Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1C(=O)C2=CC=CC=C2C1=O.CO.O.NN>O>[ClH:1].[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cl
Product: NOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reaction time: 1 h
Yield: 184.7 %

Procedure:
Then, 9.1 g of N-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)propyloxy)phthalimide was added to 150 ml of methanol, to which 1.9 g of hydrazine hydrate was added. The reaction mixture was stirred for 1 hour with heating under reflux, and returned to room temperature. To the reaction mixture was added 50 ml of water, from which the methanol was evaporated under reduced pressure. Further added were 15 ml of concentrated hydrochloric acid and 25 ml of water. The reaction mixture was stirred for 30 minutes with heating under reflux, returned to room temperature, and filtered. The crystals collected by filtration were added to 10% aqueous sodium hydrogencarbonate solution, and extracted with diethyl ether. The diethyl ether layer was washed with 10% aqueous sodium hydrogencarbonate solution and water. To this diethyl ether layer was added 3 ml of concentrated hydrochloric acid, and the mixture was concentrated and the dried, which afforded 6.8 g (yield, 92%) of O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)hydroxylamine hydrochloride, m.p., 171.8° C.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[FH:14].[F:15][C:16]1[C:21]([CH:22]2[O:24][CH2:23]2)=[C:20]([F:25])[C:19]([F:26])=[C:18]([F:27])[C:17]=1[F:28]>>[F:14][CH:22]([C:21]1[C:16]([F:15])=[C:17]([F:28])[C:18]([F:27])=[C:19]([F:26])[C:20]=1[F:25])[CH2:23][OH:24]
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Reactant: F
Solvent: CCCCN(CCCC)CCCC
Product: OCC(F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 40 °C
Reaction time: 10 h
Yield: 31.9 %

Procedure:
To Teflon vessel containing 4.2 g (22.5 mmol)of tributylamine was cooled in a dry-ice methanol bath, and to this was added dropwise 2.3 g (112.5 mmol) of anhydrous hydrogen fluoride to prepare 6.4 g (22.5 mmol) of n-Bu3N.5HF. To this was added dropwise 3.15 g (15 mmol) of (+)-pentafluorostyrene oxide at 0° C., and was stirred for 10 hours at 40° C. After it was left to cool, the same treatment as that provided in Example 16 gave 1.1 g of (+)-2-fluoro-2-(pentafluorophenyl)ethanol. Its GC purity was 96%, while its [α]D25 was +10.8° (c=0.54, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:15]12[O:20][CH:19]1[CH2:18][CH2:17][CH2:16]2>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C@@H:18]3[CH2:17][CH2:16][CH2:15][C@H:19]3[OH:20])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: C1CC2OC2C1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Solvent: CCO
Product: O[C@@H]1CCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Following General Procedure A, a solution of 4-(4-chlorobenzyl)-piperidine (17.86 g, 85.05 mmol) and 6-oxa-bicyclo[3.1.0]hexane (50 g, 0.6 mol) in EtOH (170 mL) was stirred at 95° C. for 40 hours, allowed to cool to room temperature, and concentrated. The residue was crystallized in hot CH2Cl2 (80 mL), the crystallization mixture was concentrated to half the volume, and kept at 0° C. overnight and filtered, and the precipitate was rinsed with cold hexanes to give the product (18.2 g, 73%) as a tan solid. The mother liquors were concentrated to half the volume, diluted with CH2Cl2 and kept at −10° C. for 1 hour, and the precipitate was rinsed with cold CH2Cl2 and hexanes to give additional product (1.8 g, 7%) as a tan solid: mp 104.1–105.5° C.; IR 3436, 2928 cm−1; 1H NMR δ 1.19–1.75 (m, 8H), 1.81–1.99 (m, 4H), 2.06 (dt, J=2.5, 11.7 Hz, 1H), 2.47 (m, 1H), 2.50 (d, J=7.0 Hz, 2H), 2.90 (m, 1H), 3.07 (m, 1H), 4.10 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); 13C NMR δ 21.63, 27.35, 32.01, 32.15, 34.31, 37.87, 42.47, 50.47, 52.97, 75.15, 75.22, 128.27, 130.43, 131.55, 139.04; MS m/z 294 (M+H)+. Anal. (C17H24ClNO.0.1H2O) C, H, N.
Reaction SMILES: N[C:2](=[O:35])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.[OH-].[Na+].C([OH:40])C.Cl>O>[C:23]([O:22][C:21]([NH:20][CH2:19][C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:6][C:5]([CH2:4][CH2:3][C:2]([OH:40])=[O:35])=[CH:14][CH:13]=2)=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(N)=O)cc23)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(=O)O)cc23)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of tert-butyl [6-(3-amino-3-oxopropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (2.38 g, 5.0 mmol), 4N aqueous sodium hydroxide solution (12.5 ml, 50 mmol) and ethanol (20 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]propanoic acid (2.01 g, yield 84%) as white crystals.
Reaction SMILES: CNN(CCC)NC.[CH3:9][C:10]1([CH3:30])[O:17][CH2:16][CH2:15][C@H:14]2[N:11]1[C:12](=[O:29])[C@@H:13]2[N:18]1C(=O)C2=CC=CC=C2C1=O>CO.ClCCl>[NH2:18][C@H:13]1[C:12](=[O:29])[N:11]2[C@@H:14]1[CH2:15][CH2:16][O:17][C:10]2([CH3:30])[CH3:9]
Reactant: CC1(C)OCC[C@@H]2[C@@H](N3C(=O)c4ccccc4C3=O)C(=O)N21
Agent: CCCN(NC)NC
Solvent: ClCCl
Solvent: CO
Product: CC1(C)OCC[C@@H]2[C@@H](N)C(=O)N21
Reaction time: 2 h
Yield: 59.5 %

