Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:8]([N+]([O-])=O)[CH:7]=1)[CH:2]=[CH2:3].Cl[Sn]Cl.O.C[N:41](C=O)C>>[CH2:1]([O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[NH2:41])[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Product: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of 4-[tert-butoxycarbonyl-(4-trifluoromethoxy-benzyl)-amino]-3-nitro-benzoic acid allyl ester (4.0 mmol) were dissolved in 20 ml DMF. 2.8 g SnCl2×2 H2O (12 mmol) are added and the reaction stirred at room temperature for 16 h. The crude was filtered over Kieselgel and the solvent evaporated. MS(ISP): 467.3 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1cc(CO)ccc1Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)ccc1Sc1ccccc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-3-methyl-4-phenylthiobenzene obtained above is dissolved in methylene chloride (100 ml), and thereto is added with stirring thionyl chloride (23.34 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (100 ml×3), and thereto is added ethyl acetate (500 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (50 ml×4) and saturated aqueous sodium chloride solution (100 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-chloromethyl-3-methyl-4-phenylthiobenzene.
Reaction SMILES: [ClH:1].C(OC1C=CC=CC=1NC(NC(=N)CCCC)=O)C1C=CC=CC=1.Cl.C([O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45](=[NH:52])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[S:43])=[CH:37][CH:36]=1)C1C=CC=CC=1>>[OH:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45](=[NH:52])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[S:43])=[CH:37][CH:36]=1.[ClH:1]
Reactant: CCCCCCC(=N)NC(=S)Nc1ccc(OCc2ccccc2)cc1
Agent: CCCCC(=N)NC(=O)Nc1ccccc1OCc1ccccc1
Agent: Cl
Product: CCCCCCC(=N)NC(=S)Nc1ccc(O)cc1

Procedure:
By following a procedure similar to that described in Example 19 but substituting for 1-[2-(benzyloxy)phenyl]-3-(pentanimidoyl)urea hydrochloride an equivalent amount of 1-(4-benzyloxyphenyl)-3-(heptanimidoyl)-2-thiourea hydrochloride there is obtained 1-(4-hydroxyphenyl)-3-(heptanimidoyl)-2-thiourea and its hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].CCCCCC.Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:20][CH2:21][OH:22])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,5-dibromo-4-nitropyrazole (2) (11.0 g, 41 mmol) in DMF (52 ml) was added dropwise over 20 min to a stirred solution of NaH (1.76 g, 46 mmol; 60% dispersion in oil, prewashed with hexane under an inert atmosphere) in DMF (88 ml). After stirring for 10 minutes, a solution of 2-bromoethanol (6.4 g, 49 mmol) in DMF (14 ml) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 2 hours and then the DMF was evaporated off under reduced pressure. A mixture of DCM/water (100 ml, 1/1) is added to the residue and the organic phase is washed with water (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude brown solid obtained was subsequently purified by column chromatography (5%/95% EtOAc/hexane). The yellow solid product (3.4 g) was recrystallized from a mixture of toluene/hexane (20 ml, 55%/45%) to give the 2-(3,5-dibromo-4-nitropyrazol-1-yl)ethanol (3) in the form of a white solid (2.8 g, 22%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-]>COCCOC.CO>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 110 °C
Yield: 80 %

