Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[NH2:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:12][CH:11]=1)=[O:6].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>O1CCCC1>[NH2:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1)=[O:6].[F:25][C:26]([F:31])([F:30])[C:27]([O-:29])=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCNC(N)=O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: NCc1ccc(CCNC(N)=O)cc1
Product: O=C([O-])C(F)(F)F
Yield: 61 %

Procedure:
Prepared analogously to Example 61e), but using tetrahydrofuran as solvent instead of dichloromethane, from 4-[2-(aminocarbonylamino)ethyl]-N-[(1,1-dimethylethoxy)carbonyl]benzenemethanamine and trifluoroacetic acid in a yield of 61% of theory. Colourless crystals, which were used in the following step without total purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:45])([CH3:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:44])([CH3:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2=O)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
To a 0° C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide in 7 ml. of tetrahydrofuran is slowly added a solution of 2.48 g. (5.0 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10 ml. of tetrahydrofuran. The resultant mixture is stirred for one hour and is then added to 250 ml. of saturated ammonium chloride-250 ml. ether. The ether phase is dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 200 g. of silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:27]=1[CH2:38][CH3:39])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].CC(OC)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:38]([C:27]1[CH:28]=[CH:29][C:30]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[CH:31][C:26]=1[CH2:25][N:9]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[C:7]([C:6]1[S:5][C:4]2[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:3]=2[C:2]=1[Cl:1])=[O:8])[CH3:39]
Reactant: CCc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
tert-Butyl carbamate 238 (40 mg, 0.06 mmol) is deprotected using Method F. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) TBME (5 mL). The resultant precipitate is isolated by filtration and dried to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[OH:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OC[C@H]1CCCC[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of (1S,2R)-2-(hydroxymethyl)cyclohexanol (0.44 g, 3.85 mmol) and N,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) in anhydrous CH2Cl2 (10 mL) was added a solution of p-toluenesulfonyl chloride (0.767 g, 4.02 mmol) in anhydrous CH2Cl2 (5 mL) under argon at room temperature. The reaction mixture was stirred at room temperature for 22 hrs and triethylamine (0.5 mL) was added. The mixture was stirred for additional 100 min, concentrated under reduced pressure, water was added and the product was extracted with EtOAc twice. Combined organic layers were washed with brine, concentrated under reduced pressure and purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to give ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield (0.732 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.76 (m, 2H), 7.42-7.47 (m, 2H), 4.60 (d, J=5.5 Hz, 1H), 4.12 (dd, J=3.1, 9.2 Hz, 1H), 3.90 (dd, J=7.2, 9.2 Hz, 1H), 3.00-3.10 (m, 1H), 2.40 (s, 3H), 1.73-1.80 (m, 1H), 1.46-1.65 (m, 3H), 1.34-1.42 (m, 1H), 0.85-1.16 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][C:4]=1[CH3:15]>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[CH:5]=1)#[CH:10]
Reactant: COc1ccc(C#C[Si](C)(C)C)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of [(4-methoxy-3-methylphenyl)ethynyl](trimethyl)silane (7.167 g) tetrahydrofuran was treated with TBAF (30 mL, 1.0 M solution in tetrahydrofuran), stirred for 1 hour and evaporated to dryness. The residue was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate and evaporated. This residue was applied on a pad of silica and eluted with hexane:ethyl acetate (4:1). The elute was evaporated to dryness to give the alkyne intermediate as a brown solid (4.77 g). The compound was characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)#[CH:11]>C1(C)C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12](/[CH:10]=[CH:11]/[B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(CN(C)C)cc1
Reactant: CC1(C)OBOC1(C)C
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(/C=C/B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 50 °C
Yield: 84.8 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.20 mL, 8.23 mmol) was added to an argon-purged solution of 1-(4-ethynylphenyl)-N,N-dimethylmethanamine (262 mg, 1.65 mmol) and HRuCl(CO)(PPh3)3 (104.1 mg, 0.11 mmol) in toluene (9.0 mL). The resulting mixture was heated at 50° C. for 12 h. The product was extracted into Et2O (250 mL), and the organic layer was washed sequentially with water (3×20 mL) and brine (20 mL), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography (silica gel, 50-100% CH2Cl2 in Et2O) gave (E)-N,N-dimethyl-1-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)methanamine (402 mg, containing 20% pinacol impurity by 1H NMR, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8 Hz, 2H), 7.4 (d, 1H), 7.28 (d, 2H), 6.16 (d, 1H), 3.42 (s, 2H), 2.24 (s, 6H), 1.32 (s, 12H); MS ESI 288.0 [M+H]+, calcd for [C17H26BNO2+H]+ 288.2.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(=O)C>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COC(=O)Cc1c(C)cccc1C
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)ccc(Br)c1C
Temperature: 15 °C
Reaction time: 2.5 h

