Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (50.34 g, 0.279 mol) in 500 mL of methylene chloride cooled to 0° C. was added slowly at 0° C. 30.5 mL (0.418 mol) of thionyl chloride, the mixture was stirred 10 h at room temperature and the solvent was removed in vacuo. The residue was dissolved in 1000 mL of methylene chloride, cooled to 0° C., and 40.92 g (0.306 mol) of aluminum chloride was added in small portions and the resulting mixture was stirred at room temperature for 1 h. The above mixture was poured onto ice, the resulting mixture was filtered through celite, and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was extracted with hexane to afford 40 g (88%) of 6-methoxy-1-indanone.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][N:3]=1.BrC1N2CCN(C(OC(C)(C)C)=O)CC2=NN=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:58][C:59]1[C:67]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:65]=[CH:64][C:60]=1[C:61](Cl)=[O:62]>ClCCl>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:61]([C:60]3[CH:64]=[CH:65][CH:66]=[C:67]([C:68]([F:69])([F:70])[F:71])[C:59]=3[Cl:58])=[O:62])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: Brc1nnc2n1CCNC2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reaction time: 4 h

Procedure:
3-Bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (prepared by standard BOC deprotection of tert-Butyl 3-bromo-5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate, CAS [723286-80-4], commercially available e.g. from Allichem, Ark Pharm or Bepharm) (0.6 mmol) and diethylaminomethyl polystyrene (0.6 g, 1.92 mmol) were slurried in Dichloromethane (DCM) (7 mL) under argon. 2-Chloro-3-(trifluoromethyl)benzoyl chloride (0.16 g, 0.66 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added to the reaction. The mixture was stirred for 4 hours. The resin was filtered, washed with Dichloromethane (50 mL) and concentrated in vacuo to afford crude product. The crude product was purified by using mass-directed automated (preparative) HPLC (MDAP). The fractions containing the products were evaporated, diluted with diethyl ether and treated with 1 mL of HCl in diethyl ether; the solutions were stirred for 30 min. and solvent evaporated to give 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.268 g). LC/MS [M+H]+=410.9, retention time=2.07 minutes (5 minute method).
Reaction SMILES: Cl.Cl.Cl.[N+:4]([C:7]1[CH:48]=[CH:47][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH2:45])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].CCN(CC)CC.[C:56](Cl)(=[O:58])[CH3:57]>C(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH:45][C:56](=[O:58])[CH3:57])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:47][CH:48]=1)([O-:6])=[O:5]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a stirred solution of (5R,7R)-4-(4-(aminomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate trihydrochloride (30 mg, 0.042 mmol) and Et3N (0.034 mL, 0.19 mmol) in DCM (1 mL) was added acetyl chloride (0.0033 mL, 0.046 mmol) at about 0° C. under N2. The reaction was stirred at about 0° C. for about 30 minutes and diluted with DCM. The reaction mixture was washed with saturate aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH/DCM) to give (5R,7R)-4-(4-(acetamidomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (28 mg, 68%) as an oil. LCMS (APCI+) m/z 647 [M+H]+; Rt=3.21 min.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[NH2:3].C(OC(OCC)[CH:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[CH2:28][CH3:29])C.[C:44](=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C>[O:35]=[C:34]1[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31](=[O:40])[N:30]1[CH2:27][CH2:28][CH2:29][CH:44]=[N:3][NH:2][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc(NN)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)C(CC)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(NS(=O)(=O)c2ccc(NN=CCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydrazino-N-(4-ethoxyphenyl)benzenesulphonamide hydrochloride (1.2 g) in 25% aqueous acetic acid (100 ml) was added to phthalimidobutyraldehyde diethyl acetal (1 g). The resulting suspension was stirred at room temperature for 1 h, basified (sodium carbonate) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and evaporated in vacuo to give a solid which gave the title compound (1.5 g) on trituration with ethyl acetate, m.p. 156°-158°.
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Br-].[Na+].BrBr.[OH2:19]>>[CH3:2][N:3]1[CH2:4][CH2:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:19])[CH:7]([Br:1])[CH2:8]1
Reactant: O
Reactant: Br
Reactant: CN1CC=C(c2ccccc2)CC1
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Product: CN1CCC(O)(c2ccccc2)C(Br)C1
Reaction time: 1 h

Procedure:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrobromide (110.0 g, 0.434 mole, described in Example 3) is dissolved in water (1250 ml). A solution of sodium bromide (128.0 g, 1.24 moles) and bromine (70.0 g, 0.440 mole) in water (1000 ml) is added dropwise with stirring to the above solution over a period of 1 hour. The mixture is concentrated under reduced pressure to half its original volume. The precipitate is isolated by filtration and recrystallized from glacial acetic acid to give the title compound as the hydrobromide salt, mp 191°-192° C. (R. E. Lyle and W. E. Krueger, supra, reported mp 195°-197° C.).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]([F:29])([F:28])[C:12]([F:27])([F:26])[C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CC#N>C(Cl)Cl.CO>[F:29][C:11]([F:28])([C:12]([F:26])([F:27])[C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: O=P(O)(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 6 h

