Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Cc1ccnc2cc(O)ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7-hydroxy-4-methylquinoline (71 mg, 0.46 mmol), (Chem. Berich. 1967, 100, 2077), in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The DMF solvent was removed by evaporation and the residue was taken up in 2N aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and then filtered through phase separating paper. The solution was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(4-methylquinolin-7-yloxy)quinazoline (84 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:17]([CH2:18][CH2:19][CH:20]=C)=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:22]([CH3:30])([CH3:29])[O:23][SiH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:17](=[C:16]3[C:11](=[CH:10][CH:9]=2)[CH2:12][CH2:13][C@H:14]([C:22]([CH3:30])([CH3:29])[O:23][SiH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[O:15]3)[CH2:18][CH2:19][CH:20]1[OH:33])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC3
Reaction time: 6 h
Yield: 81.2 %

Procedure:
To a solution of (2R)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamic acid tert-butyl ester (3.6 g, 8.0 mmole) in tetrahydrofuran (150 mL) and water (15 mL) at 0° C. was added osmium tetroxide (0.4 mL, 5% in water), followed by sodium periodate (5.16 g, 24 mmole). The mixture was stirred for 6 hours. The solution was diluted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate, filtered, and the solvent evaporated in vacuum. Column chromatography on silica gel (10% ethyl acetate/hexane) afforded 2.92 g (81%) of the title compound as an oil, [α]25D=−36.75° (4.9, THF).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH3:18][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[C:12]1[NH:8][N:9]=[N:10][C:11]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1nnn(Cc2ccc(OC)cc2)c1N(C)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nn[nH]c1N(C)S(C)(=O)=O
Yield: 100.9 %

Procedure:
Methyl 1-(4-methoxybenzyl)-5-[methyl(methylsulfonyl)amino]-1H-1,2,3-triazole-4-carboxylate (0.54 g) was stirred in trifluoroacetic acid (5 mL) at 60° C. for 6 h. The mixture was evaporated and the residue was co-evaporated with toluene. Purification by flash chromatoraphy (1:49 methanol/DCM) gave the subtitle compound as a gum (0.36 g).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5])#[N:2].[NH3:14]>C1C=CC=CC=1>[C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:14])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)c1ccccc1
Reactant: N
Solvent: c1ccccc1
Product: N#CC(C(N)=O)c1ccccc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A 10% solution of methyl 2-cyano-2-phenylacetate in benzene is saturated with ammonia under ice cooling. The reaction mixture is allowed to stand at room temperature for 2 hours, and then the product is filtered off. 2-Cyano-2-phenylacetic acid amide is obtained with a yield of 75%; m.p.: 148.5°-150° C.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>C1(C)C=CC=CC=1>[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:27]1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CC1CCCNC1
Solvent: Cc1ccccc1
Product: CC1CCCN(CC(C)N2c3ccccc3Sc3ccc(C#N)cc32)C1

Procedure:
A solution of (2RS)-2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate (14.4 g) and (3RS)-3-methylpiperidine (9.4 cc) in toluene (75 cc) is stirred under reflux for 20 hours. After cooling, the mixture is extracted with N aqueous hydrochloric acid solution (2×100 cc). The combined aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl acetate (2×200 cc). The combined organic phases are washed successively with distilled water (2×50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (14.4 g) is purified by chromatography on a column (height: 40 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (80:20 by volume) (2.5 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. The combined fractions 10 to 12 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-((2RS)-1-[(3RS)-3-Methyl-1-piperidyl]-2-propyl}-2-phenothiazinecarbonitrile (7.2 g) is thereby obtained in the form of a yellow oil, which is subsequently used as it is.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].[Cl-].[NH4+].CCO>[Zn].C1COCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:11]
Reactant: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1OCCF
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccncc1-c1ccc(N)cc1OCCF
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Intermediate 16C (254 mg, 0.919 mmol), Zinc (361 mg, 5.52 mmol), and ammonium chloride (344 mg, 6.44 mmol) were taken in a flask followed by addition of EtOH (2 mL) and THF (2 mL). The reaction mixture was stirred at room temperature for 2 hours and filtered through a pad of CELITE®. The filtrate was concentrated to give Intermediate 16 (220 mg, 0.893 mmol, 97% yield) as a yellow solid. MS (ES): m/z=247.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3 H) 4.07 (dd, J=7.40, 3.39 Hz, 1 H) 4.13-4.20 (m, 1 H) 4.53 (dd, J=4.64, 3.14 Hz, 1 H) 4.65 (dd, J=4.77, 3.26 Hz, 1 H) 5.29 (s, 2 H) 6.28 (dd, J=8.03, 2.01 Hz, 1 H) 6.33 (d, J=2.01 Hz, 1 H) 6.81 (d, J=8.03 Hz, 1 H) 7.23 (d, J=5.02 Hz, 1 H) 8.22 (s, 1 H) 8.32 (d, J=4.77 Hz, 1 H). Intermediate 16 was used in the synthesis of Example 22.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[N:3]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccc(-c2ccccc2F)n1
Product: CN(C(=O)On1ccc(-c2ccccc2F)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-fluorophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:25]([I:31])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[I:31][C:25]1[CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:22]([NH:20][CH2:19][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:23][CH:24]=1
Reactant: COc1ccc(COc2ccc(CN)cc2OC)cn1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(COc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (9.11 g, 33.21 mmol) in acetonitrile (150 mL) was added 2-chloro-5-iodo-3-nitropyridine (9.90 g, 34.81 mmol) and N,N-diisopropylethylamine (6.44 g, 49.81 mmol). The yellow solution was heated to reflux and stirred. After 3 h, the red-brown mixture was cooled to 0° C. resulting in the formation of a precipitate. The precipitate was isolated by filtration and washed with acetonitrile (50 mL) and water (200 mL). The moist solids were dissolved in dichloromethane, and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 14.67 g (85%) of 5-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine as a yellow-brown solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=O.C([BH-](CC)CC)C.[Li+].Cl>O1CCCC1>[OH:2][CH2:3][CH2:5][CH:6]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: COC(=O)CC1Oc2ccccc2Oc2ccccc21
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1Oc2ccccc2Oc2ccccc21
Yield: 106.6 %

