Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([N:18]([CH3:20])[CH3:19])[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[Cl:9].N.[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:2].[CH2:22]([C:12]1([OH:17])[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH:10]([C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1)[N:18]([CH3:20])[CH3:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.1 %

Procedure:
The base was freed from 3.5 g (10.4 mmole) of the hydrochloride of 2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 10 ml of ammonia solution (25 vol. %), extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 3.0 g (10.0 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling with an ice bath to 6.0 ml (12.0 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.05 g of crude base (77.9% of theory) were obtained, from which 2.88 g of 1-benzyl-2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride (67.1% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 200° C.
Reaction SMILES: C(OC(=O)[N:5]([CH2:29][CH:30](OC)OC)[CH:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:18]([O:27][CH3:28])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)C.Cl.[C:37]([O:40][CH2:41][CH3:42])(=[O:39])C.CCCCCC>CC(C)=O.O>[CH2:41]([O:40][C:37]([N:5]1[CH:29]=[CH:30][C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=2)[CH:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:39])[CH3:42]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1cccc(OC)c1)c1ccc(OCCCO)c(OC)c1
Agent: Cl
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
To a stirred solution of crude (2,2-dimethoxy-ethyl)-[1-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-2-(3-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester in acetone (30 mL) was added 6N hydrochloric acid (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with water. The solvent was evaporated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (130, 32% yield in two steps) as a colorless oil.
Reaction SMILES: N([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[N:5]([CH3:7])[CH3:6])=O.C[N:13](C)C1C=CC=CC=1.N([O-])=O.[ClH:24]>>[NH2:13][C:10]1[CH:9]=[CH:8][C:4]([N:5]([CH3:7])[CH3:6])=[CH:3][CH:11]=1.[ClH:24]
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccccc1N=O
Agent: Cl
Agent: O=N[O-]
Product: CN(C)c1ccc(N)cc1

Procedure:
In step (a), nitrosodimethylaniline is prepared from dimethylaniline by treatment with nitrite (NaNO2) in aqueous acid (HCl) solution. In step (b), the nitroso compound is reduced to form p-aminodimethylaniline in aqueous acid (HCl) solution using zinc dust solution. In steps (c), (d), and (e), the p-aminodimethylaniline is oxidized in aqueous acid solution with another molecule of dimethylaniline, and simultaneously a thiosulfonic acid group is introduced; the ring is then closed using manganese dioxide or copper sulfate. More specifically, a clear neutral solution of p-aminodimethylaniline is acidified (H2SO4), and a non-reducing zinc chloride solution is added (ZnCl2 with Na2Cr2O7). Aluminium thiosulfate (Al2(S2O3)3) and sodium thiosulfate (Na2S2O3) are added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated and aerated. Dimethylaniline is added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated, and becomes dark greenish-blue in colour due to the formation of the thiosulfonic acid of Bindschedler green. Manganese dioxide or copper sulfate is added, and the mixture heated, and the dye precipitates from the concentrated zinc chloride solution.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C4C=CC=C5C(NC(=O)C=45)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.[NH2:31]N.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CO.C(O)C.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c(CCN3CCC(c4noc5cc(F)ccc45)CC3)cccc21
Reactant: NN
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: NCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimide (4.6 in, 11.7 mmol) and hydrazine monohydrate (1.17 gm, 23.4 mmol) in methanol (50 ml) was heated at reflux overnight. At the end of the reaction, methanol was removed to leave a crude solid. This was stirred with water (150 ml) and acidified with HCl to pH=2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH then extracted with DCM (2×250 ml). The DCM solution was washed with brine and dried over MgSO4. The solvent was removed to produce a colorless oil: 2.12 gm. This oil was treated with a solution of fumaric acid (935 mg, 1.0 eq) in ethanol. The salt crystallized out: 0.99 gm, 203°-205° C. A second crop of 0.73 in (m.p.=198°-200° C.) was collected later.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCC.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][N:17]=1.[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[F:9])=[CH:18][N:17]=1
Reactant: Fc1cccc(Br)c1F
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (0.114 g, 0.746 mmol) in 3 ml of dry THF was added, at −78° C., n-butyl lithium (1.6 M in hexane, 0.47 ml, 0.749 mmol). The reaction mixture was stirred at this temperature for 1 hour. A solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (0.13 g, 0.68 mmol) in 5 ml of THF was added and the reaction mixture was allowed to warm to RT and stir for 6 hours. Saturated NH4Cl was added and the mixture was extracted with CH2Cl2 (3×10 ml). The organic layers were combined, washed with brine, and dried over NaSO4. The solvents were removed in vacuo and the residue was purified by column chromatography (Hex/AcOEt 9:1) to give 130 mg (77%) of an oily product. IR, NMR.
