was extracted into water and washed with ether. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.CC(C)([O-])C.[K+].O>CS(C)=O.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoro-nitrobenzene (0.728 mL, 6.96 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (1.40 g, 6.96 mmol) and potassium tert-butoxide (1.09 g, 9.74 mmol) in anhydrous DMSO (7.5 mL) and the resulting mixture was stirred for 2 hours at room temperature. Water and EtOAc were added to the mixture and the phases were separated. The aqueous phase was extracted with EtOAc, then the combined organic extracts were washed with water, brine and dried over Na2SO4. The volatiles were evaporated under reduced pressure and the residue was adsorbed onto silica gel and purified by column chromatography (SiO2 cartridge, 0-15% EtOAc in cyclohexane) to give the title compound A111 as an oil (2.20 g, 98%); 1H NMR (300 MHz, CDCl3); δ 8.09 (d, J=9.4 Hz, 2H), 6.91 (d, J=9.3 Hz, 2H), 4.58 (m, 1H), 3.65 (m, 2H), 3.33 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H), 1.41 (s, 9H). LCMS-B: rt 8.22 min; m/z 323.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[C@H]1[C@H](B)C[C@@H]2C[C@H]1C2(C)C.B.B(F)(F)F.[OH-].[Na+].OO>C(Cl)Cl.C1COCC1.O.CO>[CH2:1]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=Cc2ccc([C@H]3CC[C@]4(COC(=O)N4)C3)cc2CC1
Agent: B
Agent: B[C@@H]1C[C@@H]2C[C@H]([C@H]1C)C2(C)C
Agent: FB(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCCCCCC1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2A, 2.1 g, 5.94 mmol) in DCM (10 ml) was added dropwise to a solution of ((1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane in DCM (30 ml) at −35° C. under nitrogen. (The borane reagent was made as following: To a mixture of S-Alpine-Boramine (8.4 g, 20.18 mmol) in THF (35 ml) was added BF3 ethereate (5.11 ml, 40.4 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 h, filtered under nitrogen, and the cake was washed with cold THF (2×6 ml). The filtrate and washes were combined and concentrated under vacuum. To the residue was added DCM (20 ml) and the solution was concentrated again. The reagent obtained was redissolved in DCM (30 ml) and used directly for the hydroboration step). After stirring at −35° C. to −30° C. for 4 h and at −25° C. to −20° C. for 2 h, MeOH (3.6 mL) was added and the reaction mixture was stirred at −10° C. for 10 min and at 0° C. for 10 min. The mixture was diluted with THF (25 ml), then a solution of NaOH (6N, 9.9 ml, 59.4 mmol) was added dropwise followed by H2O2 (30%, 6.07 ml, 59.4 mmol) and the mixture was stirred at room temperature for 16 h. To the mixture was added DCM (100 ml) and water (50 ml). The whole solution was filtered through a pad of CELITE® and the cake was washed with DCM. The two layers were separated, the aqueous layer was extracted with DCM (50 ml) which was combined with the organic layer. The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-50% EtOAc over 55 minutes) to afford 1.9 g (86%) of (5R,7S)-7-(6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one in a 8:1 ratio of two isomers. The mixture was carried into the next step without separating the diastereomers.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C(O)=O)[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:19]1CCC[CH2:20]1>>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:20][OH:19])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc2[nH]ccc12

Procedure:
To a solution of 6-indole carboxylic acid (500 mg, 3.1 mmol) in tetrahydrofuran (31 ml) is added lithium aluminum hydride (590 mg, 15.5 mmol) at 0° C. The reaction mixture is refluxed for 6 hours. The resulting mixture is then quenched with 5% potassium hydrogen sulfate (20 ml) and extracted with ether (20 mL). The organic layer is then dried with sodium sulfate and concentrated to give a yellow solid (230 mg). MS (ESI) m/z 146.6 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:3][CH2:2][CH2:9][CH3:8])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C=O)cc1O
Reaction time: 8 h
Yield: 48.6 %

Procedure:
n-Bromopentane (0.90 mL, 7.25 mmol, 1 eq) was added dropwise to a stirred solution of 3,4-dihydroxybenzaldehyde (1 g, 7.25 mmol, 1 eq) and cesium carbonate (7.07 g, 21.7 mmol, 3 eq) in N,N-dimethylformamide. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), and the organic solution washed with water (2×50 mL), and brine (50 mL), then dried over magnesium sulfate and evaporated. Chromatography on silica with dichloromethane:petroleum ether (4:1) as eluent gave the product as a brown oil (367 mg, 24%). 1H NMR (CDCl3) δ 9.79 (s, 1H, O═C—H), 6.21 (s, 1H, OH), 4.08 (t, 2H, OCH2), 1.81 (m, 2H, OCH2CH2), 1.40 (m, 4H, CH2CH2CH3), 0.89 (t, 3H, CH3).
