Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][O:10][C:11]([NH:13][C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:22]>CN(C=O)C.O>[CH3:22][N:13]([C:11]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:12])[C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 247.7 %

Procedure:
Sodium hydride (995 mg, 41.466 mmol) was taken up in DMF (50 mL) and was cooled to 0° C. for 30 min. Then a mixture of methyl 1-({[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (6.46 g, 25.916 mmol) in DMF (25 mL) was slowly added over 10 min. The resulting mixture was allowed to stir for 45 min, and then iodomethane (4.84 mL, 77.74 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The mixture was then carefully diluted with water (10 mL), and the aqueous layer was extracted with Et2O (5×50 mL). The organic extracts were washed with water (5×50 mL), then dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via Combiflash, utilizing a 0%-50 EtOAc/Hex gradient to provide methyl 1-(methyl{[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (16.9 g, >100%) LCMS: (M+H)+: 264.1.
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][C:10](Cl)=[CH:11][CH:12]=2)[N:7]=1.O>CN(C)C=O.C(O)C>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][C:10]([S:2][CH3:1])=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CSc1ccc2ccc(N)nc2n1
Temperature: 0 °C

Procedure:
To a solution, close to saturation, of methyl mercaptan in dimethylformamide (200 cc) maintained at 0° C., sodium hydride (13.3 g) in 50% strength suspension in mineral oil is added in small portions. 2-Amino-7-chloro-1,8-naphthyridine (25 g) is then added to this solution, and the mixture is heated at 100° C. for 2 hours. After being cooled, the reaction mixture is poured into water (500 cc) and extracted with methylene chloride (5×250 cc). The organic extracts are then washed with distilled water (2×200 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The product produced (22.9 g; m.p. 130° C.) is dissolved in boiling ethanol (150 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and then isopropyl ether (3×10 cc), and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-methylthio-1,8-naphthyridine (9.6 g) is produced, m.p. 158° C.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([N:19]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[N:20]3)[CH2:9][C:8]2=1>C(O)C.[Fe]>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([N:19]3[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]3)[CH2:9][C:8]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc([N+](=O)[O-])cn1)CO3
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Yield: 22 %

Procedure:
Ammonium chloride (4.0 g, 73.54 mmol, 6.0 eq) is added at room temperature to a stirred suspension of 6-methoxy-3-(4-nitro-pyrazol-1-yl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene (4.0 g, 12.26 mmol, 1.0 eq) and iron powder (8.22 g, 147.10 mmol, 12.0 eq) in ethanol (600 mL). The resulting mixture is heated under reflux for 2 hours, then filtered through decalite, solvent is removed and the crude is extracted with ethyl acetate (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:methanol, 1:1:0 to 0:25:1, v/v/v) to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H-pyrazol-4-ylamine as a white solid (800 mg, 22% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)cn1
Temperature: 90 °C
Yield: 4.6 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and 2-Aminopyridine-5-boronic acid pinacol ester (MW 220) (243 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichioro 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 14 h 45 min, cooled and diluted with EtOAc (9 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from=% MeOH in DCM to 5% MeOH in DCM) gave a colorless solid (4.40 mg, 5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 83.2 %

Procedure:
A mixture of 0.37 g of 3-chloropropanol, 5.0 g of toluene and 0.06 g of tetra-n-butylammonium iodide was heated to 80° C. Thereto was added dropwise a mixed solution of 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of water and 0.51 g of a 27% aqueous sodium hydroxide solution with stirring over 6 hours. After completion of the addition, the mixture was further stirred at 80° C. for 20 hours. In this period, 0.20 g of 3-chloropropanol was further added at each time point of 7, 9, 12 and 17 hours, and 0.20 g of a 27% aqueous sodium hydroxide solution was further added at each time point of 12 and 17 hours. Then, the reaction mixture was cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.0 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 87%, yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:37])[C:19]2[CH:24]=[N:23][C:22](S(C)(=O)=O)=[N:21][C:20]=2[N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:37])[C:19]2[CH:24]=[N:23][C:22]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:21][C:20]=2[N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COc1ccc(CCN)cc1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCc3ccc(OC)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-(4-methoxy-phenyl)-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 35 (Step E), 35 mg, 0.09 mmol). 8-Cyclohexyl-5-oxo-2-[2-(4-methoxy-phenyl)-ethylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (30 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H30N4O4: 451.23 (M+H). Found: 451.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:30]=1)[CH3:36]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int c) and ethyl 3-hydroxybenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (32%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: C(OC(=O)[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH2:8][C:9]([F:12])([F:11])[F:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:7][CH2:8][C:9]([F:12])([F:10])[F:11]
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)CNc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester (120 mg, 310 μmol) in CH2Cl2 (2 mL) at 0° C. was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was extracted with 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (79 mg, 89%). MS (ESI): m/z=287.055 [M+H]+.
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18]/[CH:2]=[C:4](\[CH2:7][C:8]#[N:9])/[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: N#CCC(C#N)C=O
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Product: N#CC/C(C#N)=C\NC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (6.67 g, 45.6 mmol) and 1,1-bis(4-fluorophenyl) methaneamine (11.0 g, 50.2 mmol) in water (19 ml) was added acetic acid (19 ml) at room temperature, and the mixture was stirred 100° C. for 30 minutes. The solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as oily matter. Yield (amount) 14.0 g, yield (rate) 99.3%
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(OCC)(=O)C>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:1]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.25 g (29.5 mmol) of diethyl 3,5-pyrazoledicarboxylate (1) in 225 mL of acetone was added 11.7 g (36 mmol) of cesium carbonate, followed after 10 min by the addition of 5.3 mL (36 mmol) of t-butyl bromoacetate and the mixture was stirred overnight at room temperature. Since TLC analysis confirmed that the reaction was complete (Rf product=0.6 (7:3 hexanes:ethyl acetate)), the mixture was filtered and concentrated to give quantitatively 1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (2) as a clear oil as indicated by 1H NMR (containing a trace of t-butyl bromoacetate). (δ(300 MHz, CDCl3) 7.14 (s, 1H), 5.15 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (s, 9 H), 1.27 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H)). This material was used without further purification in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 4-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-chlorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[O:16]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[N:17]1>>[O:16]1[C:20]([CH:21]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:19][CH:18]=[N:17]1
Reactant: O=Cc1ccno1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccno1)C2=O
Yield: 55 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and isoxazole-5-carbaldehyde (200 mg, 2.0 mmol) according to Method A3 in 55% yield. ES-MS m/z 284 (M+H)
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5](/[CH:7]=[C:8](\[CH3:12])/[C:9]([OH:11])=[O:10])=[O:6])[CH2:2][CH3:3]>[Pd].O1CCCC1>[CH2:13]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[CH2:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH2:14][CH3:15]
Reactant: CCCN(CCC)C(=O)/C=C(\C)C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)CC(C)C(=O)O
Reaction time: 18 h
Yield: 66.2 %