Reaction SMILES: [CH:1]1([NH:4][S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[CH:1]1([N:4]([S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)NC1CC1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCS(=O)(=O)N(CCOC(C)=O)C1CC1
Yield: 85.2 %

Procedure:
A mixture of propane-1-sulfonic acid cyclopropyl amide (1.3 g, 8 mmol), K2CO3 (2.4 g, 14.4 mmol) and acetic acid 2-bromo-ethyl ester (9.5 g, 16 mmol) mmol) in 10 ml acetone was heated for 6 h to 120° C. in the microwave (Biotage). After cooling the mixture was filtered and the solvent evaporated to obtain 1.7 g of product as an oil which was used without further purification in the next step.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:14](=[O:46])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]4[CH2:37][CH2:36][CH:35]([N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[O:31])[CH:24]=3)=[CH:18][C:17]=2[F:45])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.O>O1CCCC1.C(O)C.[Pd]>[F:45][C:17]1[CH:18]=[C:19]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)[CH:20]=[CH:21][C:16]=1[NH:15][C:14]([C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH2:12]1)=[O:46]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (800 mg) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and ethanol (4 ml), palladium on carbon (400 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.15 MPa) for 4 hours. Water (4 ml) was added to the reaction mixture, which was filtered, and the residue was washed with a 50% aqueous ethanol (8 ml) and water (4 ml), and the filtrate was concentrated. Tetrahydrofuran (8 ml) and ethanol (8 ml) was added to the residue, which was concentrated. Tetrahydrofuran (8 ml), ethyl acetate (8 ml) and ethanol (2 ml) were added to the residue, which was concentrated. Tetrahydrofuran (8 ml) and ethanol (16 ml) were added to the residue, which was concentrated to precipitate crystals. The crystals were suspended in tetrahydrofuran (16 ml), stirred at room temperature for 40 minutes, filtered, and dried to give the title compound (550 mg) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.ClCCl.C(OCC)C>[ClH:24].[F:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (937 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (13.6 ml) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to yield 4-(4-fluoro-benzenesulfonyl)-piperazine hydrochloride salt (819 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si](C)(C)[Si](C)(C)C.[Li].[NH3:39]>C1COCC1.CO.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH2:39])[CH:3]=2)[NH:7][CH:6]=1
Reactant: N
Reactant: CN(C)CCCc1c[nH]c2ccc(Br)cc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCc1c[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an argon purged vial fitted with a magnetic stirbar and containing 54 (324 mg, 1.15 mmol) was cannulated a solution of Pd2(dba)3 (53 mg, 0.058 mmol), and Tri-t-butyl phosphine solution (0.34 mL, 10%, 0.11 mmol) in dry THF (8 mL). The flask was fitted with a condenser and a 1M solution of lithium hexamethyldisilane in THF (3.45 mL, 3.45 mmol) was added. The reaction was placed in a metal heating block and heated to reflux. The reaction was stirred at this temperature for 16 hours. TLC (10% 2M ammonia in methanol, 90% dichloromethane) revealed all starting material had reacted. The reaction was cooled to room temperature and quenched with 1M aqueous hydrogen chloride (15 mL). The acidic reaction was extracted with ethyl acetate (3×10 mL). The aqueous phase was basified with 3N sodium hydroxide (8 mL) and partitioned into ethyl acetate (3×10 mL). The organics were washed with brine, dried over magnesium sulfate, and treated with charcoal. Filtration through celite, concentration and further drying under high vacuum afforded a dark yellow oil. Purification of the product was performed using silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane) Yield: 162 mg of brown oil, compound 55 (65%). 1H NMR (CDCl3) δ 7.76 (br s, NH), 7.17-7.14 (d, 1H, J=8.4 Hz), 6.92-6.90 (dd, 2H, J=2.1, 4.5 Hz), 6.67-6.64 (dd, 1H, J=2.1, 8.4 Hz), 2.73-2.68 (t, J=7.5, 2H), 2.41-2.36 (t, J=7.5 Hz, 2H), 2.26 (s, 8 H).
