Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:22]([F:25])([F:24])[F:23])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
After adding 5.85 g of toluene to 1.95 g (4.81 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile, 1.14 g (9.62 mmol) of thionyl chloride and 0.76 g (9.62 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of toluene and 10 ml of water. After washing the toluene phase with an aqueous solution of 0.39 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.59 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile (yield 85.2%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[CH:22]=[CH:23][S:24][C:20]=3[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]2[CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:25][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[S:24][CH:23]=[CH:22][C:21]=2[N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3C2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC1c2ccccc2-c2sccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 158.5 %

Procedure:
A solution of 4-[(4-methoxyphenyl)sulfonyl]-5-methyl-4,5-dihydrothieno[3,2-c]isoquinoline (0.45 g, 1.2 mmol) and tetrabutylammonium iodide (1.33 g, 3.6 mmol) in dry methylene chloride (9 mL) was treated dropwise with a solution of boron trichloride in methylene chloride (1.0 M, 3.6 mL, 3.6 mmol) at −78° C. during ca. 5 min. After a further 5 min., the solution was warmed to 23° C. After 16 h the reaction solution was concentrated in vacuo and the residue was taken up in ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (25 mL) and water (10×25 mL), dried (MgSO4), and concentrated in vacuo to give a dark, oily solid (0.68 g) which was suspended in 20% ethyl acetate-hexane and slurried onto a column of silica gel (10 g). Flash chromatography eluting 20-, and then 30% ethyl acetate-hexane gave the product (0.35 g) as a yellow solid. Recrystallization from hot ethyl acetate-hexane gave the title compound (0.28 g, 65%, m.p. 163-65° C.) as shiny white needles.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[Br:14][C:15]1[C:23]2[CH:22]=[C:21]([S:24]([O-:26])=[O:25])[O:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.[Li+].BrC1C=CC2C=C(S([O-])=O)OC=2C=1.[Li+].[Cl:42]N1C(=O)CCC1=O>CCOCC.C1CCCCC1.ClCCl>[Br:14][C:15]1[C:23]2[CH:22]=[C:21]([S:24]([Cl:42])(=[O:26])=[O:25])[O:20][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S([O-])c1cc2c(Br)cccc2o1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])c1cc2ccc(Br)cc2o1
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc2c(Br)cccc2o1
Reaction time: 0.5 h