Procedure:
At about 15° C., a solution of 3.67 kg [23 mol] of bromine in 91 of glacial acetic acid is added dropwise to a solution of 3.175 kg [17.82 mol] of methyl 2,6-dimethylphenylacetate in 18 l of glacial acetic acid. The mixture is then stirred at 15° C. for another 2.5 hours, in order to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture is poured into 170 l of ice-water and extracted twice with in each case 60 l of methylene chloride. After removal of the solvent, 4 kg of a residue remain which, according to GC/MS, comprise 81.2% of methyl 3-bromo-2,6-dimethylphenylacetate (70.9% of theory),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CO[C:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: COC1=CCCCCC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC2=CCCCCC2)c1
Yield: 72.3 %

Procedure:
The compound 1 (401 mg, 1.20 mmol) was converted to the enol ether with 1-methoxy-1-cycloheptene (1.51 g, 12.0 mmol) in the same manner as the example 7 to give the compound 7 (372 mg, 77%) as oil. Rf 0.75 (Al2O3 60-type E, 2:1 hexane -EtOAc).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>N1C=CC=CC=1>[CH3:48][S:49]([NH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1)(=[O:51])=[O:50]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N)nc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(NS(C)(=O)=O)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
To a solution of 4-(2-amino-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (90 mg) in pyridine (1 ml) was added methanesulfonyl chloride (18 mg) in ice water bath under nitrogen and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-methanesulfonylamino-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (15 mg) as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:35]([NH:34][CH2:32][CH3:33])=[O:36])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CCN=C=O
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)NCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
The product of Example 157 (42.5 mg., 0.0001 mol) stirring at 23° in dry THF (5 mL), under Ar, was treated with ethyl isocyanate (9.6 mg, 0.0001 mol) in one portion. After 30 min., the resulting red solution was stripped to dryness; taken up in methylene chloride (5 mL) and applied to a Chromatotron™ Rotor Plate (1000 u thickness); plate eluted with methylene chloride-methanol gradient (0% to 2% MeOH), to afford 30 mg (60.4%) of pure title compound. (m.p. 130′-133′). LC MS (m/e)=497 (MH+). Rt=2.04 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH:14]=[N:13]1.O>N1C=CC=CC=1>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:21]([C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[NH:12][N:13]=[CH:14]4)(=[O:23])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OC2)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.385 g, 2.07 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 1H-indazole-5-sulfonyl chloride (0.45 g, 2.07 mmol) and the resulting orange solution stirred at room temperature for 0.5 h. The reaction was warmed to 50° C. for 2 h and then the pyridine was removed under reduced pressure to afford a sticky residue. This was treated with water (40 mL) and sonicated for 5 h at 70° C. The fine precipitate that formed was collected by filtration, washed with water and dried in vacuo generating 0.402 g (59%) of the title compound as a yellowish orange solid. mp 222° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.19 (s, 1H), 8.24 (s, 2H), 7.67 (s, 2H), 7.48 (d, J=1.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 4.84 (s, 2H); MS (ESI) m/z=330 (M+1, positive); HPLC purity: 97.30% (MaxPlot 200-400 nm), 97.30% (220 nm).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.C[C@H]1CC2C=C(C)C=C([N+]([O-])=O)C=2O1>>[CH3:1][C@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1
Reactant: Cc1cc(N)c2c(c1)C[C@@H](C)O2
Agent: Cc1cc2c(c([N+](=O)[O-])c1)O[C@@H](C)C2
Product: Cc1cc(N)c2c(c1)C[C@H](C)O2

Procedure:
The title compound 5e was prepared according to the method for preparation of compound 3f of Example 3 by replacing 3e with 5d. MS-ESI (m/z): 164 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].CO.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)#[N:12]>C(OCC)(=O)C>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:21])=[CH:17][CH:18]=1)#[N:12]
Reactant: NCCC(=O)O
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)NCCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 61.3 %

Procedure:
Under a nitrogen blanket, a mixture of β-alanine (4.4 g; 49 mmoles), sodium hydroxide (2.0 g; 50 mmoles) and methanol (300 ml) was added rapidly to a suspension of 4-cyanophenylisocyanate (8.0 g; 55 mmoles) in ethyl acetate (300 ml). The mixture was stirred at 40° C. for 15 hrs and the volume was reduced to about 150 ml by distillation at reduced pressure. The solid was filtered off, washed with ethyl acetate and dried to yield 7 g of crude product. FAB-MS: MH+=232.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 5-nitro-2-phenyl-4(3H)-pyrimidinone (6 g) and phosphorus oxychloride (8.5 g) is stirred at 90° C. for four hours. After cooling, the reaction mixture is concentrated under reduced pressure, and the residue is dissolved in chloroform. To the mixture is added ice-water, and the mixture is stirred. The mixture is neutralized with 1N aqueous sodium hydroxide solution, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ethanol to give the desired compound (5.6 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>CCOCC>[ClH:1].[ClH:1].[CH2:9]([N:15]1[CH2:16][CH2:17][N:18]([CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7])[CH2:19][CH2:20]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)CCl
Reactant: CCCCCCN1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCN1CCN(CC(=O)CCCC)CC1
Product: Cl
Reaction time: 1 h

