Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19].O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:12].[F:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Nc1c[nH]c2ccccc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1cnccc1Nc1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 121.7 %

Procedure:
A solution of 3-aminoindole (7 g) and 4-chloro-3-fluoropyridine hydrochloride (13 g) in 200 mL of 1-methyl-2-pyrrolidinone was stirred at 75°-80° C. for two hours, after which additional 4-chloro-3-fluoropyridine hydrochloride (5 g) was added. After stirring a total of three hours the mixture was cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated to 20 g of a dark oil. Elution through silica gel first with dichloromethane and then with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 17 g of a dark oil. This oil was eluted through silica with ether via flash column chromatography to yield 10.6 g of a dark oil. This oil was eluted through silica with 20% ethyl acetate in dichloromethane via HPLC to yield 8 g of a dark oil. A six gram portion was converted to the hydrochloride salt in methanol/ether to yield 3.5 g of a solid, m.p. >250° C. Recrystallization from 30% methanol in ether yielded 2.7 g of crystals, m.p. 256°-258° C. (dec.).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.[NH:21]1[C:25]([CH2:26][CH2:27][O:28][CH2:29][C:30](O)=[O:31])=[CH:24][N:23]=[N:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)CC)C>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:30](=[O:31])[CH2:29][O:28][CH2:27][CH2:26][C:25]3[N:21]=[N:22][NH:23][CH:24]=3)[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: O=C(O)COCCc1cnn[nH]1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 60.4 %

Procedure:
Add N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (4.2 g, 15.8 mmol) to a mixture of 2-[2-(1H-triazol-5-yl)ethoxy]acetic acid (2.7 g, 15.8 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol), and dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.44 g, 28.4 mmol) in dichloromethane (40 mL) at 25° C. Add triethylamine (4.40 mL, 31.6 mmol) to the reaction mixture and stir for 16 h. Wash with water (2×50 mL) and concentrate the organic layer. Purify by silica gel column chromatography, eluting with ethyl acetate/methanol, to give the title compound (4.0 g, 60%) as a solid. MS (m/z): 420 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(=O)C)(=[O:19])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:19])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2ccc[n+]([O-])c2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
3-(4-Nitrophenyl)pyridine-1-oxide (P2, 2.5 g, 11.6 mmol) was stirred at reflux in acetic anhydride (25 mL) for 18 hours, then allowed to cool. The reaction mixture was concentrated and concentrated hydrochloric acid (25 mL) was added. The solution was stirred at reflux for 4 hours, then allowed to cool. The reaction mixture was poured onto ice/water and filtration followed by drying under high vacuum afforded the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[N:19]1([NH2:24])[CH:23]=[CH:22][CH:21]=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:24][N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: Nn1cccc1
Reactant: Fc1ccccc1Cn1cnc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Fc1ccccc1Cn1cnc2c(Nn3cccc3)ncnc21
Yield: 91.2 %

Procedure:
A solution of 6-chloro-9-(2-fluorobenzyl)-9H-purine (4.2 g, 16 mmole) and 1H-pyrrol-1-amine (3 g, 36 mmole) in 25 ml isopropanol was stirred at reflux for thirty minutes then was cooled, diluted with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride, was dried (anhydrous MgSO4), filtered and evaporated to 6 g of a solid. The solid was purified by flash chromatography (silica, 15% ethyl acetate in dichloromethane) to give 4.5 g of 9-(2-fluorobenzyl)-N-(1H-pyrrol-1-yl)-9H-purin-6-amine, m.p. 204°-206° C.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Na].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[H-].[Na+]>CN(C)C=O.ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:18]=[CH:17]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triisopropylsilyl chloride (6.87 g) was added to the sodium salt prepared from 5bromoindole (6.35 g) and sodium hydride (1.71 g, 50% suspension in oil) in dimethylformamide (32 ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150 ml). The crude intermediate obtained by evaporation of the dichloromethane extract was column chromatographed (silica gel, 40°-60° C. petroleum ether) to give 5-bromo-1-triisopropylsilylindole isolated as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=1.Br[CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:24]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:20][C:4]2[CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:24]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Reactant: Cc1cc(O)cc(OCc2ccc3ccccc3n2)c1
Product: CCOC(=O)COc1c(C)cccc1COc1cc(C)cc(OCc2ccc3ccccc3n2)c1

