Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH3:20])[C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][C:17]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:12]([O:11][CH3:10])[C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: COc1ccc(Br)c(OC)c1-c1ccccc1C
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cccnc2)c(OC)c1-c1ccccc1C
Yield: 82.8 %

Procedure:
Pyridine-3-boronic acid (5.81 g, 47.27 mmol, Frontier Scientific, Inc.), 1,3-dimethoxy-2-(tol-2-yl)-4-bromobenzene (2) (10.7 g, 34.8mmol), glyme (200 mL), and tetrakis(triphenylphosphine) palladium (Ph3P)4Pdo (4 g, 3.46 mmol) were stirred for 15 minutes followed by the addition of potassium carbonate (16 g in 70 ml of water). After refluxing for 10 hr, the reaction mixture was poured into 800 ml of 1:1 mixture of water and ethyl acetate. The organic layer was washed with water (300 ml×2) and brine (200 ml), the solvent was removed, and the crude product was purified by silica-gel chromatography eluting with hexane and ethyl acetate (10% to 25% ethyl acetate) yielding 8.8 g (83%) of 3.
Reaction SMILES: ClC(C)=[CH:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].C(C1C=C(SC2C=C(C)C(O)=C(C(C)(C)C)C=2)C=C(C)C=1[OH:30])(C)(C)C.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+].[Cl:62][CH2:63][CH2:64]Cl>>[Cl:62][CH2:63][C:64](=[O:30])[CH2:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6]
Reactant: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: ClCCCl
Reactant: CC(Cl)=CC(C#N)(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: N#CC(CC(=O)CCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A 265 g. portion of 4-chloro-2,2-diphenylpentenenitrile and 3.84 g. of bis(3-t-butyl-4-hydroxy-5-methylphenyl) sulfide were dissolved in 1 liter of 1,2-dichloroethane and heated to the reflux temperature, about 75°-80° C. To the mixture was added dropwise a solution of 276.9 g. of 3-chloroperbenzoic acid dissolved in 2.5 liters of 1,2-dichloroethane. The resulting solution was heated for 24 hours, and was then cooled to ambient temperature. Sodium sulfite solution was added until starch-iodide paper showed a negative test for peracid. The reaction mixture was then made basic by the addition of 135 g. of sodium bicarbonate in saturated aqueous solution, and the organic layer was then separated, washed with water and dried over sodium sulfate. The solvent was then evaporated away under vacuum to obtain 294.5 g. of crude product, which was crystallized from ethanol to obtain 194.3 g. of the product named in the heading, m.p. 102°-104° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1C)[CH3:3].[CH2:11]=O.Cl.[CH:14]([Cl:17])(Cl)Cl>[Cl-].[Zn+2].[Cl-]>[Cl:17][CH2:14][C:7]1[O:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:9][C:8]=1[CH3:11]
Reactant: Cc1ccoc1CN(C)C
Reactant: C=O
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc(CN(C)C)oc1CCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-dimethylaminomethyl-3-methylfuran (6.5 g; 37.0 mmoles) [prepared in Step A] in 250 ml of chloroform was added paraformaldehyde (1.67 g; 55.7 mmoles) and zinc chloride (312 mg), and a slow stream of HCl gas was bubbled through while stirring at ambient temperature for 15 minutes. Stirring was continued for 2 hours, then HCl gas was bubbled through for 15 minutes and the mixture stirred for 1 hour. At this time additional paraformaldehyde (1.67 g; 55.7 mmoles) was added to the reaction mixture and a slow stream of HCl gas was passed through for 15 minutes. After stirring at ambient temperature for 18 hours, the reaction mixture was filtered through Celite and the filtrate evaporated under reduced pressure to yield the title compound (4.97 g) which crystallized upon standing and was used without further purification in Step C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:25][C:24]([O:21][C@@:18]12[C@H:19]3[CH2:20][C:7]4[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]5[O:12][C@H:13]([C@@:5]1([C:6]=45)[CH2:4][CH2:3][N:2]3[CH3:1])[C:14](=[O:15])[CH2:16][CH2:17]2)=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@]4(OC(C)=O)[C@@H](C2)N(C)CC[C@]314

