Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39]([C:40]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=3)=[C:41]3[C:46]=1[CH:45]=[C:44](B(O)O)[CH:43]=[CH:42]3)=[CH:38][CH:37]=[CH:36][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39]([C:40]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=3)=[C:41]3[C:46]=1[CH:45]=[C:44]([C:2]1[CH:3]=[CH:4][C:5]([N:8]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=[C:9]4[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:6][CH:7]=1)[CH:43]=[CH:42]3)=[CH:38][CH:37]=[CH:36][CH:35]=2
Reactant: OB(O)c1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3ccccc3n2-c2ccc(-c3ccc4c(-c5ccc6ccccc6c5)c5ccccc5c(-c5ccc6ccccc6c5)c4c3)cc2)cc1
Yield: 83.9 %

Procedure:
1.0 g (2.9 mmol) of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole, 1.5 g (3.2 mmol) of 9,10-di(2-naphtyl)anthracene-2-boronic acid, and 0.067 g (0.058 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 1.7 g of a greenish white solid (84% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 698 with respect to a molecular weight of 698.27.
Reaction SMILES: NC(N)=O.[CH2:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[CH2:6][CH3:7].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 49.8 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-chlorophenylisocyanate (108 mg, 0.71 mmol) were coupled to form the desired urea (148 mg, 50%). LC-MS (m/z) 418.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>O.[OH-].[Na+].CN(C=O)C>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1sc(C)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing 2,4-dimethylthiazole-5-carboxylic acid (2.50 g, 15.9 mmol) was added DCM (75 mL) and DMF (3 mL) to afford a homogeneous solution. Then, carbonyldiimidazole (2.84 g, 17.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. N,O-dimethylhydroxylamine hydrochloride (1.90 g, 19.9 mmol) was then added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with water and 1 N NaOH and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (10-40% EtOAc-DCM) provided the title compound as a colorless oil.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:44])[CH2:15][C@H:16]([C:39]1[CH:43]=[CH:42][O:41][N:40]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[O:41]1[CH:42]=[CH:43][C:39]([C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[CH2:26][CH3:27])=[CH:21][CH:22]=2)[CH2:15][C:14]([OH:44])=[O:45])=[N:40]1
Reactant: OO
Reactant: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(COc1ccc([C@H](CC(=O)O)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of the oxazolidinone (49.2) (23.0 mg, 0.038 mmol) dissolved in THF (2 mL), was added a 30% hydrogen peroxide solution (43 μL, 0.38 mmol) followed by a 2 M lithium hydroxide solution (94 μL, 0.19 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 49 (5.5 mg). MS ESI (pos.) m/e: 450.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1 H, d, J=1.6 Hz), 7.51 (2 H, d, J=8.6 Hz), 7.12 (2 H, d), 6.95 (2 H, d, J=8.6 Hz), 6.78 (2 H, d, J=8.6 Hz), 6.16 (1 H, d, J=1.6 Hz), 4.44 (1 H, t, J=7.8 Hz), 4.02 (2 H, t, J=6.1 Hz), 3.94 (2 H, t, J=6.1 Hz), 3.09 (1 H, dd, J=16.6, 8.4 Hz), 2.84 (1 H, dd, J=16.4, 7.4 Hz), 1.81-1.84 (4 H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=1.B([C:29]1[CH:40]=[CH:39][C:32]([CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[CH:31][CH:30]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:35][C@@H:34]([CH2:33][C:32]1[CH:39]=[CH:40][C:29]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=2)=[CH:30][CH:31]=1)[C:36]([OH:38])=[O:37]
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 17.8 %

Procedure:
In a microwave vial, 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (30 mg, 0.081 mmol), 4-borono-L-phenylalanine (20 mg, 0.098 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 7.2 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.96(m, 3H), 7.61(m, 5H), 6.81(s,1H), 6.77(d, J=6.8 Hz, 1H), 6.74(d, J=4.8 Hz, 1H), 4.27(q, J=5.6 Hz, 1H), 3.36(m, 1H), 3.21(m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:18]=[C:19]=S)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([NH:18][C:19]2[NH:1][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[S:9](=[O:11])(=[O:10])[N:12]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cc(F)ccc1S(N)(=O)=O
Reactant: S=C=NC1CCCC1
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NC2CCCC2)Nc2cc(F)ccc21
Temperature: 140 °C
Yield: 23.2 %

