Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(O)C.O1CCOCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Tin(II) chloride (11.87 g, 62.6 mmol) was added portionwise over 5 min to a stirred mixture of 3-(2-chloro-5-nitrophenyl)pyridine (3.53 g, 15.1 mmol) in ethanol (100 ml) and 1,4-dioxane (100 ml) at 0° C. The mixture was then stirred overnight, gradually warming to room temperature, and then concentrated under reduced pressure. 20% Aqueous ammonia solution (200 ml) and ethanol (300 ml) were added and again the mixture concentrated under reduced pressure. Ethyl acetate (300 ml) was added and the mixture heated to reflux, the solids were filtered off and the process repeated twice more. The combined organic filtrates were concentrated under reduced pressure to yield the title compound (2.69 g, 87%): 1H NMR (360 MHz, CDCl3) δ 6.65-6.70 (2H, m), 7.26 (1H, dt, J 8.5, 1.1 Hz), 7.33 (1H, dd, J 7.8, 4.8 Hz), 7.77 (1H, dt, J 7.8, 1.9 Hz), 8.59 (1H, dd, J 4.8, 1.6 Hz), 8.66 (1H, d, J 1.8 Hz); MS (ES+) m/z 205, 207 (3:1) [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>>[CH3:24][C:21]1([CH3:25])[O:20][CH:19]([CH2:18][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:23][O:22]1
Reactant: NN
Reactant: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(Cl)nc2)O1
Solvent: O
Product: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(NN)nc2)O1
Yield: 99 %

Procedure:
According to process 5.2, starting with 0.54 g of 6-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N-phenylpyridine-3-sulfonamide and 30 μL of hydrazine hydrate, 0.53 g of N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-hydrazinyl-N-phenylpyridine-3-sulfonamide is obtained in the form of a white solid.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].BrCC#N>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:2][C:3]#[N:5])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h
Yield: 125.2 %

Procedure:
LDA (2M solution in THF/heptane/ethylbenzene, 97.15 ml, 0.194 mol) was added under an argon atmosphere to THF (300 ml) at −5° C., piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (25 g, 0.097 mol) in THF (100 ml) was then added dropwise and the mixture was stirred for 3 hour at −5° C. Then bromoacetonitrile (23.3 g, 0.194 mol) was added at −5° C. and the mixture was stirred overnight at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer was washed with brine, dried over sodium sulphate and then concentrated to give 4-cyanomethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (36 g) as a dark brown oil which was essentially pure and used in the next step without further purification. MS (ESI): 197.3 [(M-Boc)H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>CO>[CH3:17][N:18]([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)c1ccc(C(=O)c2cncn2C)cn1
Temperature: 75 °C

Procedure:
In a 50-mL round-bottom flask was placed a solution of 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 22, step c), dimethylamine hydrochloride (96 mg, 1.2 mmol), and Et3N (342 mg, 3.39 mmol) in methanol (15 mL). The resulting mixture was heated at 75° C. overnight and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:0-20:1 CH2Cl2/MeOH) to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 86.9 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (Intermediate 7, 0.9 g, 2 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.04 g, 6 mmol) in water (2.5 mL). The reaction mixture was stirred at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-3,4-difluoro-N2-(2-fluoro-4-iodo-phenyl)-benzene-1,2-diamine as a brown solid (730 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (2H, bs), 4.54 (2H, d, J=5.2), 5.34 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 5.66 (1H, bs), 6.02-6.09 (1H, m), 6.20 (1H, d, J=8.4), 6.62-6.66 (1H, m), 7.33 (1H, dd, J=2, 8.4), 7.63 (1H, d, J=2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Product: CC(=O)CC(=O)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 22.8 g (0.111 mol) of N-3-hydroxypropyl phthalimide and 14.46 g (0.111 mol) of ethyl acetoacetate was heated at 145°-150° C. for 12 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was cooled to room temperature, dissolved in dichloromethane, and washed with brine. The separated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 211°-219° C. (0.125 mm Hg) to yield 17.3 g (54%) of a white solid; m.p. 67°-71° C. NMR: (CDCl3) δ2.0 (2H,m), 2.2 (3H,s), 3.3 (2H,s), 3.7 (2H,t), 4.05 (2M,t), 7.62 (4H,d).
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4].Cl.[O:20]([NH2:23])[CH2:21][CH3:22]>C(O)C>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[N:23][O:20][CH2:21][CH3:22])[C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCON
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
1 N Sodium hydroxide solution (8.5 ml.) was added to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl)-glyoxylate (1.9 g.) in ethanol (30 ml.) at room temperature and stirred at the same temperature for 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to the solution, the solution was stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was added to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with a mixture of diethyl ether and petroleum ether to give 2-(6-formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (920 mg.), mp. 155° to 156° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Cl:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-Chloroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation G, 3.3 g, 9.8214 mmol) and triethylamine (1.34 g, 12.74 mmol) in CH2Cl2 (120 mL) was added over 40 min to a solution of triphosgene (3.5 g, 11.7852 mmol) in 80 mL of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture was stirred for 20 min at this temperature then quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound. Yield: 1.2 g (34%); 1H NMR (DMSO-d6, 300 MHz): δ 12.190 (s, 1H), 8.921 (s, 1H), 8.069-8.100 (d, 1H, J=8.7 Hz), 7.807-7.835 (d, 2H, J=8.4 Hz), 7.641-7.694 (m, 3H), 6.808-6.815 (d, 1H, J=2.1 Hz), 1.766 (s, 6H); MS: m/z 363 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c(C)noc2C)c1C#N
Temperature: 120 °C
Yield: 39 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (107 mg, 0.395 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (100 mg, 0.593 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.2 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 45% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (62 mg, 39%). 1H NMR (500 MHz, CD3OD) δ ppm 1.31-1.42 (m, 3 H), 2.01 (s, 2 H), 2.15 (s, 1 H), 2.19 (s, 1 H), 2.32 (d, J=4.39 Hz, 5 H), 3.86 (s, 3 H), 5.39-5.48 (m, 1 H), 6.65-6.69 (m, 1H), 7.59 (d, J=3.42 Hz, 1 H), 7.68-7.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C2H22N8O, 403; found 403.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Yield: 97.6 %

