Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((S)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (460 mg, 1.7 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (243 mg, 84%). 1H NMR (400 MHz, DMSO, d6): δ 4.28-4.18 (1 H, m), 3.72-3.17 (10 H, m), 2.11-2.10 (1 H, m), 1.81-1.80 (2 H, m)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1(Cl)[CH2:9][CH2:8][CH2:7][C:6]([Cl:11])([Cl:10])[CH:5]1O.C([O:16]CC)C>O>[Cl:3][C:4]12[O:16][CH:9]1[CH2:8][CH2:7][C:6]([Cl:11])([Cl:10])[CH2:5]2
Reactant: CCOCC
Reactant: OC1C(Cl)(Cl)CCCC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClC1(Cl)CCC2OC2(Cl)C1
Reaction time: 0.25 h

Procedure:
7 g (175 mmol) of sodium hydroxide pellets were added in three portions at 10°-15° C. to 15.2 g (63.88 mmol) of 2,2,6,6-tetrachlorocyclohexanol 1a in suspension in 70 cm3 of distilled water. The reaction mixture was kept at room temperature for 1 h 15 min, 20 cm3 of ethyl ether were then added, stirring was continued for 5 min and then the phases were separated and the aqueous phase was extracted with ether (6×50 cm3). The ether phases were combined, dried over MgSO4, filtered, and the mixture was concentrated with a rotary evaporator. A liquid epoxide 2a (m=12.42 g) was obtained, representing 96.5% of the theoretical yield. The compound 2a will be frequently employed without further purification in the following stages (semicapillary GC purity>96%). The epoxide 2a can be purified by distillation at reduced pressure (boiling at 40° C. at 0.1 mm Hg); after distillation, the yield of compound 2a was 92%.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])([CH2:8][C:9]#[N:10])[CH2:4][C:3](=[CH:5][C:6]#[N:7])[CH2:2]1.[NH:14]1[CH:18]=[C:17]([C:19]2[C:20]3[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[N:15]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:25]1[C:21]2[N:22]=[CH:23][N:24]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([C:3]4([CH2:5][C:6]#[N:7])[CH2:2][C:1]([CH2:8][C:9]#[N:10])([CH2:11][C:12]#[N:13])[CH2:4]4)[CH:18]=3)[C:20]=2[CH:27]=[CH:26]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=C1CC(CC#N)(CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CC#N)(CC#N)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
The crude 2,2′,2″-cyclobutane-1,1-diyl-3-ylidenetriacetonitrile (1 g, 0.006 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.2 g, 0.0006 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.001 mol) was added under nitrogen. The mixture was heated at 50° C. over night. The reaction was concentrated and purified with Combiflash (silica gel, 0-100% EtOAc/Hex) to give the desired product as light brown oil. LCMS calculated for C25H31N8OSi(M+H)+: 487.2; Found: 487.4.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+].O>CC(C)=O>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][NH:13][C:2]([O:4][CH3:5])=[O:3])=[CH:9][CH:8]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
Into a 50 mL-single neck flask, 260 mg of methyl chloroformate in acetone (5 mL) was added dropwise to 500 mg of 4-bromophenethyl amine and 291 mg of Na2CO3 in acetone (20 mL) while stirring at room temperature under a nitrogen atmosphere. The reaction was then stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield the intermediate title compound (714 mg) as a white solid. This material was taken to the next reaction without further purification. Ion spray M.S. 259.2 (M*+1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].C([Li])CCC.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][C:6]=2[N:7]=1)([OH:20])[CH2:18][Cl:17]
Reactant: N#Cc1ccc2ncsc2c1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1
Temperature: -98 °C
Yield: 42.5 %