Procedure:
To a solution of the mixture obtained in Step 2 (100 g) in anhydrous ether (430 ml) was added dropwise 1.5 M lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (430 ml) under nitrogen atmosphere at -70° C. After stirring for 30 minutes, into the solution was bubbled sulfur dioxide for 1 hour with stirring at -60° C. Then the solution was stirred for 3 hours at room temperature and the formed precipitate was separated by filtration to give a mixture of lithium 4-bromobenzo[b]furan-2-sulfinate and lithium 6-bromobenzo[b]furan-2-sulfinate. To the suspension of the products in dichloromethane (2 1) was added N-chlorosuccinimide (96 g) at -50° C. and stirred for 3 hours under ice-cooling. Insoluble matters were filtered off and dichloromethane was removed in vacuo and the residue was purified by silica gel column chromatography to give 14.1 g of the objective compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](O)([CH3:10])[CH3:9])[CH2:4][CH2:3]1.[BrH:12]>[Br-].[Zn+2].[Br-]>[Br:12][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:9]
Reactant: Br
Reactant: CC1CCC(C(C)(C)O)CC1
Agent: [Br-]
Agent: [Zn+2]
Product: CC1CCC(C(C)(C)Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-(4-Methylcyclohexyl)propan-2-ol (0.99 g, 6.39 mmol) was added to a mixture of anhydrous zinc bromide (0.72 g, 3.2 mmol) and 48% HBr (aq). The mixture was stirred at room temperature for 2 h. The mixture was then extracted with diethyl ether (2×20 ml) and the combined extracts were washed with water, dried (MgSO4 /K2CO3) and evaporated under reduced pressure to give the crude title compound as an oil (1.12 g, 80%), νmax (film) 2940, 2915, 2860, 1450, and 1370 cm-1 ; δH (60 MHz, CDCl3) 0.8-2.2 (m), 7.2 (s). Distillation from K2CO3 under reduced pressure removed the impurity resonating at δ7.2.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccccc21
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccccc21
Yield: 63.8 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (0.3 g, 0.93 mmol), piperazine (0.80 g, 9.33 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.74 mmol) in acetonitrile (15 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 0.23 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 144 mg (40%) of N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)chroman-4-amine: 1H NMR (400 MHz, CD3Cl): δ 7.63 (d, 1H), 7.31 (d, 1H), 7.28 (m, 1H), 6.91 (m, 1H), 6.85 (d, 1H), 6.47 (d, 1H), 6.42 (d, 1H), 6.21 (s, 1H), 4.80 (br s, 2H), 4.65 (m, 1H), 4.23 (m, 2H), 3.04 (m, 4H), 2.88 (s, 3H), 2.21 (m, 2H), 2.20 (br d, 1H). MS (ESI) m/z: Calculated: 387.16; Observed: 388.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].S([O-])([O-])(=O)=O.[Mg+2].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[CH:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)C=NCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture containing 16.82 g (0.101 mole) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25° is added a solution of 10.05 g (0.114 mole) of methyl glyoxalate in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature overnight (15 hours) and then is filtered and the solvents are removed in vacuo to afford the imine as a dark orange gum.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:34](OCC)(=[O:36])C>CO.CCCCCC>[F:28][CH:26]([F:27])[CH2:25][O:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([O:36][CH3:34])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CCOC(C)=O
Reactant: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(OCC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 7-chloro-5-(2,2-Difluoro-ethoxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.14 mmol), and 30% sodium methoxide-methanol (0.12 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(2,2-Difluoro-ethoxy)-7-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.96 (s, 3H), 4.22 (m, 4H), 4.73 (s, 2H), 5.94-6.32 (m, 1H), 6.45 (d, 2H), 7.17 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 417 (M)+, 399 (M−18)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.Br[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)nc1
Reactant: Fc1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(-c2c(F)cccc2F)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
In a three neck round bottle flask, to a mixture of 1,3-difluorobenzene (23.24 mmol, 2.29 ml) in THF (30 ml) at −78° C. under argon atmosphere, a solution of n-BuLi (10.2 ml) in THF (2.5M) was added. The mixture was stirred at −78° C. for 30 minutes and then it was heated to −50° C. A solution of ZnCl2 (51 ml) in THF (0.5M) was added drop wise and the mixture was stirred at this temperature for 20 minutes. A solution of 6-bromopyridin-3-amine (11.56 mmol, 2.0 g) in THF (20 ml) and Pd(PPh3)4 (1.16 mmol, 1.3 g) were added respectively and the crude mixture was heated at 40° C. overnight. The solvent was evaporated and the crude mixture was purified by reverse phase chromatography eluting with a water-MeOH/AcN system affording 0.72 g (yield 30%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:30]1([CH2:35][C:36]([OH:38])=O)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][C:36]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CC1CCCC1
Product: CN(C(=O)CC1CCCC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cyclopentylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 548.3 [M]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:2]1=2.S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([NH2:36])[N:30]=2)=[CH:25][C:24]=1[CH3:37].C(N(CC)CC)C>ClCCl.CN(C=O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([NH:36][C:31]4[N:30]=[C:29]([C:26]5[CH:27]=[N:28][C:23]([O:22][CH3:21])=[C:24]([CH3:37])[CH:25]=5)[C:34]([CH3:35])=[CH:33][CH:32]=4)=[O:16])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:2]1=2
Reactant: COc1ncc(-c2nc(N)ccc2C)cc1C
Reactant: O=C(O)C1(c2ccc3c(c2)OCCO3)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCCO5)CC3)ccc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)cyclopropanecarboxylic acid (44.04 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride (14.6 μL, 0.20 mmol) followed by DMF (1 drop) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by rotovap. Toluene (˜1 mL) was added and mixed with the residue and then removed by rotovap. The toluene step was repeated once more and then the residue was placed under high vacuum for 10 minutes. It was then dissolved in dichloromethane (1 mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (46 mg, 0.20 mmol) and triethylamine (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added. The reaction was stirred at room temperature for 12 hours. The reaction was then concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (10-99% CH3CN in water) to yield 16 mg of the product. ESI-MS m/z calc. 431.2. found 432.5 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:15]([C:14]#[N:18])[C:16]#[N:17])[CH2:8][CH2:7]2
Reactant: N#CCC#N
Reactant: COc1ccc2c(c1F)C(=O)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Temperature: 140 °C
Yield: 27.6 %