Procedure:
(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)phosphonic acid diethyl ester (0.79 g, 1.6 mmol) was dissolved in CH2Cl2 (5 ml) under N2. Bromotrimethylsilane (0.8 ml, 6.1 mmol) was added via syringe and the mixture was stirred for 6 hours. Volatiles were removed in vacuo to give a thick orange oil; this was dissolved in MeOH (20 ml) with fuming to give a yellow solution. The mixture was stirred overnight and evaporated to dryness to give a pale yellow powder. Addition of MeCN caused separation of a white solid from the yellow solution. The solid was collected by filtration, affording the desired product as a white powder. Yield 0.56 g, 1.3 mmol, 82%. Analysis found (calculated) %: C, 22.35 (22.45); H, 1.25 (1.41). 1H NMR (d6-DMSO, 400 MHz, 298 K): δ 2.35 (m, 2H), 1.73 (m, 2H). 13C{1H} NMR (d6-DMSO, 100 MHz, 298 K): δ 121-105 (m, C-F coupling unresolved), 25.13 (t, JC-F=23 Hz), 17.10 (d, JC-P=138 Hz). 31P{1H} NMR (d6-DMSO, 162 MHz, 298 K): δ 22.87. MS (FAB, m/z): 429 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:9][Br:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(Cl)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-bromo-6-chloro-2-methylpyridine (105 g, 509 mmol) in CCl4 (2 L) was added N-bromosuccinimide (95 g, 534 mmol) followed by AIBN (8.35 g, 50.9 mmol). The reaction was brought to reflux for 24 hours and then cooled to r.t., filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 60% methylene chloride/heptanes afforded semi-pure product. Further purification by SFC on a Chiralpak AD-H column with 20% IPA/CO2 [the conditions of the preparative separation were as follows: column Chiralpak AD-H (2.1×25 cm, 5 μm particle size) (Chiral Technologies, West Chester, Pa., USA); mobile phase 20% 2-propanol/CO2; elution mode isocratic pump-mixed; flow rate 50 mL/min; pressure 100 bar.] gave 3-bromo-2-(bromomethyl)-6-chloropyridine. LCMS=285.7 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 4.63 (s, 2H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1CCN2C(=NCCC2)CC1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (27.6 mmol, 4.13 mL) was injected followed by cyclohexylmethyl bromide (23.0 mmol, 3.21 mL) and the reaction was warmed to 55° C. After stirring for 15 hours, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was removed under vacuum, and the crude product was triturated with hexanes providing 3.05 g (64%) of an off-white colored solid. H1-NMR (CDCl3): δ7.80 (2H,m), 7.73 (2H,m), 3.98 (2H,d), 2.03-1.65 20 (5H,m), 1.31-1.03 (6H,m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[CH:18]=[O:19].[BH4-].[Na+]>CO.O.CCOC(C)=O>[OH:19][CH2:18][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)n1ncc2cc(C=O)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(CO)c(F)cc21
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of tert-butyl 6-fluoro-5-formyl-1H-indazole-1-carboxylate (22E, 3.55 g, 13.4 mmol) in methanol (50.00 mL) was treated with NaBH4 (1.02 g, 26.9 mmol) at 0° C. and stirred for 1 h. The reaction mixture was diluted with water and EtOAc (500 mL). The organic layer was separated and washed with aq. HCl (1M, 200 mL), aq. NaOH (1M, 200 mL) brine (200 mL) dried (MgSO4), filtered, concentrated in vacuo and residue was purified by chromatography (SiO2, EtOAc/hexanes) to yield tert-butyl 5-(hydroxymethyl)-6-fluoro-1H-indazole-1-carboxylate (22F, 3.00 g; Yield=83.9%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[Cl:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20]([OH:30])=[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]3=[N:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:30])[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]=3[N:23]([CH2:8][CH3:9])[CH:24]=2)=[O:18])=[CH:31][CH:32]=1
Reactant: CCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (0.87 g) and iodoethane (0.5 mL) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (2.0 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (60 mL). The reaction mixture is stirred at room temperature for 18 h. The mixture is diluted with water (150 mL) and filtered. The resulting white powder is washed with water (15 mL) followed by diethyl ether (15 mL) and dried in a vacuum oven to afford 1.64 g of the title compound as a white solid. Physical characteristics. M.p. 169-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.65, 8.74, 7.37, 7.29, 5.81, 4.70, 4.54, 4.32, 1.44. HRMS (FAB) m/z 377.0720 (M+H)+. Anal. Found. C, 56.87; H, 4.77; N, 7.38; Cl, 9.35; S, 8.44.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.Cl.[CH:16]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[CH:16]1([N:24]2[C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[N:5]=[C:4]([CH3:11])[C:3]=3[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: NC1CCCCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1nc2ncnn2c2c1CCN2C1CCCCCCC1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1.45g of cyclooctylamine hydrochloride, 4 ml of triethylamine and 20 ml of isopropyl alcohol was stirred under reflux for 1.5 hours, and treated thereafter as described in Example 5. The crystals thus obtained were recrystallized from ethanol to give 1.25g of colorless needles of m.p. 188.5° - 190.5° C.
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25]Cl)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].C(=O)([O-])[O-:30].[K+].[K+].[CH2:35]([CH2:37][NH2:38])O>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][NH:38][CH:37]([OH:30])[CH3:35])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: NCCO
Reactant: ClCCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)NCCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 85 °C
Yield: 24 %