Procedure:
After 6-cyanobenzothiazole (1.60 g) was dissolved in tetrahydrofuran (80 ml), and the solution was cooled to -98° C. in a nitrogen atmosphere, a 1.6M solution (5.9 ml) of n-butyllithium in hexane was added dropwise over 10 minutes, and the resultant mixture was stirred for 5 minutes. A solution of 2-chloro-2',4'-difluoroacetophenone (2.85 g) in tetrahydrofuran (20 ml) was added dropwise to this mixture. After the liquid reaction mixture was heated to -10° C., an aqueous solution of ammonium chloride was added thereto. After the mixture was heated to room temperature, an organic layer was taken out, and the solvent was distilled out under reduced pressure. A water layer was extracted with ethyl acetate and the extract was then put together with the residue of the organic layer. This organic layer was washed with water and then with saturated saline, dried over magnesium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography on silica gel (solvent: hexane/ethyl acetate=20/1, next, hexane/ethyl acetate=5/1), thereby obtaining the intended compound (1.49 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH:16](N4CCOCC4)[CH2:15][CH2:14][C:13]=3[CH:25]=2)=[N:6][CH:7]=1.NC1C=CC2CCC([OH:51])CCC=2C=1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH:16]([OH:51])[CH2:15][CH2:14][C:13]=3[CH:25]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc2c(c1)CCC(O)CC2
Reactant: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(O)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
The desired product was also isolated from Example 622, as starting material 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclo hepten-2-ylamine of Example 622 was contaminated with a small amount of its respective alcohol, 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol. The product 2-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol was isolated as a lyophylate (10%); 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.23 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.02 (d, J=8.62 Hz, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.19 (d, J=7.95 Hz, 1H), 7.00 (d, J=8.98 Hz, 1H), 6.90 (d, J=8.20 Hz, 1H), 6.54 (s, 1H), 3.87 (s, 3H), 3.71 (bm, 1H), 2.68 (m, 1H), 2.5 (DMSO-d+H), 1.86 (m, 2H), 1.30 (m, 2H); MS (m/e) 477.43 (M+H).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].[CH2:15]([C:23]1[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl.FC(F)(F)C(O)=O.CCOC(C)=O>[CH2:15]([C:23]1[CH:24]=[CH:25][C:26]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:10])=[CH:30][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(C(=O)N2CCC[C@H]2C#N)cc1
Temperature: 50 °C
Yield: 40 %

Procedure:
General procedure D was used to deprotect 0.4 grams (2.05 mmols) of 28 in 21 mL of dichloromethane and trifluoroacetic acid. After work-up, the TFA salt of 28 was then coupled to 0.6 grams (2.05 mmols) of 4-octylbenzoic acid with 1.1 grams (2.05 mmols) of PyBOP and 1.1 grams (8.2 mmols) of N,N-diisopropylethylamine in 21 mL of dichloromethane according to general procedure E and heating at 50° C. After previously described work-up and purification procedures (column chromatography, 25% EtOAc in hexanes) 0.256 grams (0.82 mmols, 40%) of the title product was recovered.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.NN>>[C:2]1([CH2:1][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Cc2ccccc2)cc1

Procedure:
4-Phenylmethylbenzoic acid was prepared according to the method of Van Herwijnen et. al., 2001. 4-Benzoylbenzoic acid (452 mg, 2 mmol), powdered NaOH (350 mg), hydrazine hydrate (0.35 mL) and tri(ethylene glycol) (15 mL) were stirred at 190° C. for four hours.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccccc2)c(C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(CBr)o1
Reaction time: 0.08 h

Procedure:
A mixture of 2,5-dimethyl-4-phenyloxazole (6.0 g), N-bromosuccinimide (6.6 g), azobisisobutyronitrile (0.3 g) and carbon tetrachloride (120 ml) was refluxed with stirring for 5 minutes. The reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue was left standing to give 5-bromomethyl-2-methyl-4-phenyloxazole as crystals, yield 9.2 g (98.9%). Recrystallization from ethanol gave colorless needles, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2C(=O)C3=CC=CC=C3C2=O)[CH:13]=1)[CH2:9][CH3:10].NN>C(O)C>[CH3:29][C:2]([CH3:1])([CH3:30])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)[CH2:9][CH3:10]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
150 mg of the resulting benzylamine compound was dissolved in 5 ml of ethanol, and 23 mg of hydrazine was added. The mixture was stirred at room temperature for 30 minutes. The precipitate was separated by filtration, and the solvent was evaporated. The residue was distributed between methylene chloride and water. The organic layer was worked up in a customary manner and purified by silica gel column chromatography [Wakogel C-100, 5 g; eluting solvent: hexane/ethyl acetate=10/1→3/1] to give 95 mg (yield 95%) of the captioned compound as a pale yellow crystalline powder, m.p. 65°-66 ° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COc1ccc(C=O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 37.5 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7.3 ml (60 mmol) of 4-methoxybenzaldehyde in 70 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:23]=2)[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:28]([C:27]2[C:22]([CH:19]3[CH2:21][CH2:20]3)=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:11][C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1C
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][C:23](=[O:44])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:26]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[CH:25]=1)C>CCCCCC.C(OCC)(=O)C>[C:39]([CH2:38][CH2:37][C:26]1[CH:25]=[C:24]([C:23](=[O:44])[CH2:22][CH2:21][CH2:20][C:19]([OH:45])=[O:18])[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])([OH:41])=[O:40]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 53.5 %

Procedure:
Starting with 0.135 g (0.66 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.31 g (0.64 mmol) of 4-[(5-bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester, the title compound (0.190 g; 62.8% overall yield) was obtained as a white solid, mp 151°-153.5° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CN1CCCC1=O>O>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NCCOCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)NCCOCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-benzyloxyethylamine (50 g), ethyl 2-bromo-2-methylpropionate (97.5 g) and N-methyl-2-pyrrolidone (1 l) was heated at 100° C. for 7 h. The mixture was cooled to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic phases were washed with water (4×500 ml) and brine (2×500 ml), dried (Na2SO4) and the solvents were evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (ethyl acetat containing 4% triethylamine) gave ethyl 2-(2-benzyloxyethylamino)-2-methylpropionate as an oil: 30 g
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:9][C:10]1[N:11]=[C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[S:13][C:14]=1[C:15](O)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:15]([C:14]1[S:13][C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:11][C:10]=1[CH3:9])=[O:16])([CH3:3])[CH3:2]
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a stirred solution of isopropylamine (216 mg, 3.65 mmol) in dioxane (4 mL) under argon and at room temperature was added trimethylaluminium (1.83 mL of a 2M solution in toluene, 3.7 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (300 mg, 0.91 mmol) in dioxane (4 mL) was added and the reaction mixture warmed to 90° C. After 4 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (182 mg, 54%) as a light yellow gum. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([O:3][CH3:4])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([O:17][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([O:3][CH3:4])=[O:2]
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(CC(=O)OC)cc(OCC=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2.00 g (9.0 mmoles) if 3,5-di-(carbmethoxymethyl)phenol in 75 ml acetone is added 1.24 g (9.0 mmoles) of K2CO3 followed by 1.77 g (9.0 mmoles) of cinnamylbromide. This reaction mixture is refluxed for 2 hours, cooled to room temperature, filtered and concentrated down in vacuo. Purification by flash chromatography affords 1,3-di-(carbomethoxymethyl)-5-cinnamyloxybenzene which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].CCN(C(C)C)C(C)C>C(C#N)(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([I:12])[CH:14]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NCc1cccc(I)c1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a solution of 4,6-dichloronicotinamide (296 mg, 1.55 mmol) in AcCN (3 mL) was added 3-iodobenzylamine (396 mg, 1.70 mmol) and DIPEA (0.383 mL, 2.32 mmol). After stirring at 80° C. for 15 h, the mixture was concentrated and added water, the resulting precipitate was collected by filtration to give 6-chloro-4-(3-iodobenzylamino)nicotinamide (588 mg).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:52][CH3:53])([C@@H:41]([O:48]C(C)=O)[C@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@@H:31]5[N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.CC[C@@]1(O)CN2C[C@H](C[C@](C(OC)=O)(C3C=C4[C@]56[C@@H]7[C@](CC)([C@@H](OC(C)=O)[C@](O)(C(OC)=O)[C@@H]5N(C)C4=CC=3OC)C=CCN7CC6)C3NC4C=CC=CC=4C=3CC2)C1.OS(O)(=O)=O>NN.C(O)C>[CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C:32]56[C@@H:31]([N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[C@@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@H:41]([OH:48])[C@:37]3([CH2:52][CH3:53])[CH:38]=[CH:39][CH2:40][N:35]([C@H:36]53)[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1
Reactant: CC[C@]1(O)C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Agent: NN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1

Procedure:
Vinca alkaloids such as vinblastine can be conjugated directly to aldehyde-bearing linkers following conversion to a hydrazide form as described by Brady et al. (J. Med. Chem., 45:4706-4715, 2002). Briefly, vinblastine sulfate is dissolved in 1:1 hydrazine/ethanol and heated to 60° C.-65° C. for 22 hours to yield desacetylvinblastine 3-carboxhydrazide (Table 2, DAVCH). Alternatively, amine-reactive forms of vinblastine may be generated in situ as described by Trouet et al. (U.S. Pat. No. 4,870,162) by (1) initially converting vinblastine sulfate to the desacetyl form (e.g. as described by Brady et al., reacting with 1:3 hydrazine/methanol at 20° C. for 20 hours), (2) reacting the resulting free base with approximately 2-fold excess succinic anhydride to generate the hemisuccinate (Table 2, DAVS), and (3) reacting with isobutyl chloroformate to form the reactive mixed anhydride.