Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[N:14]=1)[N:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 120 °C
Yield: 57.1 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-1-phenethyl-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (54 mg, 0.11 mmol), 3-tributylstannanyl-pyridine (0.054 mL, 0.17 mmol) and PdCl2(PPh3)2 (16 mg, 0.023 mmol) in 3 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (10-90% EtOAc/hexanes) to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 478.39 (M+1).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][CH3:13])[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:20]1CCCC1>>[C:1]1([CH:7]2[CH2:12][CH2:13][CH:10]([OH:20])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(CC(C)=O)c1ccccc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC1CCC(c2ccccc2)CC1
Yield: 74 %

Procedure:
4-Phenylhexanone (1.74 g; 10 mmoL) is mixed with 1M lithium aluminum hydride (LiAlH4) solution in tetrahydrofuran (THF) (10 mL; 10 mmoL). The reaction mixture is stirred and refluxed for 6 hrs. After the starting ketone is consumed as determined by thin-layer chromatography (TLC) and gas phase chromatography (GC), the reaction mixture is carefully quenched with water (40 mL) whereupon a precipitate forms. Then, hydrochloric acid (10 mL) is added to dissolve the precipitate, and the solution is twice extracted with diethyl ether (20 mL twice). The combined ether portions are dried with Na2SO4, and the solvent is evaporated to yield 4-phenylcyclohexanol (1.71 g; 74%). The purity and identity of the compound are established by TLC and GC using an authentic sample of the material obtained from Lancaster Company.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:26])([F:27])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1cccc(OC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.23 g, 1.0 mmol), 3-(3-trifluoromethoxy-phenyl)-propylamine (0.219 g, 1.0 mmol), and K2CO3 (0.25 g, 1.8 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-trifluoromethoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.153 g, 46%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.72 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.02-7.56 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 335 (M)+.
Reaction SMILES: CCCP(=O)=O.[CH2:7]([O:9][C:10]([C:12]1[N:13]([CH3:20])[N:14]=[CH:15][C:16]=1[C:17]([OH:19])=O)=[O:11])[CH3:8].[NH:21]1[CH2:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:7]([O:9][C:10]([C:12]1[N:13]([CH3:20])[N:14]=[CH:15][C:16]=1[C:17]([N:21]1[CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:11])[CH3:8]
Reactant: C1CNC1
Reactant: CCOC(=O)c1c(C(=O)O)cnn1C
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 111.3 %

Procedure:
Propylphosphonic anhydride solution (50% in ethyl acetate, 8.0 ml) was added to a cooled (0° C.) solution of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester (1.00 g, 5.0 mmol), azetidine (576 mg, 10.1 mmol), and N,N-diisopropylethylamine (2.0 g) in ethyl acetate (40 ml). The mixture was stirred for 30 min at 0° C. and overnight at r.t. The reaction mixture was taken up in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The obtained title compound (1.32 g, 99%) was used in the next step without further purification. MS (m/e)=238.3 [M+H+].
