Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:41])([F:40])[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[CH:38]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][C:27]([F:40])([F:26])[F:41])[CH:30]=4)[NH:34][N:33]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(OC(F)(F)F)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(OC(F)(F)F)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.103 g, 0.295 mmol) in methanol (1.2 mL) was added with 5-(trifluoromethoxy)-1H-indazole-3-carbaldehyde (0.0680 g, 0.295 mmol), and piperidine (0.00251 g, 0.0295 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-hydroxy-3-oxo-2-{[5-(trifluoromethoxy)-1H-indazol-3-yl]methylene}-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0660 g, 40%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:17](=[O:19])(=[O:18])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([O:28]CC5CCCCC5)=[O:27])=[CH:22][CH:21]=4)[C:15](=[O:36])[N:14]([CH3:37])[C:13]=3[CH:38]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCOCC1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:16]2[C:15](=[O:36])[N:14]([CH3:37])[C:13]3[CH:38]=[C:9]([O:8][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:10]=[CH:11][C:12]=3[S:17]2(=[O:18])=[O:19])=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: CN1C(=O)N(c2ccc(C(=O)OCC3CCCCC3)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccc(C(=O)O)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21

Procedure:
A solution of 6-cyclohexylmethoxy-2-(4-cyclohexylmethoxycarbonylphenyl)-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.12 g) in a mixture of conc. hydrochloric acid (1 ml), water (2 ml) and 1,4-dioxane (8 ml) was refluxed overnight. The mixture was concentrated in vacuo. The residue was treated with a mixture of ethyl acetate and aqueous 1N sodium hydroxide solution. The precipitates were collected by filtration, washed with ethyl acetate and then dissolved in a mixture of ethyl acetate and aqueous 1N hydrochloric acid. The organic layer was washed with water, dried, and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2 -(4-carboxyphenyl)-6-cyclohexylmethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:19][C:18]1[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Cc1cccnc1N
Solvent: CN(C)C=O
Product: Cc1cccnc1NC(=O)N=C1NC(=O)CN1C
Yield: 2.6 %

Procedure:
A mixture of 5.0 g (21.4 mM) of the phenyl carbamate 8 and 1.2 g (10.7 mM) of 2-amino-3-methyl-pyridine in 25 ml of anhydrous DMF was heated at 55° for 3 hrs. and then cooled. The solid was collected via filtration and washed successively with cold DMF, ethyl acetate and ether. Recrystallization from ethanol and a final wash with water gave 0.07 g of the above urea as a pale yellow solid, m.p. 219°-221° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33]>>[CH3:33][C@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C[C@@H]1CNCCN1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.53 (m, 3H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (br. s., 3H) 2.93-4.70 (m, 7H) 7.63 (d, J=7.07 Hz, 1H) 7.71-7.80 (m, 1H) 7.88-8.77 (m, 4H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].FC(F)(F)S(OC1[CH:21]=[C:22]2[C:26](=[C:27]([Cl:30])[C:28]=1[Cl:29])[C:25](=[O:31])[C:24]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)([CH3:32])[CH2:23]2)(=O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:29][C:28]1[C:27]([Cl:30])=[C:26]2[C:22]([CH2:23][C:24]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)([CH3:32])[C:25]2=[O:31])=[CH:21][C:3]=1[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CC1(CC2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Diethyl malonate (18.3 g., 0.114 mole) is added with stirring under nitrogen at 10°-15° C. to a suspension of sodium hydride (56% in mineral oil, 4.89 g., 0.114 mole) in dry dimethylformamide (85 ml.). The reaction mixture is stirred for 1 hour at room temperature, cooled to 5° C. and then 6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl trifluoromethanesulfonate (18.8 g., 0.0426 mole dissolved in dry toluene (20 ml.) is added over 1 hour at 5°-7° C. After stirring at room temperature for 18 hours, the reaction mixture is poured into ice water (1000 ml.) and extracted with ether (4×150 ml.) and then with methylene chloride (2×50 ml.). The combined organic extracts are washed three times with water and concentrated under vacuum. The residual oil is dissolved in ethanol (150 ml.) and added to a solution of 20 g. of sodium hydroxide in water (150 ml.). The mixture is refluxed for 3 hours, cooled and the ethanol removed under vacuum. The residue is diluted with water, extracted with hexane and then acidified with hydrochloric acid. The gum that separates is extracted with ether. The combined etheral extracts are washed with water and then extracted repeatedly with dilute sodium bicarbonate. The combined aqueous extracts are acidified with hydrochloric acid and extracted with ether. The ether extracts are washed with brine, dried over magnesium sulfate an concentrated under vacuum to obtain the crude (6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid, 9.3 g., m.p. 145.5°-148° C., in 62% yield. Recrystallization from butyl chloride affords material which melts at 149°-151° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:15][CH:16]=1)=[O:19]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CN(CCOc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 52 %

