Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: NCCCCCCNc1ccc(Cl)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCNc2ccc(Cl)cc2)c(Nc2ccncc2)c1=O
Yield: 89 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and N-(4-chlorophenyl)-hexane-1,6-diamine.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[C:12]2[N:13]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)C.CO.[OH-].[Na+]>C1COCC1>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][N:13]1[C:12]2[C:7]([NH:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:8][CH:9]=[CH:10][C:11]=2[O:16][CH2:15][C:14]1=[O:17]
Reactant: CCOC(=O)CNc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2

Procedure:
A mixture of (4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetic acid ethyl ester, I-63 (105 mg), methanol (3.0 mL), THF (2.0 mL) and 2.0 M NaOH (0.5 mL) was stirred at room temperature for 18 h. Methanol was evaporated and the residue was taken water (3.0 mL) and acidified to pH 1 with 2.0 M HCl resulting in the precipitation of a white solid. Solid was extracted with chloroform (10 mL×2), and the combined extracts were dried (brine, anhydrous sodium sulfate), concentrated and dried on high vacuum to afford (4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetic acid, I-64 (102 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].O.NN.C(O)C.Cl>O>[NH2:13][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:1]([NH2:2])=[O:3]
Reactant: NC(=O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCc1cccc(C(N)=O)c1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 15.42 g (0.05 mole) N-[3-(3-carbamoylphenyl)propyl]phthalimide (the product of step (e)), 2.76 g (0.055 mole) hydrazine monohydrate and 100 ml ethanol was refluxed for about four hours under argon with heat, and then allowed to stir overnight. The reaction mixture was acidified with 30% (v/v) hydrochloric acid to a pH of about 1. Additional ethanol (about 10 to 20 ml) was added to the thick mixture. The mixture was filtered; the solids were rinsed with ethanol. The filtrate was evaporated to give a solid. Water (about 15 ml) was added to the solid; the resulting mixture was filtered. The filtrate was basified with dry potassium carbonate until saturated, then extracted three times with 20 ml butanol. The butanol extracts were dried over sodium sulfate and potassium carbonate overnight, filtered and stripped to give 4.25 g of the above-identified product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CO>[N:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
4-aminothiophenol (8.9 g) was dissolved in methanol (178 ml), aqueous solution of sodium hydroxide (6.8 g, 53.4 ml) was added to the mixture, 4-(chloromethyl)pyridine hydrochloride (14.0 g) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-[(4-pyridinylmethyl)sulfanyl]aniline (13.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: Oc1cncc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 3-chloro-5-hydroxypyridine (2.0 g, 17.0 mmol), 4-methoxybenzyl alcohol (2.85 g, 25.5 mmol) and triphenylphosphine (6.68 g, 25.5 mmol) in dry THF (100 ml) DEAD (4.44 g, 25.5 mmol) was added dropwise. The resulting solution was stirred 3 hours at room temperature. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 20% ethyl acetate/hexane to provide the title compound (1.9 g, 53%). MS (DCI/NH3) m/e 250 (M+1)+.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[O:9]([CH2:27][C:28]1[C:53]([CH3:54])=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:30]([CH3:55])[CH:29]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:56]([N:60]([CH2:71][CH2:72][CH2:73][CH3:74])[C:61]1[CH:68]=[CH:67][C:64]([CH:65]=O)=[C:63]([O:69][CH3:70])[CH:62]=1)[CH2:57][CH2:58][CH3:59].O>O1CCCC1.C(OCC)(=O)C>[CH2:56]([N:60]([CH2:71][CH2:72][CH2:73][CH3:74])[C:61]1[CH:68]=[CH:67][C:64]([CH:65]=[CH:32][C:31]2[CH:52]=[C:53]([CH3:54])[C:28]([CH2:27][O:9][Si:10]([C:23]([CH3:25])([CH3:24])[CH3:26])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:29][C:30]=2[CH3:55])=[C:63]([O:69][CH3:70])[CH:62]=1)[CH2:57][CH2:58][CH3:59]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: Cc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2C)c(OC)c1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
In a stream of argon, to 20 ml of tetrahydrofuran was added 2.54 g of phenyllithium (19% solution in dibutylether) (5.74 mmol), and 3.57 g (4.89 mmol) of 4-(tert-butyldiphenylsiloxymethyl)-2,5-dimethylbenzyltriphenylphosphonium bromide was added thereto under ice cooling. Next, 1.26 g (4.78 mmol) of 4-dibutylamino-2-methoxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.7 g of an orange liquid (yield: 89.1%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl>C(Cl)Cl>[Cl:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][C:13]([C:5](=[O:7])[CH3:6])=[C:14]([OH:16])[CH:15]=1
Reactant: COc1ccc(OC)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)cc1Cl
Temperature: 25 °C
Yield: 527.3 %