Procedure:
N,N-Dimethylaminopropylamine (91 μl) was added to a solution of (6R,7R)-2,2-dimethyl-7-phthalimido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (80 mg) in a mixture of methanol (1.4 ml) and dichloromethane (0.7 ml) at 0° C. under a nitrogen atmosphere. The solution was stirred at the same temperature for two hours and left at ambient temperature for 24 hours. The mixture was evaporated and the residue was chromatographed on silica gel (1.5 g; eluting with 3 to 5% methanol in dichloromethane) to give 27 mg (59.5%) of (6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one: IR (CH2Cl2): 3100-3600 (broad) and 1735 cm-1 ; NMR (CDCl3) δ: 1.41 (s, 3H), 1.72 (s, 3H), 1.5-2.1 (m, 4H), 3.34 (ddd, J=2, 5 and 10 Hz, 1H), and 3.7-3.9 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])=[CH:7][CH:8]=2)[N:3]=1.[CH3:35]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:35])[S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:20])=[O:21])[C:14]3=[O:34])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.4 g, 0.81 mmol), prepared as in EXAMPLE 15, Part F, is dissolved in DMF (20 mL) and cooled to 0° C. To the solution is added methyl iodide (0.28 g, 2.01 mmol) and sodium hydride (34 mg, 0.85 mmol, 60% mineral oil dispersion). The ice water bath is removed and the mixture is stirred at room temperature for 3 hours. The resulting solution is poured into a separatory funnel and diluted with EtOAc (100 mL). The organic layer is washed with 1N HCl, H2O and saturated NaCl. The organic phase is then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with 10% EtOAc/CH2Cl2 to give the title compound (0.36 g, 0.71 mmol) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OCC1CCC2CN(c3ncc(Cl)cc3Cl)CCN2C1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 0.75 g (4.4 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 4.02 g (22.1 mmol) of 2,3,5-trichloropyridine, 1.12 g (10.6 mmol) of sodium carbonate and 30 mL of isoamylalcohol was refluxed for 72 h. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and evaporated, and the crude product was purified by flash chromatography on silica gel eluting with 95:5 chloroform:methanol to give 1.10 g (80%) of (7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: Br.C(O)(=[O:4])C.C([O:9][C:10]1[C:18]2[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH:24]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:25][C:26]#[N:27])[CH:23]=3)=[N:16][C:15]([O:33]C)=[N:14][C:13]=2[NH:12][CH:11]=1)(=O)C>>[CH:28]1([C@H:24]([N:22]2[CH:23]=[C:19]([C:17]3[C:18]4[C:10](=[O:9])[CH2:11][NH:12][C:13]=4[N:14]=[C:15]([OH:33])[N:16]=3)[CH:20]=[N:21]2)[CH2:25][C:26]([NH2:27])=[O:4])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2c(OC(C)=O)c[nH]c2n1
Reactant: CC(=O)O
Agent: Br
Product: NC(=O)C[C@H](C1CCCC1)n1cc(-c2nc(O)nc3c2C(=O)CN3)cn1
Reaction time: 1 h