Procedure:
A solution of N-(2-hydroxyethyl)-N-methylcarbamic acid, 1,1-dimethylethyl ester (7.05 g, 40.2 mmol; W. S. Saari and all, J. Med. Chem. 33, 97 (1990)), 4-hydroxybenzaldehyde (3.75 g, 30.7 mmol) and triphenylphosphine (10.57 g, 40.3 mmol) in dry benzene (120 ml) was cooled to 15° C. and treated with diisopropyl azodicarboxylate (8.15 g, 40.3 mmol) in dry benzene (20 ml) added dropwise over 20 min. After 16 h at 22° C., and chromatography on silica gel (elution toluene-ethyl acetate 9:1-8:2) gave 4.40 g (52%) of the title material as white cubes: mp 62-65° C. (ether-hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=2[O:3]1.C([Li])CCC.[C:18](=[O:20])=[O:19]>O1CCCC1>[CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([F:11])=[C:10]([C:18]([OH:20])=[O:19])[C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(F)cc2O1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(F)c(C(=O)O)c2O1

Procedure:
In a flask were placed 29.3 g (0.174 mole) of 2,2-dimethyl-5-fluoro-1,3-benzodioxole and 200 mL of dry tetrahydrofuran, and the resulting solution was cooled to -78° C. To this solution was added dropwise 66.4 mL (0.166 mole) of a 2.5 M solution of n-butyllithium in hexanes. This mixture was stirred at -78° C. for one hour after which a carbon dioxide atmosphere was placed above the reaction mixture. The temperature was allowed to warm to ambient conditions during a 16 hour period while maintaining the carbon dioxide atmosphere. At the conclusion of this period the solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. This mixture was extracted with water, and the water extract was in turn extracted with diethyl ether. The aqueous phase was separated and acidified with hydrochloric acid. The acidified mixture was then extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving 19 g of 2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-ylcarboxylic acid as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[OH:15]>O1CCOCC1>[CH3:19][O:18][C:13]([CH:14]([O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:16])=[O:17]
Reactant: COC(=O)C(C)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
First, 0.8 g of sodium hydride was added to a mixture of 3.17 g of 2-chloro-3-nitropyridine, 2.19 g of methyl lactate, and 20 ml of 1,4-dioxane at 10° C., and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 3.3 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1O.C(O[S:26]([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC(=O)C)(=O)C>O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:26]
Reactant: Nc1c(O)ccc2ccccc12
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(S)ccc2ccccc12
Yield: 73 %

Procedure:
5 mmol of 1-aminonaphthalene-2-ol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of acetic anhydride was added for 5 minutes. An acetylated product was precipitated in in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain 1-aminonaphthalene-2-thiol at a yield of 73%.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)([Cl:15])=O>>[S:1]1[C:5]2[C:6]([C:10]([Cl:15])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1cccc2nnsc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc2nnsc12
Temperature: 90 °C