Procedure:
To a solution of 38.1 (740 mg, 4.13 mmol) and malononitrile (0.275 mL, 4.96 mmol) in toluene (10.0 mL), was added ammonium acetate (79.6 mg, 1.03 mmol) followed by acetic acid (0.284 mL, 4.96 mmol). The resulting mixture was heated at reflux at 140° C. with a Dean-Stark trap for 18 hours. The reaction was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography to yield 38.2 (260 mg, 27% yield). MS ESI (neg.) m/e: 227.1 (M−H)−.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:19]1(=[O:23])[CH2:22][CH2:21][CH2:20]1.CCOC(C)=O>C1COCC1.CCCCCC.CCOC(C)=O.O>[OH:23][C:19]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([OH:18])=[O:17])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)C(c1ccccc1)C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a dried 250 mL round bottom flask containing 2 M lithium diisopropyl amide in THF (2 eq.) in THF (60 mL) at 0° C., was added phenyl acetic acid (1.0 g, 7.35 mmol, 1 eq). The resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to −78° C. and a mixture of cyclobutanone (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.617 g, 8.82 mmol, 1.2 eq.) in THF (20 mL) was added dropwise. The resulting mixture was then stirred at −78° C. and then at ambient temperature for 3 hours. Reaction progress was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was poured into an EtOAc/water mixture and the aqueous layer was extracted with EtOAc. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with DCM. The DCM solution was washed with brine and concentrated. The residue was purified by column chromatography using silica gel eluting with 15% EtOAc in hexane to yield 2-(1-hydroxycyclobutyl)-2-phenylacetic acid (1.1 g, 73%). 1H NMR (300 MHz, CDCl3) δ: 7.42-7.26 (m, 5H), 3.88 (s, 1H), 2.24-2.19 (m, 2H), 2.10-2.05 (m, 2H), 1.93-1.87 (m, 3H). m/z (ESI) 189 (M+H)+ (-Dehydroxy mass observed).
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[C:30]#[N:31])[NH2:26])#[N:22]>ClC1C2C(=CC=CC=2)C=CC=1>[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[C:30]#[N:31])[NH:26][C:4]1[C:3]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[C:23]([C:21]#[N:22])[CH:24]=2)=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18])#[N:22]
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: N#Cc1ccc(N)cc1C#N
Solvent: Clc1cccc2ccccc12
Product: N#Cc1ccc(Nc2c(F)c3c(c(F)c2Nc2ccc(C#N)c(C#N)c2)C(=O)c2ccccc2C3=O)cc1C#N
Reaction time: 9 h
Yield: 78.5 %

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone, 35 g of 3,4-dicyanoaniline and 60 ml of α-chloronaphthalene were charged in a 200 cc, four necked flask and then the reaction was carried out at 180° C. for about 9 hours. After completion of reaction, 3,4-dicyanoaniline and α-chloronaphthalene were distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 2.95 g of 2,3-bis(3,4-dicyanoanilino)-1,4-difluoroanthraquinone (Dye 26') (yield 78.5 mol %). The physical properties of Dye 26' and analytical values defining the compound are tabulated in Table 23. Its UV spectral is shown in FIG. 6.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:23][CH2:24][OH:25])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[C:26]1([NH:33][C:20]([C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11]([C:8]4[CH:7]=[CH:6][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:23][CH2:24][OH:25])=[CH:10][CH:9]=4)=[N:12][C:13]=3[CH:19]=2)=[O:22])[CH:31]=[CH:30][C:29]([NH:32][C:20]([C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11]([C:8]4[CH:7]=[CH:6][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:23][CH2:24][OH:25])=[CH:10][CH:9]=4)=[N:12][C:13]=3[CH:19]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Reactant: Nc1ccc(N)cc1
Product: O=C(Nc1ccc(NC(=O)c2ccc3[nH]c(-c4ccc(N(CCO)CCO)cc4)nc3c2)cc1)c1ccc2[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1

