Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.[C:22]([C:26]1[CH:57]=[CH:56][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][NH:40][CH:41]2[CH2:50][CH2:49][CH2:48][C:47]3[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]2=3)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].ICCC1C=CC(C(OC)=O)=CC=1>C(#N)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:41]2[CH2:50][CH2:49][CH2:48][C:47]3[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]2=3)=[CH:56][CH:57]=1)([CH3:24])([CH3:23])[CH3:25]
Reactant: COC(=O)c1ccc(CCCl)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(C(C)(C)C)cc1
Agent: COC(=O)c1ccc(CCI)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(C(C)(C)C)cc1

Procedure:
129 mg (0.65 mmol) of methyl 4-(2-chloroethyl)benzoate and 91 mg (0.86 mmol) of anhydrous sodium carbonate were added to a solution of 210 mg (0.43 mmol) of ethyl 5-[(2-{2-[(4-tert-butylbenzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride in 4 ml of dry acetonitrile, and the mixture was initially heated under reflux for 4 hours. A further 0.1 ml of methyl 4-(2-chloroethyl)benzoate was then added, and the mixture was stirred under reflux for 4 hours. Another 0.1 ml of methyl 4-(2-chloroethyl)benzoate was metered in, and the mixture was then heated under reflux overnight. Subsequently, another 0.1 ml of methyl 4-(2-chlor-oethyl)benzoate and 100 mg of anhydrous sodium carbonate were added, and the mixture was stirred under reflux for a further 5 hours. Finally, another 0.1 ml of methyl 4-(2-chloroethyl)-benzoate and 0.2 ml of methyl 4-(2-iodoethyl)benzoate were added, and the reaction mixture was stirred under reflux for 2 days. The reaction was then concentrated to dryness. The residue obtained was purified by preparative HPLC. This gave 38 mg (0.06 mmol, content 92%, 14% of theory) of the title compound as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccccn1
Reactant: OCc1cccc(NO)c1
Product: [O-][N+](=Cc1ccccn1)c1cccc(CO)c1
Yield: 65 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 2-pyridinecarboxaldehyde (63) (1.07 g, 10 mmol) afforded, after workup, a yellow oil. The crude product was purified by passing through a short column of silica gel with 20:1 ethyl acetate/methanol as the eluant then recrystallized from acetone/petroleum ether to obtain 1.48 g (6.5 mmol, 65%) of 95 as a yellow crystalline solid: mp 117°-119° C.; IR (CH2Cl2) 3610, 3340, 1580, 1550, 1390, 1090 cm-1 ; 1H NMR (CDCl3) δ 4.53 (t, J=5.8, 1H), 4.65 (d, J=5.6 Hz, 2H), 7.28-9.27 (m, 9H); 13C NMR (CDCl3) δ 63.86, 119.70, 120.37, 124.33, 124.91, 128.59, 129.31, 135.80, 137.25, 143.61, 148.62, 149.50, 149.84. Anal. Calcd for C13H12N2O2 : C, 68.42; H, 5.26. Found: C, 68.52; H, 5.30.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[BH4-].[Na+]>CO.C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1ccccc1Sc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccccc1Sc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 2-(2-naphthylthio)benzaldehyde (7.24 g; 27.4 mmol from Example 6, step 1) in 70 mL of methanol and 30 mL of THF at 0° C. was added NaBH4 (54.8 mml) portionwise. After 1 h at 0° C., the solution was brought to r.t. and quenched with water. After dilution with EtOAc, the solution was washed with water and brine. The organic phase was dry over Na2SO4, filtered and the crude purified by silica gel chromatography to yield 6.71 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>CC(C)=O.CCCCCC>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 13.7 g of 3-hydroxybenzamide and 25.6 of benzyl bromide in acetone (400 ml) were added 25.6 g of potassium carbonate at RT. The mixture was then refluxed for 6 h after which time the reaction was completed according to TLC analysis (CH2Cl2/MeOH: 20/1). The reaction mixture was cooled to RT and partitioned between EtOAc and water, the organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The crystalline residue obtained was suspended in n-hexane (200 ml), the crystals were filtered off under suction and dried in a vacuum to give 3-benzyloxy-benzamide as a white crystalline solid, mp 136°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.[F:21][C:22]([F:26])([F:25])[CH:23]=[O:24]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([CH:23]([C:22]([F:26])([F:25])[F:21])[OH:24])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=CC(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)F
Yield: 53.8 %

Procedure:
A mixture of 2.55 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 1.3 g (0.011 mole) of trifluoroacetaldehyde hydrate in 75 ml toluene was heated at reflux for 3.5 hours. The mixture was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel to give 1.9 g of product, m.p. 121°-122°.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(I)nc1
Reactant: COCOc1cccc(B(O)O)c1
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: CCO