Procedure:
1 g (2.23 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.4 g (2.67 mM) of 4-methoxyphenylboronic acid, 1.6 g (4.46 mM) of carbonate resin and 0.02 g (0.004 mM) of [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane are mixed in 7 ml of DME and 5 ml of methanol. The reaction mixture is heated for 20 minutes at 110° C. by microwaves. It is filtered, the material on the filter is rinsed with methanol and the organic phases are concentrated. The product is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 98/2, then 70/30; v/v) to give the expected product in the form of a cream-colored powder with a yield of 80%.
Reaction SMILES: [CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(CO)cc3)C3CCCC3)c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=O)cc3)C3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.0 g (8.63 mmol) of (+/−)-tert-butyl 1-[3-({cyclopentyl[4-(hydroxymethyl)phenyl]-acetyl}amino)benzyl]cyclopropanecarboxylate in 20 ml of dichloromethane was cooled to 0° C., and 4.39 g (10.35 mmol) of Dess-Martin reagent [1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one] were added. After the addition had ended, cooling was removed and the reaction mixture was stirred at RT for 3 h. The solution was then diluted with dichloromethane and washed successively with water, saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried with magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→3:1). This gave 2.27 g of the target compound (53.2% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:27][C:28](=[O:39])[CH2:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][O:25]C)[CH:22]=3)[S:17][C:10]=12.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:27][C:28](=[O:39])[CH2:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH2:24][OH:25])[CH:22]=3)[S:17][C:10]=12
Reactant: COCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CCO)cn4)sc23)c(F)c1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a solution of 91 (85 mg, 0.156 mmol) in dry DCM (2 mL) was added, at −78° C., BBr3 (0.6 mL, 4 eq, 0.62 mmol, 1M soln in DCM) and the reaction mixture was slowly warmed to 0° C. and allowed to stir at 0° C. for 30 mins. The reaction mixture was quenched with MeOH and the solvents were removed under reduced pressure. Purification by column chromatography (Gilson, 25% MeOH in water to 75% MeOH in water) afforded title compound 89 (26 mg, 27% yield). MS (m/z): 532.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[S:22][CH:23]=[C:19]([CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[N:20]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1nc(CN2CCOCC2)cs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Brc1cnc(Nc2nc(CN3CCOCC3)cs2)c2ncnn12
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
Intermediate 3 (5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine, 140 mg, 0.50 mmol), Intermediate 6 (4-(1-morpholinomethyl) thiazol-2-ylamine, 120 mg, 0.60 mmol), sodium tert-butoxide (68 mg, 0.71 mmol), palladium dibenzylidene acetone (19 mg, 0.02 mmol) and Xantphos (23 mg, 0.04 mmol) were suspended in toluene (4 mL). The mixture is degassed with nitrogen for 5 min and then stirred at 90° C. for 16 h. The solvent is evaporated in vacuo to leave a brown residue. The residue is purified by column chromatography, eluting with 2% methanolic ammonia (7 N) in dichloromethane to give the title compound as a yellow powder (53 mg, 27%). 1H NMR (400 MHz, d6-DMSO) δ 2.53 (s, 4H, CH2CH2), 3.51 (s, 2H, CH2), 3.61 (m, 4H, CH2CH2), 6.99 (s, 1H), 8.13 (s, 1H), 8.61 (s, 1H), 8.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1ccc(O)cc1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzaldehyde (400 mg) in dichloromethane (4.00 mL) were added anhydrous magnesium sulfate (615 mg) and tert-butyl glycinate hydrochloride (679 mg), followed by stirring at room temperature overnight. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (12.0 mL), and sodium borohydride (193 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain tert-butyl N-(2-chloro-4-hydroxybenzyl)glycinate (613 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>[Pd].CO>[N:11]1([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(N2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(N2CCNCC2)c1
Yield: 98.9 %

Procedure:
A mixture of 120c (2.6 g, 8.5 mmol), p-toluene sulfonic acid (1.6 g, 8.5 mmol), 10% Pd/C (0.52 g) and MeOH (40 mL) were shaken on a Parr hydrogenation apparatus at 49 psi of H2. After TLC indicated complete reaction, the catalyst was removed by filtration through a Celite pad, and solvent was evaporated to yield a white solid (3.3 g). IR(KBr): cm-1 3416, 1724. 1H NMR(300 MHz, CDCl3): 8.70 (br, 1H), 7.51-7.28 (m, 6H), 7.12 (d, 2H, J=8 Hz), 4.10 (br, 1H), 3.85 (s, 3H), 3.41-3.24 (m, 8H), 2.29 (s, 3H). HR-MS: Calc'd. 221.1290, Found 221.1294.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Cl)[S:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:19][CH3:20])[CH3:15]
Reactant: CCOC(=O)C(Cl)SC
Reactant: Cc1cc(O)cc2cc(I)cnc12
Product: CCOC(=O)C(Oc1cc(C)c2ncc(I)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-iodo-8-methyl-quinolin-6-ol, was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-iodo-8-methyl quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester as a yellow coloured solid (MH+ 418).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:40][C:39](=[O:41])[NH:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[NH:37][N:38]=[C:39]([O:41][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:40]=2)=[CH:34][CH:35]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCC5CCN(CCS(C)(=O)=O)CC5)c(OC)cc34)n[nH]2)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (115 mg, 0.28 mol) and 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (65 mg, 0.33 mol), (prepared as described for the starting material in Example 10), in DMF (1.5 ml) containing potassium carbonate (60 mg, 0.42 mol) was heated at 100° C. for 30 minutes. After cooling, water was added. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in methylene chloride/methanol and pentane was added. The precipitate was collected by filtration, washed with pentane and dried under vacuum to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (120 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][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@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][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@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:32])[CH3:31]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=C2CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h