Procedure:
33.7 g of 11-(methoxycarbonyl methyl) [dibenzo (b,e)-1,4-dioxepin] were added to 50 ml of tetrahydrofuran. This clear solution was cooled between 0° and 10° C. and one N solution of lithium triethylborohydride in tetrahydrofuran was very slowly added. This reactive solution was added for about 6 hours while the stirring and cooling were maintained. The mixture was then left between 0° and -5° C., and the excess of the reactive solution was hydrolyzed with 100 ml of a 3N hydrochloric acid solution. The tetrahydrofuran was evaporated. The residual aqueous phase was extracted thrice with isopropyl ether. The organic solutions were joined together, washed with hydrochloric acid and then water. The solvent was distilled off and there were obtained 32.2 g of 11-hydroxyethyl dibenzo (b,e)-1,4-dioxepin. This product recrystallized from the tetrahydrofuran gives 19.6 g of pure product (yield: 65%). The hydroxy ethyl compound distills at 160°-163° C. under 0.1 mmHg M.P.=62°-64° C. (M.K.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH:23](C)[CH2:24][CH2:25][OH:26]>ClCCl.O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(N)CCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCCO
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 4-chloro-3-nitro[1,5]naphthyridine (18.0 g, 85.9 mmol) in dichloromethane (220 mL) at room temperature was added triethylamine (15.6 mL, 112 mmol) and 3-amino-1-butanol (7.20 mL, 94.5 mmol). The solution was stirred for 4 hours and then was concentrated under reduced pressure to yield an orange solid. The solid was slurried in water (250 mL) for 30 minutes, isolated by filtration, washed with water (3×30 mL), and dried at 70° C. in a vacuum oven to afford 20.9 g of 3-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (0.103 g, 0.15 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-tert-butylsulfonylpropan-2-yl)pyrimidine (1.10 g, 2.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.833 g, 3.80 mmol) and 2M aqueous sodium carbonate (5.27 mL, 10.53 mmol) in DMF (6 mL), DME (5 mL), ethanol (5 mL) and water (12.5 mL) at RT under nitrogen. The reaction was purged with nitrogen for 15 minutes and the resulting mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-100% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.19 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[OH:10])[N:15]=[CH:14][N:13]=1
Reactant: OC1CCCCC1O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1CCCCC1Oc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
In 30 ml of tetrahydrofuran was suspended 1.78 g of sodium hydride (60% in oil), to which 3 ml of a tetrahydrofuran solution containing 2.35 g of 1,2-cyclohexanediol (mixture of cis-form and trans-form) was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 7 ml of a tetrahydrofuran solution containing 3 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at 0° C. for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.6 g of 4-chloro-6-(2-hydroxycyclohexyloxy)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-].[CH:16](O)=O>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:16]=[N:8][C:7]=12
Reactant: O=CO
Reactant: Nc1nccc(-c2cccs2)c1N
Agent: [NH4+]
Agent: [OH-]
Product: c1csc(-c2ccnc3[nH]cnc23)c1
Yield: 96 %

Procedure:
A solution of Compound 3 (956 mg, 5.0 mmol) in formic acid (15 ml) was refluxed for 12 hours. To the reaction mixture, 24 ml of 28% NH4OH was added on an ice-cold bath. The resulting precipitate was filtered, washed with H2O and ethyl ether, and then dried at 60° C. for 12 hours to give 7-(2-thienyl)-3H-imidazo[4,5-b]pyridine (970 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCOCC1>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[NH:1][C:14](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 42 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 6, Step A) (97 g, 520 mmol) stirred in dry dioxane (750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise. The reaction mixture exothermically warmed slowly to 42° C., and the solid almost completely dissolved before a thick suspension formed again. After the suspension was stirred at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether, and dried to yield the title product compound, obtained as a white solid (98 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][NH:5][C:4](=[O:9])[CH:3]=1.CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:8][C:7]1[C:2]([O:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH2:16]2)=[CH:3][C:4](=[O:9])[NH:5][CH:6]=1
Reactant: Cc1c[nH]c(=O)cc1O
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c[nH]c(=O)cc1OC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.9 %