Procedure:
4 M of HBr in acetic acid (2 mL, 8 mmol) was added to 4-[1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl]-2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl acetate (0.050 g, 0.13 mmol) and the reaction was stirred for 1 h. Volatiles were removed in vacuo. The residue was reconstituted and preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) was used to afford purified product (12 mg, 26%). 1H NMR (500 MHz, d6-DMSO): δ 9.20 (s, 1H), 8.69 (s, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 4.49 (dt, 1H), 3.89 (s, 2H), 2.80 (dd, 1H), 2.64 (dd, 1H), 2.36-2.26 (m, 1H), 1.83-1.74 (m, 1H), 1.63-1.36 (m, 4H), 1.32-1.20 (m, 2H), 1.15-1.05 (m, 1H); LCMS (M+H)+: 357.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (64 ml), p-anisidine (65 mg), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(αmethyl-benzylidene)-p-anisidine (VII) (50 g). VII had a melting point of 81°-82° C.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:32]=[CH:31][C:30]2[C@@H:29]3[C@H:13]([C@H:14]4[C@@](C[CH2:28]3)(COC3CCCCO3)C(=O)[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=1.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1.[H-].[C:40]([O:44][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>CCOCC>[OH:7][C:8]1[CH:32]=[CH:31][C:30]2[C@@H:29]3[C@H:13]([C@H:14]4[C@@:34]([CH2:35][CH2:28]3)([CH2:40][OH:44])[C@@H:38]([O:37][CH3:36])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=1
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Reactant: O=C1CC[C@H]2[C@@H]3CCc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12COC1CCCCO1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CO[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 450 mg. of 3,18-bis(tetrahydropyranyloxy)-1,3,5(10)-estratrien-17-one in 10 ml. of absolute THF is combined at 0° C. with 500 mg. of lithium tri-tert.-butoxyaluminum hydride and agitated for one-half hour at room temperature. Then, the mixture is poured into ice water, taken up in ether, washed neutral with water, dried, and evaporated. The residue of crude 3,18-bis(tetrahydropyranyloxy)-1,3,5(10)-estratrien-17β-ol is dissolved in 5 ml. of DMF, and under N2 100 mg. of sodium hydride (50% suspension in oil) is added thereto. After 1 hour of agitation at room temperature, 0.19 ml. of dimethyl sulfate is added. The mixture is stirred for another hour and then introduced into water. After extraction with ether, the organic phase is washed with water and dried. The residue of 3,18-bis(tetrahydropyranyloxy)-17β-methoxy-1,3,5(10)-estratriene remaining after evaporation is heated to the boiling point in 4 ml. of methanol with 4 ml. of water and 0.4 g. of oxalic acid. After 1 hour, the mixture is taken up in ether, washed neutral with water, dried, and evaporated, and after purification by chromatography over silica gel, 3,18-dihydroxy-17β-methoxy-1,3,5(10)-estratriene is produced.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: NCCCO
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(c1)cc(C(=O)NCCCO)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 3-amino-1-propanol in a manner similar to that described in Example 11.
Reaction SMILES: [Cl:1][N:2]1[CH:7]=[N:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[NH+:3]1[O-:12].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)(C)C>[ClH:1].[N:13]1([C:7]2[N:2]=[N+:3]([O-:12])[C:4]3[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=3[N:6]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: [O-][NH+]1c2ccccc2N=CN1Cl
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: Cl
Product: [O-][n+]1nc(N2CCNCC2)nc2ccccc21
Reaction time: 0.25 h