Procedure:
To a mixture of AlCl3 (8.89 g, 59 mmol) in CH2Cl2 at −10° C. was added acetyl chloride (4.1 ml, 58 mmol) drop-wise while maintaining the internal temperature below 0° C. After 20 min 2-Chloro-1,4-dimethoxybenzene (10.0 g, 8.3 mmol) was dissolved in 8 ml CH2Cl2 and added to the above solution drop-wise while maintaining the internal temperature below 0° C. After 20 min the mixture was warmed to room temperature for 1 hour then warmed to reflux. After 21 h the solution was cooled, poured over a mixture of ice and concentrated HCl and extracted with dichloromethane. The combined organics were concentrated in vacuo and recrystallized from H2O/EtOH to afford 1-(4-chloro-2-hydroxy-5-methoxy-phenyl)-ethanone (8.78 g, 85%) as a solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([C:30]([Cl:32])=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CC1C=CC=CC=1>[ClH:32].[CH:27]1([C:30]([N:7]([C:8]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N(C(=O)C2CC2)c2ccccc2)CCN(CCc2ccccc2)CC1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 3.52 parts of ethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate, 1.25 parts of cyclopropanecarbonyl chloride, 1.8 parts of N,N-diethylethanamine and 45 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled to room temperature and washed with water. The organic phase is separated, dried, filtered and evaporated. The oily residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The oily residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding ethyl 4-[N-(cyclopropylcarbonyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate hydrochloride; mp. 194.8° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(=O)[C:2]1=[O:3].[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC>C(O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:20]([O:19][C:12]1([O:16][CH2:17][CH3:18])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])[CH3:21]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCOC(OCC)OCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC1(OCC)C(=O)Nc2ccccc21
Yield: 128.9 %

Procedure:
In 500 ml of ethanol were dissolved 14.7 g of isatin and 10.6 g of triethyl orthoformate, and 100 mg of camphorsulfonic acid was added thereto. The mixture was heated under reflux for 12 hours, followed by concentration. To the residue was added chloroform, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give 20.4 g (92%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:25]([Cl:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2>>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[CH:21][C:12]=3[O:11][CH2:10][CH2:9][NH:8][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[N:17]=[CH:16][N:15]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CN(C)CC(=O)O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(C)CC(=O)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 31 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 31% yield; NMR spectrum (DMSO-d6) 2.08 (s, 6H), 2.79 (s, 2H), 3.68 (q, 2H), 4.36 (t, 2H), 5.29 (s, 2H), 7.13 (d, 1H), 7.21 (d, 1H), 7.34 (m, 2H), 7.55 (m, 2H), 7.70 (t, 1H), 7.86 (dt, 1H), 7.98 (d, 1H), 8.11 (t, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.80 (s, 1H); Mass Spectrum MH+ 507.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19].[Na+].C(OC(=O)CC)(=O)CC>>[CH3:19][C:18](=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)=[CH:10][CH:11]=1)[C:17]([OH:21])=[O:20]
Reactant: CCC(=O)[O-]
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cn1
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CC(=Cc1ccc(Oc2ccc(C)nc2)cc1)C(=O)O
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of 5 g of 4-(2-methyl-5-pyridyloxy)benzaldehyde, 5 g of sodium propionate and 35 ml of propionic anhydride was stirred for 3 hours at a temperature of 150° to 155° C. and then concentrated under reduced pressure. Water was added to the mixture which was then heated to crystallize the product. The resulting crystals were separated by filtration, washed with water and recrystallized from a mixture of acetic acid and water to obtain 3.3 g (52% yield) of 2-methyl-3-[4-(2-methyl-5-pyridyloxy)phenyl]propenoic acid as colorless needles having a melting point of 211°-213° C. Recrystallization from a mixture of methanol and isopropyl alcohol yielded colorless prisms having a melting point of 211°-214° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:14](=S)=[S:15].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Yield: 80.1 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-carbohydrazide (535 mg, 3.00 mmol), carbon disulfide (0.397 mL, 6.60 mmol) and triethylamine (0.460 mL, 3.30 mmol) in ethanol (5 mL) was heated under reflux for 24 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 0.1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (529 mg, yield 80%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](=O)[O:10]1.C(O)(=O)C.O.[NH2:29][NH2:30]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](=[O:10])[NH:30][N:29]=1
Reactant: O=C1OC(=Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc21
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc12
Yield: 85 %

