Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Reactant: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cnc2s1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide (236 mg, 0.732 mmol), 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (300 mg, 0.0.732 mmol) and tris(2-furyl)phosphine (34 mg, 0.146 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.0732 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 5 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product. Obtained product purified by HPLC to give the title compound (90 mg): 1HNMR (DMSO-d6): 3.07 (s, 3H), 4.27-4.39 (m, 1.5H), 4.40-4.48 (m, 0.5H), 4.52-4.60 (m, 0.5H), 4.64-4.71 (m, 2.5H) 4.88-4.94 (m, 1H), 6.22 (t, 1H), 7.50 (d, 2H), 7.83 (d, 2H), 8.22-8.33 (m, 1H), 8.62 (bs, 1H), 8.85 (d, 1H), 8.94 (s, 1H). m/z (Cl) M+H 489.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:29].C(OCC)(=O)C.O>CN1CCCC1=O.[Cu-]=O>[NH2:29][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Agent: O=[Cu-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 80 °C
Yield: 70 %

Procedure:
Copper (I) oxide (9.2 mg, 0.06 mmol) was added to (5-bromopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (285 mg, 0.64 mmol) (see Preparation 26) and concentrated ammonia solution (2 mL) in 1-methyl-2-pyrrolidinone (0.5 mL). The mixture was heated in a sealed vessel at 80° C. for 17 hours. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture and then filtered through a glass fibre filter. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (gradient of EtOAc:MeOH:cNH3 100:0:0 to 95:5:0.5) to afford the title compound as a colourless oil in 70% yield, 171 mg.
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=[O:32].[Na+]>O.CC#N>[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([C:29]([OH:32])=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C=O)o1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of NaClO2 (2.8 mmol) in 3 mL water was added dropwise to a stirred solution of 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde (798 mg, 2.22 mmol) from step (a) in 3 mL MeCN, with cooling in an ice bath. After 2.5 h, the ice bath was removed, 2 mL more MeCN was added, and the two-phase liquid reaction mixture was stirred at room temperature for 25 h. The reaction mixture was diluted with water, made basic with saturated NaHCO3, and extracted with ethyl acetate (3×50 mL). The separated aqueous solution was acidified to pH 2 with 5% aqueous HCl and extracted with ethyl acetate (3×50 mL). This second ethyl acetate solution was washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness under vacuum to give the carboxylic acid (287 mg, 34%) which was used in the next step without further purification. The compound can be activated and esterified direct to a drug or further modified as described below.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.CC(CC1C=CC=C(OC)C=1)CC(=O)C=C.[CH2:38]([CH:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]>[OH-].[K+]>[CH2:38]([C:40]1([CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]
Reactant: CCC1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CC(C)Cc1cccc(OC)c1
Agent: C=CC(=O)CC(C)Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1(CCC(=O)CC(C)Cc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Add a mixture of 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one and 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one (6 g, prepared by slow distillation of the former substance) to 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% methanolic potassium hydroxide (10 cc) and heat the mixture under reflux for 6 hours. Remove most of the solvent under reduced pressure and add ether (25 cc) and benzene (25 cc) to the residue. Wash the solution with 5% aqueous sodium hydroxide, water, dilute hydrochloric acid, and brine, and dry. Evaporate the solvent to obtain a viscous brown gum, which is the triketone 2-ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione.
Reaction SMILES: C([S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])=[CH:6]1)(=O)C.N>CO>[SH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])=[CH:6]1
Reactant: CC(=O)S[C@@H]1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: N
Solvent: CO
Product: C[C@]12CC[C@H](S)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A solution of 1.3 g of 3β-acetylthio-androst-4-en-17-one (IV-a, Prep 7) in 20 ml of methanol, was saturated with gaseous ammonia and kept on standing for 3 hrs at room temperature. The mixture was evaporated to dryness under reduced pressure and purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 95/5 as eluant to give 1.1 g of the title compound (IIIa) as a white solid.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[Cl:25][C:26]1[C:27]([C:36]([OH:38])=[O:37])=[N:28][C:29](S(C)(=O)=O)=[N:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:29]1[N:28]=[C:27]([C:36]([OH:38])=[O:37])[C:26]([Cl:25])=[CH:31][N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(=O)O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ncc(Cl)c(C(=O)O)n1)CC2
Temperature: 60 °C