Procedure:
Add 40% palladium on carbon (0.064 g) to a solution of (E)-3-dipropylcarbamoyl-2-methylacrylic acid (0.20 g, 0.94 mmol) in tetrahydrofuran (20 mL). Hydrogenate at 60 psi for 18 hours. Filter through a filtering agent and concentrate filtrate under reduced pressure. Subject residue to silica gel chromatography, eluting with dichloromethane containing 10-40% of 5% (2:1 methanol:acetic acid) in dichloromethane to provide the title compound (0.134 g, 66.4%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of n-butyllithium (3.46 mL of a 1.6 M solution in hexanes) in THF (18 mL) was cooled to −78° C. and treated with a solution of 5-bromo-2-methoxypyridine (Johnson, C. R.; Sirisoma, N. S. Tetrahedron Lett. 1998, 39, 2059) 18-1 (1.04 g, 5.53 mmol) in THF (2 mL). The heterogeneous mixture was stirred for 40 min and neat DMF (1.5 mL) was added. The solution was stirred for 90 min at −78° C. and quenched with satd aq NH4Cl solution (2 mL). The cold bath was removed and the mixture warmed to room temperature. The mixture was extracted with EtOAc (2×30 mL) and the combined organic solutions washed with brine, dried over MgSO4, filtered, and concentrated to the desired aldehyde 18-2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Temperature: 26 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate (15 g, 50.63 mmol, 1.00 equiv), oxolane (150 mL), lithiumol (2.4 g, 100.22 mmol, 2.00 equiv) and water (50 mL). The resulting solution was stirred overnight at 26° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration and washed with water. This resulted in 10 g (74%) of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.37-7.41 (m, 2H), 7.65-7.69 (m, 1H), 7.96-8.03 (m, 2H), 8.20-8.22 (m, 1H), 8.56-8.61 (m, 2H); MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([O:14][P:13]([C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1)(=[O:20])[O:17][CH2:18][CH3:19])[CH3:16]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOP([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])c(OC)c1
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27 mmol), XantPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-45% ethyl acetate:heptane) to afford the desired product (0.504 g, 33% yield).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][C:28](=[CH2:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH3:36][C:28](=[CH2:27])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31]1
Reactant: C=C(C)CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one, 3.5 gm of sodium carbonate and 4.6 gm of 1-(2-methyl-allyl)-piperazine were refluxed in 100 ml of absolute ethanol for 2 hours. Then, the reaction mixture was suction-filtered while still hot, and the filtrate was evaporated to a volume of 40 ml and cooled. The precipitated crystals were recrystallized from ethanol in the presence of activated charcoal, yielding 75% of theory of the compound of the formula ##STR9## which had a melting point of 205°-207° C.
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[O:25]([C@H:33]([CH3:56])[C@H:34]([CH2:37][N:38]1[CH:46]=[N:45][C:44]2[C:39]1=[N:40][CH:41]=[N:42][C:43]=2[NH:47][C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:35][OH:36])[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>N1C=CC=CC=1>[O:25]([C@H:33]([CH3:56])[C@H:34]([CH2:37][N:38]1[CH:46]=[N:45][C:44]2[C:39]1=[N:40][CH:41]=[N:42][C:43]=2[NH:47][C:48](=[O:55])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:35][O:36][C:1]([C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 20 h
Yield: 88 %

Procedure:
DMTCl (0.8 g. 2.37 mmol) was added in one portion to a stirred solution of 12 (0.82 g, 1.8 mmol) in 20 ml of anhydrous pyridine. The reaction was kept at room temperature for 20 hrs, concentrated and partitioned between ethyl acetate and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resultant crude product was chromatographed on silica eluting with 50% ethyl acetate in hexane. Concentration of the pure product fractions afforded 1.2 g (88%) of 13 as a white amorphous solid. 1H NMR (DMSO-d6): δ 11.12 (s, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.65 (m, 1H), 7.55 (t, J=7.5 Hz. 2H), 7.18 (m, 5H), 7.04 (t, J=8.7, 4H), 6.77 (m, 4H), 4.36 (m, 1H), 4.24 (m, 1H), 4.02 (m, 1H), 3.60 (s, 6H), 3.12 (m, 1H), 2.95 (m, 1H), 2.39 (m, 1H), 1.14 (d, J=6.6 Hz, 3H), 0.74 (s, 9H), 0.00 (s, 3H), −0.10 (s, 3H).