Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
A mixture of 12A (95.5 mg, 0.30 mmol) and Fe powder (135 mg, 2.4 mmol) in HOAc/EtOAc (1/1) (2 ml) was heated at 70° C. for 3.5 h. The mixture was cooled to rt, filtered through an 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (40 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 12B (83.1 mg, 79% pure) which was used in next step without further purification. Analytical HPLC retention time=2.08 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Product: Cc1ccccc1-c1c(F)ccc2c1OC(CN=[N+]=[N-])C2
Yield: 86 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (10.06 g, 58.84 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.16 mmol), and sodium carbonate (6.2 g, 58.84 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (37%) of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether. A solution of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether (2.35 g, 10.86 mmol) in hydrogen bromide (40 mL, 30 wt. % in acetic acid) was heated to 55° C. for 12 h. The reaction mixture was concentrated under in vacuo and the crude residue diluted with ethyl acetate (200 mL). The organic layer was carefully extracted with saturated bicarbonate solution (3×200 mL) was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Treatment of 6-fluoro-2′-methybiphenyl-2-ol (2.17 g, 10.84 mmol) with sodium hydride (0.65 g, 16.26 mmol, 60 wt. %) and allyl bromide (0.96 g, 16.26 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.77 g, 7.3 mmol) with 3-chloroperoxybenzoic acid (3.2 g, 10.96 mmol, 77%) followed by potassium carbonate (1.2 g, 8.76 mmol) generally according to the procedure described for Intermediate 9 afforded 1.5 g (80%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 2.17 g (90%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.23 g, 0.56 mmol) with sodium azide (0.23 g, 3.54 mmol) generally according to the procedure described for Intermediate 98 afforded 0.135 g, (86%) of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran (0.135 g, 0.4 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.30 g, 0.9 mmol) generally according to the procedure described for Example 154 provided 0.11 g (67%) of (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])[CH:12]=1)=[O:6].[H-].[Na+]>CN(C=O)C>[CH3:20][C:15]1[C:14]([CH2:13][N:11]2[CH:12]=[C:8]([N:7]3[CH2:2][CH2:3][NH:4][C:5]3=[O:6])[CH:9]=[N:10]2)=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCNC2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (example 10-88b) (115 mg, 0.39 mmol) and 60% sodium hydride (17 mg, 0.42 mmol) in DMF (2 mL) were stirred at 0° C. for 15 minutes then allowed to warm up to room temperature with stirring for 2 hours. The reaction was quenched with methanol and concentrated on the rotovap. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (98 mg, 97%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.10 (s, 3H), 2.37 (s, 3H), 3.35-3.39 (m, 2H), 3.61 (d, J=8.8 Hz, 1H), 3.63 (d, J=10.4 Hz, 1H), 5.07 (s, 2H), 6.71 (s, 1H), 7.42 (s, 1H), 7.74 (s, 1H). MS M+H calculated 262.12; found 262.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][O:5][C:4]([C:7]2[C:8]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:11][CH:12]=2)=[N:3]1.Cl.[OH-:30].[Na+]>O1CCCC1>[NH2:3][C:2]([CH3:1])([CH3:28])[CH2:6][O:5][C:4](=[O:30])[C:7]1[C:8]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:11][CH:12]=1
Reactant: CN1CCN(c2cc(C(=O)c3ccccc3)c(C3=NC(C)(C)CO3)cn2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(=O)c3ccccc3)c(C(=O)OCC(C)(C)N)cn2)CC1
Temperature: 50 °C

Procedure:
To a solution of 1.13 g (3 mmol) [5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-phenyl-methanone in 30 ml tetrahydrofuran were added 3 ml of 2 N aqueous hydrochloric acid and the reaction mixture was heated at 50° C. for 18 h. After cooling to room temperature, 1 N sodium hydroxide solution was added to adjust pH 11 and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to yield 1.18 g (quantitative) of the product as yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]([OH:5])=[O:4].[CH3:38]N(C=O)C.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:37][C:2]([CH3:1])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[C:3]([O:5][CH3:38])=[O:4]
Reactant: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.81 g of 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoic acid and 50 mL of DMF were added 2.59 g of methyl iodide and 3.16 g of potassium carbonate, followed by stirring for 1 hour at room temperature. Water was added to a reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol, thereby obtaining 3.24 g of methyl 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoate as a yellowish white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:10]3[C:11]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:19][CH:20]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3cccs3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3cccs3)cc21
Reaction time: 0.01 h
Yield: 149 %