Procedure:
A mixture of compound 1B (309 mg, 1 mmol), 5-chloro-2-methanesulfonyl-pyrimidine-4-carboxylic acid (236 mg, 1 mmol) and cesium carbonate (975 mg, 3 mmol) in 2 ml of DMSO was heated to 60° C. for 6 h. The product was precipitated out of solution by addition to water and collected by filtration. The crude material was chromatographed (SiO2, 20% methanol in dichloromethane) to afford title compound 123 as a white powder: LCMS (96% purity): m/z 465.9 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][CH:5]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1nocc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 65.5 %

Procedure:
Using 3-methylisoxazole-4-carboxylic acid (127 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (143 mg, yield 65%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.IC.[C:14](=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1F
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (30.8 g) in DMF (150 mL) was added iodomethane (17.5 mL) and powdered sodium hydrogencarbonate (23.5 g). The mixture was stirred for 18 hours and partitioned between ethyl acetate and brine. The organic phase was isolated, washed with dilute sodium bisulfite solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 7-20% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (500 mg, 2.43 mmol) in DCM at −78° C., DIBAL-H (2.67 mL, 2.67 mmol) was added dropwise and stirred for 3 h at −78° C. The mixture was allowed to warm up to 0° C. then water (0.12 mL) was added dropwise to the mixture followed by aq. NaOH (15%, 0.12 mL). H2O (0.3 mL) was added then the mixture was warmed up to room temperature and stirred for 15 min and the organic layer collected, dried over MgSO4 and filtered with the filtrate concentrated to give the desired product with was used without further purification (280 mg, Yield 65%). LCMS (m/z): 176.1 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.CC(=O)OCC>C(Cl)Cl>[CH:9]1([CH2:12][O:13][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)COCC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac2O)2]2 (3.1 g, 7.02 mmol) in anhydrous CH2Cl2 (800 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 4 h. CH2Cl2 extractive work up and silica gel chromatography (PE:EA=100:1-50:1) gave the title compound (100 g, 90.4% yield) as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.10-1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH3:29])([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([CH3:27])[CH:15]=2)[CH3:11])=[O:8])=[CH:4][CH:3]=1.[I-].[Na+].[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(N(CC)CC)C>O1CCOCC1.N.O.C(#N)C.C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:32][Si:33]([CH3:35])([CH3:34])[C:36]#[C:37][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH3:11])([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([CH3:27])[CH:15]=2)[CH3:29])=[O:8])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(Br)s2)ccc1N1CCOCC1=O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(C#C[Si](C)(C)C)s2)ccc1N1CCOCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.00 g (2.08 mmol) of 5-bromo-N-{1-methyl-1-[3-methyl-4-(3-oxomorpholin-4-yl)phenylcarbamoyl]ethyl}thiophene-2-carboxamide, 40 mg (0.208 mmol) of copper(I) iodide, 0.62 g (4.16 mmol) of sodium iodide and 0.044 ml (0.416 mmol) of N,N-dimethylethylene-1,2-diamine in 2.5 ml of dioxane is stirred at 100° C. for 20 h, cooled to room temperature, diluted with conc. ammonia and water and extracted with ethyl acetate. The combined organic phases are extracted with ethyl acetate, dried with sodium sulphate and concentrated in vac. The crude product (0.86 g) is directly reacted further. A suspension of the above crude product (0.86 g), 0.45 ml (3.26 mmol) of trimethylsilylacetylene and 0.68 ml (4.8 mmol) of triethylamine in 10 ml of acetonitrile/20 ml of THF is saturated with argon several times, and 67 mg (0.082 mmol) of PdCl2(dppf) and 15 mg (0.082 mmol) of copper(I) iodide are added. The initially reddish brown suspension becomes lemon-yellow after about 15 min. After stirring for 16 h, the mixture is diluted with ethyl acetate, washed with 5% ammonia solution, dried with sodium sulphate and concentrated in vac.
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([C:3]2[C:4](=[O:8])[N:5]([CH3:7])[CH2:6][C:2]=2[OH:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CN1CC(O)=C(c2cccc([N+](=O)[O-])c2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CC(O)=C(c2cccc(N)c2)C1=O
Yield: 83.1 %

