Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 47.4 %

Procedure:
A solution of 4-pyridyl piperazine (9.78 g), 4-fluorobenzonitrile(7.26 g) and powdered potassium carbonate(10 g) was stirred and heated in DMSO(100 ml) at 100° C. for 18 hours. The solution was poured into water (500 ml) to give a precipitate which was filtered and washed with water. The crude solid was dried in a vacuum oven for 18 hours. The residue was dissolved in dichloromethane and purified by flash chromatography on alumina (ICN Alumina N 32-63) using an increasing concentration of ethyl acetate in dichloromethane (up to 100% ethyl acetate) as eluant to give a solid which was recrystallised from ethyl acetate/isohexane to give 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (7.5 g) as a solid. m.p. 157-158° C.; microanalysis. found: C, 72.7; H, 6.1; N, 21.0%; C16H16N4 requires: C, 72.7; H, 6.1; N, 21.2%. NMR (dmso-d6):3.45-3.55(8H,bs),6.8-6.9(2H,d);7.0-7.1(2H,d); 7.55-7.65(2H,d);8.1-8.2(2H,d); MS m/Z 265 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 25.2 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.072 g, 0.18 mmol) and EtOH (2 mL), p-anisaldehyde (0.079 g, 0.20 mmol) in EtOH (2 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.54 mL, 0.54 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.022 g, 25%); 1H-NMR (500 Mz, DMSO-d6): δ 2.75 (m, 4H, piperazine N(CH2)2), 3.65-3.73 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 3.95 (s, 2H, NCH2), 7.11 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.14 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.21 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.36 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 4.10 min—485/487 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 485.0759, calculated for C21H22BrN6OS (M+H)+: 485.0748.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[C:7]2[N:12]=[CH:13][C:14]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:15][C:6]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CN1CCN(Cc2cc(Cl)ccc2Cl)c2cc(I)cnc21
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4C)cn2)CC1
Yield: 43 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (83 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (43% yield). LCMS: m/z=483.33 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.52 (4H, t, J=5.1 Hz), 3.16 (3H, s), 3.53 (8H, m), 4.45 (2H, s), 6.45 (1H, d, J=1.8 Hz), 6.65 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.5, 4.8 Hz), 7.25 (1H, d, J=2.3 Hz), 7.32 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.6, 2.5 Hz), 7.75 (1H, d, J=1.8 Hz), 8.22 (1H, d, J=2.5 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].[N:17]#[C:18]Br>O1CCCC1.O>[Br:7][C:8]1[N:9]([C:18]#[N:17])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: N#CBr
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(C#N)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Potassium t-butoxide (614 mg, 5.74 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (1.50 g, 4.56 mmol) in anhydrous tetrahydrofuran (20 mL). After 15 minutes a solution of cyanogen bromide (177 mg, 5.74 mmol) in tetrahydrofuran (5 mL) is added dropwise. The reaction solution is stirred at room temperature overnight as it turns cloudy. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried over (Na2SO4). Evaporation of the solvent and crystallization of the residue from ether gives a white solid (1.20 g); mp 195.0°-197.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH:1][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccc(C)cc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.836 g, 0.00152 mol) and p-toluenesulfonyl chloride (0.440 g, 0.00231 mol) in 40 mL of methylene chloride qas added 4 mL of pyridine. The reaction mixture was stirred for 54 h at room temperature, washed with 1N HCl, 1N NaOH solutions, dried over Na2SO4 and evaporated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 0.933 g (87%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:27]([NH:26][C@H:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:8]3[N:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=3)[CH2:17][CH2:16]2)=[CH:19][CH:20]=1)[CH3:25])(=[O:29])[CH3:28]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)O)cn3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 1.52 g (8.5 mmol) 2-chloropyrimidine-5-carboxylic acid methyl ester in 80 mL NMP are added 2.1 g (8.5 mmol (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 2.9 mL (17.1 mmol) DIPEA and the mixture is stirred for 4 h at 100° C. The solvent is removed in vacuo. The residue is treated with 100 mL MeOH and 10 mL 4N sodium hydroxide solution is added. The mixture is stirred for 1 h at 60° C. After cooling to rt 4N HCl solution is added until the pH is acidic. The precipitate is collected and dried to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2=CCCCC2)cc1