Procedure:
A solution of 3-(3,5-dichloro-pyridin-4-ylmethylen)-6-difluoromethoxy-3H-isobenzofuran-one (14.4 g, 21 mmoles), prepared as described in example 97, in CH3OH (100 ml), under N2, was added with acetic acid (3.6 ml, 63 mmoles) and hydrazine monohydrate (3.15 ml, 63 mmoles). A precipitate formed and the mixture was refluxed for 2 hours. After 1 night to stand the mixture was cooled over ice and the solid filtered and washed with little CH3OH. After drying under vacuum at 50° C., 6.64 g of the title compound were obtained [yield: 85% from (5-difluoromethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide].
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[Cl:5][C:6]1[C:11](Cl)=[CH:10][CH:9]=[N+:8]([O-:13])[C:7]=1[CH3:14]>CO>[Cl:5][C:6]1[C:11]([O:2][CH3:1])=[CH:10][CH:9]=[N+:8]([O-:13])[C:7]=1[CH3:14]
Reactant: Cc1c(Cl)c(Cl)cc[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1Cl
Temperature: 25 °C

Procedure:
To a solution of sodium methylate, prepared from 0.51 g of sodium and 20 ml of methanol, at -10° C. were added 3.5 g of 3,4-dichloro-2-picoline-N-oxide in 20 ml of anhydrous methanol. The mixture was allowed to warm slowly to room temperature and was then heated to reflux for 1 hour. The solvent was now removed by distillation under reduced pressure, water was added to the residue, the mixture was extracted with dichloromethane, and the solvent was evaporated off. Colorless crystals from diisopropyl ether, melting point 94°-97° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Si:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Br[C:25]1[C:26]([NH2:32])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>COCCOC.O.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>[NH2:32][C:26]1[C:25]([C:18]2[CH:17]=[CH:16][C:15]([OH:14])=[CH:20][CH:19]=2)=[CH:30][C:29]([Cl:31])=[CH:28][N:27]=1.[Si:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:25]2[C:26]([NH2:32])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)=[CH:17][CH:16]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Cl)cc1Br
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: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(Cl)cnc2N)cc1
Product: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of sodium carbonate (4.09 g), tetrakis(triphenylphosphine)palladium(0) (0.668 g), 4-(tert-butyldimethylsilyloxy)phenylboronic acid (6.32 g) and 3-bromo-5-chloropyridin-2-amine (4.00 g) in DME (100 mL) and water (20 mL) was stirred at 80° C. overnight. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 4-(2-amino-5-chloropyridin-3-yl)phenol (3.05 g) as a pale yellow solid and 3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-chloropyridin-2-amine (1.55 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1)[NH2:8]
Reactant: CS(=O)(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Solvent: CO
Product: CS(=O)(=O)Cc1cc(N)cc(Cl)c1
Yield: 93.9 %