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.CC(C)CN.NCC(C)(O)C.B(Br)(Br)Br>ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)C
Agent: BrB(Br)Br
Agent: CC(C)(O)CN
Solvent: CC(C)CN
Solvent: ClCCl
Product: CC(C)Cn1c(CO)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a chilled solution (ice bath) of 2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0 g, 6.69 mmol, prepared according to the general methods of Example 6 using 2-methylpropan-1-amine in lieu of 1-amino-2-methylpropan-2-ol) in dichloromethane (50 mL) was added boron tribromide (20 mL, 1M solution in dichloromethane). The mixture turned light purple and was stirred at ambient temperature for 44 hours. The reaction was quenched with methanol (20 mL) and aqueous hydrochloric acid (6N, 10 mL). After stirring for 4 hours, the pH was adjusted to 10 by the addition of aqueous sodium hydroxide (50%). Dichloromethane (50 mL) was added with stirring and the layers were separated. The aqueous fraction was extracted with chloroform (2×250 mL). The combined organic fractions were concentrated to provide 1.4 g of [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as a white powder, mp 226-228° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:12][Mg]Br.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]([OH:11])[CH3:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=Cc1cc2ccoc2cn1
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
Under an argon atmosphere, furo[2,3-c]pyridine-5-carbaldehyde (488 mg, 3.31 mmol) was dissolved in tetrahydrofuran (11 mL), and added methylmagnesium bromide (5.5 mL (1.0 M in THF solution), 4.97 mmol) under ice-cold conditions. Then, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was added 1N-aqueous solution of hydrochloric acid under ice-cold conditions, and then a saturated aqueous solution of sodium hydrogen carbonate was added. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (356 mg (yield 66%)) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37].[ClH:38]>O1CCOCC1.CCOCC>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The tert-butyl (3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.785 g, 1.50 mmol) was dissolved in 15 ml of dioxane and treated with 7.5 ml of anhydrous 4N HCl in dioxane at room temperature. The reaction mixture was stirred at room temperature for two hours. The mixture was then diluted with 25 ml of ether and stirred until product separated as a solid. Solid product was filtered and washed with ether. The solid was dissolved in MeOH (20 ml) and concentrated to dryness twice. The product was dried at high vacuum to yield 0.709 g of yellow solid (bis HCl salt) (95%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.65 (br. s, 2H), 9.60 (br. s, 1H), 8.90 (br. s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.61 (m, 1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (dd, J=11.7, 8.6 Hz, 1H), 7.20 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.55 (d, J=6.3 Hz, 1H), 4.50-4.40 (m, 1H), 3.86 (s, 3H), 3.48-3.38 (m, 1H), 3.22-3.10 (m, 1H), 3.06-2.88 (m, 2H), 2.12-2.02 (m, 1H), 2.00-1.84 (m, 2H), 1.78-1.64 (m, 1H). LCMS: 425 [M+H].
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26]CC)(=[O:25])[CH:23]=[CH2:24].[OH-].[Na+]>CO>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 108.4 %

Procedure:
A mixture of 146 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 73.0 g of ethyl acrylate and 500 ml of methanol was refluxed for 1 hr and then 675 ml of 2N sodium hydroxide aqueous solution was added to the reaction mixture. The reaction mixture was refluxed for 1 hr and concentrated. Water was added to the residue and adjusted to pH 4 with hydrochloric acid. The precipitate was collected by filtration to give 200 g of colorless crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 198 g of colorless crystals. This compound was identified by comparing its mp, IR spectrum and NMR spectrum with those of the compound of Example 21.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14]1)(=O)C.N1C=CC=CC=1.Cl.O>O1CCOCC1>[C:21]1([C:15]2[C:16](=[O:20])[N:17]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:18](=[O:19])[NH:13][N:14]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)n1nc(-c2ccccc2)c(=O)[nH]c1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1c(=O)[nH]nc(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Benzoyl chloride (0.253 ml, 2.180 mmol) was added to a solution of 2-acetyl-6-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (420 mg, 1.817 mmol) and pyridine (0.441 ml, 5.45 mmol) in 1,4-Dioxane (5 ml) at 5° C. Mixture was stirred at r.t. overnight. Solids were filtered off and rinsed with DCM, solvent was concentrated under reduced pressure. Residue was diluted in ethanol (20 ml), hydrochloric acid 37% in water (0.250 ml, 3.04 mmol) was added and mixture heated at 90° C. for 3 h. Solvent was concentrated and residue purified on biotage 25M silica cartridge, eluting with Cy/AcOEt 8:2 to AcOEt 100%, to give 87 mg of title compound (16% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]O)[C:5]2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=[C:15]([Cl:16])[C:4]=2[N:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:16][C:15]1[C:4]2[N:3]=[C:2]3[NH:1][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:5]=2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(N)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 4-[2-amino-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (3.40 g, 10.8 mmol) in pyridine (50 mL) was added methanesulfonyl chloride (2.60 mL, 32.9 mmol) dropwise at 0° C. After stirring for 1 hr, aqueous sodium bicarbonate was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with 2N hydrochloric acid, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (100 mL) and potassium carbonate (4.50 g, 32.9 mmol) was added. The mixture was stirred at 110° C. for 15 hr. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (1.51 g, 5.17 mmol, 47%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of 2-amino-2-methyl-1-propanol (0.097 g, 1.09 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.135 g, 63%). MS (ISP) 597.3 [(M+H)+]; mp 221° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH:4]=1.Cl.C(C[OH:66])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CCOC(C)=O.CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:66])[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH2:4]1
Reactant: OCC(F)(F)F
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(Cl)cc34)[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: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(Cl)cc34)[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
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (52.6 mg, 0.109 mmol, 30 equiv) in H2O was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-chloroanhydrovinblastine (18a, 3.0 mg, 0.0036 mmol, 1 equiv) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (2.7 mg, 0.073 mmol, 20 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 minutes before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:EtOAc=3:3:97) provided 10′-chlorovinblastine (18b, 1.3 mg, 0.0015 mmol, 42%) as a white solid and 10′-chloroleurosidine (0.8 mg, 0.00095 mmol, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-6-methoxy-6-oxohexanoic acid (23.5 g, 85 mmol) in anhydrous THF (100 mL) was added Et3N (14.2 mL, 102 mmol, 1.2 equiv.). The solution was cooled down to 0° C. and isobutyl chloroformate (12.2 mL, 93.5 mmol, 1.1 equiv.) was added dropwise. The solution was stirred for 30 min. The precipitate was filtered off. The filtrate was cooled down to 0° C. and a suspension of sodium borohydride (6.5 g, 170 mmol, 2 equiv.) in H2O (3 mL) was added in one portion. The reaction was stirred for 1 h, and quenched with saturated NH4Cl. THF was removed. The residue was dissolved into EtOAc (400 mL) and extracted with saturated NH4Cl twice. The organic layers were combined, dried and concentrated. The residue was purified on silica gel column (hexanes/EtOAc 1:1) to give (S)-methyl 5-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (20 g, 90%) as a colorless oil. LRMS (M-Boc+H+) m/z 162.1.
Reaction SMILES: C1(C2(C3C=CC=CC=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16]([N:19]4[CH2:24][CH:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH2:23][CH2:24][N:19]([S:16]([C:14]3[CH:15]=[C:9]([OH:8])[C:10]([OH:11])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)c(O)c1)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (3.2 g, 6.2 mmol) was dissolved in methylene chloride (100 ml). Trifluoroacetic acid (50 ml) was added dropwise and the reaction was stirred for 5 hours at room temperature. The solvent was evaporated and the residue was purified by column chromatography on silica gel (100 g, methylene chloride then ethyl acetate as eluant). The product was crystallized from ether/hexane to give a white solid (2.1 g, 96%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>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>[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30]([C:2]3[C:3]4[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=4[N:5]=[CH:6][N:7]=3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cnn([C@@H](CC#N)C3CCCC3)c2)OC1(C)C
Reactant: CCOC(OCC)n1ccc2c(Cl)ncnc21
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(OCC)n1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 95 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
Into a 100 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3b, 3.30 g, 0.0129 mol), (3S)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((S)-24, 5.12 g, 0.0146 mol, 1.13 equiv), 1,4-dioxane (33.4 mL, 0.428 mol), water (16.7 mL, 0.929 mol) and potassium carbonate (K2CO3, 8.03 g, 0.0581 mol, 4.5 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (1.49 g, 0.00129 mol, 0.10 equiv). The mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 21 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (20 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were washed with 20% aqueous brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution) afford (3S)-3-cyclopentyl-3-{4-[7-diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propanenitrile ((S)-25, 4.11 g, 5.27 g theoretical, 78% yield) as colorless oil, which was solidified upon standing at room temperature. For (S)-25: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.71 (d, 1H, J=3.8 Hz,), 7.12 (d, 1H, J=3.8 Hz), 6.76 (s, 1H), 4.53 (td, 1H, J=19.4, 4.3 Hz), 3.68 (m, 2H), 3.52 (m, 2H), 3.26 (dd, 1H, J=9.6, 17.3 Hz), 3.19 (dd, 1H, J=4.3, 17.2 Hz), 2.41 (m, 1H), 1.80 (m, 1H), 1.63-1.09 (m, 13H); C22H28N6O2 (MW, 408.50), LCMS (EI) m/e 409 (M++H).