Procedure:
A suspension of 1,5-dihydro-4-hydroxy-N-methyl-3-(3-nitrophenyl)-2H-pyrrol-2-one (1.23 g, 5.3 mmol)in ethanol (70 ml) was hydrogenated at 40 psi using a palladium on carbon catalyst (300 mg, 24% (w /w)) for 30 min. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was azeotroped with toluene (2×30 ml) and then triturated with anhydrous ether (30 ml). The tetramic acid (0.90 g, 83%) was isolated as a yellow solid. 1H NMR (360MHz, D6 -DMSO ) δ2.85 (3H, s), 3.87 (2H, s), 6.37 (1H, dd, J=7 and 1Hz), 6.93 (1H, t, J=8Hz), 7.12 (1H, d, J=8Hz), 7.20 (1H, t, J=2Hz). MS (CI, NH3) 222 (M+NH4 +).
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]([F: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]([F: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(F)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: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(F)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: 2 h
Yield: 39 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (60.4 mg, 0.125 mmol, 10 equiv) in H2O (50 mL) was stirred 2 hours. The reaction mixture was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-fluoroanhydrovinblastine (19a, 10.1 mg, 0.0125 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 (9.5 mg, 0.25 mmol, 1 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′-fluorovinblastine 19b (4.0 mg, 0.0048 mmol, 39%) as a white solid and 10′-fluoroleurosidine (2.7 mg, 0.0033 mmol, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Product: COc1ccn2c(C3CCN(C(=O)OC(C)(C)C)CC3)cnc2c1

Procedure:
The title compound was prepared from 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) and 2-amino-4-methoxypyridine (prepared using procedures analogous to those described by R. J. Sundberg et al, Org. Preparations & Procedures Int. 1997, 29, (1), 117-122) using a procedure similar to that described in Example 235 Step A. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 1.63˜1.75 (m, 2H), 2.05 (br d, J=13 Hz, 2H), 2.85˜3.00 (br, 3H), 3.88 (s, 3H), 4.15˜4.35 (br, 2H), 6.58 (d, J=7.4 Hz, 1H), 6.93 (br s, 1H), 7.25 (br s, 1H), 7.79 (d, J=7.5 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:25][N:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:31]
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)nc1C
Yield: 90.6 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (369 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)=O.C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH2:39]([N:42]([CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:40][CH3:41]>>[CH2:48]([N:42]([CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:1][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)[CH2:49][CH3:50]
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1
Reactant: CCCN(CCC)CCCCN
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that the compound 18 was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and N,N-dipropyl-1,4-butanediamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[O:25])[C:9]([NH:11][CH:12]([C:17]([N:19]([CH3:22])[NH:20][CH3:21])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[N:37]#[C:38]Br>CO>[CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[O:25])[C:9]([NH:11][CH:12]([C:17]([N:19]([CH3:22])[N:20]([C:38]#[N:37])[CH3:21])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CNN(C)C(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1)C(=O)N(C)N(C)C#N
Reaction time: 4 h
Yield: 64.5 %

Procedure:
N2-[1-benzyl-2-(1-[(1,2-dimethylhydrazino)carbonyl]-3-methylbutylamino)-2-oxoethyl]-2-pyrazinecarboxamide (100 mg, 0.23 mmol) and sodium acetate (53 mg, 0.64 mmol) were dissolved in methanol (1 mL). Cyanogen bromide (49 mg, 0.46 mmol) was added and the solution was stirred for 4 h. Methanol was concentrated by rotary evaporation. The pH value was adjusted (5% NaHSO3) to 1-2. The solution was extracted by EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 1/1: Hexane/EtOAc, Rf=0.3) afforded N2-[1-benzyl-2-(1-[(2-cyano-1,2-dimethylhydrazino)carbonyl]-3-methylbutylamino)-2-oxoethyl]-2-pyrazinecarboxamide as pale yellow solid (67 mg, 65%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([F:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1.C(CN)O>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([F:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Solvent: NCCO
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(F)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-carbaldehyde following General Procedure F. The compound was converted to the corresponding ethanolamine salt following General Procedure T.