Procedure:
To a stirred solution of p-hydroxybenzoic acid (1.38 gm, 10 mmol) in THF (30 ml) is added sodium hydride (0.48 g, 20 mmol), followed by cyclohexenyl bromide (1.63 gm 10 mM). The mixture is heated to reflux for 12 hours. After cooling the reaction mixture is poured into ethyl acetate and extracted with 1N NaOH (3×). The combined aqueous extracts are combined, acidified to pH 2 with concentrated HCl, and extracted 3× with ethyl acetate. The combined organic extracts are dried over Na2SO4 and evaporated under reduced pressure to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH2:6][OH:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Cl)cc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(C)c1CO
Temperature: 0 °C

Procedure:
Dissolve 4-chloro-2,6-dimethyl benzaldehyde (5.0 g, 168.64 g/mol) in 100 mL dry methanol. Cool to 0° C. while stirring under N2. Portionwise add powdered NaBH4 (0.76g, 37.85 g/mol) over 5 minutes. Stir at 0° C. for 2 hours, monitoring by TLC until aldehyde consumed, then evaporate to a yellow oil. Add H2O (50 mL) and bring to pH. 7.0 by addition of saturated NH4Cl. Extract the neutral aqueous layer with CH2Cl2 (3×75 mL) and dry the pooled organic layers over Na2SO4. Filter and concentrate to a yellow oil. Flush through a pad of silica to remove baseline material, then evaporate to a yellow solid (3.0 g) which can be used without further purification. LCMS=171.6 (MH+), 169.6 (M−)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[CH2:7][CH:8]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:33]=2[C:34]([NH:36][CH3:37])=[O:35])[C:28]([Cl:43])=[CH:27][N:26]=1>>[Cl:43][C:28]1[C:29]([NH:31][C:32]2[C:33]([C:34](=[O:35])[NH:36][CH3:37])=[CH:38][CH:39]=[CH:40][C:41]=2[F:42])=[N:30][C:25]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([CH3:20])([CH3:21])[CH2:7][CH:8]([NH:12][C:13]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[O:14])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:26][CH:27]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)N2CCCC2)C(=O)Nc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)N2CCCC2)CC3(C)C)ncc1Cl

Procedure:
Pyrrolidine-1-carboxylic acid {8-[5-chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl}-amide was prepared from Pyrrolidine-1-carboxylic acid (8-amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-amide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (29 mg, 22%), HPLC purity=94%, LCMS 597 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 9.40 (s, 1H), 9.33 (s, 1H), 8.54 (d, 1H), 8.19 (s, 1H), 7.52-7.42 (m, 2H), 7.38-7.25 (m, 2H), 7.15-7.07 (m, 2H), 5.92 (m, 1H), 4.09 (m, 1H), 3.22-3.18 (m, 4H), 2.73 (d, J=3.5 Hz, 3H), 1.81-1.77 (m, 4H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>C(O)(=O)C.[Fe]>[F:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:15]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])C(N)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: NC(=O)c1cc2cc(F)ccc2nc1N

Procedure:
Iron powder (8.52 g., 0.152 mole) is gradually added over a forty minute period to a slurry of α-cyano-β-(2-nitro-5-fluorophenyl)acrylamide (7.97 g., 0.034 mole) in acetic acid (100 ml.) at 85° C. When addition of the iron powder is complete, the mixture is heated to 95°-100° C. for 1.5 hours and then filtered hot through diatomaceous earth. The filtrate is cooled in an ice bath and then filtered to give a tan crystalline solid. The solid is partitioned between ethyl acetate and water, the organic phase separated, dried over anhydrous sodium sulfate and concentrated to yield 6.34 g. (90%) of the title amide as yellow crystals. M.P. 232°-236° C.
Reaction SMILES: [OH-].[K+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=O)C>CO>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2C(C)=O)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Yield: 76.5 %

Procedure:
A solution of potassium hydroxide (0.22 g) in methanol (4 ml) was added at room temperature to tert-butyl 5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (1.00 g) obtained in Reference Example 47, and heated at reflux for 2 hours with stirring. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane: ethyl acetate=1:1) to give the title compound as a pale yellow oil (700 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]cc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]cc(Br)cc1OCc1ccccc1
Temperature: 60 °C
Yield: 38.7 %