Procedure:
A solution of bromine (0.31 mL, 5.9 mmol) in carbon tetrachloride (10 mL) was added to a suspension of N-(4-acetylphenyl)acetamide (1 g, 5.6 mmol) (Lancaster Synthesis) in carbon tetrachloride (20 mL). The reaction mixture was stirred for several hours but TLC indicated only starting material. Acetic acid (10 mL) was added, and the reaction mixture was stirred overnight. Filtration gave N-[4-(bromoacetyl)phenyl]acetamide (1.4 g) as a solid. HPLC indicated that the purity was approximately 80%. This material was used directly in subsequent steps without purification.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)[CH3:4].[OH:19][NH:20]Cl>CO>[C:3](=[N:20][OH:19])([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4]
Reactant: CC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: ONCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 1.0 g of potassium hydroxide in 25 ml of methanol, there is added a mixture of 0.85 g of 3-acetyl-β-carboline, 75 ml of methanol and 1.0 g of hydroxyamino hydrochloride. The reaction mixture is allowed to stand for 4 hours at room temperature. After evaporation, water is added and then the mixture is brought to pH 7 with glacial acetic acid. The solid reaction product is filtered and washed with water and ether. 0.6 g of 3-acetyl-β-carboline-oxime with an m.p. of 250° C. (decomposition) is obtained. In analogous manner there is obtained: 3-pentanoyl-β-carboline-oxime, m.p. 95°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:35]([C:39](N)=[NH:40])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:39]([NH2:40])=[NH:35]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][CH2:13][C:14]1[CH2:31][N:29]2[CH2:30][C@H:16]([CH2:17][C@:18]([C:65]([O:67][CH3:68])=[O:66])([C:32]3[CH:33]=[C:34]4[C@:42]56[C@@H:46]7[C@:47]([CH2:62][CH3:63])([C@@H:51]([O:58][C:59]([CH3:61])=[O:60])[C@:52]([OH:57])([C:53]([O:55][CH3:56])=[O:54])[C@@H:41]5[N:40]([CH3:64])[C:35]4=[CH:36][C:37]=3[O:38][CH3:39])[CH:48]=[CH:49][CH2:50][N:45]7[CH2:44][CH2:43]6)[C:19]3[NH:27][C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]=3[CH2:28]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:12][CH2:13][C:14]1[CH2:31][N:29]2[CH2:30][C@@H:16]([CH2:17][C@:18]([C:65]([O:67][CH3:68])=[O:66])([C:32]3[CH:33]=[C:34]4[C@@:42]56[C@@H:41]([N:40]([CH3:64])[C:35]4=[CH:36][C:37]=3[O:38][CH3:39])[C@@:52]([OH:57])([C:53]([O:55][CH3:56])=[O:54])[C@H:51]([O:58][C:59]([CH3:61])=[O:60])[C@:47]3([CH2:62][CH3:63])[CH:48]=[CH:49][CH2:50][N:45]([C@H:46]53)[CH2:44][CH2:43]6)[C:19]3[NH+:27]([O-:6])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[CH2:28]2)[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1=C[C@@H]2CN(C1)Cc1c([nH]c3ccccc13)[C@@](C(=O)OC)(c1cc3c(cc1OC)N(C)[C@H]1[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]4(CC)C=CCN5CC[C@]31[C@@H]54)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1=C[C@H]2CN(C1)CC1=C([NH+]([O-])c3ccccc31)[C@@](C(=O)OC)(c1cc3c(cc1OC)N(C)[C@H]1[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]4(CC)C=CCN5CC[C@]31[C@@H]54)C2
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Vinorelbine N′b-oxide was synthesized using essentially the same procedure used to prepare vinblastine N′b-oxide. m-Chloroperoxybenzoic acid (45 mg, 0.26 mmol) in CHCl3 (2.5 mL) was added at 0° to a stirred solution of purified vinorelbine (150 mg, 0.20 mmol) in CHCl3 (4.5 mL) under nitrogen. After 15 min, the mixture was poured into an aqueous sodium carbonate (27 mL, 40 g/L) and was extracted by CHCl3 (20 mL). After drying over sodium sulfate and filtration, the CHCl3 extract was evaporated under reduced pressure affording crude vinorelbine N-oxide (125 mg, 83%). Thin-layer chromatography (silica; 9:1 CHCl3/MeOH) indicated the presence of a small amount of starting vinorelbine (vinorelbine Rf=0.37, vinorelbine N′b-oxide Rf=0.18). Radial chromatography on silica gel (eluent, 9:1 CHCl3/MeOH) gave vinorelbine N′b-oxide as an off-white solid (100 mg; 75%). The sample was dissolved in ethyl acetate/hexanes and then the open flask was placed in a sealed container containing an open flask of hexanes. As the hexanes diffused slowly into the vinorelbine N′b-oxide solution, vinorelbine N′b-oxide precipitated out as an off-white powder (80 mg; 53%). The 300 MHz 1HNMR spectrum was consistent with the assigned structure. The configuration of the N′b-oxide oxygen atom is assigned the same stereochemistry as that found in vinblastine N-oxide by x-ray crystallography.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1.[CH2:15]([CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH:27]=[O:28])[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1COCC1>[CH3:1][Si:2]([CH3:13])([CH3:14])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:27]([OH:28])[CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(CO[Si](C)(C)C)cc1
Reactant: CCCCCC1CCC(CC=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CC(O)C#Cc2ccc(CO[Si](C)(C)C)cc2)CC1
Temperature: 25 °C