Procedure:
4-Hydroxy-5-methylpyridin-2(1H)-one (554 mg, 4.43 mmol), benzyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2081 mg, 6.64 mmol), and potassium carbonate (1224 mg, 8.86 mmol) were stirred in DMF (12 mL) at 100° C. under nitrogen for 14 hours. 100 mL water and 100 mL EtOAc was added and then washed the EtOAc layer with 2×100 mL additional water. The organic layer was dried with Na2SO4, filtered, and concentrated to give 1454 mg of a brown oil. The oil was purified by flash chromatography (0-5% MeOH/CH2Cl2) to give product (280 mg, 0.82 mmol, 18%) as a pale tan foam. MS (ESI) 343.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])C(OC)=O.[Cl-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120° C. (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105° C. 1H NMR (CDCl3) 8.3 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.12 (s, 2H), 3.60 (s, 3H). MS (FAB) m/z: 275.2 (M++1).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1)[CH3:3]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(=O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 60 °C

Procedure:
To a solution of 4-[5-(1-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one (0.100 g, 0.35 mmol) (Example 12) in dioxane (2 mL) is added manganese dioxide (0.46 g, 5.2 mmol) and the reaction mixture is heated to 60° C. overnight. Filtration through celite and concentration in vacuo gave a residue, which is purified by semi-preparative reverse phase HPLC to give 4-(5-acetyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 285.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (s, 3 H), 1.55 (s, 3 H), 2.61 (s, 3 H), 6.90 (s, 1 H), 7.38 (d, J=7.1 Hz, 1 H), 7.47 (s, 1 H), 7.57-7.62 (m, 1 H), 7.63-7.69 (m, 1 H), 7.93 (s, 1 H), 8.28 (dd, J=7.6, 1.5 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]1([CH:19]2[O:21][CH:20]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C.[H-].[Na+]>CO.ClCCl.ClCCl>[OH:21][CH:20]([CH:19]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1OC1c1ccccc1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C(O)C(Oc1ccc(OC)cc1[N+](=O)[O-])c1ccccc1

Procedure:
To a stirred mixture of 4-methoxy-2-nitrophenol (11.87 g, 70 mmol), ethyl 3-phenyloxirane-2-carboxylate (10.39 g, 54 mmol) and ethanol (175 mL) was added portionwise 60% sodium hydride (0.65 g, 16 mmol) and the red mixture stirred at reflux for 9 days. The solvent was removed in vacuo, the residue dissolved in ethyl acetate and extracted three times with 10% aqueous potassium carbonate. The organic layer was washed with water and brine, dried (MgSO4), filtered and the solvent stripped in-vacuo to yield an oil. Column chromatography (dichloromethane then 5% methanol/dichloromethane) afforded (9.5 g, 49%) of slightly impure title compound that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ1.21 (t, 3H) 3.25 (d, 1H, J=7.5 Hz) 3.77 (s, 3H), 4.20 (q, 2H) 4.67 (q, 1H, J=3.5, 7.5 Hz), 5.51 (d, 1H, J=3.5 Hz), 6.82 (d, 1H, J=9.2 Hz), 6.92 (dd, 1H, J=9.2, 3.0 Hz), 7.3-7.4 (m, 6H). HPLC (Method A): 3.24 min
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:20]([C:22]([OH:40])([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][C:35](=[O:39])[CH2:36][CH2:37]Cl)=[CH:27][CH:26]=2)[CH3:23])=[O:21])([OH:19])[CH3:18])=[CH:12][CH:11]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CC(C)=O>[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:20]([C:22]([OH:40])([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][C:35](=[O:39])[CH:36]=[CH2:37])=[CH:27][CH:26]=2)[CH3:23])=[O:21])([OH:19])[CH3:18])=[CH:14][CH:15]=1)(=[O:5])[CH:3]=[CH2:2]
Reactant: CC(O)(Cc1ccc(OCCOC(=O)CCCl)cc1)C(=O)C(C)(O)Cc1ccc(OCCOC(=O)CCCl)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)OCCOc1ccc(CC(C)(O)C(=O)C(C)(O)Cc2ccc(OCCOC(=O)C=C)cc2)cc1
Temperature: 25 °C

Procedure:
7 g (22 mmol) of 4-(2-(3-chloropropionyloxy)ethoxy)phenyl-2-hydroxy-2-propyl-ketone was dissolved in 70 ml acetone. 4.6 g (33 mmol) K2CO3 and 50 mg 2,6-di-tert.butyl-4-methylphenol were added. The mixture was refluxed for 3 hours. After cooling down to room temperature, the inorganic salts were removed by filtration and the solvent was removed under reduced pressure. The residue was treated with 75 ml n.-hexane. 4-(2-acryloyloxyethoxy)phenyl-2-hydroxy-2-propyl ketone crystallized from the medium. 4.2 (67.7%) of 4-(2-acryloyloxyethoxy)phenyl-2-hydroxy-2-propyl ketone was isolated.