Procedure:
To a solution of 4.4 g (23.2 mmol) 5-bromo-3-hydroxy-1H-pyridin-2-one and 1.2 g (30 mmol) NaOH in 116 mL MeOH was added benzyl bromide dropwise at room temperature. The resulting mixture was heated to 60° C. overnight. After cooling, the volatiles were removed in vacuo, 20 mL water and 40 mL EtOAc were added, and the aqueous phase was extracted 2× with 20 mL EtOAc. The combined organics were dried over Na2SO4 and evaporated. Purification by automated flash chromatography (80 g silica gel cartridge 0-100% EtAOc/hex over 30 min) afforded 2.51 g (38.7%) 3-benzyloxy-5-bromo-1H-pyridin-2-one. LCMS [M+H]+=280.1
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].N1C=NC=N1.[OH-].[Na+].[C:14]([C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17]Br)#[N:15]>O.CS(C)=O>[C:14]([C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)#[N:15]
Reactant: c1nc[nH]n1
Reactant: CCCCC(C#N)(CBr)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a dimethyl sulfoxide solution (25 ml) of sodium 1,2,4-triazole, generated from 3.2 g (0.046 m) of 1H-1,2,4-triazole and 1.85 g (0.046 m) of sodium hydroxide, is added 2-cyano-2-(2,4-dichlorophenyl) hexyl bromide dropwise at 110°. The whole is stirred at 110° for 11/2 hours. The reaction mixture is poured into 400 ml of water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Drying agent was filtered and to the filtrate is added conc. nitric acid dropwise until no more precipitates form. The precipitate (8.0 g) is filtered and is characterized as the nitric acid salt (RH 45,136) of the desired product.
Reaction SMILES: C([O-])(=O)C.[Na+].I[CH2:7][C:8]#[N:9].[CH3:10][C@@H:11]1[O:16][C@@H:15]([O:17][C@@H:18]2[C:23]3=[C:24]([OH:41])[C:25]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][C:35]=5[O:39][CH3:40])[C:29](=[O:30])[C:26]=4[C:27]([OH:28])=[C:22]3[CH2:21][C@@:20]([OH:45])([C:42]([CH3:44])=[O:43])[CH2:19]2)[CH2:14][C@H:13]([NH2:46])[C@@H:12]1[OH:47]>CN(C=O)C>[CH3:10][CH:11]1[O:16][CH:15]([O:17][CH:18]2[C:23]3[C:22](=[C:27]([OH:28])[C:26]4[C:29](=[O:30])[C:31]5[CH:32]=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[C:36]=5[C:37](=[O:38])[C:25]=4[C:24]=3[OH:41])[CH2:21][C:20]([OH:45])([C:42]([CH3:44])=[O:43])[CH2:19]2)[CH2:14][CH:13]([NH:46][CH2:7][C:8]#[N:9])[CH:12]1[OH:47]
Reactant: N#CCI
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)CC(O)(C(C)=O)CC3OC1CC(NCC#N)C(O)C(C)O1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A sample of 0.017 grams (0.21 mmol) of anhydrous sodium acetate and 15 μl (0.033 g, 0.197 mmol) of iodoacetonitrile were added to a solution of 0.065 grams (0.123 mmol) of daunorubicin, free base, in 1 ml of dry DMF, and the dark red mixture thus obtained stirred at room temperature in the dark for 44 hours until thin layer chromatography (TLC) run on aliquots of the reaction mixture showed conversion to the desired product. The reaction mixture was then evaporated at low temperature and pressure (about 35°, <5 mm), the residue dissolved in 10 ml chloroform/methanol (9/1) and the solution washed with acetic acid, water, and sodium bicarbonate and dried. The organic layer was evaporated, and the residue further purified to obtain 0.059 g (84%) of the desired N-cyanomethylDau. Daunorubicin (0.010 g) was recovered from the acetic acid extract.
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)[C:7](/C=C(\CC2C=CC=CC=2)/C(O)=O)=[C:8]([CH2:10][OH:11])N=1)CCC.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][OH:39])=[CH:36][CH:35]=1>>[C:10]([O:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)(=[O:11])[CH:8]=[CH2:7]
Reactant: COc1ccc(CO)cc1
Reactant: CCCCc1nc(CO)c(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Product: C=CC(=O)OCc1ccc(OC)cc1

