Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.60 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 3.3-3.8 (m, 12H), 3.18 (m, 2H), 2.0-2.25 (m, 6H); MS (DCI) m/z 406 (M+H)+;
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:25])[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30 mL) was added sodium hydride (a 60% fluidized paraffin dispersion, 314 mg, 7.84 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (1.11 g, 7.84 mmol) and the mixture was stirred for at room temperature 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%) of the title compound as an oily matter.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([Cl:10])[CH2:9][CH2:8]1)=[O:6].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:4][C:5]([C:7]2([Cl:10])[CH2:9][CH2:8]2)=[O:6])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C1(Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
50 ml of water and 10 pellets of solid sodium hydroxide are added at room temperature to a mixture of 0 g (0.5 mol) of 1-chlorocyclopropyl methyl ketone, 70 g (0.5 mol) of 4-chlorobenzaldehyde and 250 ml of ethanol. The mixture is stirred at room temperature for 16 hours. The precipitated solid is then filtered off with suction. In this manner, 108.5 g (89% of theory) of 1-chlorocyclopropyl 4-chlorophenylethenyl ketone are obtained in the form of a solid substance of melting point 92° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:16][CH2:17][NH2:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N)C>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([NH:18][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CCN
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.7 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Pyrrolidin-1-yl-ethylamine (0.201 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diispropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine as a yellow solid (0.352 g, 1.50 mmol, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]#[N:37])=[CH:4][CH:3]=1.[OH-:38].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]([NH2:37])=[O:38])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C#N)C1)c1cccnc1CO2
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C(N)=O)C1)c1cccnc1CO2
Temperature: 80 °C

Procedure:
To a solution of 1-(4-chloro-phenyl)-4-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperazine-2-carbonitrile (0.12 g, 0.23 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added 1.0 N NaOH (0.5 mL, 0.5 mmol) and the resulting mixture was heated to reflux at 80° C. for 18 h. Additional 2.0 N NaOH (0.5 mL, 0.5 mmol) was added to the reaction mixture and refluxed further for 18 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate and concentrated. The crude product was purified on a short plug of silica gel using gradient elution from ethyl acetate/methanol (2–10%) to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)=[O:5]
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Diketene (160.13 g, 1.904 mol) and a solution of N-phenyl-p-phenylenediamine (344.00 g, 1.867 mol) in 40% strength acetic acid (1300.00 g) were simultaneously added dropwise at 60° C. in the course of about 4.5 h to 40% strength acetic acid (300.00 g). After addition of the starting materials had taken place, the reaction mixture was stirred at 65° C. for 30 min and then cooled to 15° C. The resulting precipitate was filtered off on a suction filter, washed with 40% strength acetic acid (2×200 g) and with water (2×200 g) and dried at 50° C. in vacuo (20 mbar). 415.31 g (95.3% content, 79% yield) of 3-oxo-N-[4-(phenylamino)phenyl]butyramide were obtained as a light grey solid. Mp: 89.5° C.;
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:41](OC)[CH2:42][NH2:43]>C(Cl)Cl>[CH2:1]([N:4]1[CH:41]=[CH:42][N:43]=[C:5]1[C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of N-allyl-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxamide (150 mg, 0.406 mmol) in DCM (2.64 mL) was added phosphorus pentachloride (101 mg, 0.485 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.0154 mL, 0.0614 mmol) and the mixture was heated to 60° C. for 1.5 h. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (0.486 mL, 4.46 mmol) was added. The resulting mixture was heated at 60° C. for 2 h. The mixture was cooled to room temperature, diluted with DCM (10 mL), washed with water (2×2 mL) and brine (2 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DCM (3.0 mL) and 4 M hydrochloric acid in 1,4-dioxane (0.608 mL, 2.43 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL) and saturated sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→5/95) to give 99 mg of the title compound (62% yield). LC/MS (FA) ES+ 393. 1H NMR (300 MHz, CDCl3) δ: 8.72-8.70 (m, 2H), 7.80-7.72 (m, 2H), 7.26 (m, 1H), 7.22-7.14 (m, 4H), 7.06 (m, 1H), 5.84-5.71 (m, 1H), 5.23-5.19 (m, 1H), 5.01-4.96 (m, 1H), 4.38-4.34 (m, 2H), 4.20 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>CN(C)C=O.CCOCC>[CH3:17][C:16]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Reactant: Nc1ccccc1S