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].Cl>O>[N+:1]([C:4]1[C:9]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2-fluorophenol (5.8 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was stirred for 5 hours at 130° C. To the reaction mixture was added conc. hydrochloric acid and water, and the mixture was extracted with benzene. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetic acid.
Reaction SMILES: CCC([O:5][C@@H:6]1[C@:28]2([CH3:30])[O:29][C@H:27]2[C@H:26]([CH3:31])[C@H:25]2[O:32][C:33]([NH:35][C@:23]([OH:36])([CH2:24]2)[C@H:22]([O:37][CH3:38])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:39])[CH2:17][C:15]2=[CH:16][C:11](=[C:12]([Cl:42])[C:13]([O:40][CH3:41])=[CH:14]2)[N:10]([CH3:43])[C:8](=[O:9])[CH2:7]1)=[O:34])=O>O1CCCC1>[CH3:31][CH:26]1[CH:27]2[O:29][C:28]2([CH3:30])[CH:6]([OH:5])[CH2:7][C:8](=[O:9])[N:10]([CH3:43])[C:11]2=[C:12]([Cl:42])[C:13]([O:40][CH3:41])=[CH:14][C:15](=[CH:16]2)[CH2:17][C:18]([CH3:39])=[CH:19][CH:20]=[CH:21][CH:22]([O:37][CH3:38])[C:23]2([OH:36])[NH:35][C:33]([O:32][CH:25]1[CH2:24]2)=[O:34]
Reactant: CCC(=O)O[C@H]1CC(=O)N(C)c2cc(cc(OC)c2Cl)CC(C)=CC=C[C@@H](OC)[C@@]2(O)C[C@H](OC(=O)N2)[C@@H](C)[C@@H]2O[C@@]12C
Agent: CCC(=O)O[C@H]1CC(=O)N(C)c2cc(cc(OC)c2Cl)C/C(C)=C/C=C/[C@@H](OC)[C@@]2(O)C[C@H](OC(=O)N2)[C@@H](C)[C@@H]2O[C@@]12C
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: C1CCOC1
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -50 °C
Reaction time: 2 h

Procedure:
In 800 ml of dry tetrahydrofuran (THF) is dissolved 15.0 g of antibiotic Ansamitocin mixture (12% of ansamitocin P-2, 71% of P-3 and 17% of P-4) and under dry nitogen gas streams, the solution is cooled to -50° C. in a dry ice-acetone bath. Then, 13.0 g of lithium aluminum hydride (LAH) is added in a single dose and the mixture is stirred at -50° C. to -22° C. for 2 hours. Then, at -28° C., a further 3 g of LAH is added and the reaction mixture is stirred at -28° C. to -22° C. for 80 minutes. Thereafter, at -50° C., 750 ml of 2N HCl is added dropwise with caution and the reaction mixture is extracted three times with 2.6 l, 1.6 l and 0.8 l portions of ethyl acetate. The extracts are pooled, washed with a saturated aqueous solution of sodium chloride (100 ml×2) and dried (MgSO4, 250 g). The solvent is distilled off under reduced pressure and the residue (13.6 g) is chromatographed on a column of silica gel (1.2 kg), elution being carried out with ethyl acetate-water (98.5: 1.5, V/V). The eluate is collected in 400-gram fractions. Fractions 35 through 52 are pooled, the solvent distilled off and the residue dried in vacuo to obtain 7.25 g of maytansinol. Then, fractions 53 through 68 are similarly treated to obtain 1.55 g of a substantially equimolar mixture of maytansinol and dechloromaytansinol. Similarly, fractions 69 through 86 yield 0.78 g of dechloromaytansinol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>ClCCl>[CH3:14][N:15]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:4]([C:3]1[CH:7]=[C:8]([OH:13])[C:9]([O:11][CH3:12])=[CH:10][C:2]=1[Br:1])=[O:5]
Reactant: CNCCc1ccc(O)cc1
Reactant: COc1cc(Br)c(C(=O)Cl)cc1O
Solvent: ClCCl
Product: COc1cc(Br)c(C(=O)N(C)CCc2ccc(O)cc2)cc1O
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The previously prepared 2-bromo-5-hydroxy-4-methoxy benzoyl chloride (B13-Cl) in dichloromethane solution was transferred into the slurry of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine at about 5° C. and then stirred for about 0.5 hours under an atmosphere of nitrogen. The solution was concentrated under vacuum and then cooled to between 25 to 35° C. To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) and was then heated to between 25 to 35° C. The solution was stirred for about 8 hours and then the pH was adjusted to between 2 to 5 with 32% hydrochloric acid (˜0.6 Kg). The solution was concentrated and the residue was cooled to about 30° C. Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture and then cooled to about 5° C. and was then stirred for about 2 hours. The solidified product was filtered and washed twice with dichloromethane (0.663 Kg each) to provide crude N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[CH:18][C:17]=4[N:26]=[C:14]3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[NH4+:38].