Procedure:
The title compound is prepared using essentially the same procedure used in example 35 except using 3-methyl-5-(quinolin-2-ylmethoxy)-phenol (example 55) in place of 3-(quinolin-2-ylmethoxy)-phenol and ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (example 43b) in place of (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH:26]([CH3:28])[CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)OC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)OC(C)C)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), isopropyl salicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (38 mg, yield 21%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1cc(Br)ccc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(Br)cc12
Yield: 46.1 %

Procedure:
5-Bromo-2-mercaptobenzoic acid (4.10 g, 17.6 mmol), 2-cyanopyridine (1.70 g, 16.3 mmol) and pyridine (50.0 ml) were refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected and recrystallized from hexane-chlorobenzene to give the titled compound (2.40 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH:16]1(O)[CH2:20]C[CH2:18][CH2:17]1>>[CH:1]1([O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:20]1
Reactant: OC1CCCC1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclopentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.66 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](N1C2C=CC=CC=2OCC1)=[O:4].C(Cl)Cl.ICl.S(=O)(O)[O-].[Na+].[OH2:27]>C(O)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]([O:4][C:3](=[O:4])[C:2]([F:16])([F:15])[F:1])=[O:27]
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Reactant: O
Agent: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
A mixture of 0.5 g (2.16 mmol) of this 4-(trifluoroacetyl)-3,4-dihydro-2H-1,4-benzoxazine, 20 ml of glacial acetic acid and 5 ml of methylene chloride was cooled to 10° in an ice bath. A solution of 1 ml of iodine monochloride in 1 ml of acetic acid was added slowly over a period of 5 minutes Following the addition, the mixture was stirred for 45 minutes and was then diluted with water and a aqueous solution of sodium bisulfite. The product was extracted with ether. The extracts were washed with water, dried and evaporated. Crystallization of the residue from hexane yielded colorless crystals with m.p. 78°-80°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].ClCCl.S([O-])(O)(=O)=O.[K+]>C1COCC1.[Zn]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:18])[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 27.1 %

Procedure:
To a solution of the target compound in step (2) (7.16 g, 28.5 mmol) in dichloromethane (85 mL) were added successively triethylamine (15.8 mL, 113.9 mmol) and a solution of sulfur trioxidepyridine complex (18.1 g, 113.9 mmol) in dimethylsulfoxide (85 mL). The resulting mixture was stirred at room temperature for 15 min, poured into a mixture of ice and saturated brine (300 mL), and then extracted with cold ether. The organic layer was washed successively with cold 10% aqueous citric acid solution and cold saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and hexane was added to the obtained residue to suspend same. Insolubles were collected by filtration to give 6.41 g (90%) of N-tert-butoxycarbonylphenylalaninal. To a suspension of zinc powder (5.59 g, 85.5 mmol) in THF (1 mL) was added dropwise a solution of the above-mentioned N-tert-butoxycarbonylphenylalaninal (6.41 g, 25.7 mmol) and ethyl bromodifluoroacetate (11.1 mL, 85.5 mmol) in THF (16 mL) with ultrasonication. After 3 hr of ultrasonication, dichloromethane (200 mL) and 1N aqueous potassium hydrogensulfate solution (100 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 75:25) to give 2.60 g (27%) of ethyl 4(S)-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoate as colorless crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([OH:18])[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.C1(C)C=C[C:22]([S:25](Cl)(=[O:27])=[O:26])=CC=1>N1C=CC=CC=1>[CH3:22][S:25]([O:17][CH2:16][C@@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[OH:18])(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H](O)c1cccc(Cl)c1

