Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:33]([O:35]C)=O)=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])[C:33](=[O:35])[NH:2][N:3]=2)=[O:14])[CH2:11][CH2:12]1)[CH3:5]
Reactant: NN
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C(=O)OC)c(C)n(C)c3C)ccc2F)CC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.7 %

Procedure:
Hydrazine hydrate (0.028 mL, 0.38 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (55) (0.158 g, 0.34 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.049 g, 32.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.41 (1H, m), 1.72 (1H, m), 1.86 (1H, m), 2.29 (3H, s), 2.60 (3H, s), 3.05 (1H, m), 3.28 (3H, s), 3.46 (2H, m), 3.53 (3H, s), 3.96 (1H, m), 4.12 (2H, s), 7.16-7.28 (3H, m), 11.17 (1H, s); m/z (LC-MS, ESI+), RT=1.78 min (M+H=441.11).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7]C1C=CC=C2C=1/C(=C/C1NC=CC=1OC)/C(=O)N2.[F:27][C:28]1[C:29](I)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:38]\[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7][C:29]1[C:28]([F:27])=[CH:36][CH:35]=[C:34]2[C:30]=1/[C:31](=[CH:38]/[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44])/[C:32](=[O:37])[NH:33]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) (Aldrich) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 15 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
To a solution of example 67(0.080 g, 0.156 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 0.8 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.035 g, 45% yield). MP: 235-237° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.17(s,1H), 8.20(s, 1H), 8.06(dd, J=8.2,1.6 Hz, 1H), 7.80(m,1H), 7.51(m,2H), 7.38(q, J=7.8 Hz, 1H), 7.17-7.07(m,3H), 6.84(t, J=1.7 Hz, 1H), 6.81(td, J=79.3,2.1 Hz, 1H), 6.66(td, J=10.2,2.2 Hz, 1H), 5.53(s,2H). Mass: 497.87(M+).
Reaction SMILES: C([O:4][CH:5]([C:33]1[N:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:36]=[N:35][CH:34]=1)[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C.C(NC1(C2C=CC=CC=2)CCNCC1)(=O)C.C(OC(C1N(C2C=CC=CC=2)N=NC=1)C(C1C=CC(Cl)=C(Cl)C=1)CC=O)(=O)C>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:6]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH:5]([C:33]2[N:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:36]=[N:35][CH:34]=2)[OH:4])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(OC(C)=O)c2cnnn2-c2ccccc2)CC1
Agent: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: CC(=O)OC(c1cnnn1-c1ccccc1)C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(O)c2cnnn2-c2ccccc2)CC1

Procedure:
5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole. Using a procedure similar to that described in Example 7, except using 4-acetamido-4-phenylpiperidine as the amine component, and 5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole as the aldehyde component, the coupling product was prepared as a white foam (61%); NMR: 7.75 (s,1), 7.50-7.01 (m,10), 6.79 (d,1), 6.53 (dd,1), 5.94 (d,1), 5.41 (s,H), 3.03 (m,1), 2.65-2.45 (m,2), 2.33 (m,2), 2.16 (s,3), 2.10-1.98 (m,6), 1.97 (s,3), 1.65 (broad m,2).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[CH2:13]([S:20][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: SCc1ccccc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CSc2nccs2)cc1
Yield: 85 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-bromothiazole (700 mg, 4.2 mmol), K2CO3 (884 mg, 6.4 mmol), benzylmercaptan (795 ml 6.4 mmol) in DMSO (6 ml) at 150° C. for 4 h in sealed tube gave the title compound (740 mg, 83%) after purification by column chromatography with n-hexane/EtOAc (98:2) as the eluent.
Reaction SMILES: NN.CO[C:5]([S:7][Cl:8])=O.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[ClH:8].[NH2:11][CH2:10][CH:15]=[CH:14][CH2:5][S:7][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Sc1ccccn1
Reactant: COC(=O)SCl
Agent: NN
Product: Cl
Product: NCC=CCSSc1ccccn1