Procedure:
A mixture of 2-amino-4-fluorobenzenesulfonamide (1.71 g, 9 mmol) and cyclopentyl isothiocyanate (4.6 ml, 36 mmol) was heated at 140° C. for 4 h. The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate. The precipitate was isolated by filtration and recrystallised from ethanol to give 591 mg (23%) of the title compound; m.p. 295-298° C.; 1H-NMR (DMSO-d6): δ 1.37-2.02 (m, 8H, cyclopentyl), 4.05 (sext, 1H, CH), 6.97-715 (m, 2H, ArH), 7.32 (br.s, 1H, NH), 7.72 (dd, 1H, ArH), 10.35 (br.s, 1H, NH; MS: m/e 283 (M+, 21%); (C12H14N3F1O2S1) calc. C, 50.87; H, 4.98; N, 14.83; found C, 50.75; H, 5.12; N, 14.93.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O.CN(C=O)C>[Zn].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.O>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: COC(=O)c1ccc(CN2CCOc3cc([N+](=O)[O-])ccc32)cc1
Agent: Cl[Fe](Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Yield: 87.7 %

Procedure:
The same operation as in Example (100b) was performed using methyl 4-[(7-nitro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101a) (0.35 g, 1.07 mmol), zinc (0.7 g, 10.7 mmol), iron trichloride hexahydrate (0.12 g, 0.4 mmol), DMF (5 mL) and water (5 mL), to obtain 0.28 g of the crude title compound as a brown oily substance (88%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](N)CC2
Yield: 90.5 %

Procedure:
(S)-4-[2-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (396 mg) was dissolved in dichloromethane (5 ml), a solution of trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was added to the solution under ice-cooling with stirring, and the mixture was still stirred for 15 minutes. After reaction at room temperature for 15 minutes, the reaction mixture was concentrated in vacuo. Dichloromethane, water and sodium bicarbonate were added to the resulting residue and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give (S)-4-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylbutyramide (263 mg) as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:18]([C:19]([CH3:30])([CH3:29])[CH2:20][C:21]([OH:28])([CH2:26][OH:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:31][C:32]#[N:33].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13]1[C:18]([C:19]([CH3:30])([CH3:29])[CH2:20][C:21]([OH:28])([CH:26]=[O:27])[C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:31][C:32]#[N:33]
Reactant: COc1c(CC#N)cccc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(CC#N)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F

Procedure:
0.26 ml (2.99 mmol) of oxalyl chloride is cooled in 6.6 ml of dichloromethane to −78° C. After dropwise addition of 0.42 ml (5.98 mmol) of dimethyl sulfoxide, dissolved in 1.2 ml of dichloromethane, it is stirred for 10 more minutes, and then 900 mg (2.72 mmol) of [2-methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl]acetonitrile in 2.6 ml of dichloromethane is added in drops. After two hours of stirring at −78° C., 1.88 ml (13.58 mmol) of triethylamine is added in drops, the batch is allowed to come to room temperature, and then it is stirred for one and one-half hours at room temperature. After mixing with water, it is extracted three times with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, with saturated sodium bicarbonate solution and with brine. After the solvent is dried and spun off, the residue is chromatographed on a Flashmaster. 599.4 mg (67.1%) of the desired aldehyde remains.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].Cl>CO>[C:1]([CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)CC(=O)CBr
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)CC(=O)CC#N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
10.0 g of potassium cyanide was dissolved in 400 ml of methanol, to which then 24.8 g of methyl 4-bromo-3-oxobutanoate was added dropwise from a dropping funnel over 20 minutes. Methyl 4-bromo-3-oxobutanoate remaining in the dripping funnel was dissolved further in 10 ml of methanol and added dropwise, and the mixture was stirred with cooling on ice for 1 hour and at room temperature for 2 hours. Subsequently, the reaction mixture was cooled on ice, and treated dropwise with 3 ml of a concentrated hydrochloric acid. The reaction mixture was extracted three times with diethylether (2000 ml of diethylether in total). The organic layers were combined, washed twice with 100 ml of saturated brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain 15.3 g of methyl 4-cyano-3-oxobutanoate (purity: 83%).
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(OCC)(=O)C>[CH:26]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C:22](=[CH:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:27])[CH3:28]
Reactant: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C)C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4C3=CC[C@]12C)C(C)C