Procedure:
4-Trimethylsilyloxymethylphenylacetylene (20 mmol) was dissolved in THF (20 ml), followed by dropwise adding n-butyllithium-hexane solution (1.61M, 12.4 ml) while stirring the above solution under ice-cooling, stirring the reaction solution under ice-cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (4.0 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (150 ml), washing the organic phase with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, and recrystallizing it from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-trimethylsilyloxymethylphenyl)-4-(trans-4-pentylcyclohexyl)-1-butyn-3-ol (white crystals) (5.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccccn2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (prepared by reaction of 1-methyl-4-piperidone with phenyl lithium; 3.83 g, 20 mM) in dry DMSO (50 ml) was treated with sodium hydride (960 mg of 50% dispersion in oil, 20 mM), stirred for 1 hour then treated with 2-fluoro-pyridine (1.94 g, 20 mM). After 48 hours the reaction was poured on to water (200 ml) and extracted with ether (3×200 ml). The organic extract was washed with brine, dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (2.0 g,) m.p. 95°-6° C.
Reaction SMILES: CN(C)C(N(C)C)=N.[N+:9]([CH3:12])([O-:11])=[O:10].[C:13]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C@H:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:32]=[O:33])[CH2:21]2)[CH:14]=1>O1CCCC1>[N+:9]([CH2:12][CH:32]([C@@H:22]1[CH2:21][C@@H:20]([O:19][C:15]2[CH:14]=[C:13]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][N:23]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:33])([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C=O
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C(O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1,3,3-Tetramethylguanidine (52 μL) and nitromethane (222 μl) were added to a solution of crude (2S,4R)-4-(3-biphenyloxy)-N-tert-butoxycarbonyl-2-pyrrolidinecarboxaldehyde (B, 754 mg) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 3 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give crude the titled compound (877 mg), which was used in the subsequent step.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[C:14]([Br:31])[CH:13]=2.[Cl:32][CH2:33][C:34](Cl)=O>ClCCl>[Br:31][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:34]([CH2:33][Cl:32])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
Triethylamine (26.7 g, 264 mmol) was added to a solution of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate (52.17 g, 132.0 mmol) in dichloromethane (370 mL). Chloroacetyl chloride (15.65 g, 138.6 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was stirred in ethanol (1 L) overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed twice with water, concentrated under reduced pressure, and dried under high vacuum to provide 41.63 g of tert-butyl 3-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH:13]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:18]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:17]=1)([CH3:15])[CH3:14].[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45]O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([C:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:45][CH2:44][NH:43][C:41](=[O:42])[O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:26]=2)[N:18]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Diethylazodicarboxylate (259 mg) was added to a mixture of 4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained by Example 1-3 (305 mg), 2-t-butoxycarbonylaminoethanol (479 mg), and triphenylphosphine (390 mg) in tetrahydrofuran (3 ml). After stirring at room temperature for 7 hrs, diethylazod icarboxylate (17 mg) and triphenylphosphine (26 mg) was added to the reaction mixture.