Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)(=[O:4])=[O:3].[CH3:20][N:21]1[C:26]([N:27]2[CH2:32][CH2:31][N:30](CCCN(S(C)(=O)=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:29][CH2:28]2)=[CH:25][C:24](=[O:50])[N:23]([CH3:51])[C:22]1=[O:52].C(N(CC)CC)C>C(O)C>[ClH:16].[CH3:20][N:21]1[C:26]([N:27]2[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[N+:17]([O-:19])=[O:18])[CH2:29][CH2:28]2)=[CH:25][C:24](=[O:50])[N:23]([CH3:51])[C:22]1=[O:52]
Reactant: CS(=O)(=O)Nc1ccc(OCCCCl)c([N+](=O)[O-])c1
Reactant: Cn1c(N2CCN(CCCN(c3ccc([N+](=O)[O-])cc3)S(C)(=O)=O)CC2)cc(=O)n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cl
Product: Cn1c(N2CCN(CCCOc3ccc(NS(C)(=O)=O)cc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
0.31 g of 3-(4-methanesulfonamido-2-nitrophenyloxy)propyl chloride, 0.22 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157) and 0.5 ml of triethylamine were dissolved under heat in 10 ml of ethanol to give a uniform solution. The solvent was distilled off under reduced pressure. After heating the residue at 110° C. for 2 hours, 10 ml of n-butanol were added and the resulting mixture was heated under stirring at 110° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a dilute aqueous solution of sodium hydroxide. The thus-prepared solution was washed with chloroform. The water layer was then adjusted to pH 1-2 with dilute hydrochloric acid, washed with ethyl acetate, and then added with sodium hydrogencarbonate to raise the pH to 7-8. Precipitated insoluble matters were collected by filtration. The thus-collected substance was dried under reduced pressure and then dissolved in methanol. 15% HCl/methanol was added to convert it into the hydrochloride by a method known per se in the art, thereby obtaining 0.2 g of 1,3-dimethyl-6-{4-[3-{4-methanesulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 142 as crystals.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]([CH3:49])([CH3:48])[CH2:8][O:9][C:10]([N:12]1[C:25]2[C:17](=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C@@H:16]([N:26]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11])=[O:6].Cl.C(OCC)(=O)C>CO.O>[C:5]([C:7]([CH3:49])([CH3:48])[CH2:8][O:9][C:10]([N:12]1[C:25]2[C:17](=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C@@H:16]([N:26]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11])([OH:6])=[O:4]
Reactant: COC(=O)C(C)(C)COC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OCC(C)(C)C(=O)O)c3cc4c(cc32)CCC4)n1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
Add aqueous 5 M NaOH (2.4 mL, 12 mmol) to a solution of (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester (86 mg, 0.13 mmol) in methanol (3.4 mL). Heat the mixture at 60° C. for 1 h. Cool down to room temperature. Dilute with water and neutralize with 2 M HCl. Extract aqueous phase with ethyl acetate. Dry organic layers with anhydrous sodium sulphate and evaporate the solvent. Purify the residue by chromatography (elution with dichloromethane/methanol) to afford the title compound (62 mg, 73%). MS (ES+): 655 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[O:22][CH2:21][CH2:20][O:19]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.[BH4-].[Na+]>[Pd].C(O)C.O.C(OCC)(=O)C>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:5]1[C:4]([NH2:23])=[CH:3][C:2]([F:1])=[C:7]([C:8]2[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH:6]=1
Reactant: COc1cc(OC)cc(-c2cc(C3OCCO3)c([N+](=O)[O-])cc2F)c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2cc(C3OCCO3)c(N)cc2F)c1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2-(6-fluoro-3′,5′-dimethoxy-4-nitrobiphenyl-3-yl)-1,3-dioxolane (1.8 g, 5.2 mmol), sodium borohydride (587.9 mg, 15.5 mmol) and 10% palladium on carbon (0.2 g) in ethanol/water (33 mL, v/v=10/1) was heated at 90° C. for 1 hour. After that, the mixture was diluted with ethyl acetate (150 mL), and washed by water (50 mL) and brine (50 mL). The organic layer was dried over sodium, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1 to 4/1) to afford the title compound (1.4 g, 88%) as a yellow solid. MS (ES+) C17H18FNO4 requires: 319, found: 320 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)(C)(C)C.[F:25][C:26]([F:38])([F:37])[C:27]1[N:36]=[C:30]2[C:31](=S)[NH:32][CH2:33][CH2:34][N:29]2[N:28]=1>COCCO>[F:23][C:16]1[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=1[CH2:14][C@@H:8]([NH2:7])[CH2:9][C:10]1[N:32]2[C:31]([C:30]3[N:29]([N:28]=[C:27]([C:26]([F:38])([F:37])[F:25])[N:36]=3)[CH2:34][CH2:33]2)=[N:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nc2n(n1)CCNC2=S