Procedure:
(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-hydroxymethyl-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid, prepared as in Example 28, is esterified with p-methoxy-benzyl alcohol to give the p-methoxybenzyl propenoate. The 4-hydroxymethyl group is oxidized using Jones reagent in acetone and the ester is hydrolized using 10% sodium hydroxide to give the title compound.
Reaction SMILES: C(OP([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C:30](=O)[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH:31]=[C:30]([CH2:9][P:10]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])=[O:11])[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]
Reactant: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(CP(=O)(OCC)OCC)=CCN1C(=O)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 5.3 ml of bis-(diethylphosphono)methane in 30 ml of anhydrous tetrahydrofuran (THF) under nitrogen is cooled to -78° and 8.5 ml of 2.5M butyl lithium is added dropwise. After stirring 5 minutes a solution of 4.64 g of ethyl 1-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylate [J. Am. Chem. Soc. 86, 5297 (1964)]in 30 ml dry THF is added dropwise rapidly. The solution is heated at reflux for 18 hours, cooled to room temperature and concentrated; 40 ml of 1N hydrochloric acid is added and the mixture is extracted with 100 ml of methylene chloride. The organic fraction is washed with 25 ml water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography using ethyl acetate as solvent yields ethyl 1-ethoxycarbonyl-3-(diethylphosphono- methyl)-2,5-dihydropyrrole-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:17])[CH2:9][CH:10]2[S:14][C:13](=[NH:15])[NH:12][C:11]2=[O:16])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[CH2:23]Br.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH:25]([CH2:23][C:3]1[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([NH:7][C:8](=[O:17])[CH2:9][CH:10]2[S:14][C:13](=[NH:15])[NH:12][C:11]2=[O:16])[S:6][C:2]=1[Br:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1c(NC(=O)CC2SC(=N)NC2=O)sc(Br)c1CBr
Reactant: Nc1ccccc1
Product: CCOC(=O)c1c(NC(=O)CC2SC(=N)NC2=O)sc(Br)c1CNc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To ethyl 5-bromo-4-(bromomethyl)-2-{[(2-imino-4-oxo-1,3-thiazolidin-5-yl) acetyl]amino}thiophene-3-carboxylate (25 mg, 0.05 mmol) in N,N dimethyl formaide (1 mL) was added aniline (10 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was concentrated and purified by reverse phase column to yield ethyl 4-(anilinomethyl)-5-bromo-2-{[(2-imino-4-oxo-1,3-thiazolidin-5-yl)acetyl]amino}thiophene-3-carboxylate (5.0 mg, 20% yield).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([CH:23]=[O:24])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
N-(6-fluoropyridin-2-yl)pivalamide(1.67 g, 8.5 mmol) was dissolved in THF(15 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under nitrogen gas over 10 min. The resulting yellow solution was continued stirring at −78° C. for 3 hr, followed by dropwise addition of DMF(2.0 mL, 25.5 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), partitioned between H2O/EtOAc (100 mL/100 mL). After separation, the organic phase was washed with brine(30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids(343 mg, 18% yield), plus the recovered starting material(622 mg); 1H NMR (400 MHz, CDCl3) δppm 1.23-1.30 (s, 9H), 8.12 (s, 1H), 8.18-8.27 (m, 2H), 10.13 (s, 1H); Mass spec. 225.13 (MH+), Calc. for C11H13FN2O2 224.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][N:14]=3)[N:4]2[N:3]=1
Reactant: O=C(O)c1cnccn1
Reactant: NNc1nnc(Cl)c2ccccc12
Product: Clc1nn2c(-c3cnccn3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 1-chloro-4-hydrazinophthalazine and pyrazine-2-carboxylic acid as described for Intermediate 1 part c, 1H NMR (250 MHz, CDCl3) δ 7.99 (1H, t, J=7.2 Hz, Ar—H), 8.09 (1H, t, J=8.2 Hz, Ar—H), 8.33 (1H, d, J=6.8 Hz; Ar—H), 8.80 (1H, m, Ar—H), 8.82-8.88 (2H, m, 2 of Ar—H), 9.67 (1H, d, J=1.5 Hz, Ar—H).