Procedure:
Tert-butyl (1-(4-(1-methyl-2-oxo-7-(thiophen-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.024 mmol) was dissolved in dichloromethane (1.5 ml). TFA (1 ml) was added at room temperature and the reaction mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (14 mg, 78% yield). LCMS (Method D): RT=0.781 min, M+1=393. 1H-NMR (500 MHz, CD3OD) δ 7.66 (1H, s), 7.53-7.49 (2H, dd), 7.48-7.44 (2H, dd), 7.42-7.39 (1H, dd), 7.01-7.97 (1H, dd), 6.97-6.95 (1H, dd), 4.97 (2H, s), 3.44 (3H, s), 2.84-2.74 (2H, m), 2.64-2.55 (2H, m), 2.31-2.21 (1H, m), 2.07-1.93 (1H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCCCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: c1ccc(OCCCCCNc2ncnc3ccccc23)cc1
Yield: 19.5 %

Procedure:
To a solution of 1.7 g (0.01 mol) of 4-chloroquinazoline in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.8 g (0.01 mol) of 5-phenoxypentylamine, and the mixture was refluxed for 3 hours. After completion of the reaction, the benzene was evaporated under reduced pressure to leave crystals, which were washed with water, collected by filtration and recrystallized from aqueous ethanol, giving 0.6 g of 4-(5-phenoxypentyl)aminoquinazoline in the form of colorless flakes.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl (R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C1(S([C:15](Br)([F:17])[F:16])(=O)=O)C=CC=CC=1>CN(C=O)C>[CH3:1][Si:2]([CH3:4])([CH3:15])[C:3]([F:17])([F:16])[C:15]([Si:2]([CH3:4])([CH3:3])[CH3:1])([F:17])[F:16]
Reactant: C[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)C(F)(F)Br
Solvent: CN(C)C=O
Product: C[Si](C)(C)C(F)(F)C(F)(F)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Into a mixture of 0.42 g (17.5 mmol) of Mg turnings, 1.92 g (17.7 mmol) of TMSCl and 10 mL DMF, was added 1.60 g (5.9 mmol) of bromodifluoromethyl phenyl sulfone (23). The reaction mixture was stirred at 0° C. for 30 min, and at room temperature for another 30 min until 19F NMR showed all of 23 was consumed (the yield of 20 was 76% and by-product TMSCF2TMS, 18% by 19F NMR analysis). The reaction mixture was washed with ice water followed by extraction with pentane (10 mL×4). The pentane phase was washed with cold 98% sulfuric acid (10 mL×3) to remove most of the siloxane and silanol. Then the pentane solution was washed with cold NaHCO3 aqueous solution three times until the pH paper indicated neutral pH. After drying over MgSO4 and solvent removal, the crude product was further purified by fractional distillation and then recrystallization at −20° C. to give 0.40 g crystalline product 20, m.p. 40˜42° C., yield 55%. 1H NMR (500 MHz, CDCl3): δ0.24 (s, 18H). 13C NMR (125 MHz, CDCl3): δ−4.0 (m, CH3); 126.6 (tt, 1JC-F=265.0 Hz; 2JC-F=45.9 Hz). 19F NMR (470 MHz, CDCl3): δ−122.3.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.ClC1C=CN=CC=1.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:21]>O1CCOCC1>[N:21]1([C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]([O:27][CH3:28])=[O:26])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-n1cccc1
Yield: 92.7 %