Solvent: COCCO
Product: N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCn1nc(C(F)(F)F)nc1-2

Procedure:
A mixture of 208 mg (0.6 mmol) of of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 100 mg (0.45 mmol) of 2-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrazine-8(5H)-thione (Intermediate 7), and 5 mL of 2-methoxyethanol was stirred at reflux for 18 h, resulting primarily in ring closure of the initial adduct as well as loss of the Boc group. The cooled solution was purified by preparative HPLC (C18 reverse phase column, 30-75% acetonitrile in water containing 0.05% trifluoroacetic acid) to afford the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[C:25]([Br:29])(Br)(Br)Br.OC[CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1>C(Cl)Cl.O>[Br:29][CH2:25][CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1
Reactant: Nc1ncc(SCCO)s1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(SCCBr)s1

Procedure:
Triphenylphosphine (12.1 g), imidazole (3.86 g), and carbon tetrabromide (4.44 g) were added to a suspension of 5-(2-hydroxyethylthio)thiazol-2-amine (2.00 g) in methylene chloride (74.6 mL) under cooling with ice, and the mixture was stirred under cooling with ice for 4 hours. Methylene chloride (200 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (neutral spherical silica gel, ethyl acetate:hexane=1:10 and then 1:2) and washed with hexane to give the title compound as white powder crystals (1.06 g, yield: 39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH3:24])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:28]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][OH:28])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CO)=CC1(C)C
Yield: 23.1 %

Procedure:
A solution of N-tert-butyloxycarbonyl-1,2-dihydro-2,2,4-trimethyl-6-phenyl quinoline (structure 10, where R1 -phenyl) (310 mg, 0.888 mmol) and selenium dioxide (345 mg, 3.11 mmol) in 17 mL of dioxane was heated to reflux for 3 h. The reaction mixture was quenched with 1:1 NaS2 O3 (10%) /Na2HCO3 (10%), extracted with dichloromethane, dried (MgSO4), and the organic phase was concentrated in vacuo. Purification by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) gave 212 mg of the intermediate aldehyde along with 75 mg of the desired alcohol of structure 11, where R1 =phenyl. The aldehyde was treated with sodium borohydride in 25 mL of methanol at 0° C. After 1 h at 0° C., the reaction mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo to give an oil that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) providing structure 11, where R1 =phenyl (240 mg, 84%). 1H NMR (acetone d6) 7.68 (d, J=9, 2H), 7.61 (d, J=1.8, 1H), 7.47 (dd, J=6.2, 1.8, 1H), 7.41 (d, J=6.4, 2H), 7.29 (m,2H), 5.80 (s, 1H), 4.51 (d, J=6.8, 2H), 4.12 (t, J=6.8,1H), 1.52 (br s, 15H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Br[C:10]1[S:14][N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=1.C(N(CC)CC)C.C(Cl)Cl>O>[CH3:16][CH:15]([C:12]1[N:11]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[S:14][N:13]=1)[CH3:17]
Reactant: OCC1CCNCC1
Reactant: CC(C)c1nsc(Br)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nsc(N2CCC(CO)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 4-piperidinylmethanol (115 mg, 1 mmol), 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole (Example 182, Step 6, 207 mg, 1 mmol), triethylamine (0.42 mL, 3 mmol) and CH2Cl2 (3 mL) was stirred at ambient temperature overnight. The mixture was charged with additional 4-piperidinylmethanol (58 mg, 0.5 mmol) and was stirred at ambient temperature for 3 h. The mixture was charged with water, and extracted with CH2Cl2. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 159 mg (66%) of {1-[3-(1-methylethyl)-1,2,4-thiadiazol-5-yl]-4-piperidinyl}methanol as a golden oil. 1H NMR (400 MHz, CDCl3): δ 3.98-3.88 (m, 2H), 3.54 (d, 2H, J=6.3 Hz), 3.20-3.05 (m, 2H), 3.02 (septet, 1H, J=6.9 Hz), 1.90-1.80 (m, 2H), 1.82-1.70 (m, 1H), 1.42-1.25 (m, 8H); LRMS (ESI), m/z 242 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.F[B-](F)(F)F.[CH3:15][O+:16](C)C>ClCCl>[OH:16][CH2:15][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][N:6]=1
Reactant: C[O+](C)C
Reactant: COc1cc[n+]([O-])cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