Procedure:
12.54 g (0.070 mol) of benzo-1,2,3-thiadiazole-7-carboxylic acid are mixed with 80 ml of thionyl chloride. The mixture is heated and maintained at a bath temperature of 90° C. for 8 hours. The excess thionyl chloride is then removed by distillation in a rotary evaporator at a bath temperature of 40° C. The resulting oil solidifies; m.p. 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 2-chloro-5-nitrophenol (13.0 g, 75.1 mmol) in DMF (150 mL) was added K2CO3 (15.5 g, 113 mmol). The mixture was cooled to 0° C., and allyl bromide (9.60 mL, 113 mmol) was added dropwise. The reaction was then allowed to stir overnight at rt under nitrogen. The reaction was concentrated to remove DMF, then EtOAc was added to the residue. The mixture was washed with water and brine. The organic layer was dried (Na2SO4), and concentrated in vacuo to afford the highly yellow solid 2-(allyloxy)-1-chloro-4-nitrobenzene (11.5 g, 72% yield). LC-MS (M+H)+212.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.81-7.77 (2H, m), 7.52 (1H, d, J=8.8 Hz), 6.12-6.02 (1H, m), 5.54-5.37 (2H, m), 4.72-4.70 (2H, m).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)[CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Nc2cccc(CNc3nc4ccccc4[nH]3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
246 mg (1H-Benzoimidazol-2-yl)-[3-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 59) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (146 mg, 50% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1cccc(Cl)c1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2cccc(Cl)c2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 3-Chloroaniline instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=342.0, 344.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C1CCCCC1.C(OCC)(=[O:36])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:36])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3cccc(I)c3)ccc2O1
Solvent: C1CCCCC1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3cccc(I)c3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-2-H-1-benzopyran-4-yl]pyridine N-oxide of melting point 128°-130° C. (from cyclohexane/ethyl acetate).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1.C1C(=O)N([Br:22])C(=O)C1>C(O)C.ClCCl>[Br:22][C:12]1[N:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][C:8]2=[N:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1csc(-c2ccn3ccnc3c2)n1
Solvent: CCO
Solvent: ClCCl
Product: Brc1cnc2cc(-c3nccs3)ccn12
Yield: 67.5 %

Procedure:
Dissolve 7-thiazol-2-yl-imidazo[1,2-a]pyridine (1.14 g, 5.66 mmol) in 25 mL absolute ethanol, then add NBS (1.0 g, 5.66 mmol), stir the mixture at room temperature for 15 minutes, dilute with 35 mL dichloromethane and apply to a 10 g SCX Mega Bond-Elut™ cartridge (Varian) pre-washed with 150 mL 1:1 CH2Cl2:MeOH. Wash the SCX cartridge with 300 mL 1:1 CH2Cl2:MeOH, elute with 150 mL CH2Cl2:2 M NH3-MeOH, and concentrate the eluates and dry to provide 1.07 g (67%) of the title compound as a tan solid. MS (ES) 280, 282.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15](F)[CH:14]=1.C(N(CC)C(C)C)(C)C>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:4][OH:5])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NC(CCO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Temperature: 140 °C
Yield: 59.9 %