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCCl.C(Cl)(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[C:18]([NH2:38])[C:17]=4[N:26]=[C:14]3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc4cnc5ccccc5c4n32)cc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc4c(N)nc5ccccc5c4n32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline (0.55 g, 1.5 mmol) in 1,2-dichloroethane (15 mL) was placed in a 48 mL heavy wall glass pressure flask and treated with 3-chloroperoxybenzoic acid (0.56 g, 2.3 mmol). After 1.5 h the reaction was treated with concentrated NH4OH (5 mL, 30%); the flask was sealed and heated to 70° C. Once at temperature, p-toluenesulfonyl chloride (0.31 g, 1.7 mmol) was quickly added, the flask was resealed and heated to 75° C. After 1 h additional NH4OH (1 mL) and p-toluenesulfonyl chloride (50 mg) were added and the flask heated for another hour. After 2 h total, the flask was cooled to ambient temperature, and the reaction mixture was diluted with chloroform (15 mL) and water (10 mL). The phases were separated and the organic portion was washed with 10% Na2CO3 aqueous solution (10 mL) and water (10 mL). The combined aqueous washes were back-extracted with chloroform (20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange solid. The solid was recrystallized twice from acetonitrile to yield 0.14 g of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinolin-6-amine as tan crystals, mp 204-206° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.55-8.53 (m, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.68-7.67 (m, 2H), 7.66-7.64 (m, 2H), 7.41-7.389 (m, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.24 (s, 2H), 6.64 (d, J=2.0 Hz, 1H), 3.29 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 148.1, 147.6, 147.4, 142.8, 131.7, 131.3, 131.0, 130.9, 128.4, 127.2, 125.9, 125.5, 123.4, 122.7, 111.3, 90.8, 21.5; MS (APCI) m/z 378.06 (M+H)+; Anal. Calcd for C19H15N5O2S: C, 60.47; H, 4.01; N, 18.56. Found: C, 60.21; H, 3.84; N, 18.52.
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].C(N(CC)CC)C.Br[CH2:21][CH2:22][CH3:23].CN(C)C=O>O>[CH2:21]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH2:22][CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCON1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
A mixture of 212 g. of N-hydroxyphthalimide, 132 g. of triethylamine, 160 g. of 1-bromopropane and 500 ml. of dimethylformamide is stirred overnight. The reaction mixture is poured into 4.5 liters of water and is stirred at ice temperature for 11/2 hours. The solid is removed by filtration, washed with water and dried in vacuo to give N-propoxyphthalimide, m.p. 51°-3° C.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:12][N:13]2[C:17]([C:18](OCC)=[O:19])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]([I:28])=[N:14]2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1>[I:28][C:15]1[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]2[C:18](=[O:19])[NH:8][C:9]3([CH2:11][CH2:10]3)[CH2:12][N:13]2[N:14]=1
Reactant: CCOC(=O)c1c(I)nn(CC2(NC(=O)OC(C)(C)C)CC2)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)NC1(CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred solution of Intermediate 350A (2.1 g, 4.14 mmol) in 1,4-dioxane (10.0 mL) was added 4 M HCl in dioxane (10 mL, 41 mmol) and the resulting solution stirred at RT for 1 h. The reaction mixture was concentrated and diluted with EtOAc (50 mL) The organic layer was washed successively with water, a saturated aq. solution of NaHCO3, and brine, then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue obtained was heated in a ROTAVAPOR® at 60° C. for 5 h. The solid product was triturated with diethyl ether to afford Intermediate 350B as a pale yellow solid (1.1 g, 60%). MS(ES): m/z=362 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 6.93 (s, 1H), 4.41 (q, J=7.0 Hz, 2H), 4.26 (s, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.11-0.85 (m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[C:16]1([CH3:21])[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccccc1OC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: Cc1ccccc1OC1CCNCC1

Procedure:
By following the manipulative procedure described in Example 1(b), a solution of 8.3 g of 1-benzyl-4-(o-tolyloxy)piperidine in 100 ml. of ethanol produces a colorless oil of 4-(o-tolyloxy)piperidine.