Procedure:
To a mixture of 2-chloroethyl (1R)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether in DMF (20 mL) is added sodium iodide (1.0 g, 6.7 mmol), potassium carbonate (2.0 g, 14.5 mmol), and ethanolamine (0.42 mL, 7.0 mmol). The mixture is heated to 85° C. for 18 h. The mixture then is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (200 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel (60 mL) using CH3OH/CH2Cl2 (2/98) and then rechromatographed with CH3OH/CH2Cl2/NH4OH (4/96/0.1) gave 0.62 g (24%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:10])[N:6]([C:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])=[C:29]([CH3:31])[CH3:30])[C:5]1=[O:45])[CH3:3].[N+:46]([C:49]1[CH:59]=[CH:58][C:52]([CH2:53][O:54][C:55](Cl)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([NH:14][CH2:13][CH2:12][S:11][C:9]([CH2:8][C@H:7]2[N:6]([C:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])=[C:29]([CH3:30])[CH3:31])[C:5](=[O:45])[C@@H:4]2[C@H:2]([O:1][C:55]([O:54][CH2:53][C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:59][CH:58]=2)=[O:56])[CH3:3])=[O:10])=[O:16])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 51.3 %

Procedure:
125 mg (0.194 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-([2-(p-nitrobenzyloxycarbonylamino)ethylthio]-carbonylmethyl)-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)-prop-1-enyl]-2-azetidinone were dissolved in 4 ml of methylene chloride. To the solution were added, in turn, 71 mg (0.58 mmole) of 4-(N,N-dimethylamino)-pyridine and 126 mg (0.58 mmole) of p-nitrobenzyloxy-carbonyl chloride, with stirring at 0° C. The reaction mixture was then stirred at room temperature for 1 hour, after which it was diluted with methylene chloride and washed with a saturated aqueous solution of sodium chloride. The solvent was distilled off and the residue was subjected to chromatography using a Lobar column B eluted with a 2:3 by volume mixture of hexane and ethyl acetate, to afford 82 mg (yield 51%) of the title product as an oily substance. Infra-red and nuclear magnetic resonance spectra of the product agreed with those of the product of Preparation 7.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:14]#[N:15]
Reactant: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][CH2:24]I>CN(C=O)C>[Cl:21][CH2:22][CH2:23][CH2:24][S:11]([C:8]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: O=C(O)c1cc(S(=O)O)ccc1O
Reactant: ClCCCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(S(=O)(=O)CCCCl)ccc1O
Temperature: 40 °C

Procedure:
To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane, and the mixture heated at 40° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{37Cl}M−H]−, 33%), 277.0 ([{35Cl}M−H]−, 100%)
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].[NH4+:18].[OH-]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:18][C:1]([CH3:2])=[CH:4]2
Reactant: [NH4+]
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Agent: [OH-]
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 25 °C
Yield: 74 %

Procedure:
Cyclic anhydride 42 (405 mg; 1.73 mmol) was dissolved in aqueous NH4OH and heated at reflux for 1.5 h. The mixture was cooled to RT and the solid was filtered then dried overnight to give 270 mg (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.7 g of 4-aminoandrosta-4,6-dien-3,17-dione in 10.8 ml of dry pyridine are added 5.4 ml of acetic anhydride at room temperature dropwise. After 90 minutes of additional stirring, the reaction mixture is cooled to 0° C. and worked up by the addition of cold water, followed by extraction with ethyl acetate. The organic phase is separated, washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by column chromatography on silica gel. Elution with ethyl acetate:methanol 9:1 yields 2.6 g of the title compound as yellow crystals, m.p. 235°-236° C. (dec.);