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(C)C(O)=CC=CC=1.Cl.[H][H].[OH-].[Na+]>[Pd].C.[Ta].O.C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Pd]
Agent: [Ta]
Agent: Cc1ccccc1O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
131 parts of a tetrachloroaniline/pentachloroaniline isomer mixture (according to Example 2), 200 parts of o-cresol and 20 parts of a Pd/charcoal catalyst (1% strength) and 5 parts of concentrated hydrochloric acid are reacted with hydrogen at 175° C. and under 50 bar in a tantalum autoclave, in the course of 10 hours. After the autoclave has been cooled and the pressure released, the mixture is rendered alkaline with 200 parts of toluene, 400 parts of water and 250 parts of aqueous concentrated sodium hydroxide solution, and is heated to the boil, and thereafter the catalyst is separated off by filtering under suction. After extracting the aqueous alkaline phase by shaking with toluene, the toluene solutions of 3,5-dichloroaniline are distilled. 85 parts of a 98% strength 3,5-dichloroaniline, bp. 130°-136°/18 mbar, are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6](Cl)[C:5]([Cl:10])=[C:4](Cl)[C:3]=1[Cl:12].C1(O)C=CC=CC=1.[H][H]>[Pd].O.[Ta]>[Cl:10][C:5]1[CH:6]=[C:7]([CH:2]=[C:3]([Cl:12])[CH:4]=1)[NH2:8]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Pd]
Agent: [Ta]
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
131 parts of a mixture of 2,3,4,5- and 2,3,5,6-tetrachloroaniline and pentachloroaniline in the ratio of 38:60:2 percent by weight and 200 parts of phenol are reacted with hydrogen over 20 parts of a 1% strength palladium/charcoal catalyst and a maximum pressure of 50 bar and at 170° C. in a tantalum autoclave, in the course of 10 hours, while stirring. After the autoclave has been cooled and the pressure released, the reaction mixture is diluted with 500 parts of water and separated off from the catalyst, and after the addition of toluene, the mixture is rendered alkaline with sodium hydroxide solution. The solution of 3,5-dichloroaniline in toluene, obtained by separation of the layers, is distilled. Yield: 90 g (=98%) of a 99% strength 3,5-dichloroaniline. The phenol can be recovered from the aqueous phase by acidifying the latter and extracting it by shaking with toluene. It was possible to re-use the catalyst 20 times without it losing any of its activity.
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH3:11][CH2:12][O:13][CH2:14][CH:15](Cl)Cl>CN(C)C=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:15]=[CH:14][O:13][CH:12]=[CH:11]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NNC(C)=O
Reactant: CCOCC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 80 °C

Procedure:
39.6 g of potassium hydroxide powder 85% (0.6 mol) are introduced into a mixture of 35 g of diacetylhydrazine (0.3 mol) and 560 ml of solvent (see Table 1). When the heat of reaction has died away, 85.8 g of 2,2-dichlorodiethyl ether (0.6 mol) are added; the reaction mixture is heated to 80° C. and maintained at 80-90° C. for 5 hours. The mixture is then cooled to 20° C. and filtered, and the filtration residue is washed with the solvent. The yield is given by the content of title compound in the combined filtrate. It will be seen that the solvents used according to the invention (tests 4-7) give far better yields of 4,5-diacetyl-[1,4,5]-oxadiazepine than N,N-dimethylformamide, which is known from the above prior art (DMFA, comparison test 8).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[K+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.Cl[Si](C)(C)C.C1CCN2C(=NCCC2)CC1>CC#N.CCOC(C)=O.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-5-iodobenzoic acid (Prep. 1, 4.03 g) in 11 mL freshly distilled THF is added 1,1-carbonyldiimidazole (CDI) (2.96 g) in small portions. Vigorous gas evolution is observed. The reaction is stirred overnight. In a separate flask, ethyl malonate potassium salt (2.84 g) is suspended in 10 mL CH3CN. To this solution is added chlorotrimethylsilane (2.15 mL) and the reaction is stirred at room temperature overnight. The latter reaction is cooled to 0° C. and DBU (5.00 mL) is added dropwise. This reaction is stirred at 0° C. for 3 h. The solution of the CDI adduct is then cannulated over and the mixture is stirred at 0° C. for 2 h. Upon complete conversion to product as evidenced by TLC, the solution is quenched with water and 6N HCl (8 mL). The reaction is partitioned with diethyl ether. The organic layer is washed with 1N HCl and then brine, dried over Na2SO4, filtered, and concentrated to give a light orange oil. The oil is dissolved in EtOAc and adsorbed onto silica. Purification by chromatography (eluent 3% EtOAc/hexanes) affords the desired product as a colorless oil which crystallized upon standing (2.51 g, 49%). Physical characteristics are as follows: m.p. 54-56° C.; 1H NMR (300 MHz, CDCl3) δ12.67, 8.18, 7.70, 6.89, 5.54, 4.28, 1.35; IR (drift) 2984, 1627, 1558, 1476, 1422, 1390, 1358, 1292, 1262, 1221, 1201, 1071, 1028, 823, 807 cm−1; MS (EI) m/z 336 (M+), 336, 249, 122, 107, 94, 86, 84, 69, 68, 51; Anal. Calcd for C11H10FIO3: C, 39.31; H, 3.00; Found: C, 39.35; H, 2.92.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl[Si](C)(C)C.[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30]C([O-])=O.[K+].C1CCN2C(=NCCC2)CC1>C1COCC1.C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:30][C:29]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cc(I)ccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a stirred solution of 5.32 g of 2-fluoro-5-iodobenzoic acid from Preparation No. 7 in 20 mL of THF, under argon, is added 3.9 g of carbonyldiimidazole. In a separate flask, 2.8 mL of chlorotrimethylsilane is added to a mixture of 3.74 g of potassium ethyl malonate in 20 mL of acetonitrile. The mixture is stirred under argon for 18 h, then cooled to 0° C. for the dropwise addition of 6.6 mL of DBU. The mixture is stirred for 3 h at 0° C., then the solution of acyl imidazolide prepared above is added via cannula. After 2 hours, the mixture is partitioned between ether and excess dilute HCl, and the organic phase is washed with dilute HCl and brine and dried (MgSO4). Removal of the solvent under reduced pressure left a colorless oil, which is flash chromatographed on silica using 10% ethyl acetate in hexane to provide 5.07 g of the title compound as dense pinkish prisms.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[CH3:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cnc(Cl)nc1
Product: Cc1cnc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using benzyl 4-(aminomethyl)-1-piperidinecarboxylate (298 mg, 1.20 mmol), 2-chloro-5-methylpyrimidine (EXAMPLE 144, Step 1) (51 mg, 0.40 mmol) as starting materials and using no solvent and gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of methyl 2,2′-dimethyl-1,1-biphenyl-4-carboxylate, prepared in Step 1 (15 g, 62.2 mmol) in THF (100 mL) was added 10% sodium hydroxide (100 mL) and the mixture was heated at 100° C. overnight. THF was removed under reduced pressure and the aqueous residue was washed with EtOAc. The aqueous layer was then acidified with HCl (3 N to pH 2-3) and extracted with DCM. The organic phase was washed with water and dried over sodium sulfate and concentrated under reduced pressure to obtain get the title compound as a white solid (13.5 g, 95%). 1H NMR: (DMSO-d6, 400 MHz) δ 12.89 (bs, 1H), 7.89 (s, 1H), 7.82-7.80 (m, 1H), 7.32-7.23 (m, 3H), 7.19-7.11 (m, 1H), 7.07-7.05 (m, 1H), 2.04 (s, 3H), 1.98 (s, 3H). LC/MS (Method A): 227.0 (M+H)+. HPLC (Method B), Rt: 4.1 min (purity: 99.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>C1COCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: C1CCOC1
Product: C/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 52 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol) in THF (6 mL) stirred under N2 at 0° C. was added trans-crotonyl chloride. A yellow solid formed upon addition. The solid was collected by Buchner filtration after 2.5 hours and sonicated with EtOAc to give the title compound (216 mg, 52%), mp 279-281° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.N1C2C(=CC=CC=2)C=C1.CN([CH:30]=[O:31])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C)c(C=O)c2c1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Phosphorous oxychloride (12.7 ml, 0.136 mol) is added dropwise at 0° C. to dimethylformamide (42.4 ml, 0.544 mol) over 30 minutes. A solution of 5-methoxy-2-methylindole (20 g, 0.124 