Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[CH:4]=O.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:13](/[N:17]=[CH:4]/[C:3]1[C:6]([F:12])=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[F:1])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: COc1ccc(F)c(C=O)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(OC)c1F

Procedure:
Butyl-[1-(2,6-difluoro-3-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-3-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): red oil; MS (ISP): 228.4 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li+].CC([N-]C(C)C)C.[CH:19](N1CCCCC1)=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([C:5]([F:9])=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: O=CN1CCCCC1
Reactant: Fc1cc(F)c(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)c(F)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 1-bromo-2,4,5-trifluoro benzene (25 g, 0.12 mol) in THF (200 mL at -78° C. was added LDA (80 mL, 1.5 M) dropwise. The mixture was stirred at -78° C. for 1 hour, then N-formylpiperidine (16 g, 0.144 mol) was added in one portion and stirring continued for 2 hours. An additional 15 g of N-formylpiperidine was then added every 0.5 hour in 5 g portions. The reaction was quenched with 3N HCl (pH 3) at -78° C. The reaction was warmed to 0° C. and partitioned between H2O and ether. The ether layer was dried and concentrated and the residue was distilled to provide 13 g (45%) of the desired aldehyde; bp 63°-65° C. (0.2 mm).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C-:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH3:7].[Li+].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C1COCC1>[CH3:1][Si:2]([CH3:10])([CH3:11])[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH2:7][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(=[C-][Si](C)(C)C)C=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=C[Si](C)(C)C)C=C(C)C[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a solution initially at -35° C. of 3.609 g (20.7 mmol) of lithium (1-(trimethylsilyl)-2,4-dimethylpentadienide) in 30 mL of THF was added about 5 g (-46 mmol) of trimethylsilyl chloride. Copious precipitate formed immediately. After stirring overnight, the solvent was removed and the residue was extracted with pentane. After filtering, the solvent was removed under reduced pressure to give the product as a pale yellow liquid. The yield was 4.05 g, 81.3 percent. Major isomer: 1H NMR (C6D6) δ 5.72 (s, 1H), 5.50 (s, 1H), 1.88 (s, 3H), 1.85 (s, 2H), 1.69 (s, 3H), 0.20 (s, 9H), 0.06 (s, 9H). 13C NMR (C6D6) δ 151.8, 135.6, 128.9, 126.4, 27.8, 24.6, 23.5, 0.7, -0.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([NH:19][S@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.Cl[C:38]([O:40][CH3:41])=[O:39].[Cl-].[NH4+]>C1COCC1>[CH3:15][C:14]([CH3:17])([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][C@:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:38]([O:40][CH3:41])=[O:39])([CH3:18])[NH:19][S@@:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:16]
Reactant: CC(C)(C)[S@](=O)N[C@@](C)(CO[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc([C@](C)(CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 403 mg of (S)—N-[(2R)-2-(3-bromophenyl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-2-methylpropane-2-sulfinamide in 4 ml of THF was added 1.4 ml of a 1.63 M n-butyllithium/hexane solution at −78° C., followed by stirring for 30 minutes, and then 283 μl of methyl chloroformate was added dropwise thereto, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 280 mg of methyl 3-[(6R,8S)-2,2,3,3,6,9,9-heptamethyl-8-oxo-4-oxa-8λ4-thia-7-aza-3-siladecan-6-yl]benzoate.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 37.5 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7.3 ml (60 mmol) of 4-methoxybenzaldehyde in 70 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: C(CC1N([C@@H:9]2[O:15][C@H:14](CO)[C@@H:12](O)[C@H:10]2[OH:11])C=NC=1C(N)=O)#N.C([O:24][C:25](=[O:27])[CH3:26])(=O)C.C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.CO>[CH3:9][C:10]([CH2:12][C:14]([CH2:26][C:25]([OH:24])=[O:27])=[O:15])=[O:11]
Reactant: N#CCc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of 5-cyanomethyl-1-β-D-ribofuranosylimidazole-4-carboxamide (1.41 g, 5 mmol), acetic anhydride (15 ml) and p-dimethylaminopyridine (20 mg) was stirred at RT for 8 hr. Tlc (silica gel, CHCl3 --MeOH, 4:1) indicated three products. Additional p-dimethylaminopyridine (20 mg) and acetic anhydride (5 ml) was added and stirring continued at RT for 36 hr. The solution was evaporated in vacuo to a syrup which was dissolved in chloroform and placed on a column of silica gel (60 g). Elution with chloroform-methanol (20:1) provided the triacetate (2.0 g, 95%) as a white foam; pmr (DMSO-d6): δ 2.08, 2.10, 2.16 (s,3,COCH3), 4.40 (s,2,CH2), 6.13 (d,1,H1'), J = 5Hz, 7.39, 7.58 (s,2,NH), 8.19 (s,1,C2H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15].I[CH2:21][CH3:22].[BH4-].[Na+]>C(O)C>[CH2:21]([N:11]1[CH2:10][CH:9]=[C:8]([C:7]2[C:2]([F:1])=[C:3]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1)[CH3:22]
Reactant: CCI
Reactant: CN(C)S(=O)(=O)c1cccc(-c2ccncc2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(S(=O)(=O)N(C)C)c2F)CC1

Procedure:
Preparation according to preparation 6: 2-fluoro-N,N-dimethyl-3-pyridin-4-ylbenzene sulfonamide (0.59 g, 2.11 mmol), 1-iodoethane (3 ml), ethanol (40 ml), sodium borohydride (0.4 g, 10.5 mmol). Yield: 0.27 g. MS m/z (rel. intensity, 70 eV) 312 (M+, bp), 311 (33), 297 (93), 146 (36), 110 (32).
Reaction SMILES: C([O:3][C:4]([N:6]1[CH:10]([C:11](=[O:20])[CH:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:17]([NH:16][CH:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH:10]1[N:9]=[C:8]([C:21]([CH3:23])([CH3:24])[CH3:22])[S:7][N:6]1[C:4]([OH:5])=[O:3])=[O:20])(=[O:19])[CH3:18]
Reactant: CCOC(=O)N1SC(C(C)(C)C)=NC1C(=O)C(NC(C)=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC(C(=O)C1N=C(C(C)(C)C)SN1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 38 (0.301 g, 0.84 mmol) in MeOH (10 mL) was added 1N NaOH solution (1.7 mL, 1.7 mmol). The reaction was stirred at room temperature for 2 hours and solvent was evaporated. The residue was dissolved in EtOAc and washed with 0.5N NaHSO4 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give the title compound as a yellow solid (0.277 g, quantitative).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([CH3:26])=[CH:21][N:20]=1>C(#N)C>[Cl:18][C:19]1[N:24]=[C:23]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]2)[C:22]([CH3:26])=[CH:21][N:20]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nc(Cl)ncc2C)nc1C
Temperature: 80 °C
Yield: 60.5 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate (4.7 g, 30.6 mmol) in acetonitrile were added potassium carbonate (10.6 g, 75.0 mmol) and 2,4-dichloro-5-methylpyrimidine (5.0 g, 30.6 mmol) at room temperature. The resulting suspension was heated at 80° C. for 3 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). Volatiles were partially removed and the residue was extracted with ethyl acetate. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was recrystallized in a mixture of heptanes and ethyl acetate to afford the desired intermediate 5 as a pale yellow solid (5.2 g, 61%); MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[C:5]([NH:15][C:16](=[O:29])[CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:4]=1)#[N:2].O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[C:5]([NH:15][C:16](=[O:29])[CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:4]=1)#[N:2]
Reactant: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)O)c1cccc2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)Nc1cc(C#N)ccc1CCCCO)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.9 %

Procedure:
Under an atmosphere of argon, to a solution of the compound prepared in Example 2(6) (169 mg) in THF (1 ml), a solution of borane-THF complex (0.47 ml) was added at 0° C. The mixture was stirred for 5 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (65 mg) having the following physical data.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:22](=[O:23])[NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: O=C=Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
A solution of quinolin-6-ol (0.29 g., 2 mmol) in dry dimethylformamide (3 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (2 ml) at −10° C. during 5 min. The reaction mixture was stirred for ½ hours. Then 3-bromo-phenyl isocyanate (0.475 g., 2.4 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1 hr. during which the temperature was allowed to rise to room temperature (21° C.). The reaction mixture was quenched with water (0.2 ml), diluted with water (2 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vaccum. The residue was washed with methanol (2×2 ml) to give 1d; yield: 0.35 g. (51.01%), m.p. 260° C., C16H11BrN2O2; 1H NMR δ ppm (pyridine d5): 7.09-7.58 (m, 9H), 8.28 (bs, 2H), 9.58 (bs, 1H); IR vmax (KBr) (cm−1). 522, 645, 743, 782, 877, 928, 992, 1069, 1227, 1286, 1406, 1470, 1581, 1637, 1875, 1946, 2374, 3290, 3753, 3872, 3952.