Procedure:
A solution of N,N-diisopropyl-estr-1,3,5(10)-triene-3-ol-17β-carboxamide (380 mg, 1 mmol) in 10 mL dioxane is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (250 mg, 1.1 mmol) for two hours. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried, and concentrated. Chromatography of the residue yields N,N-diisopropyl estr-1,3,5(10),9(11)-tetraene-3-ol-17β-carboxamide.
Reaction SMILES: [Cl-].[Li+].C([O:5][C:6]([C:8]1[C:19]2[CH:18]3[CH:14]([CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)[CH2:13][CH2:12][C:11]=2[S:10][CH:9]=1)=O)C.[BH4-].[Li+]>C1COCC1>[C:23]([O:22][C:20]([N:16]1[CH2:15][CH:14]2[CH:18]([C:19]3[C:8]([CH2:6][OH:5])=[CH:9][S:10][C:11]=3[CH2:12][CH2:13]2)[CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1csc2c1C1CN(C(=O)OC(C)(C)C)CC1CC2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCc3scc(CO)c3C2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Lithium chloride (2.77 g, 0.066 mol) was added to the product of step e) (5.8 g, 0.016 mol) in 200 mL of THF followed by the addition of 2.0 M lithium borohydride (58 mL, 0.115 mol). The reaction was stirred overnight at 60° C. and was then cooled to room temperature. The reaction mixture was filtered through Celite, diluted with 100 mL of water and was extracted with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were dried (MgSO4) and the solvent evaporated in vacuo to give the subtitle compound that was used without further purification. MS calculated for C16H23NO3S +H: 310, observed: 310.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1F.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[N:17]=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1N=[N+]=[N-]
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of 7 g (28.16 mmol) of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester (known from WO 03/077914) in 140 mL of DMF, 5.49 g (84.44 mmol) of sodium azide and 908 mg (2.82 mmol) of tetrabutyl ammonium bromide is added. Then the mixture is stirred and heated at 50° C. for 4 h. After cooling to ambient temperature, the mixture is diluted in EtOAc and washed with H2O (5 times). The organic phase is dried on Na2SO4, filtrated and evaporated. The crude compound (7.3 g, 26.88 mmol, 95%) obtained as a yellow solid is used without more purification in the next step. 1H-NMR (CDCl3, 300 MHz): ? ppm=3.95 (s, 3H), 8.82 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.[Cl-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:33])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(Br)cc4)CC3)c2cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)N(C)c4ccc(Br)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 1.01 g (2.15 mmol) of N-(4-bromophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 45 in 15 ml of dimethylformamide was added 171.9 mg (4.30 mmol) of 60% sodium hydride under ice-cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 0.27 ml (4.34 mmol) of methyl iodide, followed by overnight stirring at room temperature. The resulting mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals.
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].[CH:40]1([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C1(N=C=NC2CCCCC2)CCCCC1.CCOCC>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[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].[CH2:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:46]([O-:48])=[O:47])[CH2:41]1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
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: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C([O-])C1CCCCC1
Temperature: 25 °C

Procedure:
To a mixed solution of maytansinol (103.2 mg, 0.183 mmoles) and cyclohexanecarboxylic acid (140 mg, 1.094 mmoles) in 5 ml of dry dichloromethane is added dicyclohexylcarbodiimide (DCC) (267 mg, 1.296 mmoles), and after stirring at a room temperature for a short while until insolubles begin to separate out, p-dimethylaminopyridine (DMAP) (50.8 mg, 0.416 mmoles) is added. The mixture is stirred at a room temperature overnight. Then, the insolubles are filtered off, and the filtrate is washed with 0.5 N-HCl (ca. 10 ml) and with saturated aqueous sodium hydrogen carbonate (ca. 10 ml) in that order and is dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is chromatographed on a column of silica gel (75 g), followed by eluting with ethyl acetate and collecting the eluate in 16 g fractions. The fractions No. 14 through No. 30 are pooled and concentrated to remove the solvent, resulting in 59 mg of the crude product. The crude product is dissolved in ethyl acetate, followed by adding ether. There is obtained 24.3 mg of maytansinol 3-cyclohexanecarboxylate as crystals melting at 202°-206° C. (decomp.).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:31])C(=O)C1>CC#N>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([I:31])=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3OC)c(C)nc12
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.75 g, 2.28 mmol) and CH3CN (10 mL) is added NIS (0.54 g, 2.39 mmol). The solution is stirred overnight, concentrated, diluted with EtOAc (30 mL), washed with water (30 mL), sat. NH4Cl (30 mL), 20% (NaHSO3) (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.91 g, 2.00 mmol, 88%). 1H NMR (CDCl3) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46 (s, 3H), 2.52 (s, 3H), 3.25-3.35 (m, 1H), 3.83 (s, 3H), 6.64 (s, 1H), 7.12 (s, 1H). LC/MS (m/z): calcd. for C18H22IN3OS (M+H)+: 456.4; found: 456.0.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[O:21][CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
18.7 g of 1-acetylisonipecotoyl chloride, Example 1(bare added slowly to a stirred mixture of 40.0 g of m-dimethoxybenzene and 19.2 g of aluminum chloride in 75 ml of carbon disulfide. The reaction mixture is stirred at ambient temperature for an hour, poured into ice-water and extracted with chloroform, the combined extracts are dried and the chloroform is removed, leaving a yellow oil. The oil is triturated with ether to give a white solid, which is recrystallized twice from ethyl acetate to give the pure solid, mp 132°-134° C., 1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine.