Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)CC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(Br)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Temperature: 112.5 °C
Yield: 78.1 %

Procedure:
A stirred suspension of 7-bromoquinolin-4-ol (162 g, 0.723 mol) in propionic acid (1500 mL) was brought to 110° C. Nitric acid (85 g of 70%) was added dropwise over 1 h such that the temperature was maintained between 110-115° C. After half of the nitric acid had been added, stirring became difficult due to the formation of solids and an additional 200 mL of propionic acid was added. Upon complete addition, the reaction was stirred for 1 hour at 110° C., cooled to room temperature, and the solid was collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless (800 mL), and the product was dried at 60° C. under vacuum to afford 152 g of 7-bromo-3-nitro-quinolin-4-ol as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.C([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3cn[nH]c3)cc2Cl)CCN1C1CCCCC1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.238 g, 2.61 mmol), 1-boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.3 g, 7.83 mmol) tetrakis(triphenylphosphine)palladium (0.302 g, 0.261 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 4.6 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate to 1/3 hexane in ethyl acetate) to yield 0.545 g (53%) of the title compound: mass spectrum (m/z): 394(M+2).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[Cl-].[NH4+]>C(Cl)Cl.O>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (8.8 g, 47 mmol) in DCM (188 mL) at 0° C., triethylamine (7.8 mL, 56 mmol) was added in one portion. Then, neat methanesulfonyl chloride (4.38 mL, 56 mmol) was added via an additional funnel over 30 minutes. The resulting mixture was stirred at 0° C. for 1.5 h. Upon completion of the reaction, water (100 mL) and sat'd aqueous ammonium chloride (100 mL) were added respectively. The organic phase was separated and washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate as a pale yellow oil (12.5 g). This compound was used directly for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:34])=[O:32]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(=O)(=O)C(F)(F)F)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added Tf2O (203 mg, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 to 1:1 hexanes:EtOAc) to yield a colorless oil (312 mg, 82% yield). 1H NMR (CDCl3, 300 MHz): δ 9.39 (brs, 2H), 7.54 (d, J=3.0 Hz, 1H), 7.26 (m, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.08 (brs, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.27 (m, 2H), 1.50 (s, 9H), 1.39 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.7, 154.9, 154.3, 133.2, 132.8, 128.1, 113.2, 112.0, 84.7, 79.3, 65.8, 46.7, 40.7, 32.4, 28.5, 28.2; 19F NMR (CDCl3, 282 MHz): δ-75.5 (s).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:26][N:25]=1>>[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31]([N:15]2[CH2:14][CH2:13][C:12](=[CH:11][C:10]3[CH:18]=[CH:19][CH:20]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:22][CH:21]=4)[CH:9]=3)[CH2:17][CH2:16]2)=[O:32])[O:26][N:25]=1
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Agent: Cl
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(F)cc4)c3)CC2)c1C
Yield: 116.3 %

Procedure:
Following the procedure in Example 1, Step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol, from Example 18, Step 3) and phenyl 3,4-dimethylisoxazol-5-ylcarbamate (160 mg, 0.40 mmol) were used to provide the title compound (196 mg). MS (APCI 10 V) AP+ 422.2, 284.2, AP− 420.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.42 (td, J=5.76, 1.10 Hz, 2H) 2.51 (td, J=5.88, 1.13 Hz, 2H) 3.47-3.52 (m, 2H) 3.57-3.63 (m, 2H) 6.40 (s, 1H) 6.77-6.84 (m, 2H) 6.94-6.98 (m, J=7.78, 1.45, 0.77, 0.77 Hz, 1H) 6.98-7.03 (m, 2H) 7.05-7.13 (m, 2H) 7.29 (t, J=7.85 Hz, 1H).
Reaction SMILES: [CH2:1](Br)[CH3:2].FC(F)(F)C(O)=O.[NH:11]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@H]1CCNC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC[C@H](C(=O)OCc2ccccc2)C1
Reaction time: 25 h