Reaction SMILES: [NH2:1][NH2:2].[NH2:3][C:4]1[C:5]2[C:30]([CH3:36])([C:31]([O:33]CC)=O)[C:29](=[O:37])[NH:28][C:6]=2[N:7]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[N:11]=2)[N:9]=1>>[NH2:3][C:4]1[C:5]2[C:30]([CH3:36])([C:31]([NH:1][NH2:2])=[O:33])[C:29](=[O:37])[NH:28][C:6]=2[N:7]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:24])([F:23])[F:25])[N:11]=2)[N:9]=1
Reactant: NN
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Product: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 80 °C

Procedure:
Hydrazine (2 mL, 63.7 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (400 mg, 0.761 mmol) and the reaction mixture was heated to 80° C. for 30 min. The reaction was then cooled to room temperature and concentrated in vacuo. Excess hydrazine was azeotropically removed by treatment with acetonitrile (3×4 mL). The product was lyophilized from water/acetonitrile overnight to give the title compound as a pale yellow solid which was used in the next step without further purification. m/z=486.01 (M+H).
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>[N:36]1([C:42]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
After neutralizing 203 g (500 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate•p-toluenesulfonate with a 10% sodium carbonate solution, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solid material was filtered off, and after adding 56 g (550 mmol) of triethylamine to the chloroform layer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was added dropwise, and the mixture was heated in an oil bath (60° C.) for 3 days. After completion of the reaction, the reaction mixture was washed successively in the order of water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting crystals were washed with ether to obtain 151 g (Yield: 87%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=O)[CH2:3]1.[C:14]([CH2:22][C:23]#[N:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=[C:22]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[C:23]#[N:24])[CH2:3]1
Reactant: N#CCC(=O)c1ccccc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC2=O
Product: Cc1ccc2c(c1)C(C)(C)CC2=C(C#N)C(=O)c1ccccc1

Procedure:
3,3,5-Trimethyl-1-indanone are reacted with benzoylacetonitrile analogously to Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:25]([O:27][C:28](=[O:39])[C@@H:29](OS(C(F)(F)F)(=O)=O)[CH3:30])[CH3:26].O>C1COCC1>[CH2:25]([O:27][C:28](=[O:39])[C@H:29]([N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:30])[CH3:26]
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a 0° C. suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (Preparation #2, Step A, 55 g, 283 mmol) in THF (1.1 L) was added drop-wise KHMDS (1M solution in THF, 283 mL, 283 mmol) and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 142 g, 567 mmol) was added drop-wise and the reaction mixture was stirred for 30 min. Water (1 L) was added and the aqueous solution was extracted with EtOAc (3×1 L). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give (R)-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80.0 g, 96%) as an oil. 1H NMR (CDCl3, 400 MHz): δ 7.96 (dd, J=2.4, 8.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 5.34 (q, J=7.2 Hz, 1H), 4.81-4.66 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H). SFC (Table 2, Method 3) Rt=5.39 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:31])=[C:4]([C:11](/[C:13](=[CH:29]/[CH3:30])/[CH:14]=[C:15]2\[C:16](=C)[N:17]=C(C3C=CC=CC=3)[O:19][C:20]\2=[O:21])=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[K+].Cl>O.CN1C(=O)CCC1>[NH2:17][C:16]1[CH:30]=[CH:29][C:13]([C:11]([C:4]2[N:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[C:2]([Br:1])[C:3]=2[CH3:31])=[O:12])=[CH:14][C:15]=1[C:20]([OH:19])=[O:21]
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)c(Br)c2ccccn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Yield: 109.4 %

Procedure:
The (5E)-5-{(2E)-2-[(1-bromo-2-methylindolizin-3-yl)carbonyl]but-2-en-1-ylidene}-4-methylidene-2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (18.6 g; 40.4 mmol) is added portionwise to potassium hydroxide (22.7 g; 0.40 mol) in 100 mL of water and 140 mL of NMP. The reaction mixture is heated at reflux for 18 h, cooled to ambient temperature and poured into a hydrochloric acid solution (1 M). The yellow precipitate formed is filtered off and dried under vacuum to give 16.5 g (99%) of a yellow powder.
Reaction SMILES: [CH2:1]([C@H:8]([NH:32]C(=O)OC(C)(C)C)[C@H:9]([OH:31])[CH2:10][CH:11]([O:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[S:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[N:18]2)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:32][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:31])[CH2:10][CH:11]([O:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[S:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[N:18]2)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture of tert-butyl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate (563 mg, 1.01 mmol) and trifluoroacetic acid (5 mL) was stirred under an Argon atmosphere for 0.5 hrs. The acid was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with dichloromethane : methanol (98:2). Fractions containing the product were combined and evaporated in vacuo and dried under high vacuum to provide (3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinylsulfonyl)-3-pentanol as a foam (379 mg, 82%). H1-NMR (chloroform-D3): 1.66 (m, 11H), 2.51 (m, 1H), 2.86 (m, 1H), 3.07 (m, 1H), 3.23 (m, 1H), 3.32 (m, 1H), 3.84 (m, 1H), 4.90 (m, 1H), 7.20 (m, 5H), 8.16 (m, 1H), 8.28 (d, 1H), 8.70 (m, 1H), 8.99 (m, 2H<. MS(ESI): 457(M+H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>>[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(CCCCC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A 3 L flask equipped with a stirrer, a thermometer, and a dehydration tube was charged with 438 g of adipic acid, 779 g of benzyl alcohol, and 5.7 g of paratoluenesulfonic acid monohydrate, and the components were reacted at 120° C. for 4 hours under a reduced pressure of from 6 to 10.7 kPa, while blowing nitrogen (500 mL/minute) into a space portion. The reaction mixture had an acid value of 1.2 (KOH mg/g). Eight grams of an adsorbent KYOWAAD 500SH (manufactured by Kyowa Kagaku Kogyo) was added to the reaction mixture, and the mixture was stirred at 80° C. and 2.7 kPa for 45 minutes. Thereafter, benzyl alcohol was distilled off at a liquid temperature of from 120° to 183° C. and a pressure of 0.27 kPa, and cooled to 80° C., and the residue was filtered under a reduced pressure, to provide dibenzyl adipate as a filtrate. The resulting dibenzyl adipate had an acid value of 0.16 (KOH mg/g), a saponification value of 512 (KOH mg/g), a hydroxyl value of 1 or less (KOH mg/g), and a hue APHA of 80.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:42]1>CO>[CH3:42][CH:24]1[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]2[CH:36]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:25]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CCOC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC(C)N3c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (230 mg) was dissolved in tetrahydrofuran (15 ml) and methanol (15 ml), after which an aqueous 1N sodium hydroxide solution (5 ml) was added. The mixture was stirred for 3 hours at 90° C. After adding water at 0° C., the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (220 mg) as a yellow amorphous material.