Procedure:
In yet another preferred embodiment, a novel thiosemicarbazide bifunctional compound was formed (FIG. 4). In this embodiment, potassium phthalimide was reacted with 1,4-dibromo-2-butene to form 1-bromo-4-(N-phtalimido)-2butene. This compound was reacted with potassium thioacetate to form 1-(acetylthio)-4-(N-phthalimido)-2-butene which was then reacted with hydrazine and was treated with methoxycarbonylsulfenyl chloride followed by 2-mercaptopyridine to form 1-amino-4-[(2-pyridinyl)dithio]-2-butene hydrochloride. This compound was combined with TEA followed by di-2-pyridyl thionocarbonate, then t-butyl carbazate was added to form the t-boc derivative of N-[4-[(2-pyridinyl)dithio]-2-butenyl]-hydrazinecarbothioamide, compound 12. This compound was dissolved in TFA to form a compound in the form of a gum, which was then reacted with adriamycin hydrochloride and TFA to form the thiosemicarbazone derivative of ADM having a thiosemicarbazone bond at the C-13 position of the ADM (compound 3, FIG. 1) and having a reactive pyridinyldithio moiety.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[Cl:11][C:12]([Cl:16])([Cl:15])[C:13]#[N:14]>>[C:3](/[C:2](=[C:13](/[NH2:14])\[C:12]([Cl:16])([Cl:15])[Cl:11])/[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Product: CCOC(=O)/C(C(C)=O)=C(\N)C(Cl)(Cl)Cl
Temperature: 50 °C

Procedure:
to 130.14 g (1.00 mole) of ethyl acetoacetate was added 1.5 g of sodium. The reaction temperature increased spontaneously to 50° C. The reaction mixture was cooled with an ice bath. To the cooled reaction mixture was added, with vigorous stirring at 30°-50° C., 144.3 g (1.00 mole) of trichloroacetonitrile in 30 minutes. After complete addition of the trichloroacetonitrile, the reaction mixture was cooled with a dry ice bath. No precipitate of the ethyl 2-acetyl-3-amino-4,4,4-trichlorocrotonate formed. Part of the above product was stirred with 100 ml. of concentrated 28-30% ammonium hydroxide for 2 hours. The reaction mixture was then extracted with ether. The ether solution was dried (CaSO4) and concentrated to give 180 g (82.5%) of crude ethyl 3-amino-4,4,4-trichlorocrotonate. Part of this crude material (20 g) was distilled at 0.5 mm Hg to give 11.7 g of pure product, m.p. 91°-95° C. To a cold (10° C.) solution of 21.8 g (0.0937 mole) of crude ethyl 3-amino-4,4,4-trichlorocrotonate in 15 ml. of chlorobenzene was added 13.5 g (0.103 mole) of chlorocarbonylsulfenyl chloride. The reaction temperature rose spontaneously to 35° C. after the ice water bath was removed. The reaction mixture was stirred at 65° C. for 1 hour, cooled and triturated with petroleum ether to give 10.3 g (38%) of ethyl 2,3-dihydro-2-oxo-4 -trichloromethyl-5-thiazolecarboxylate, m.p. 109°-110° C. A mixture of 14.5 g (0.05 mole) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, 10.4 g ) 0.05 mole) of phosphorus pentachloride, and 100 ml. of phosphorus oxychloride was held at reflux for 7 days. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with ice water and the aqueous mixture was extracted with ether. The ether solution was extracted with 10% sodium hyroxide, dried (CaSO4) and concentrated under reduced pressure to give 3.2 g of oil which was chromatographed on silica gel using 5% ethyl acetate-petroleum ether as eluant. The first 1.2 l. of eluant gave 2.27 g of solid which was recrystallized from petroleum ether at low temperature to give 2.13 g (13.8%) of ethyl 2-chloro-4-trichloromethyl-5-thiazolecarboxylate, m.p. 42.5°-43.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3]NCC(O)CO.C([O:13][C:14](=[O:16])[CH3:15])(=O)C.N1C=CC=CC=1.[CH3:23][C:24](N(C)C)=[O:25]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:23][C:24]([CH2:3][C:2]([CH2:15][C:14]([OH:13])=[O:16])=[O:1])=[O:25]
Reactant: OCCNCC(O)CO
Reactant: CC(=O)N(C)C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
As in Example 12, the title compound is prepared stepwise by first reacting 5-amino-2,4,6-triiodo-3-N-methylaminocarbonylbenzoyl chloride with 3-(N-2-hydroxyethyl)amino-1, 2-propanediol dissolved in DMAc in the presence of sodium carbonate. The product, 5-amino[N-(2,3,-dihydroxypropyl)-N-(2-hydroxyethyl]-2,4,6-triiodo-3-N-methylaminocarbonylbenzamide, is reacted with acetic anhydride in the presence of pyridine to produce the triacetate, [N-(2-acetoxyethyl)-N-(2,3-diacetoxypropyl)]-5-amino-,4,6-triiodo -3-N-methylaminocarbonylbenzamide. This compound is then reacted with 2,4-dibromobutryl bromide, prepared as in Example 12, Step B, and the product is then cyclized, hydrolyzed, and purified as in Example 12, Steps D and E to produce the final product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99498.5 %

Procedure:
A solution of (R)-4-benzyl-2-oxazolidinone (2 g, 0.011 mmol) in dry THF (33 mL) was cooled to −78° C. To this solution n-butyllithium (1.6 M in hexanes, 6.87 mL, 0.011 mmol) was added over a ten-minute period. Following this addition, 4-pentenoyl chloride (1.32 mL, 0.012 mmol) was added in a single portion. The reaction mixture was stirred under argon at −78° C. for 30 minutes and then warmed to room temperature. The reaction progress was monitored by TLC (˜1 h). The reaction mixture was quenched with saturated aqueous ammonium chloride (60 mL) and the product was extracted with dichloromethane (2×80 mL). The combined organic layers were washed successively with 1 N sodium hydroxide and brine, dried over Na2SO4, and filtered. The solution was concentrated in vacuo and the residue was cooled at 4° C. overnight. The resulting solid was triturated using cold hexanes and dried to give a white solid, 1a (2.838 g, 99%). 1H NMR (CDCl3, 500 MHz): δ 7.33-7.37 (m, 1H), 7.28-7.32 (m, 1H), 7.20-7.24 (m, 1H), 5.84-5.96 (m, 1H), 5.13 (dd, J=17.1, 1.5 Hz, 1H), 5.05 (dd, J=10.3, 1.0 Hz, 1H), 4.69 (ddd, 1H), 4.15-4.25 (m, 1H), 3.31 (dd, J=13.2, 3.4 Hz, 1H), 2.99-3.16 (m, 1H), 2.77 (dd, J=13.2, 9.8 Hz, 1H), 2.44-2.51 ppm (m, 1H). 13C NMR (126 MHz, CDCl3): δ 172.8, 136.9, 135.5, 129.6, 129.2, 127.6, 116.0, 110.0, 66.4, 55.4, 38.2, 35.0, 28.4. HRMS calcd for C15H17NO3 (M+H) m/z 260.1286, found 260.1277.
Reaction SMILES: O=[CH:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[CH:14]([NH:13][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[CH2:15][OH:16]
Reactant: NC(CO)C(F)(F)F
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CNC(CO)C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (3.15 g, 18.18 mmol), and DCM (91 ml) was added 2-amino-3,3,3-trifluoropropan-1-ol (2.230 g, 17.28 mmol). Stirred at ambient temperature for 10 minutes and then added sodium triacetoxyborohydride (5.78 g, 27.3 mmol). The mixture was stirred overnight. The reaction was diluted with DCM and then washed with 1 N NaOH, brine dried over MgSO4, filtered and the solvent removed to provide 4.0 grams of tert-butyl ((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamate as a colorless oil that was used without further purification. LRMS m/z (M+H)+ 287.3 found, 287.3 required.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[C:25]([C:29]1[CH:30]=[C:31]([CH3:37])[C:32](=[C:34]([CH3:36])[CH3:35])[CH:33]=1)([CH3:28])([CH3:27])[CH3:26]>C1COCC1.O>[C:25]([C:29]1[CH:30]=[C:31]([CH3:37])[CH:32]([C:34]([C:12]2[C:24]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)([CH3:36])[CH3:35])[CH:33]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(C)C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(C)(C)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.2 %

Procedure:
In a nitrogen atmosphere, a hexane solution of n-butyllithium (40 ml, 61.6 mmol) was added dropwise to a solution of fluorene (10.1 g, 60.8 mmol) in THF (300 ml) with ice cooling. The mixture was stirred at room temperature for 5 hours (resulting in a dark brown solution). The solution was ice cooled again, and a solution of 3-tert-butyl-1,6,6-trimethylfulvene (11.7 g, 66.5 mmol) in THF (300 ml) was added thereto dropwise in a nitrogen atmosphere. The reaction solution was stirred at room temperature for 14 hours. The resultant brown solution was ice cooled, and water (200 ml) was added. The obtained solution was extracted with diethyl ether. Then the organic phase was separated therefrom, and dried over magnesium sulfate. The organic phase was filtered, and the solvent was removed from the filtrate under reduced pressure, resulting in an orange-brown oil. The oil was purified by silica gel column chromatography (developing solvent: hexane) to give 3.8 g of a yellow oil. The analytical data are given below.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:9]([NH:1][C@@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC[C@@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC[C@@H](C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
A sample of 0.65 mL (4.4 mmol) of (R)-(−)-2-aminoheptane (R-44) 0.44 mL (4.4 mmol) of benzaldehyde and 0.1 mL of HOAc were combined in 40 mL of CH2Cl2 and then cooled to 0° C. To the reaction mixture was added 2.75 mg (13 mmol) of sodium triacetoxyborohydride in one portion, which was stirred under argon at room temperature for 28 hours. The reaction mixture was diluted with 30 mL of CH2Cl2, cooled in an ice bath and 80 mL of 5% NaOH (in water) was added. Fractions were separated, organics (Na2SO4) dried and evaporated to 638 mg (71%) of (R)-15. 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.08 (d, 3H J=6.6 Hz), 1.20-1.39 (m, 6H), 1.41-1.67 (m, 2H), 3.62-3.77 (m, 1H), 3.75 (p, 2H, J=12 Hz), 7.17-7.41 (m, 5H); MS (APCI+) m/z (rel): 206 (100); [α]D=+6.9° (c=1.0, MeOH).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:26])[CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)O)[CH3:3].S(Cl)([Cl:33])=O>C(#N)C>[ClH:33].[Cl:1][CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)[CH:11]([NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=1[O:4][CH2:2][CH3:3])[CH3:26]
Reactant: CCOc1ccccc1OCCNC(C)C(O)c1ccc(OC)c(S(N)(=O)=O)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: CCOc1ccccc1OCCNC(C)C(Cl)c1ccc(OC)c(S(N)(=O)=O)c1
Reaction time: 48 h
Yield: 84.8 %