mol) in 40 ml of DMF is added dropwise over 45 minutes. When 30 ml of the indole solution has been added, it becomes necessary to add 10 ml of DMF to break up the heavy paste which forms. The reaction mixture is then warmed to 35° C. for one hour. After 30 minutes the reaction again becomes too pasty, and 5 ml more of DMF is added. The bath is removed, and 60 g of crushed ice is added quickly to the reaction mixture. The reaction mixture is stirred for 30 minutes followed by addition of 20 ml of water and 40 g of ice. A solution of sodium hydroxide (25 g) in water (200 ml) is added dropwise to the red solution. After the first one-third of this sodium hydroxide solution has been added, the color changes to yellow, and the remainder of the sodium hydroxide solution is added quickly. It is rapidly brought to a boil (100°-120° C.) for 10 minutes, cooled and refrigerated overnight. The solid is filtered and washed four times with cool water. It is dried in a vacuum oven at 50° C. for 22 hours to give 23.0 g (98%) of powdery yellow crystals of pure 5-methoxy-2-methyl-lH-indole-3-carboxaldehyde; mp 190°-191° C.
Reaction SMILES: O=O.[CH3:3][C:4]1([CH3:11])[C:9](=[O:10])[C:7](=[O:8])[O:6][CH2:5]1.CC(OC(N1[C@H](CP(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C1)=O)(C)C.FC1C(C([O-])=O)=C(F)C(F)=C(F)C=1F.C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:11])[C@@H:9]([OH:10])[C:7](=[O:8])[O:6][CH2:5]1
Reactant: CC1(C)COC(=O)C1=O
Agent: CC(C)(C)OC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@@H]1O

Procedure:
A 500 ml steel autoclave was loaded in a glove box (O2 -content less than 1 ppm) with 40.0 g (0.31 mol) of ketopantolactone, 210 ml of toluene, 180.6 mg (0.389 mmol) of [Rh(COD)2 ]PF6, 215.2 mg (0.389 mmol) of BPPM and 176.4 mg (0.389 mmol) of tetrabutylammonium pentafluorobenzoate. The hydrogenation was carried out at a constant pressure of 40 bar of H2, at 30° C. and with intensive stirring. By virtue of the exothermic reaction the temperature rose to 40° C. After a hydrogenation time of 3 hours the mixture was worked-up as described in Example 2. Pure (R)-pantolactone was obtained. [α]D20 =-45.8°. Optical purity 88.8%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.000 g, 3.12 mmol) in methanol (5 ml) at rt was added 4M HCl in dioxane (15 ml). After stirring for 20 h the solution was concentrated to give the deprotected amine as the hydrochloride salt (0.785 g, 98%). LC-MS (LCT2) m/z 221 [M+H4], Rt 2.84 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccccc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylboroxine (27.2 μL, 0.24 mmol) were added to a dry flask under an atmosphere of nitrogen, then stirred for 1.5 hr to form a solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added and the reaction stirred for 30 minutes. Then, a solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) was added at the rate of 9 mL/hr by means of a syringe pump. After 1.5 hr, methanol was added to quench the reaction and then, the solvent was removed by evaporation. The resulting residue was chromatographed on silica gel (hexane/ethyl acetate 20:1) and combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (130 mg, 98.7% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO.Cl>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H](CBr)c1ccccc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-bis(2-naphthyl)ethanol (79.1 mg, 0.2 mmol) and dry tetrahydrofuran (2 mL) and trimethylboroxine (27.2 μL, 0.24 mmol) were added to a dry flask under an atmosphere of nitrogen, then stirred for 1 hour to form a solution of (R)-4-cyclohexyl-5,5-bis(2-naphthyl)-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added and the reaction was stirred for 30 minutes. Then, a solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (3 mL) was added at the rate of 9 mL/hr by means of a syringe pump. After 2 hours, methanol was added to quench the reaction, followed by 0.5 N ethanolic HCl (0.4 mL). The solvent was removed by evaporation under vacuum and the resulting residue was chromatographed on silica gel (hexane/ethyl acetate 25:2). Combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (130 mg, 93% yield, 98.3% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).