Procedure:
A solution of 1-chloro-3-[(methylsulfonyl)methyl]-5-nitrobenzene (4.6 g) in methanol (40 mL) was treated similarly as described in example 35.3. Crystallization of the crude product (4.6 g) from diethyl ether furnished the pure title compound (3.8 g)
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([O:25][CH2:26][CH3:27])[CH3:24]>>[C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([O:15][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)Cl
Reactant: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Product: CCOC(C)OC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1

Procedure:
The N-benzoyl-(2R,3S)-3-phenylisoserine, as prepared in Example 34, is treated with 1-chloroethyl ethyl-ether in the presence of a tertiary amine to produce optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2). 7-tri-ethylsilyl baccatin III (1), as synthesized according to Denis et at. (J. Amer. Chem. Soc. 110:5417, 1988), is added to 6 equiv of optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2), 6 equiv of di-2-pyridyl carbonate (DPC), and 2 equiv of 4-(dimethylamino) pyridine (DMAP) in toluene solution (0.02M). This mixture reacts at 73° C. for 100 hours to produce the C-2', C-7-protected taxol derivative (3).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH2:8](Br)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:8]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(C(C)=O)C(C)=O
Yield: 55.4 %

Procedure:
2,4-pentanedione (205.4 ml, 2.0 mol), acetone (100 ml), n-butyl bromide (54 ml, 0.5 mol) and potassium carbonate (34.55 g, 0.25 mol) were put in a reaction vessel, purged with nitrogen and refluxed for 48 hours. The generated solid was filtered, and the solvent was removed using an evaporator. Unreacted 2,4-pentanedione was then removed under reduced pressure using a diaphragm. Then, vacuum distillation was then used to obtain 3-n-butyl-2,4-pentanedione (43.25 g, yield 55%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[N:32]([CH:35]([CH3:37])[CH3:36])=[C:33]=[O:34]>C1COCC1.C(Cl)Cl>[CH:35]([NH:32][C:33](=[O:34])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)([CH3:37])[CH3:36]
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)NC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (35 mg, 0.082 mmol) in THF (2 mL) was added 2-isocyanatopropane (14.03 mg, 0.165 mmol) and stirred at rt for 10 min. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to obtained 30.2 mg of (R)-6-(3-(3-isopropylureido) piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11])#[N:2].[H-].[Na+].Br[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17].O>CN1C(=O)N(C)CCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])#[N:2]
Reactant: CCc1ccc(O)c(C#N)c1
Reactant: CC(C)(Br)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCc1ccc(OC(C)(C)C=O)c(C#N)c1
Temperature: 4 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2-Cyano-4-ethylphenol (1.47 g) was added portionwise to a stirred, ice-cooled suspension of sodium hydride (60% w/w dispersion in mineral oil, 420 mg) in DMPU (10 ml) under argon. Stirring was continued for 1 hour at ambient temperature, the mixture cooled to 4° C. and 2-bromo-2-methylpropanal (2.26 g) in DMPU (2 ml) added. Stirring was continued for 18 hours at ambient temperature. Water (50 ml) was added and the resulting mixture extracted with ether (3×50 ml). The combined extracts were washed with water (2×30 ml) and saturated brine (2×30 ml), then dried (MgSO4). Evaporation of the solvent and purification of the residual oil by flash chromatography, eluting with 20% v/v ethyl acetate in hexane, gave 2-(2-cyano-4-ethylphenoxy)-2-methylpropanal (2.04 g), as a colourless oil; NMR: 1.21 (3H, t, J=7 Hz), 1.51 (6H, s), 2.61 (2 H, q, J=7 Hz), 6.76(1H, d, J=7 Hz), 7.28 (1H, dd, J=7,2 Hz), 7.41 (1H, d, J=2 Hz), 9.85 (1H, s).