Procedure:
Compound 282 was prepared according to the procedure similar to that described in Scheme V from 2-(4-di(2-hydroxyethyl)aminophenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C42H42N8O6: 755.32; found: 755.16.
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[NH:8][C:7]1=[O:25])(=O)C.[OH-].[Na+].[ClH:28]>C(O)C>[ClH:28].[SH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[NH:8][C:7]1=[O:25]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)Nc2cccnc2)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1N[C@@H](C(=O)Nc2cccnc2)CCCCCC[C@@H]1CS
Reaction time: 1.5 h

Procedure:
3-(N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino)-pyridine (0.040 g, 0.11 mmol) is dissolved in ethanol (1.0 mL). An aqueous solution of nitrogen-degassed 1N sodium hydroxide (0.33 mL, 0.33 mmol) is added, and the reaction is stirred for 90 minutes. The reaction is quenched with 1N hydrochloric acid (0.33 mL, 0.33 mmol), and the solvent is evaporated. The residue is partitioned between ethyl acetate and water, and the aqueous layer is extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The residue is dissolved in methylene chloride (5.0 mL), and anhydrous hydrochloric acid gas is bubbled through the reaction for 5 minutes. The solvent is evaporated to give 3-(N-[[trans 3-mercaptomethyl-2-oxo-1-azacylodecan-10-yl]-carbonyl]-amino)-pyridine hydrochloride, MS: M+1=322.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:19][CH:18]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC2CC2)s1
Yield: 80 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (66 mg, 80%) which was obtained as an off white solid MS: m/e=355.2 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].OS(O)(=O)=O.[CH3:12][CH:13]1[CH:38]2[O:39][C:37]2([CH3:40])[CH:36]([O:41]C(CC(C)C)=O)[CH2:35][C:33](=[O:34])[N:32]([CH3:48])[C:25]2=[C:26]([Cl:31])[C:27]([O:29][CH3:30])=[CH:28][C:23](=[CH:24]2)[CH2:22][C:21]([CH3:49])=[CH:20][CH:19]=[CH:18][CH:17]([O:50][CH3:51])[C:16]2([OH:56])[NH:52][C:53]([O:55][CH:14]1[CH2:15]2)=[O:54]>O1CCCC1.O>[CH3:12][CH:13]1[CH:38]2[O:39][C:37]2([CH3:40])[CH:36]([OH:41])[CH2:35][C:33](=[O:34])[N:32]([CH3:48])[C:25]2=[C:26]([Cl:31])[C:27]([O:29][CH3:30])=[CH:28][C:23](=[CH:24]2)[CH2:22][C:21]([CH3:49])=[CH:20][CH:19]=[CH:18][CH:17]([O:50][CH3:51])[C:16]2([OH:56])[NH:52][C:53]([O:55][CH:14]1[CH2:15]2)=[O:54]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(OC(=O)CC(C)C)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)CC(OC(=O)CC(C)C)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
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: -5 °C
Reaction time: 2 h

Procedure:
In 1 ml of tetrahydrofuran was dissolved 15 mg of the Antibiotic C-15003 crystals obtained in Example 31 and the solution was cooled to -5° C. Following the addition of 12 mg of lithium aluminum hydride, the mixture was allowed to stand for 2 hours. Then, after the addition of 0.5 m of 1% H2SO4 in water, the reaction mixture was extracted with 2 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried by the addition of anhydrous sodium sulfate and concentrated under reduced pressure. Preparative TLC was carried out on silica gel with ethyl acetate/methanol=19/1 and the absorbing zone in the neighborhood of Rf 0.25 to 0.3 was scraped off, extracted with ethyl acetate containing a small amount of water, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crystals were recovered by filtration and dried. By the above procedure was obtained 10 mg of maytansinol, m.p. 174° C.