Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O.CN(C)C=O>C(Cl)Cl>[Cl:20][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C

Procedure:
To a mixture of 20.8 g of 2-phenylquinazolin-4(3H)-one and 195 ml of thionyl chloride was slowly added 6.85 g of dimethylformamide and the mixture was heated under reflux for 75 minutes. The mixture was poured into 1000 ml of ice and the ice allowed to melt. The precipitate was collected by filtration to give a tan solid, m.p. 135°. The still-moist solid was dissolved in methylene chloride, the solution was dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness and the residue recrystallized from hexane to give 10.45 g of 4-chloro-2-phenylquinazoline which melted at 127°-128.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12](O)[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[Na+].[I-:21]>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12]([I:21])[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(O)c21
Reactant: [I-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(I)c21
Temperature: 25 °C

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (200 mg, 0.72 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid. The residual POCl3 was removed by azeotrope with chloroform. To a suspension of the crude iminochloride in a 57% HI solution in water (5 ml) at rt was added NaI (540 mg, 3.60 mmol, 5 eq). The reaction mixture was stirred at rt overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue 2-(5-chloro-2-fluorophenyl)-4-iodo-5-methyl-6,7-dihydro-5H-cyclopentapyrimidine which was not further purified.
Reaction SMILES: C(OC(=O)C)C.Cl.[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:36][CH:35]=2)[C:14](=[O:32])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([C:28]([O:30][CH3:31])=[O:29])=[CH:17][CH:16]=2)=[O:11]>>[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[CH:38][CH:39]=2)[C:14](=[O:32])[C:15]2[C:20]([C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([C:28]([O:30][CH3:31])=[O:29])=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(C(=O)OC(C)(C)C)cc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(=O)n(Cc3ccc(C(=O)O)cc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a 4N-hydrochloric acid ethyl acetate solution (4 ml) was added 2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (200 mg), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and crystals were washed with a mixture of ethyl acetate and hexane to give the title compound (160 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C@@H:39]1[CH2:41][O:40]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:40][C@H:39]([CH3:41])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: C[C@@H]1CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OC[C@@H](C)O
Yield: 24.4 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5.5 g, 11.1 mmol), (R)-2-methyloxirane (8 ml, 111 mmol) and K2CO3 (3.1 g, 222.2 mmol) in DMF/H2O (25 mL/5 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH(V/V=40/1)) to afford the title compound as a gray-white solid (1.5 g, 25%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH3:8].[OH-].[Na+].CN([CH:27]=[O:28])C>O>[CH3:8][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:27]=[O:28])[CH3:6]
Reactant: CN(C)C=O
Reactant: CN(C)CC1CC1c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC1CC1c1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (0.08 mL, 0.85 mmol, 0.91 equiv.) and dimethyl formamide (0.32 mL, 4.09 mmol, 4.4 equiv.) were combined at room temperature with stirring. After 15 min, N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl-methylamine was added dropwise in DMF (5 mL). After 2 hs of stirring at room temperature, ice and 1 N NaOH were added, then the mixture was diluted further with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-formyl-indol-5-yl)cycloprop-1-yl-methylamine (120 mg) as an oil. 1H NMR (MeOH-d4): δ9.84 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.05 (dd, J=15.5, 1.7 Hz, 1H), 2.59 (dd, J=12.7, 6.7, 1H), 2.35 (s, 6H), 2.30 (m, 1H), 1.80 (m, 1H), 1.20 (m, 1H), 1.05 (m, 1H), and 0.88 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), phenyl isocyanate (20.9 mg, 19.2 μL, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr. The crude product was purified using preparative reverse-phase HPLC, giving 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-phenyl-urea. MS calcd. for C23H19ClN3O2 [(M+H)+] 404.1 obsd. 403.9.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]2[NH:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[CH:34]=[CH:35][CH:36]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CC(C)C>[NH2:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([N:42]2[CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH2:38][CH:37]2[C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH2:28][NH:27][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:26])[CH:32]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(c2cccc(OCCNC(=O)OCc3ccccc3)c2)C1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)OC(C)(C)C)CC3c3cccc(OCCNC(=O)OCc4ccccc4)c3)nc(N)c2cc1OC

Procedure:
A solution of 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS#23680-84-4) (105 mg, 0.439 mmol) and (+) or (−)-tert-butyl 3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazine-1-carboxylate (100 mg, 0.220 mmol) in isoamyl alcohol (5 ml) was stirred for 16 hr at 135° C. After evaporation, the crude was purified by preparative HPLC (Macherey-Nagel Nucleosil® 100-10 C18, CH3CN/H2O (0.1% TFA)) to give the title compound. MS (ESI+) m/z 659.2 (M+H).
Reaction SMILES: [H-].[Na+].O1CCCC1.F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling with ice, 377 mg of sodium hydride (30% liquid paraffin added) was added to a tetrahydrofuran solution of 2,4-difluoro-1-nitrobenzene (1 g), and then o-fluorophenol (775 mg) was added, and stirred at room temperature for 2 hours. Water was added, then extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[C:4]([O:14]COC)[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])[CH:7]=1
Reactant: COCOc1cc(Br)cc(S(=O)(=O)C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)S(=O)(=O)c1cc(O)cc(Br)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
To a solution of 1-bromo-3-methoxymethoxy-5-(propane-2-sulfonyl)-benzene (840 mg, 2.59 mmol) in THF (24.4 mL) and methanol (40 mL) was added p-toluenesulfonic acid hydrate (150 mg, 0.78 mmol) at room temperature. Then, the resulting solution was heated to 70° C. and stirred for 2 days. Then, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude residue which was purified by using an ISCO 40 g column chromatography, eluting with 5-30% ethyl acetate in hexanes to isolate 3-bromo-5-(propane-2-sulfonyl)-phenol (354 mg, 49%) as a viscous oil: ES(+)-HRMS m/e calcd for C9H11BrO3S (M+Na)+ 300.9504, found 300.9505.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:21]([NH2:23])=O)(=[O:10])[CH3:9].ClC(Cl)(Cl)C(Cl)=O>ClCCl>[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:21]#[N:23])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(Cl)cc2CC1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (0.41291 mole) was added to intermediate (8) (0.08258 mole) suspended in dichloromethane (500 ml) at 0° C. Trichloroacetyl chloride (0.20645 mole) was added over 10 minutes. When the reaction appeared sluggish, an additional portion of triethylamine (20 ml) and then more trichloroacetyl chloride (7.6 ml) were added, and the mixture was stirred for 2 hours at low temperature. The ice bath was removed, and the mixture was allowed to sit for 2 hours. This resulted in a darker colored reaction, which was re-cooled to 0° C. Ice cold water (150 ml) was slowly added, and the mixture was stirred for 5 minutes. The layers were separated, and the organic phase was washed (ice cold 3N HCl, saturated NaHCO3), dried, filtered, and concentrated. The residue was triturated in ice cold diethylether (40 ml). Filtration, rinsing with ice cold diethylether (10 ml), yielding 15.13 g of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 9, mp. 140-142° C.).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)[CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Product: COc1ncnc2sc(NC(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc12
Temperature: 25 °C
Yield: 103 %

Procedure:
A solution of (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (1.5 g, 0.0049 mol) in acetonitrile (80 mL) at 25° C. was treated with pyrrolidin-3(R)-yl-carbamic acid tert-butyl ester (0.92 g, 0.049 mol). The reaction mixture was heated at reflux for 1 h. It was then cooled to 25° C. and concentrated in vacuo. The residue was triturated with ether, filtered and dried in vacuo to afford [1-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-pyrrolidin-3(R)-yl]-carbamic acid tert-butyl ester (1.99 g, 99%); LRMS for C16H22N6O4S (M+H) at m/z 395.
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>>[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
Product: Nc1ccc(Cl)c(-c2cccnc2)c1
Yield: 87 %

Procedure:
Tin(II) chloride (11.87 g, 62.6 mmol) and 3-(2-chloro-5-nitrophenyl)pyridine (3.53 g, 15.1 mmol) were reacted as described in Example 62 to give 4-chloro-3-(pyridin-3-yl)phenylamine (2.69 g, 87%) which was used without purification on silica: δH (360 MHz, CDCl3) 6.65-6.70 (2H, m), 7.26 (1H, dt, J 8.5 and 1.1), 7.33 (1H, dd, J 7.8 and 4.8), 7.77 (1H, dt, J 7.8 and 1.9), 8.59 (1H, dd, J 4.8 and 1.6), 8.66 (1H, d, J 1.8); m/z (ES+) 205, 207 (3:1) (M++H).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([OH:18])=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH2:19]([N:21](CC)[CH2:22]C)C.ClC(OCC)=O.CNC>O1CCCC1>[CH3:19][N:21]([CH3:22])[C:16](=[O:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCN(CC)CC
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described In Example 1, in dry tetrahydrofuran (300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5° C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149°-151° C., νmaxCHCl3 3375, 1634 cm-1.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].[BrH:12]>C(O)(=O)C>[Br:12][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(Cl)c1C#N
Reactant: Br
Solvent: CC(=O)O
Product: N#Cc1c(O)ccnc1Br
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloro-4-methoxy-nicotinonitrile (M. Mittelbach et al., Arch. Pharm. (Weinheim Ger.); 1985, GE, 318, 6, 481-486) (6.92 g) was suspended in 70 mL of 30% HBr in acetic acid in a pressure vessel and heated with stirring at 100° C. for 2 h. The reaction was cooled to room temperature and filtered, washing well with H2O, and dried in vacuo overnight at 50° C. providing 4.85 g 2-bromo-4-hydroxy-nicotinonitrile as a white solid. Proton NMR(DMSO) indicated the product was a mixture of 69% bromo compound with 31% starting chloro analog.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc(=O)c12
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(N)ccc2[nH]c(=O)oc(=O)c12
Yield: 87.3 %

Procedure:
A mixture of the product of step B (13.5 g, 60.8 mmol), di-tert-butyldicarbonate (6.53 g, 30 mmol) and 20% Pd(OH)2/C (2.5 g) in 200 mL of DMF was stirred under 5 psi of hydrogen for 20 hours. The catalyst was filtered and the filtrate was evaporated under reduced pressure. The resulting yellow solid was triturated with Et2O, filtered, washed with Et2O and dried affording 10.2 g (87%) of 6-amino-5-methyl-4H-3,1-benzoxazin 2,4-dione. This material (9.0 g, 46.8 mmol) was redissolved in 100 mL of DMF and 15.35 g (70 mmol) of di-tert-butyldicarbonate was added followed by a catalytic amount of DMAP was added. The reaction mixture was stirred at room temperature under nitrogen overnight (ca. 30 hours). The reaction mixture was diluted with 200 mL of 1/2 saturated NaCl, filtered, washed with water then with hexane and dried affording 11.1 g (81%) of 1,1-dimethylethyl(1,4-dihydro-5-methyl-2,4-dioxo-2H-3,1-benzoxazin-6-yl)carbamate: Anal. Calc'd. for C14H16N2O5: C, 57.53; H. 5.52; N, 9.58. Found: C, 57.47; H, 5.80; N, 9.59.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[Br:12]Br>O>[Br:12][C:3]1[C:4](=[O:11])[NH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1cc(=O)[nH]cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Product: Cc1c([N+](=O)[O-])c[nH]c(=O)c1Br
Temperature: 10 °C
Reaction time: 4 h

Procedure:
In a 1000 ml three-necked round-bottomed flask, 5.00 g of 4-methyl-5-nitro-1H-pyridin-2-one (CA registry number: 21901-41-7) is suspended in 500 ml of water. Under stirring, the mixture is kept at a temperature of 40° C. while 1.83 ml of elemental bromine is added dropwise. Stirring at 40° C. is continued for an additional 4 hours. Afterwards, the mixture is cooled to 10° C. and the resulting precipitate collected by filtration and washed with water (4×). After drying, 6.65 g of the title compound is obtained in the form of a beige solid (MP: 237-240° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]#[N:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[F-].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:10]([C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=3)=[CH:13][C:6]=2[C:7]=1[CH3:12])#[N:11]
Reactant: Cc1c(C#N)sc2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3sc(C#N)c(C)c3c2)cc1

Procedure:
A mixture of Example 401A (557 mg, 2.68 mmol), (4-methoxycarbonylphenyl)-boronic acid (675 mg, 3.75 mmol), Pd(OAc)2 (36 mg, 0.16 mmol), 2-(di-tert-butylphosphino)biphenyl (63 mg, 0.21 mmol), and KF (467 mg, 8.04 mmol) in THF (10 mL) was heated to 60° C. for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C([C:5]1[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=1[OH:20])(C)(C)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:16]([C:7]1[C:6]([OH:20])=[CH:5][C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)Cc2cc(O)c(C(C)(C)C)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To 0.28 g of 4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran synthesized according to JP 6-206842A/94 dissolved in 5 ml of chloroform was added 0.06 ml of methanesulfonic acid and the mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was combined with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extracted layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.09 g of 6-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran as a white solid (yield 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22].N>C>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3c(F)cccc3F)c(N)nc2n1
Agent: C
Agent: N
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(F)cccc1F

Procedure:
The title compound was prepared from 0.25 g of 6-(2,6-difluoro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 63 and 0.112 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to EtOAc to afford the pure product; mp >300° C., CIMS (1% ammonia in methane): m/z (relative intensity) 373 (MH+ +1, 60), 374 (MH+ +2, 10), 274 (100).
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[O:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Reactant: c1ccc(COC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(OCc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-benzyloxypiperidine [Tetrahedron 54, 13981, (1998)] according to the method described in Example 1/c. Mp.: 258-261° C. (diethyl ether).