Procedure:
A mixture of 3-amino-3-phenyl-1-propanol (1 g, 6.6 mmol), 4-chloro-2-fluorobenzonitrile (1 g, 6.4 mmol) and N,N-diisopropylethylamine (1.2 ml, 6.9 mmol) was stirred and heated at 140° C. for 5 h. The crude reaction mixture was cooled and purified on silica gel (ether/isohexane 1:4). The product was isolated as a colourless solid (1.1 g, 58%), m.p. 88-90° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([OH:20])=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[CH:58][C:59]2[O:63][CH:62]([CH2:64][N:65]3[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]3)[CH2:61][C:60]=2[CH:71]=1>ClCCl>[O:20]=[C:18]([N:68]1[CH2:69][CH2:70][N:65]([CH2:64][CH:62]2[CH2:61][C:60]3[CH:71]=[C:56]([C:55]([F:73])([F:54])[F:72])[CH:57]=[CH:58][C:59]=3[O:63]2)[CH2:66][CH2:67]1)[CH2:17][O:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)O)CC2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(CC4Cc5cc(C(F)(F)F)ccc5O4)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.29 mmol) in dichloromethane (30 ml) was added EDAC.HCl (84.2 mg, 0.44 mmol, 1.5 eq), HOBt (59.2 mg, 0.44 mmol, 1.5 eq), triethylamine (59.1 mg, 0.58 mmol, 2 eq) and 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine (92.0 mg, 0.32 mmol, 1.1 eq). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water (30 ml). The crude product was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by Pre-TLC with 20% ethyl acetate in dichloromethane to afford 4-([4-[2-oxo-2-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethoxy]cyclohexyl]amino)-2-(trifluoromethyl)benzonitrile as a white solid (76 mg, 43%); (ES, m/z): [M+H]+ 611.30; 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 6.81-6.86 (m, 2H), 6.64-6.68 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.29 (d, J=7.8 Hz, 1H), 4.21 (s, 2H), 3.65-3.78 (m, 3H), 3.30-3.48 (m, 3H), 3.01-3.06 (dd, J=8.4 Hz, 15.9 Hz, 2H), 2.51-2.90 (m, 4H), 2.10-2.19 (m, 4H), 1.44-1.58 (m, 3H), 1.21-1.33 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].CO.[CH:7]([CH:9]=O)=O>O>[CH3:1][N:2]([CH3:4])[N:3]=[CH:7][CH:9]=[N:3][N:2]([CH3:4])[CH3:1]
Reactant: O=CC=O
Reactant: CN(C)N
Solvent: O
Solvent: CO
Product: CN(C)N=CC=NN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,1-Dimethylhydrazine (3.20 ml, 41.9 mmol) was added to a mixture of MeOH (14 ml) and a 40 wt % glyoxal solution (2.40 ml, 20.9 mmol) in water at 0° C. The resulting mixture was stirred for 24 h at room temperature. The mixture was then dried over Na2SO4, filtered, and concentrated under vacuum to afford glyoxal bis(N,N-dimethylhydrazone) (abbreviated as bis-hydrazone A) as an orange-brown oil (2.78 g, 94% yield). The 1H NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.13 (singlet, 2 H), 2.89 (singlet, 12 H). The 13C NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 134.9, 43.1. From the 1H NMR and 13C NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Reactant: COCCl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCOc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 16 h
Yield: 83 %

Procedure:
To a mixture of 10 (263.4 mg, 0.88 mmol) and diisopropylamine (DIPEA) (170.6 mg, 1.32 mmol) in CH2Cl2 (12 mL) was added slowly chloromethyl methyl ether (77.9 mg, 0.97 mmol) at room temperature. The reaction was stirred for 16 h, and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting solution was extracted with more CH2O2, dried (Na2SO4), filtered, and concentrated to yield the crude product, which was purified by column chromatography (neat CH2Cl2→100:1 CH2Cl2-Acetone) to afford 11 (250.8 mg, 83%) as a yellow amorphous solid; 1H NMR (400 MHz, CDCl3, δH) 8.20-8.08 (m, 2H), 7.07-6.97 (m, 2H), 6.97-6.82 (m, 4H), 5.13 (s, 2H), 3.62-3.51 (m, 4H), 3.48 (s, 3H), 3.30-3.18 (m, 4H); 13C NMR (100 MHz, CDCl3, δC) 154.99, 151.98, 146.31, 138.84, 126.18, 118.59, 117.58, 113.04, 95.28, 56.13, 50.42, 47.43. MALDI-MS: 344.2 (M+H+), 366.2 (M+Na+).