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.295 g., 5 mmoles) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (695 mg. of 90%, 5 mmoles). After stirring the reaction at room temperature for one hour, it is heated at 60°-65° for 24 hours. The reaction is allowed to cool down to ambient temperature and diluted with ether. The resulting yellow solution is washed thoroughly with water, 1N sodium hydroxide, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow foam (1.3 g.). This product is purified by flash chromatography (20% ethyl acetate in hexane) and the residue is recrystallized from isopropyl ether-dichloromethane to provide 2,5-dihydro-4-methyl-2-(4-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid, methyl ester as yellow needles; m.p. 149.5°-151.5° (sinters at 140°). TLC (silica gel; acetone:hexane, 30:70) Rf =0.30.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH2:24][CH2:25][O:26][C:27]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Solvent: CN(C)C=O
Product: CN(CCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1)CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.68 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methylethane-1,2-diamine {Preparation Sd Step (1), 0.5 g, 1.56 mmol} in DMF (5 mL) was added TEA (0.234 g, 2.34 mmol) followed by 2-(2-bromoethoxy)-4-nitrobenzonitrile (0.423 g, 1.56 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get 2-(2-((2-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)ethyl)(methyl)amino)ethoxy)-4-nitrobenzonitrile (0.3 g, 37.68%) as a dark brown solid. LC-MS (M+H)+=511.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.91-7.89 (1H, m), 7.85 (1H, s), 7.72-7.70 (1H, m), 7.14-7.10 (2H, m), 6.98-6.96 (2H, m), 4.42-4.39 (2H, m), 4.17-4.15 (1H, m), 3.66-3.56 (2H, m), 3.49 (3H, s), 3.35-3.26 (2H, m), 3.18-3.12 (4H, m), 2.78-2.63 (1H, m), 1.99-1.98 (1H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Product: COc1cc(N2CCCCC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and piperidine. The residue was purified using silica gel column chromatography eluting with 50-80% DCM in cyclohexanes.
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>CO>[NH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:21][CH3:1])=[O:20]
Reactant: CC(=O)Cl
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Solvent: CO
Product: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Acetyl chloride (1000 mL, 11.5 mol) was added slowly to cold methanol (10.84 L at 0±3° C.), under an atmosphere of nitrogen, while maintaining the temperature below 5° C. The reaction mixture was stirred for a further 35 min at 0±3° C. and then 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoic acid (1084.2 g, 4.06 mol) was added. The reaction mixture was heated at reflux for 2.5 h and then the volume was reduced by distillation to approximately half the volume. Isopropyl acetate (10.84 L) was added maintaining the temperature at above 50° C. and the temperature held at 60° C. for 1 hour. The solution was cooled to 0° C. over a period of 3 hours and aged at 3±3° C. for a further ca. 10 hours. The precipitate was filtered and washed with a mixture of chilled isopropyl acetate:methanol (ca. 10:1, 3.26 L at 3±3° C.) and then chilled isopropyl acetate (2.1 L at 3±3° C.). The solid was dried in vacuo at 55° C. to afford the title compound as its hydrochloride salt (933.2 g): LCMS: tRET=3.20 min; MH+=282.min. A proportion of this material (874.1 g, 2.76 mol) in a mixture of water (5.28 L) and 2-methyltetrahydrofuran (8.7 L) was treated with sodium hydroxide (1M, 2720 mL then 2M, 13 mL) (until pH=7 is reached). The organic phase was separated and washed with water (6.1 L) and the aqueous layer extracts back extracted with 2-methyltetrahydrofuran (4.4 L). The combined organic extracts were evaporated to near dryness and then toluene (4.4 L) was added and the mixture evaporated to afford the title compound (767.4 g).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[C:2]2/[C:1](=[O:11])[C:10]3[C:5]([CH2:4][CH2:3]/2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1/C(=C/c2ccc(Br)cc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.9 %