Procedure:
Ethyl bromide (0.21 mL) was added to a mixture of benzyl (S)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (Intermediate 191, 0.897 g), potassium carbonate (0.971 g) and DMF (10 mL) at room temperature and the mixture was stirred for 25 hours. Further ethyl bromide (0.11 mL) was added and stirring was continued for 24 hours. Further ethyl bromide (0.05 mL) was added and stirring was continued for 22 hours. The resultant mixture was diluted with water and extracted with diethyl ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give benzyl (S)-1-ethylpyrrolidine-3-carboxylate (0.563 g).
Reaction SMILES: [ClH:1].Cl.[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>>[ClH:1].[C:3]1([N:9]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)amide dihydrochloride and sodium hydroxide solution.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC[N:10](C(C)C)C(C)C.[C:17](Cl)(=[O:19])[NH2:18]>CO>[C:17]([CH:2]1[CH2:7][CH2:6][N:5]([NH2:10])[CH2:4][CH2:3]1)(=[O:19])[NH2:18]
Reactant: NC(=O)Cl
Reactant: NC1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Product: NC(=O)C1CCN(N)CC1
Reaction time: 8 h

Procedure:
A solution of the 4-amino-piperidine compound (˜50–100 mmol) in 5 ml MeOH is cooled to 0° C. Then ˜10 equivalent of Huenigs base and ˜3 equivalent of carbamoyl chloride are added. The vial is shaken once and allowed to stand at ambient temperature overnight. Evaporation of volatiles and purification by prep. HPLC gives the 4-carbamoyl-aminopiperidine compounds.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]([Si:30]([CH3:48])([CH3:47])[O:31][CH:32]1[CH2:37][CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27].C([O-])(=O)C.[K+].O>CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:35]3[CH2:36][CH2:37][CH:32]([O:31][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:47])[CH3:48])[CH2:33][CH:34]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1H-benzimidazol-2-yl(4-((3-chloro-2-pyrazinyl)oxy)phenyl)methanone (0.50 g, 1.4 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexen-1-yl)oxy)silane (0.68 g, 2.0 mmol), potassium acetate (1.0 g, 11.0 mmol), and bis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.066 g, 0.11 mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 100° C. After 18 hours, the mixture was diluted with 30 mL of water and extracted three times with 25 mL of 9:1 chloroform:isopropanol. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded 1H-benzimidazol-2-yl(4-((3-(4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 42.2 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (34 mg, 0.14 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (21 μl, 0.14 mmol) dissolved in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 5.5 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-bromoimidazo[5,1-b]thiazole (12 mg, 41%) as a white solid.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCS3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1CCN2c3c(cccc31)[C@H]1CNCC[C@H]12
Yield: 35.7 %

Procedure:
The title compound (28 mg, 17%) was prepared by treatment of tert-butyl(6bS,10aR)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3-oxide (110 mg) with excess TFA in CH2Cl2 at 0 C. followed by treatment with 1 N aq. NaOH. 1H NMR (300 MHz, CDCl3) 1.79-1.99 (m, 1H), 2.10 (d, 1H, J=12.2 Hz), 2.39-2.57 (m, 1H), 2.72-3.01 (m, 3H), 3.01-3.22 (m, 2H), 3.22-3.51 (m, 3H), 3.61-3.72 (m, 1H), 6.69-6.89 (m, 1H), 7.17 (d, 1H, J=7.0 Hz), 7.42 (d, 1H, J=9.6 Hz) ppm. CI MS m/z=249 [C13H16N2OS+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].Cl[C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+].O>O1CCOCC1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[C:3]([O:11][CH2:12][CH3:13])[CH:4]=1)(=[O:7])[NH2:8]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CCOc1cc(C(N)=O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12
Temperature: 25 °C

Procedure:
4-amino-3-ethoxy-benzamide (0.045 g, 0.25 mmol), methyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.061 g, 0.25 mmol, Fluorochem Ltd.) and para-toluene sulfonic acid (0.005 g, 0.025 mmol) were heated at reflux in anhydrous 1,4-dioxane (1.5 mL) for 16 hours. The solution was cooled to ambient temperature, ammonium hydroxide/water (1:4, 5 mL) added and the precipitate collected and washed successively with water and diethyl ether. The title compound was obtained as a yellow solid (0.057 g, 59%) after recrystallisation from MeOH.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[NH:14]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[O:22]>C(#N)C>[C:33]([O:32][C:30]([NH:14][C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:23]([F:25])([F:26])[F:24])[C:27]([O:29][CH2:2][C:1]#[N:4])=[O:28])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)OCC#N
Reaction time: 5.25 h
Yield: 99 %