Procedure:
315 g of oxycodone was refluxed with 1600 ml of acetic anhydride for one hour. After cooling the mixture to 50°, acetic anhydride and acetic acid were removed with the rotary evaporator. The solid remaining was dissolved in water and the solution was basified to pH9 with ammonia. The precipitated product was filtered off, washed with water and vacuum dried to yield 357 g of 14-acetyloxycodone (m.p. 215°-216°).
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: Cc1ncccc1C(=O)O
Agent: Cl
Product: Cc1ncccc1C(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-methylnicotinic acid. δH (DMSO-d6) 8.73 (1H, br d), 8.48 (1H, m), 7.7-7.46 (4H, m), 7.4-7.23 (3H, m), 7.00 (2H, d, J 8.4 Hz), 5.2) (2H, s), 4.60 91H, m), 3.27-3.12 (1H, m), 3.0-2.82 (1H, m); m/z (ESI, 60V) 509 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])(C)C.[N:23]([CH2:26][C:27]([OH:29])=O)=[N+:24]=[N-:25].C([O-])(O)=O.[Na+].[CH2:35](Cl)[CH2:36]Cl>CN(C=O)C>[N:23]([CH2:26][C:27](=[O:29])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][CH2:18][CH2:21][CH2:35][CH3:36])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Reactant: ClCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propylcarbamate (amine, 160 mg, 0.5 mmol), 2-azidoacetic acid (56 mg, 0.55 mmol, in 50% DCM solution), NaHCO3 (168 mg, 2 mmol), and 1 mL DMF was added EDC (115 mg, 0.6 mmol). The mixture was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by silica chromatography (gradient 5% to 90% EtOAc in hexane) to afford compound 141 as a clear oil (130 mg, 65%). MS (ESI) m/z 426 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)=[O:29]
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc2ccccc2c1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Yield: 75.7 %

Procedure:
By operating as described in Example 6(a), 7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are reacted with 6.15 g of 2-naphthylacetyl chloride in the presence of 4.15 g of triethylamine in methylene chloride to give 9 g of 1-(2-naphthylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; m.p. 125°-130° C.
Reaction SMILES: C([Li])CCC.[C:6]([OH:10])(C)([CH3:8])[CH3:7].C([O:18][C:19](=O)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([F:28])[CH:22]=1)C1C=CC=CC=1.C1C[O:33]CC1>>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH2:7][C@H:6]([CH2:8][OH:33])[O:10][C:19]2=[O:18])=[CH:22][C:23]=1[F:28]
Reactant: C1CCOC1
Reactant: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Product: O=C1O[C@@H](CO)CN1c1ccc(Br)c(F)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at −30° C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at −30° C., and was then allowed to warm slowly to 0° C. After 30 min at 0° C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0° C. To this ice cold mixture, R(−)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH-].[K+].[OH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:3][CH:4]=1
Reactant: OCCN1CCCC1
Reactant: Brc1ccc(Br)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(OCCN2CCCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromopyridine (15.0 g, 63.3 mmol), powdered KOH (6.39 g, 114 mmol), 1-(2-hydroxyethyl)pyrrolidine (14.58 g, 126.6 mmol), and 18-crown-6 (300 mg, 1.14 mmol) in dry toluene (100 mL) was heated to 70° C for 1 h. The solution was cooled to room temperature and water and EtOAc were added. The organic layer was washed with water and brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo. Short path distillation (153° C. @ 0.1 mmHg) provided the title compound as a colorless oil which solidified upon cooling (14.9 g, 87%). 1H NMR (250 MHz, CDCl3): δ8.15 (d, J=2.4 Hz, 1H), 7.65 (dd, J=2.4, 8.4 Hz, 1H), 6.67 (d, J =8.4 Hz, 1H), 4.38 (t, J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.62 (m, 4H), 1.82 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)([CH3:14])=[O:13].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH:11][C:12](=[O:13])[CH3:14])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1c(N)cc(N)nc1Br
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
4,6-Diamino-2-bromo-nicotinonitrile (100 mg, 0.47 mmol) was dissolved in 1.0 mL of anhydrous pyridine. AcCl (225 μL, 2.35 mmol) was dropped in slowly. The resulting mixture was shaken overnight at ambient temperature. Water (5 mL) was added to the mixture mixture. The resulting brown solid was collected through filtration, washed with cold water, and dried in a vacuum oven to provide the title compound (100 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccncc1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccncc4)c23)c1