Product: CCOC(=O)c1ccc(-c2cccc(O)c2)nc1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 1 g (6.7 mmol) of 3-methoxymethoxyphenylboronic acid (described in Example l(g)) and 1.5 g (5.6 mmol) of ethyl 6-iodonicotinate with 5.6 mL of 2.0M potassium carbonate and 320 mg of tetrakis(triphenylphosphine)palladium, followed by deprotection in ethanol, the desired product is obtained in the form of a white solid (m=354 mg; Y=26%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:13][CH:12]=[N:11][C:10]=2[N:9](COCC[Si](C)(C)C)[CH:8]=1.C(C(O)=O)(F)(F)F.C(N)CN.[OH-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(-c4ccccn4)c23)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-(5-(pyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (170 mg, 0.350 mmol) in dichloromethane (2.0 mL), was added CF3CO2H (2.0 mL). The resulting solution was stirred for 2 hours at 50° C. and then concentrated in vacuo. The residue was dissolved in methanol (2 mL), and ethane-1,2-diamine (42 mg, 0.70 mmol) and sodium hydroxide (98 mg, 1.6 mmol) were added. The resulting solution was stirred for 30 minutes at room temperature before being concentrated in vacuo. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product by reverse phase HPLC using an acetonitrile gradient in water with 0.5% TFA modifier afforded N-(3-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a white solid. LRMS (ESI) calc'd for C21H18N5O [M+H]+: 356, found 356. 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.27 (s, 1H), 8.12-8.16 (m, 1H), 7.90 (s, 1H), 7.64-7.68 (m, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=6.8 Hz, 1H), 7.37-7.40 (m, 2H), 5.72 (s, 1H), 5.52 (s, 1H), 1.91 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([O:32][CH2:33]C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:3]1([CH:9]([O:32][CH2:33][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccccc3)c3ccccc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCCCc3ccccc3)c3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of sodium hydride (44 mg, 1.1 mmol) in DMF (5 mL) at 0° C. was added dropwise a solution of Example 293 Part A compound (400 mg, 1.0 mmol) in DMF (1 mL). The reaction was stirred at 0° C. for 30 min. 1-Bromo-3-phenylpropane (219 mg, 1.1 mmol) was added dropwise to the reaction at 0° C. The reaction was stirred at 0° C. for 1 h then warmed to RT overnight. The reaction was quenched with saturated ammonium chloride solution (2 mL). Ethyl acetate (100 mL) was added to the reaction, and the organic layer was washed with water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 50% ethyl acetate in hexane. Pure fractions were combined and evaporated to give title compound (335 mg, 65%) as a white solid.
Reaction SMILES: CS([O:5][CH2:6][CH:7](O)[CH2:8][C:9]1[C:10]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[C:22]([F:25])[CH:21]=[CH:20][CH:19]=3)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=O)=O.[H-].[Na+].O>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[CH2:8][CH:7]([CH2:6][OH:5])[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:10]=2[N:11]=1
Reactant: CS(=O)(=O)OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)-2-hydroxypropyl methanesulfonate (100 mg, 0.25 mmol) in DMF (5 mL) was stirred under N2 at 0° C. After NaH (30 mg, 60% in mineral oil, 0.75 mmol) was added, the mixture was stirred at 0° C. for 0.5 h and RT for 2 h. After cooling to 0° C., water was added and the mixture extracted with EtOAc. Then the organic layer was washed with water, brine, dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatography (PE:EA=2:1˜1:1) to give the product of (2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)methanol (70 mg, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 7.50 (d, J=7.6 Hz, 1H), 7.37 (s, 1H), 7.13˜7.19 (m, 3H), 6.78 (t, J=7.6 Hz, 1H), 4.79˜4.84 (m, 1H), 3.69˜3.73 (m, 1H), 3.60˜3.62 (m, 1H), 3.38˜3.42 (m, 1H), 3.24 (d, J=16.4 Hz, 1H). MS (M+H)+: 303/305.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl.N=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[CH:10]1[CH:11]=[CH:12][C:7]2[N:1]([C:2]([NH2:4])=[O:3])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:14]=[CH:13][C:8]=2[CH:9]=1
Reactant: NC(N)=O
Reactant: N=C1C=CC=CC1C=Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (80 g, 1.333 mols) in acetic acid (100 ml), iminostilbene hydrochloride (20.5 g, 0.089 mols) was added under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].[ClH:36]>C(O)C>[ClH:36].[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:30][NH:31][C:32](=[NH:33])[NH:34][OH:35])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Br)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccsc1Br)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 7-(2-bromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.245 g) and 1-amino-3-hydroxyguanidine p-toluenesulfonate (262 mg) were added ethanol (3 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 90° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added 0.2N sodium hydroxide solution (20 ml). The mixture was extracted with a mixture of ethyl acetate (20 ml) and tetrahydrofuran (20 ml). The organic layer was washed with 0.2N sodium hydroxide solution (20 ml) and water, to which was added 2N hydrochloric acid (0.8 ml). The mixture was concentrated, and to the residue was added ethanol (3 ml). The mixture was stirred at 90° C. for 3 hours and cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-bromothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 125) (0.215 g) as pale yellow crystals.