Procedure:
N,N-Diisopropylethylamine (102 μL, 0.585 mmol) and subsequently bromoacetonitrile (185 μL, 2.66 mmol) were added to a solution of Boc-Lys(Tfa)-OH (Compound tk52) (182 mg, 0.532 mmol) in acetonitrile (0.5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 5.25 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk53) (200.8 mg, 99%).
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].[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42]>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C@H:2]1[C@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH:41]([CH3:43])[CH3:42])=[O:44])[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][C@@H:6]([O:33][CH3:34])[C@:5]2([OH:39])[NH:35][C:36]([O:38][C@H:3]1[CH2:4]2)=[O:37]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Reactant: CC(C)C(=O)Cl
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)C[C@H](OC(=O)C(C)C)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Reaction time: 2.5 h

Procedure:
In a mixture of 1 ml triethylamine and 50 ml of dimethylformamide was dissolved 100 mg of maytansinol and, while the solution was stirred under ice-cooling, 50 μl of isobutyryl chloride was added dropwise. The mixture was stirred under ice-cooling for 30 minutes and then, at room temperature for 2.5 hours, after which it was distilled under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, washed with water and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was chromatographed and recrystallized as in Reference Example 1. By the above procedure there was obtained 19.4 mg of Ansamitocin P-3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.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.CCO>[CH:16]1([N:8]([C:6]2[N:5]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]3[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=3)[CH:7]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: OB(O)c1ccnc(F)c1
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
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(-c2ccnc(F)c2)nc2c(C=O)cnn12)C1CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 3 mmol) in 29 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-Fluoropyridine-4-boronic acid (500 mg, 3.55 mmol), tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol), and 2M aqueous solution of Na2CO3 (4.4 mL, 8.9 mmol). The mixture was stirred at 85° C. for 8 hours. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (35% EtOAc/Hexanes) to provide 324 mg tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (28% yield). LCMS (M+1=398)
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C@@H:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:21][CH:20]=2)[N:3]=1.C(O)C.[O-2].[Mg+2].[H][H]>[C].[Pd].C1C=CC=CC=1.O>[F:17][C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8][C:7]1[CH:6]=[N:5][C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:24]=2)=[N:3][CH:2]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCc1ccc(-c2nc(Cl)c(CC[C@@H](F)CCCCCC)c(Cl)n2)cc1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCc1ccc(-c2ncc(CC[C@@H](F)CCCCCC)cn2)cc1
Yield: 69 %

Procedure:
72 mg of palladium-carbon (palladium=about 5%), 372 mg (0.73 mM) of (S)-4,6-dichloro-(5-3-fluorononyl)-2-(4-decylphenyl)pyrimidine, 5 ml of 99%-ethanol, 118 mg (2.92 mM) of magnesium oxide and 0.3 ml of distilled water were placed in a two-necked round-bottomed flask and subjected to hydrogen addition for 5 hours at 60° C. After the reaction, benzene was added to the reaction mixture and the catalyst as removed from the reaction mixture, followed by distilling-off of the solvent and purification by thin-layer chromatography (eluent: benzene; Rf=0.5) to obtain 222 mg (0.50 mM) of (S)-5-(3-fluorononyl)-2-(4-decylphenyl)pyrimidine (crude product). The crude product was recrystallized from hexane to obtain an objective product (Yield: 69.2%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(O[CH2:23][CH2:24][S:25][C@H:26]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:28]([CH2:29][CH2:30][C@@H:31]3[C@@H:40]2[CH2:39][CH2:38][C@@:36]2([CH3:37])[C@:32]3([OH:50])[CH2:33][CH2:34][C@@H:35]2[C:45]2[CH:49]=[CH:48][O:47][CH:46]=2)[CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][N:8]([CH3:9])[CH2:23][CH2:24][S:25][C@H:26]2[CH2:43][CH2:42][C@@:41]3([CH3:44])[C@H:28]([CH2:29][CH2:30][C@@H:31]4[C@@H:40]3[CH2:39][CH2:38][C@@:36]3([CH3:37])[C@:32]4([OH:50])[CH2:33][CH2:34][C@@H:35]3[C:45]3[CH:49]=[CH:48][O:47][CH:46]=3)[CH2:27]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCS[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1)CCN1CCCC1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 0.34 g of N-(2-(1-pyrrolidinyl)ethyl) methylamine in 5 ml of dimethylformamide, 0.045 g of NaH (60% dispersion in mineral oil) were added under nitrogen and the mixture was stirred at room temperature for half an hr; a solution of 0.50 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 51, in 2 ml of dimethylformamide was added, the mixture was stirred for another 4 hrs and then 7 ml of water were poured in. The residue was extracted with ethyl acetate, the organic solution was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.28 g of the title compound (I-ca)as an amorphous solid.