Procedure:
A 250 mL flask was charged with tetralone (3.22 g, 22 mmol) and 4-bromobenzaldehyde (5.3 g, 28.6 mmol). This was dissolved in warm tetrahydrofuran (12 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (100 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (6.61 g, 96%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc2ncn(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine in 0.2 mL of benzene and 0.1 mL of methanol was added 0.015 mL of (trimethylsilyl)diazomethane (2 M in hexanes). The solution was stirred for 30 min at room temperature then concentrated. The product was purified by chromatography to afford the title compound. Partial 1H NMR (500 MHz CD3OD): δ 8.9 (s, 1H); 8.63 (br, 1H); 8.42 (d J=5.0 Hz, 1H); 8.09 (d J=11 Hz, 1H); 7.87 (d J=11 Hz, 1H); 6.83 (d J=5.0 Hz, 1H); 5.29 m, 1H); 3.98 (s, 3H); 1.64 (d J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[CH2:22]([O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: CCO
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A suspension of crude (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.0 g, 0.00663 mole) in absolute ethanol was stirred at room temperature while 4 drops of concentrated sulfuric acid was added. The reaction mixture was refluxed for three days. Approximately 1/2 to 2/3 of the solvent was removed under reduced pressure. Saturated sodium bicarbonate solution (20 ml) was added to the remaining solution. The product was extracted into two portions of ethyl acetate and the combined organic layers were washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil which was dissolved in hot absolute ethanol. Water was added to the cloud point and upon cooling to room temperature, a solid precipitated. The solid was collected by filtration, rinsed with water and dried under high vacuum at 50° C. to give 1.48 g (68%) of title compound, mp 103°-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH2:41])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH:41][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:18])([F:17])[F:19])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[N:9]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A solution of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 0.30 g, 0.61 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.123 g, 0.73 mmol), Pd(OAc)2 (0.027 g, 0.12 mmol), tri-O-tolylphosphine (0.074 g, 0.24 mmol) and triethylamine (0.184 g, 1.82 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 hr. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 25% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene]-azetidine-1-carboxylic acid tert-butyl ester (0.072 g, 20%) as a yellow solid. LC/MS (Table 1, Method 2) Rt=1.523 min.; MS m/z: 605 [M+23]+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O:8]=[C:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](CCO)=[CH:14][CH:13]=1.O1CCCC1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9](=[O:8])[CH3:21])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)COc1ccc(CCO)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.96 g of acetic anhydride were added, whilst ice-cooling, to a mixture of 3.1 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 50 ml of anhydrous tetrahydrofuran and 2.53 g of pyridine, and the resulting mixture was stirred at room temperature for 3.5 hours. At the end of this time, 12.5 g of pyridine and 9.8 g of acetic anhydride were added, whilst ice-cooling, and the mixture was allowed to stand at room temperature for 1 day, after which the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give the title compound having an Rf=0.71 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([O:27][C:37](=[O:38])[NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(O)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(OC(=O)Nc1ccccc1)c1ccccc1

Procedure:
A mixture of 3.0 parts of the products from Example 81, 0.90 parts of phenyl isocyanate and 0.1 parts of 1,4-diazabicyclo[2,2,2]octane in 25 parts of dry benzene was heated under reflux conditions for 24 hours. The benzene solvent was removed by distillation under reduced pressure and the residue crystallised from petroleum ether (b.p. 60°-80° C.) to give 4-phenylcarbamoyloxy-1-[2'-(phenylcarbamoyloxy)-2'-phenylethyl]-2,2,6,6-tetramethylpiperidine having a melting point of 173° C. and the following elemental analysis by weight