Procedure:
17.14 mol of 2,5-dimethoxytetrahydrofuran and 19.84 g of 4-chloropyridine hydrochloride in 600 ml of 1,4-dioxane are stirred for 10 minutes at 25° C., and then 17.12 mol of methyl anthranilate are added and the suspension is heated at reflux for 3 hours. After removal of the dioxane under reduced pressure, the residue is taken up in 1 liter of water and extracted with diethyl ether. The ethereal phase is washed with water, decanted off, dried over magnesium sulfate, rendered colourless with animal charcoal, and then concentrated under reduced pressure to yield the title product in the form of an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.CC([N:44](C)C)=O>O.NN>[NH2:44][C:25]1[N:26]=[CH:27][C:22]([C:7]2[N:6]=[C:5]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:8]=2[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[CH:23][N:24]=1
Reactant: CC(=O)N(C)C
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Agent: NN
Solvent: O
Product: Nc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
0.06 g (0.1 mmol) of [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 88) was dissolved in 1 ml of DMA and 0.5 ml of hydrazine monohydrate. The mixture was heated to 100° C. for 24 h after which time the solvent was evaporated, then it was re-dissolved in EtOH and a generous spatula of Rainey nickel was added. The mixture was stirred for 1 h after which time it was filtered over Hyflo and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 8:2] afforded 0.01 g (17%) of the title compound as a colorless amorphous solid. MS: 542.2 (MH+).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[N:5]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH2:16][OH:17]>O1CCOCC1>[CH3:14][O:13][C:6]1[N:5]=[C:4]([O:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)CO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride is added to a mixture of 2-chloro-6-methoxy-3-nitropyridine, methyl glycolate and 1,4-dioxane at 10° C. The mixture is stirred at room temperature for 2 hours, then, poured into ice water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-methoxy-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:22]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[CH:22]1([NH:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:16]=[C:15]([NH2:17])[C:14]4[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=4)[N:8]=3)[CH2:2][CH2:3]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C=NC1CCCC1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)NC4CCCC4)CC3)nc(N)c2cc1OC
Yield: 83.6 %

Procedure:
In 30 ml of dioxane, there was dissolved 1.16 g. (4 mmole) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline. To the resultant solution was added dropwise 0.45 g. (4 mmole) of cyclopentyl isocyanate at room temperature and the mixture was stirred overnight at room temperature. The precipitated crystals were recovered by filtration to obtain 1.34 g. of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:26])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:34]([C:33]([F:32])([F:41])[F:42])[CH:35]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)c3c(c21)CC(C)(C)O3
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.256 mmol), thionyl chloride (2.0 mL), 3-trifluoromethyl aniline (0.124 g, 0.769 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.46 (s, 2H), 3.56 (s, 3H), 7.00 (m, 1H), 7.20 (m, 2H), 7.28 (d, 2H), 7.28 (d, 1H), 7.45 (d, 1H), 7.56 (t, 1H), 7.75 (d, J=7.2 Hz, 1H), 8.31 (s, 1H), 9.98 (s, 1H), 10.51 (s, 1H); MS [M+H]+: 533.27.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[N:9][CH:10]=3)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH2:37][CH2:36]1)=[O:33]
Reactant: CCOC(=O)c1cc2ccncc2c(Cl)n1
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc2ccncc2c(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 170 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
In a sealed high pressure container with a Teflon lining was combined ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (280 mg, 1.18 mmol), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 957 mg), and K2CO3 (1.25 g) in 15 ml tert-butanol. The container was heated at 170° C. with stirring for 8 hours. The solution was concentrated by rotary evaporation and reconstituted with EtOAc. The organic layer was washed 4× with H2O, and dried over MgSO4. Product was purified on reverse phase Si to yield 36 mg white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][N:21]=[C:22]=[O:23]>>[CH2:18]=[CH:19][CH2:20][NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 73.1 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.070 mL (0.78 mMol) prop-1-en-3-yl isocyanate, 0.149 gm (73%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][O:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.C1(=O)[NH:19]C(=O)C2=CC=CC=C12.[K].O.NN.C1(=O)NC(=O)C2=CC=CC=C12>CN(C)C=O.ClCCl.C1COCC1>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][C:3]([CH2:2][NH2:19])=[CH:12]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)C=C(CBr)CO2
Agent: NN
Agent: [K]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C=C(CN)CO2
Reaction time: 10 h

Procedure:
1.17 g (4.59 mmol) of the brominated compound obtained in Step A are dissolved in 10 ml of anhydrous N,N-dimethylformamide; 1.275 g (6.9 mmol) of potassium phthalimide are then added to the medium. After 10 hours of stirring under argon, the solvent is evaporated in vacuo. The residue obtained is taken up in dichloromethane; the organic phase is then washed with water. After drying over magnesium sulphate, the solvent is evaporated in vacuo. Chromatography on a silica column (eluant:AcOEt/PE:15/85) allows access to the corresponding phthalimide in the form of a white solid. Melting point: 141° C. 0.72 g (14.35 mmol) of hydrazine monohydrate is added to a solution of 1.15 g (3.58 mmol) of that phthalimide in 20 ml of THF; the mixture is then heated at reflux for 4 hours. After cooling the mixture and filtering off the solid, the filtrate is concentrated in vacuo to result in the pure title amine in the form of a yellow solid.