Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-tert-butylbenzene (0.62 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 61%).
Reaction SMILES: [NH2:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH3:15])(=[O:7])=[O:6])=[S:3].Br[CH:17]([CH:23]=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[Cl:14][C:10]1[C:9]([CH3:15])=[C:8]([S:5]([NH:4][C:2]2[S:3][C:17]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:23][N:1]=2)(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CC(Br)C=O
Reactant: Cc1c(Cl)cccc1S(=O)(=O)NC(N)=S
Solvent: c1ccncc1
Product: COC(=O)Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2C)s1

Procedure:
N-(aminocarbonothioyl)-3-chloro-2-methylbenzenesulfonamide (0.4 g, 1.5 mmol) and methyl 3-bromo-4-oxobutanoate (0.3 g, 1.5 mmol), dissolved in pyridine (5 mL), were irradiated in a microwave oven for 2.5 min at 130° C. The solvent was removed under reduced pressure and the product separated from the starting materials using preparative HPLC (yield 0.2 g, 30%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(CC)c2cccc(C)c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 124.5 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.0 g) and 60% sodium hydride (120 mg) in N,N-dimethylformamide was stirred at 0° C. for 1 hour and at room temperature for 3 hours. To the resultant mixture was added dropwise ethyl bromoacetate (476 mg) under cooling at 0-5° C. in an ice-bath. The mixture was stirred for 5.5 hours under the same conditions. The reaction mixture was poured into 0.1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water twice, saturated aqueous sodium bicarbonate and brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[N:53]1([C:23]([C:22]2[CH:21]=[N:20][C:19]([C:18]#[C:17][Se:16][C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH:27][CH:26]=2)=[O:25])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: C1COCCN1
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)N3CCOCC3)cn1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 75.7 mg (0.87 mmol) of morpholine in 20 ml of THF. After purification on a column of silica (ethyl acetate 20/heptane 80), 60 mg (17%) of a colourless oil are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:11].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: Cn1c(N)nc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1c(NC(=O)OCC(Cl)(Cl)Cl)nc2ccccc21

Procedure:
To a solution of 1-methyl-1H-benzimidazol-2-amine (1.00 g, 6.79 mmol) and pyridine (0.646 ml, 8.15 mmol) in tetrahydrofuran (23 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.13 ml, 8.15 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 546 mg (24.9%) of the desired product as a solid was separated by filtration.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:19])[CH3:18]>C(#N)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:19][CH2:17][CH3:18])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CCN
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CC#N
Product: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 150 °C
Yield: 56.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.40 g, 1.30 mmol), ethanamine (70% in water, 3.0 ml, 37.8 mmol) and ACN (3.0 ml) was heated in a microwave oven at 150° C. for 20 min. The volatiles were evaporated in vacuum. The residue was chromathographed twice on a silica column using EtOAc/MeOH (2:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.2 g, 57%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/DEE (0.33 g). The salt was washed with several portions of DEE. M.p. 203° C. 1H-NMR (400 MHz, MeOH): δ 7.50 (1H, dd, J1 8, J2 1.6), δ 7.41 (1H, d, J 1.6), δ 7.31 (1H, d, J 8), δ 5.27 (1H, t, J 4.8), δ 5.04 (2H, dd, J1 49, J2 16), δ 3.11 (3H, s), δ 3.01 (2H, t, J 4.0), δ 2.77 (2H, q, J 6.8), δ 1.17 (3H, t, J 7.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14](=[O:15])[NH:54][C@H:52]([C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)[CH3:53])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)C1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.5 %

Procedure:
4-(4-Fluoro-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 g, 3.092 mmol) (commercially available) was suspended in dichloromethane (10 mL). EDC (949 mg, 4.948 mmol), HOBT (758 mg, 4.948 mmol) and triethylamine (1.6 mL, 11.442 mmol) were added at room temperature, followed by slow addition of a solution of (S-)-1-(4-fluorophenyl)ethylamine (0.50 mL, 3.711 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate, the organic layers were combined and washed with aqueous ammonium chloride solution and brine, dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography over a 70 g silica gel column with n-heptane and ethyl acetate to give 735 mg 4-(4-fluoro-phenyl)-4-[(S)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester. MS ISN (m/e): 433.7 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](CC)(CC)CC)[C:5]([O:7][CH3:8])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])#[CH:13]
Reactant: CC[Si](C#Cc1ccc(C(=O)OC)cc1C)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1ccc(C(=O)OC)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate (from the previous step) (1.0 eq.) in THF (0.2 M), was added TBAF (0.2 eq.) slowly at 0° C. Then the reaction mixture was stirred at 0° C. for 1 hour. After warmed to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give methyl 4-ethynyl-3-methylbenzoate as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[O:22])[CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:31]([NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([O:12][C:10]([N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)[N:17]([CH2:18][CH2:19][CH3:20])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:40]2[C:39]([S:36]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:37])=[O:38])=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:26][CH:25]=1)=[O:22])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCN(C(=O)Nc1ccc(I)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCN(C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
1.5 g (2.883 mmol) of 405 and 1.112 g (4.324 mmol) of 2-(t-butylamino-sulfonyl)phenylboronic acid are dissolved in 100 ml of ethylene glycol dimethyl ether, treated with 63 mg (0.086 mmol) of PdCl2(dppf) and 20.0 ml of 2N sodium carbonate solution and then stirred at 110° C. under a nitrogen atomsphere for 3 h. After customary work-up, 1.32 g (75.6%) of 406 are thus obtained as crystals having a melting point of 173-174° C.; MS(FAB)=606.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>CCCCCC>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: Oc1ccccc1
Reactant: C=C(C)c1cccc(C(=C)C)c1
Solvent: CCCCCC
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.3 %

Procedure:
A 500-ml three-neck reactor was charged with Amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and hexane (60 ml). The contents were heated up to 80° C in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and hexane (60 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid chromatography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,3-diisopropylbenzene, 29.6 g, yield 90%), the intended product, and the o,p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 2.43 g, yield 7.4%), were obtained. After completion of the same aftertreatment and purification operations using p-xylene as those in Example 1, bisphenol M was isolated (22.0 g., isolation yield 67%, purity 99.5%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27]O>>[CH2:1]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=2[CH:26]=1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSCc3ccccc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)Cc3ccccc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-(4-benzylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:46])([F:45])[S+]1C2C=CC=CC=2C2C=CC(S([O-])(=O)=O)=CC1=2>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[C:24]([C:27]([F:46])([F:45])[F:26])[C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: O=S(=O)([O-])c1ccc2c3ccccc3[s+](C(F)(F)F)c2c1
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3c(C(F)(F)F)c(N)ccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
To a stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-amino-benzimidazol-1-yl]pyrimidine (330 mg, 1 mmol, 1 eq) in DMF (2 mL) was added S-(trifluoromethyl)-dibenzothiophenium-3-sulfonate (166 mg, 0.5 mmol, 0.5 eq) and the mixture was heated to 80° C. for 7 hours. The reaction was cooled and the DMF was removed under reduced pressure. The residue was diluted with water and extracted wth CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography (eluted with 3.5% MeOH/CH2Cl2) followed by preparative thin layer chromatography (eluted 2× with 3.5% MeOH/CH2Cl2) to give 46 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.63 (3H, d, J=7 Hz), 4.32 (3H, s), 5.13 (1H, br s), 5.80 (1H, br s), 6.62 (1H, br), 6.70 (1H, d, J=5.5 Hz), 7.29 (1H, m), 7.39 (2H, t, J=7.5 Hz), 7.43 (2H, d, J=7 Hz), 7.62 (1H, br), 8.38 (1H, d, J=5.5 Hz), 8.40 (1H, br). Mass spectrum (ESI) 398.14 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@H:28]2[O:30][C@@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.Cl>CO>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: Cl
Solvent: CO
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 10 mg of Cryptophycin 1 in 1 mL dry methanol was added 10 μL methanolic HCl (obtained by treating 1.25 g thionyl chloride with 25 mL MeOH). After stirring for 4 h the solvent was removed in vacuo and the sample was left under vacuum for 12 h. Reversed-phase HPLC gave 8 mg of pure Cryptophycin 9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH2:20])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32].Cl>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCN(CCCn2c(N)nc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN1CCN(CCCn2c(NC(=O)c3ccc(Cl)c(Cl)c3)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred suspension of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-aminobenzimidazole (123 g., 0.45 mole) and anhydrous potassium carbonate (182 g., 1.35 mole), in methylene chloride (110 ml.) under nitrogen at 0° C. (ice-salt bath), was added 3,4-dichlorobenzoylchloride (113 g., 0.54 mole) at a rate sufficient to maintain the reaction temperature at 0°-3° C. The total time required for the addition was 1 hour. After stirring for 5 hours at ambient temperature, the reaction mixture was cooled to 10° C. and adjusted to pH 2 by the addition of 1N HCl. The precipitated hydrochloride salt was collected by suction filtration and then partitioned between 10% aqueous NaOH (800 ml.) and chloroform (1000 ml.). The phases were separated and the basic aqueous layer was extracted with chloroform (500 ml.). The organic layers were combined, dried (MgSo4), and evaporated in vacuo giving 1-[3-(4-methyl-1 -piperazinyl)propyl]-2-(3,4-dichlorobenzamido)benzimidazole as a pale yellow solid, m.p. 170°-172° C. Treatment with 2 equivalents of methane sulfonic acid in chloroform (500 ml.), removal of solvent and recrystallization from 1-propanol gave 136 g., (47% yield) of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-(3,4-dichlorobenzamido) benzimidazole dimesylate as a white crystalline solid, m.p. 170°-173° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: OCCCCCCCl
Product: O=C1CCN(CCCCCCO)CC1

Procedure:
1-(6-Hydroxyhexyl)-4-piperidone is prepared from 4-piperidone and 6-chloro-1-hexanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)COc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ncccn1
Reaction time: 64 h
Yield: 58.9 %

Procedure:
Ethyl 2-pyrimidinyloxyacetate (1.4 g) was dissolved in ethanol (10 ml). Sodium hydroxide (2M aq) was added and the mixture was stirred for 64 h. The solvent was evaporated and the residue was dissolved in water, filtered and the acidified with concentrated hydrochloric acid. The resulting precipitate was collected and dried to give the subtitle compound (0.698 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ncccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0269 g, 0.0584 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0202 g, 96%).
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][C:23]1C=CC=CC=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCC)(=O)C1C=CC=CC=1>>[NH2:18][C:17]1[C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][CH3:23])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCOc1cc(C(=O)O)cc(N)c1Cc1ccccc1

Procedure:
By replacing in Example 24, step A, 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid with 4-benzoyl-3-ethoxy-5-nitrobenzoic acid and following the procedure described, 5-amino-4-benzyl-3-ethoxybenzoic acid is obtained with a melting point of 165°-167° C.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2C[C@@H](C)NC2=O)=CC=1.[CH3:40][C:41]1[C:42]([N:48]2[CH2:53][CH2:52][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[C@H:66]([CH3:67])[CH2:65][N:64](CC5C=CC(OC)=CC=5)[C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:50][CH2:49]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[C:42]([N:48]2[CH2:49][CH2:50][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[C@H:66]([CH3:67])[CH2:65][NH:64][C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:52][CH2:53]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: COc1ccc(CN2C[C@@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C[C@@H](C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC[C@H]4C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and (R)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 202 and by the reaction and treatment in the same manner as in Example 426, the title compound (81 mg) was obtained via (R)-3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.