Procedure:
Into toluene (30 ml) were added (R)-2-(3-chlorophenyl)-2-hydroxyethanol obtained in 1) above (7 g), pyridine (8.0 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (9.3 g), and then the resulting mixture was stirred at the same temperature for 24 hours. The solid thus precipitated was filtered off, the filtrate was concentrated, and the residue was dissolved in toluene (40 ml) and then washed with dilute hydrochloric acid. The organic layer was collected by layer separation, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether and hexane to obtain a colorless oily compound mentioned above (10.6 g, 80.0%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[N:9][CH:10]=1.[CH2:26]([O:28][C:29](=[O:42])[CH2:30][C:31]1[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][NH:34][CH:35]=1)[CH3:27].O>CN(C)C=O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:34]2[CH:35]=[C:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:42])[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (575 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (575 mg, yield: 63%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].[N+](=[CH2:22])=[N-]>CCOCC>[CH3:22][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: C=[N+]=[N-]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1Nc1c(C)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of 10 g of [o-(3-chloro-o-toluidino)-phenyl]-acetic acid (M.P. 124°-125°) in 100 ml of ether are slowly added dropwise 100 ml of 2% ethereal diazomethane solution. The solution is allowed to stand for 2 hours at room temperature, and then concentrated to dryness at 40° under 11 Torr. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ml of 2 N sodium hydrogen carbonate solution and water, dried over sodium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallised from benzine. The obtained [o-(3-chloro-o-toluidino)-phenyl]-acetic acid methyl ester melts at 47°-48°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]2COS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:13]1[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:16][CH2:17][C:10]21[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11]2)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1N=[N+]=[N-]
Temperature: 60 °C

Procedure:
10 mmol of tert-butyl 2-benzyl-6-methanesulphonyloxymethyl-2,7-diazaspiro[4.5]decane-7-carboxylate are dissolved in 20 ml of N,N-dimethylformamide and the solution is admixed with 15 mmol of sodium azide. The reaction mixture is heated at 60° C. for 6 hours, then poured into water and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH3:26].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1Cl
Reactant: CN(C)CCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCCN(C)C)c(C(=O)O)c1Cl
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of Example 389B (133 mg, 0.4 mmol), 4-(N,N-dimethylamino)butylamine (346 mg, 3.0 mmol), acetonitrile (3 mL), and triethylamine (0.3 mL, 1.9 mmol) was sealed in a vial and shaken at to 80° C. for 72 hours. The mixture was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 454 (M+H)+; (ESI(−)) m/e 452 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.43 (d, 1H), 7.36 (m, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 6.61 (t, 1H), 5.78 (br s, 1H), 3.31 (br s, 2H), 3.23 (m, 2H), 3.04 (m, 2H), 2.76 (s, 6H), 2.59 (q, 2H), 1.86 (m, 2H), 1.66 (m, 2H), 1.09 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42]>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C@H:2]1[C@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH:41]([CH3:43])[CH3:42])=[O:44])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][C@@H:6]([O:33][CH3:34])[C@:5]2([OH:39])[NH:35][C:36]([O:38][C@H:3]1[CH2:4]2)=[O:37]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
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
Agent: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Reaction time: 2.5 h

Procedure:
In a mixture of 1 ml triethylamine and 50 ml of dimethylformamide was dissolved 100 mg of maytansinol and, while the solution was stirred under ice-cooling, 50 μl of isobutyryl chloride was added dropwise. The mixture was stirred under ice-cooling for 30 minutes and then, at room temperature for 2.5 hours, after which it was distilled under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, washed with water and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was chromatographed and recrystallized as in Reference Example 1. By the above procedure there was obtained 19.4 mg of Ansamitocin P-3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>ClC(Cl)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-Nitrophenol (1.61 g, 11.6 mmol) was dissolved in dichloroethane (10 ml) and aluminum chloride (2.31 g, 17.3 mmol) was slowly added in three portions. The addition of acetylchloride (0.818 ml, 11.51 mmol) was followed by stirring at 50° C. for 2 hours. The reaction was terminated with the addition of ice water (10 ml) and 2N hydrochloric acid solution (10 ml) at 0° C. The reaction mixture was extracted with dichloroethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound (Yield 78%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=O)[S:4][N:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[N:16][OH:17])[S:4][N:3]=1
Reactant: NO
Reactant: O=C(c1ccsc1)c1snc(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccsc1)c1snc(Cl)c1Cl
Yield: 110.6 %

Procedure:
A solution of (3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methanone (3.00 g, 10.2 mmol) and hydroxylamine hydrochloride (844 mg, 25.5 mmol) in pyridine (30 mL) was stirred 4 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford 1-(3,4-dichloro-1,2-thiazol-5-yl)-N-hydroxy-1-(3-thienyl)methanimine [3.15 g, yield 99%; HPLC/MS: m/z=279 (M+H); log P(HCOOH)=3.04].