Procedure:
A solution of 8.5 g (0.07 mole) of 1-chloro-2-hexanone in 25 ml of ether was added dropwise to a mixture of 8.5 g (0.05 mole) of a n-hexyl piperazine and 10 g (0.1 mole) of triethylamine in 50 ml of ether. Addition was completed in 1 hour and the reaction mixture was stirred for 48 hours. The reaction mixture was filtered and the solvent was removed. The residue was dissolved in water, basified with 50% NaOH and extracted into toluene. The toluene was evaporated and the residue was treated with a saturated solution of HCl in isopropanol. The salt was filtered and crystallized twice from isopropanol to yield 6.2 g with a melting point of 190°-192° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C.C([Sn](=O)CCCC)CCC.CO>C1(C)C=CC=CC=1.ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([C:18]2[N:24]=[N:25][NH:26][N:19]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)N2CC(c3nn[nH]n3)C2)cc1
Temperature: 25 °C

Procedure:
1-Benzhydrylazetidine-3-carbonitrile (2.48 g, 10 mmol), trimethylsilyl azide (2.30 g, 20 mmol) and dibutyltin oxide (498 mg, 2.0 mmol) were dissolved in toluene (20 mL) and heated to reflux for 32 h. The reaction mixture was then cooled to room temperature and applied directly to ISCO system with 10% methanol in dichloromethane to give the product. 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 4H), 7.31 (m, 6H), 5.11 (s, 1H), 4.47 (m, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.91 (t, J=7.2 Hz, 2H). MS (ESI) m/z: Calculated: 291.15; Observed: 291.90 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)nn2)cc1
Temperature: 85 °C
Yield: 26.1 %

Procedure:
6-Chloro-pyridazin-3-ylamine (7 g, 54 mmol) was taken up in pyridine (54 mL) and TsCl (11.34 g, 59 mmol) was added. The solution was heated at 80-90° C. for 24 h. The solution was concentrated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine (2×50 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (ethyl acetate/hexane) afforded the title compound (4 g, 26%). 1H NMR (DMSO-d6, 300 MHz): δ 2.4 (s, 3H), 7.4 (d, 3H), 7.54 (d, 1H), 7.8 (m, 3H), 12.5 (br, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][C@H:18]2[CH2:31]SC2C=CC=CC=2)[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.O.[Ni]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:19][C@H:18]2[CH3:31])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CSc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
tert-Butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(phenylthiomethyl)cyclohexylcarbamate (150 mg) was dissolved in EtOH (2 mL) prior to the addition of Raney 2800 nickel (100 mg) in water. The reaction was heated at reflux for 12 h. After cooling to rt, the reaction was concentrated. The resulting residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-methylcyclohexylcarbamate (64 mg). MS found: (M+H)+=446.4.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=O)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C/C(=[N:56]\[OH:57])/C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:56]/[OH:57])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3

Procedure:
3, 3:17,17-Bis(ethylendioxy)-7(E)-hydroxyiminoandrostane was prepared in quantitative yield from 3,3:17,17-bis(ethylendioxy)androstane-7-one (2.20 g) by the procedure described above for the preparation of 3, 3:17,17-bis(ethylendioxy)-6(E)-hydroxyiminoandrostane (Prepn. 1). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.17 (s, 1H), 3.88-3.71 (m, 8H), 2.89 (bb, 1H), 2.23-2.05 (m, 2H), 1.89-0.97 (m, 16H), 0.90 (s, 3H), 0.80 (m, 1H), 0.77 (s, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[N:12]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]S[CH2:14][CH2:13]1.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)Cl>[O:36]=[S:34]1(=[O:38])[CH2:14][CH2:13][N:12]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH2:25]2)=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCSCC2)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCS(=O)(=O)CC2)CC1
Reaction time: 18 h

Procedure:
2.0 g of m-chloroperbenzoic acid was added to 1.0 g of tert-butyl [1-(thiomorpholine-4-carbonyl)piperidin-4-yl]carbamate in 10 ml of methylene chloride under cooling with ice-water bath. The reaction mixture was allowed to room temperature, and stirred for 18 hours. Aqueous saturated sodium thiosulfate solution was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with aqueous saturated sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting solid was washed with diisopropyl ether to obtain 607 mg of tert-butyl [1-(1,1-dioxothiomorpholine-4-carbonyl)piperidin-4-yl]carbamate.