Procedure:
To a slurry of 2-chloro-1,2,4-benzotriazine-1-oxide (12.0 g., 0.066 mol.) in 100 ml. of isopropanol is added 11.4 g. (0.132 mol.) of anhydrous piperazine with cooling under N2. The exothermic reaction is moderated at 35°-40° C. for 15 min., and then stirred 2 hours at 20°-25° C. The orange precipitate is collected by suction and partitioned between chloroform and aqueous sodium carbonate. After drying, the CHCl3 extract is concentrated under vacuum to an oil which is taken up in a boiling mixture of 200 ml. of hexane and 200 ml. benzene. The solution is filtered and concentrated under vacuum, and the residue is dissolved in 150 ml. ethanol and treated with 10 ml. of 10N anhydrous ethanolic-HCl. The yellow crystalline crude hydrochloride (9.2 g.) is recrystallized from methanol and then from aqueous ethanol to give pure 3-(1-piperazinyl)-1,2,4-benzotriazine-1-oxide hydrochloride, m.p. 306°-307° C. (dec.).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:34][N+:35]([O-])=[O:36])(C)C.C(O)(=O)C>C(O)(C)(C)C.ClCCl>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:35]([O-:36])=[O:34])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium tert-butoxide (1.70 g, 15 mM), (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed in tert-butanol and heated at reflux temperature, under argon atmosphere for 90 minutes. The combination is then cooled to room temperature and treated with one continuous portion of isopropylnitrate (0.51 mL, 5 mM). After 18 hours, the contents of the reaction vessel are acidified with 5 ml of acetic acid, and subsequently diluted with dichloromethane. The solids are then removed by filtration and further washed with additional dichloromethane. The filtrate and wash residue are purified as described in Example 1 to give a crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[S:26][C:27]([N:30]=[C:31]=[O:32])=[CH:28][CH:29]=1.C(Cl)Cl.CO>C(Cl)Cl>[Cl:24][C:25]1[S:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:32])=[CH:28][CH:29]=1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C=Nc1ccc(Cl)s1
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (98 mg, 0.307 mmol) was dissolved in 10 ml DCM. TEA (46 mg, 0.45 mmol) was added and the reaction mixture was flushed with Ar. 2-chloro-5-thienylisocyanate (58.8 mg, 0.368 mmol) was added on ice bath, and the resulting mixture was agitated at room temperature overnight. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, low boiling point solvent was evaporated under reduced pressure. Column chromatography (DCM/MeOH=100/1) afforded 87 mg white solid, yield: 59.2%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH:10]([CH2:15][C:16]23[CH2:31][CH2:30][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=42)[C:22]2[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:15][C:16]23[CH2:31][CH2:30][CH:23]([C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=42)[C:24]2[C:29]3=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(CC23CCC(c4ccccc42)c2ccccc23)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(CN2CCOC(CC34CCC(c5ccccc53)c3ccccc34)C2)cc1
Reaction time: 2 h

Procedure:
A mixture of 9-(4-benzyl-5-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene (1.07 g) and lithium aluminum hydride (400 mg) in dioxane was stirred at 50° -60° C. for 2 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-benzyl-2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene, I.R., 3060, 3010, 2860, 2800, 1215, 1139, 1099, 1030, 980, 698, 660 cm-1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:21]>C(Cl)Cl.O1CCOCC1>[ClH:21].[NH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCN)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of methyl 4-[2-(tert-butoxycarbonylamino)ethyl]benzoate (3.50 g, 12.5 mmol) in methylene chloride (35 ml) was added 4N hydrogen chloride in 1,4-dioxane (35 ml) at 5° C. and the mixture was stirred for 30 min. The solvent was removed in vacuo and the resulting solid was collected, washed with isopropyl ether and dried to give methyl 4-(2-aminoethyl)-benzoate hydrochloride (2.63 g, 97%).
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH:18]=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:15]=1)\[CH3:13])=[CH:3]\[C:4]([O:6]CC)=[O:5].CO.[Li+].[OH-].Cl>C1COCC1.CCOCC>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:24])([CH3:25])[CH2:19][CH:18]=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:15]=1)\[CH3:13])=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C)=C\C(=O)O
Reaction time: 6 h

Procedure:
To a solution of ethyl (E,E,E)-3-methyl-7-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)-2,4,6-octatrienoate (Compound 51) 85.0 mg, 0.20 mmol) in THF (1 ml) and methanol (1 ml) was added 12.0 mg (0.50 mmol) of LiOH (0.5 ml, 1M solution). The mixture was stirred for 6 hours, diluted with ether (60 ml), acidified with 10% HCl (1 ml). The solution was washed with water, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as a solid, which was purified by recrystallization from acetone. 1H NMR (acetone-d6): δ7.35-7.45 (2H, m), 7.19-7.28 (4H, m), 7.17 (1H, d, J=1.8Hz), 7.09 (1H, dd, J=11.5, 15.1 Hz), 6.48 (1H, d, J=11.5 Hz), 6.42 (1H, d, J=15.1 Hz), 5.99 (1H, t, J=4.7 Hz),5.82 (1 H, s), 2.36 (3H, s), 2.33 (2H, d, J=4.7 Hz), 2.32 (3H, s), 2.13 (3H, s), 1.32 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(OC)c1
Temperature: 0 °C

Procedure:
1,3-Dimethoxybenzene (5.00 g, 36.2 mmol) and AlCl3 (5.79 g, 1.2 eq.) were dissolved in 360 ml of CH2Cl2 and cooled down to 0° C. 4-Fluoro-benzoyl chloride (4.34 mL, 1.0 eq.) was slowly added via dropping funnel and the mixture allowed to react for another h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by short flash chromatography (SiO2, hexane/AcOEt 8/2), yielded 7.75 g of the title compound as white solid.