Procedure:
A solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.9 g, 2.34 mmole) in acetic anhydride (3mL) and pyridine (6 mL) is stirred overnight at room temperature. Water is added and the mixture is stirred for 3 hours. The solids are collected by filtration to give a brown solid which is purified by flash chromatography (hexane-50% ethyl acetate then ethyl acetate) to give 4-acetamido-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide. This compound has the following structure: ##STR6##
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH3:18])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH2:19](O)[CH2:20][CH2:21]C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: CCCCO
Reactant: COCN(C(=O)CCl)c1c(OC)cccc1OC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCOCN(C(=O)CCl)c1c(OC)cccc1OC
Temperature: 26 °C
Yield: 57 %

Procedure:
A mixture containing alpha-chloro-N-[methoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (4.0 g; 0.015 mole), 150 ml. of n-butanol and 0.2 ml. of methylsulfonic acid in 150 ml. of toluene was refluxed for 7 hours in a soxhlet extractor containing 22 g. of activated 3A molecular sieves. The reaction mixture was allowed to cool to 26° C. and was then washed with a 5% sodium carbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield a dark oil. The dark oil was distilled at 170° C. (0.05 mm) to yield alpha-chloro-N-(butoxymethyl)-N-(2,6-dimethoxyphenyl)acetamide (2.7 g; 57% yield) as a clear colorless oil having a boiling point of 170° C. at 0.05 mmHg and the following analysis:
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:5][CH3:6])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]([P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:5][CH3:6]
Reactant: CCOC(OCC)P(=O)(OCC)C(CC)CC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CC)CCN

Procedure:
73.4 g (0.264 mol) of ethyl P-(4-cyanobut-3-yl)-P-(diethoxymethyl)-phosphinate in 770 ml of dry ethanol are treated with 126 g of an 8% solution of ammonia in ethanol. Subsequently, 15 g of Raney-nickel and the resulting mixture is hydrogenated at 45° under atmospheric pressure. The catalyst is then filtered of and the filtrate is concentrated under reduced pressure. The crude product is distilled in vacuo to yield the ethyl P-(5-amino-pent-3-yl)-P-(diethoxymethyl)-phosphinate (b.p.: 100°/0.01 Torr).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=O>O.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=[N:2][OH:3]
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 140 g (2.02 mole) of hydroxylamine hydrochloride in 630 ml of water, contained in a 3-l Erlenmeyer flask, was treated with 560 ml of 10% NaOH, and a solution of 250 g (1.40 mole) of 6-methoxy-4-chromanone in 560 ml of ethanol, all with rapid stirring. The reaction mixture was heated to boiling over 15 min., and continued to boil for 5 min. The mixture was stirred rapidly at room temperature for 3 hrs., refrigerated overnight and filtered. A white crystalline solid was washed with 1-l of water and air dried for 3 days; m.p. 120°-121°, Yield: 266 g (99%).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.CCOCC>[C:1]([C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cccc2ccoc12
Temperature: 25 °C
Yield: 116.3 %

Procedure:
A solution of 0.31 g (1.22 mmol) of 7-Carbomethoxy dihydrobenzofuran and 1.66 g (3.3 mmol) of DDQ in 25 mL of toluene was heated at reflux for 7 h. The reaction mixture was then cooled to rt, diluted with ether, and washed with 3×30 mL of sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 9:1) to give 0.25 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[CH2:16][C@H:15]2[CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:35])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:23])[CH3:24])[CH3:21])[CH2:16][C@H:15]2[CH2:25][S:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:9]1=[O:35]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2C(=O)C[C@H](NC(=O)OC(C)(C)C)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2C(=O)C[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (60 mg), TFA (1 mL), and methylene chloride (3 mL) were mixed and stirred overnight at rt. The mixture was stripped and restripped from methylene chloride (3×) to yield 60 mg of an oil. LCMS detects (M+H)+=374.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)=[C:11]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:10]=1)=[O:7].[N+:35]([C:38]1[CH:43]=[CH:42]C(O)=[CH:40][CH:39]=1)([O-:37])=[O:36].[O-2].[Mg+2]>C(OCC)(=O)C>[N+:35]([C:38]1[CH:43]=[CH:42][C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]2[CH:24]=[CH:25][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:10][C:11]=2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:40][CH:39]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)Oc3ccc([N+](=O)[O-])cc3)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
Trichloromethyl 2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (50.0 g, 94.74 mmol), 4-nitrophenol (14.50 g, 1.1 eq) and magnesium oxide (1.067 mL, 1.0 eq) were taken up in 2 mL of ethyl acetate in a round bottomed flask and stirred at 22° C. for 3 hr. The magnesium oxide was filtered off. The solvent was then evaporated and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 39.1% yield. LCMS m/z (%)=532 (M+H, 100).