Reaction SMILES: Cl.N1C=CC=CC=1.C(O[CH:11](OCC)[N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[N:17][N+:18]([O-:20])=[O:19])C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCN(C)C1=O>O>[C:31]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[N:17][N+:18]([O-:20])=[O:19])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])N=C1NCCN1C=Nc1ccccc1-c1ccccc1
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
0.25 g of pyridine hydrochloride was added to a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 3.64 g of o-aminobiphenyl and 3 ml of 1,3-dimethyl-2-imidazolidinone at 100° C., followed by agitation at the same temperature for 20 minutes. The reaction mixture was poured into water, extracted with ethyl ether, washed with water, dried and concentrated, followed by addition of ether to the resultant oily residue. The resulting crystals were collected by filtration and dried to give 3.2 g of 1-(2-phenylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(C=[N+]=[N-])=O)CC1C=CC(O)=CC=1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=CC(O)=CC=1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)C.[NH:58]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:59]([C:63]([CH:65]=[N+:66]=[N-:67])=[O:64])[CH:60]([CH3:62])[CH3:61].[ClH:75]>>[NH:58]([C:68]([O:70][C:71]([CH3:73])([CH3:72])[CH3:74])=[O:69])[C@H:59]([C:63]([CH:65]=[N+:66]=[N-:67])=[O:64])[CH:60]([CH3:61])[CH3:62].[NH:58]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:59]([C:63]([CH2:65][Cl:75])=[O:64])[CH:60]([CH3:62])[CH3:61]
Reactant: Cl
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)C=[N+]=[N-]
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)CCl

Procedure:
Boc-ValCHN2 was prepared by a procedure substantially similar to that described for preparation of Boc-TyrCHN2 (Procedure C) except that Boc-Tyr-OH was replaced with Boc-Val-OH. Boc-ValCHN2 was treated with 3.45N ethanolic:HCl, as described in Procedure C, to give Boc-ValCH2Cl. After crystallization from hexane, product melted at 70°-73°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[CH2:28][CH2:29][O:30][CH2:31][CH:32]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:27]3[CH2:32][CH2:31][O:30][CH2:29][CH:28]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example 35(d)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 6.9 mmol) in DMF (15 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (828 mg, 20 mmol) and the mixture stirred at RT for 10 min. 4-(2-Methyloxiran-2-yl)pyridine (1.89 g, 13.8 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1H NMR (DMSO-d6, di-HCl salt) δ (ppm): 8.75 (m, 2H), 8.0 (dd, 2H), 7.30 (d, 1H), 6.90 (s, 1H), 6.60 (t, 1H), 6.10 (bs, 1H), 4.50 (m, 1H), 4.30 (m, 2H), 4.18 (m, 1H), 3.80 (s, 3H), 3.60 (m, 2H), 3.25 (m, 1H), 2.10 (m, 1H), 2.95 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([NH:13][C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21]3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)(O)[O-].[Na+]>>[CH3:24][S:23]([C:20]1[N:19]=[CH:18][C:17]2=[CH:16][CH:15]=[C:14]([NH:13][C:12]3[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[N:8][CH:9]=[CH:10][CH:11]=3)[N:22]2[N:21]=1)=[O:36]
Reactant: CSc1ncc2ccc(Nc3cccnc3N(C)S(C)(=O)=O)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(c1ncccc1Nc1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Methyl-N-[3-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino)-pyridin-2-yl]-methanesulfonamide (125.0 mg, 0.3430 mmol) was dissolved in Methylene chloride (5.00 mL, 78.0 mmol) and the solution was treated with m-Chloroperbenzoic acid (76.87 mg, 0.3430 mmol). The reaction was then allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 100 mg of N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide. 1H NMR (400 MHz, DMSO, d6) δ 9.11 (s, 1H), 8.24 (m, 1H), 8.07 (m, 1H), 7.46 (d, 1H, J=7.93 Hz), 7.33 (m, 1H), 7.26 (m, 1H), 7.14 (m, 1H), 3.23 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([I:16])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:2][CH3:3].[CH3:20][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1C=CC=CC=1>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([I:16])[CH:15]=1)[C:10]([O:12][CH3:20])=[O:11])=[O:6])[CH2:18][CH3:19]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).