Procedure:
In 1,000 ml of acetonitrile was suspended 17 g of 5-{2-[2-(2-ethoxyphenoxy)ethylamino]-1-hydroxy-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride and while stirring the suspension, 9 g of thionyl chloride was added dropwise to the suspension at room temperature, whereby the product first dissolved and then began to crystallize gradually. After stirring the mixture for two days, the crystals formed were recovered by filtration, washed with chloroform and dried to provide 15 g of 5-{1-chloro-2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])([CH2:9][N:10]=[N+]=[N-])[CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:13][O:14][S:15]([CH3:18])(=[O:16])=[O:17])([CH2:9][NH2:10])[CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5]1
Reactant: CON=C1CN(Cc2ccccc2)CC1(CN=[N+]=[N-])COS(C)(=O)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CON=C1CN(Cc2ccccc2)CC1(CN)COS(C)(=O)=O
Yield: 86.1 %

Procedure:
10 g of 1-benzyl-4-methanesulfonyloxymethyl-4-azidomethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 100 ml of ethyl acetate and thereto 5 ml of 50% Raney nickel slurry was added and the resulting mixture was stirred for 3 hours under the pressure of hydrogen. The reaction mixture was filtered and concentrated under the reduced pressure to give 8.0 g of 1-benzyl-4-methanesulfonyloxymethyl-4-aminomethyl-pyrrolidine-3-one-O-methyloxime(yield: 86%). The obtained compound was dissolved in 200 ml of acetonitrile and thereto 3.9 ml of 1,8-diazabicyclo[5,4.0]undec-7-ene was dropped, and the resulting mixture was stirred for 8 hours, concentrated under the reduce pressure, and dissolved in 150 ml of dichloromethane, washed with 100 ml of water and with 100 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 4.0 g of 6-benzyl-2,6-diazaspiro[3,4]octane-8-one-O-methyloxime(yield: 69.3%). The obtained compound and 2.5 ml of triethylamine were dissolved in 50 ml of dichloromethane and thereto 3.9 g of di-t-butyldicarbonate. The resulting mixture was stirred for 4 hours, washed with 50 ml of water, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The concentrated residue was purified by silicagel column chromatography(ethylacetate:normal hexane:dichloromethane=3:5:1) to live 4.6 g of the titled compound(yield: 80.9%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OCC)(=O)C.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(CNC(C)=O)OC
Reaction time: 1 h

Procedure:
8.2 mL of acetyl chloride were added to a solution of 150 ml of ethyl acetate, 11.2 mL of 2,2-dimethoxyethanamine and 21 mL of triethyl amine at room temperature. After 1 hour, 1.5 mL of ethanol were added. The resulting suspension was stirred for a further hour, and then filtered. Ethyl acetate was removed by evaporation from the filtration liquors yielding the title compound as an oil, which was used without further purifications . H1-NMR (DMSOd6), δ ppm: 7.85 (s broad, 1H); 4.30 (t; 1H); 3.25 (s, 6H); 3.10 (t, 2H); 1.80 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:13]([N:12]1[C:11](=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCn1c(CCl)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(COc2ccc(C=O)cc2)nc2ccccc2c1=O
Yield: 87.6 %

Procedure:
The title compound (4.24 g, 88%) was prepared from 2-chloromethyl-3-ethyl-4-oxo-3,4-dihydroquinazoline (3.5 g, 15.7 mmol) and 4-hydroxybenzaldehyde (2.10 g, 17.21 mmol) in the presence of K2CO3 (2.38 g, 17.26 mmol) as base by a similar procedure to that described in preparation 13.