Procedure:
Analogously to Step 32.1, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenyl-amino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 161 mg (1.5 mmol) of pyridine-4-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(pyrid-4-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 25 ml of DMEU with 8 ml (8 mmol) of DIBAL-H analogously to Example 32 and analogous working-up yield 4-(3-chlorophenylamino)-3-[(pyrid-4-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)7.7; FAB-MS: (M+H)+=352.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:15][C@@H:16]3[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]3[O:18][C:19](=[O:21])[CH3:20])=[N:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.[F-].[Cs+]>COCCOC.C(O)C.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>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[C:10]([O:15][C@@H:16]4[O:33][C@H:32]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]4[O:18][C:19](=[O:21])[CH3:20])=[N:11][NH:12][C:13]=3[CH3:14])=[CH:6][CH:7]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(-c3ccc(F)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 85 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of 4-[(4-bromophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.099 g), 4-fluorophenylboronic acid (0.046 g), cesium fluoride (0.050 g) and tetrakis(triphenylphosphine)palladium(0) (0.0038 g) in 1,2-dimethoxyethane (1.3 mL), ethanol (0.3 mL) and water (0.3 mL) was stirred at 85° C. for 18 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=1/1-1/2-1/5) to give 4-{[4-(4-fluorophenyl)phenyl]methyl}-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.061 g).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.Cl.[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[O:30][CH2:29][CH:28]([NH2:32])[CH2:27]2.C([N:35](CC)CC)C>C(O)C>[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[O:30][CH2:29][CH:28]([NH:32][NH:35][C:5]1[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19])[CH2:27]2
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1COc2c(Cl)cccc2C1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NNC4COc5c(Cl)cccc5C4)ncnc32)[C@H](O)[C@@H]1O
Yield: 47.7 %

Procedure:
A mixture of 2.25 g of 6-chloropurine riboside, 1.99 g of 8-chloro-3-chromanylamine hydrochloride, and 1.98 g triethylamine is refluxed in 55 ml of ethanol under nitrogen for 22 hrs. Upon cooling, solid material crystallizes out, which is filtered and retreated with boiling ethanol. Solid material obtained is filtered and dried affording 1.68 g (50%) of N6 -[8-chloro-3-chromanylamino]adenosine having a melting point of 137°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:26](=[O:27])[NH:11][C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a cold solution of N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonamide (0.050 g, 0.146 mmol) in CHCl3 was added pyridine (0.5 mL) and phosgene (1.0 mL) at 0-5° C. The reaction mass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched in water, neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=8.7 Hz, 1H), 7.56-7.71 (m, 4H), 7.89 (d, J=9.3 Hz, 2H), 12.69 (s, 1H). MS (m/z): 368.15 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][CH3:38].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:35][CH2:36][O:37][CH3:38])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:24]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cn2)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(CCOC)C(=O)OCc3ccccc3)cn2)cc1
Reaction time: 0.58 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4]>[OH-].[Na+].O1CCCC1.CO.O>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)=[CH:10]1
Reactant: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of the methyl ester (Example 10, part ii) (1.73 g) in aqueous sodium hydroxide (2M, 5.9 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was refluxed with stirring overnight. The reaction mixture was cooled, diluted with water until turbid and washed with diethyl ether (2×). The aqueous phase was acidified with acetic acid and the resulting precipitate filtered, washed with water and dried in vacuo at 50° C. to give the product as a white solid (1 g). A small amount was crystallised from tetrahydrofuran/ethanol m.p. 208°-212° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>ClCCCl.ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@@H:27]1[CH2:28][NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Sodium triacetoxyborohydride (15.9 g, 75.4 mmol) and enough acetic acid to bring the pH to 5 were added to a solution of N-tert-butoxycarbonyl-L-prolinal (5 g, 25 mmol) and 4-fluorobenzylamine (6.28 g, 50.3 mmol) in 200 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/ethyl acetate) afforded 6.0 g of product.
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:44]([OH:46])=[O:45])[CH2:43][CH2:42][CH2:41]1.O>ClCCl.CN(C)C1C=CN=CC=1>[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][CH:40]([C:44]([O-:46])=[O:45])[CH2:41]1
Reactant: O=C(O)C1CCC1
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
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Solvent: O
Solvent: ClCCl
Product: O=C([O-])C1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Maytansinol (127.7 mg) and cyclobutanecarboxylic acid (120 μl) was dissolved in 5 ml of dichloromethane. To the solution, were added 340 mg of N,N-dicyclohexylcarbodiimide and 55 mg of 4-dimethylaminopyridine. The mixture was stirred at room temperature for four hours. To the reaction solution was added water, and the mixture was stirred. The resulting precipitates were removed by filtration and the filtrate was diluted with ethyl acetate. The ethyl acetate layer was separated and washed with water and dried. The solvent was removed by evaporation and the residue was purified by means of a silica-gel chromatography (solvent: aqueous ethyl acetate) to collect 82.7 g of a fraction containing the desired product. The product was crystallized from a small volume of ethyl acetate to yield 47.6 mg of maytansinol 3-cyclobutanecarboxylate. Melting point: 205°-208° C. (decomp.).