The 4-methoxypyridine--N-oxide (6.3 g, 0.05 mol) was suspended in 150 ml of dichloromethane (CH2Cl2). Trimethyloxoniumtetrafluoroborate (7.5 g, 0.05 mol) was added all at once and the reaction was stirred at room temperature for 2 hrs. After evaporation of the solvent, the residue was dissolved in methanol (150 ml) and heated to reflux. To this solution was added of ammonium persulfate (2.3 g) in 20 ml of water. After 30 min. a further portion of 1.2 g of persulfate in 5 ml of water was added. After refluxing for one hour the solution was cooled and concentrated under vacuum. The residue was chromatographed over silica with 9:1 chloroform/methanol to give 3.52 g (51% yield) of the subtitle compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[Al+3:6].[CH2:7](OP([O-])([O-])=O)[CH3:8].[OH2:14].CO[CH:17](O)[CH3:18]>>[CH3:17][CH2:18][CH:7]([O-:14])[CH3:8].[CH3:17][CH2:18][CH:7]([O-:14])[CH3:8].[CH3:17][CH2:18][CH:7]([O-:14])[CH3:8].[Al+3:6]
Reactant: COC(C)O
Reactant: CCOP(=O)([O-])[O-]
Reactant: O
Agent: O=P([O-])([O-])[O-]
Agent: [Al+3]
Product: CCC(C)[O-]
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Comparative Example 1 involves the preparation of aluminum phosphate without using an organosilane. A homogeneous solution of aluminum s-butoxide (0.082 gm, 0.33 mmol) in methoxyethanol (0.5 ml) is prepared in a glass vial containing a magnetic stir bar. It is stirred for ½ hr after addition of ethylphosphate (0.06 gm, 0.33 mmol). Addition of DI water (0.010 gm, 0.56 mmol) results in the formation of a milky gel. After diluting with 0.5 ml methoxyethanol, the resulting milky solution is stirred at room temperature/overnight. Addition of DI water (0.010 gm, 0.56 mmol) followed by stirring at RT/overnight and 100° C./2 hrs generates white precipitates. The solution is applied to a glass plate to form a highly opaque non-uniform coating. White solid residues obtained after removing the volatiles are not soluble in methoxyethanol even heated to 120° C. in the presence of phenyltrimethoxysilane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The solution of 1H-indole-5-carboxylic acid (1.0 g, 6.2 mmol, Aldrich) and K2CO3 (0.939 g, 6.8 mmol) in DMF (10 mL) was heated to 65° C., and Me2SO4 (0.78 g, 6.2 mmol) was added dropwise between 65-70° C. over 15 min. The reaction was stirred for 1 h at 80° C. then the mixture was poured into ice/water. The resulting precipitate was collected by filtration and dried in vacuo to give methyl 1H-indole-5-carboxylate (0.91 g, 5.2 mmol, 85.8%). MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>CC(O)C>[F:20][C:19]([F:21])([F:22])[CH2:18][CH2:17][O:16][CH:13]1[CH2:12][CH2:11][CH:10]([C:9]([OH:23])=[O:8])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(OCCC(F)(F)F)cc1
Solvent: CC(C)O
Product: O=C(O)C1CCC(OCCC(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
10% Rh—C (14.7 mg) was added to a solution of 4-(3,3,3-trifluoro-propoxy)-benzoic acid benzyl ester (147.3 mg, 0.454 mmol) in iPrOH (1.5 mL). The hydrogen pressure was adjusted to 5 atm, and the mixture was then heated with stirring at 80° C. overnight. The reaction mixture was filtered through celite, and the filtrate was then diluted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added, and the organic layer and the aqueous layer were separated. The aqueous layer was adjusted to pH 1 with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layers were sequentially washed with water and saturated brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-(3,3,3-trifluoro-propoxy)-cyclohexanecarboxylic acid as a colorless transparent oily substance (70.2 mg, 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[Cl:21][CH2:22][CH2:23][CH2:24]O>C1(C)C=CC=CC=1>[Cl:21][CH2:22][CH2:23][CH2:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: OCCCCl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(OCCCCl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a mixture of 106.0 g of 2,4-dinitrobenzoic acid in 200 ml of toluene were added 10.0 g of concentrated sulfuric acid and 95.0 g of 3-chloropropanol. The mixture was refluxed for 4 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperature and washed with 250 ml of an aqueous 5% NaHCO3 solution followed by two 200 ml water washings. The toluene was removed at reduced pressure to yield 146 g of (3-chloropropyl)-2,4-dinitrobenzoate, mp 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([Br:1])[C:3]=1[CH:4]=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Br)cc(OC2CCCCO2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.1 %

Procedure:
To a mixture of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (1.8 g, 6.0 mmol) and anhydrous K2CO3 (1.66 g, 12.0 mmol) in DMF (10 mL) was slowly added 1-(bromomethyl)benzene (1.22 g, 7.2 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h before quenched by water (15 mL). The resulting mixture was further stirred for 20 min and white precipitate was collected by filtration. The solid was washed with ether and dried under high vacuum to give the title compound as a white powder (3.9 g, yield: 83%).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:28])=[C:24]([Cl:27])[C:25]=3[Cl:26])=[O:20])[CH2:14][CH2:13]2)(C(OC)=O)[CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C[CH2:36][O:37][C:38](C)=[O:39]>CN(C=O)C.O>[Cl:26][C:25]1[C:24]([Cl:27])=[C:23]([CH3:28])[NH:22][C:21]=1[C:19]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:3]=[C:4]([C:38]([O:37][CH3:36])=[O:39])[CH:5]=2)[CH2:13][CH2:14]1)=[O:20]
Reactant: CCOC(C)=O
Reactant: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C

Procedure:
A solution of methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylate (Example 6, 300 mg, 0.67 mmol), morpholine (58 mg, 0.67 mmol) and TEA (0.09 ml, 0.67 mmol) in DMF (3 ml) were stirred at 60° C. under nitrogen for 4 hours. The mixture was cooled to room temperature and diluted with EtOAc (75 ml) and water (10 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to yield 320 mg of the title compound. An analytical sample was purified by reversed-phase HPLC (water/acetonitrile gradient, 20-95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:19][OH:20]
Reactant: O=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl
Reactant: NO
Agent: Cl
Product: ON=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (170 mg, 0.637 mmol) with hydroxylamine hydrochloride (89 mg, 1.27 mmol) according to Method F to yield 160 mg (89%) of a white solid: mp 183-186° C.; 1H NMR (DMSO-d6): δ 6.86 (2H, d, J=8.79 Hz), 7.63 (2H, d, J=8.79 Hz), 7.76 (2H, s), 8.25 (1H, s), 9.81 (1H, s), 11.78 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−, 282/284/286 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12]C(C(O)=O)=N[CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.C[N:46]1CC[O:49][CH2:48][CH2:47]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:32]([C:33]([NH:46][CH2:47][CH2:48][OH:49])=[O:34])=[N:31][CH:15]=1
Reactant: CN1CCOCC1
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (108 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.0.0 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 17 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:4 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and then was collected by filtration, to obtain the title compound (96 mg, 0.20 mmol, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1C=C(Cl)C=C[C:3]=1[C:4]([Cl:6])=O.[CH2:12]([Mg]Br)[CH2:13][CH3:14].[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>[Cu]I>[Cl:1][CH:2]([CH2:3][CH2:4][Cl:6])[C:21]([C:20]1[CH:14]=[CH:13][CH:12]=[CH:18][CH:19]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Reactant: CCC[Mg]Br
Agent: [Cu]I
Product: O=C(c1ccccc1)C(Cl)CCCl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 2,4-dichlorobenzoyl chloride (4.5 g, 21.5 mmol) in tetrahydrofuran (30 ml) was treated with copper (I) iodide (200 mg) and cooled to -20° C. Propyl magnesium bromide (2.0M in diethyl ether, 11 ml, 11 mmol) was slowly injected (10 minutes) under nitrogen. The yellow suspension was stirred at -20° C. to -15° C. for 10 minutes, the cooling bath was removed and stirring was continued for another hour. The reaction was quenched with water, and the product was extracted with toluene. The organic phase was washed with 1N aqueous hydrochloric acid, bicarbonate and brine, filtrated through a silica gel pad and concentrated in vacuo to give 2,4-dichlorobutyrophenone as a yellowish oil (4.5 g, 96%) which was used in the next step without further purification. 1H NMR (CDCl3): 0.99 (t, 3H), 1.74 (m, 2H), 2.91 (t, 2H), 7.32 (d, 1H), 7.42 (d, 1H), 7.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([NH2:22])=[C:18]([NH2:21])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:23]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15]([CH:16]=[C:17]4[N:22]=[N:23][N:21]=[C:18]4[CH:19]=3)=[CH:14][NH:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc(-n2[nH]cc3cc4nnnc4cc32)c(Cl)c1
Yield: 113.2 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5,6-diaminoindazole [Compound No. 81] (5.0 g) in acetic acid (20 g), a solution of sodium nitrite (0.9 g) in water (3 ml) was added dropwise at room temperature. After completion of the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 5-(3-chloro-5-trifluoromethylpyridin-2-yl)[1,2,3]triazolo[4,5-f]indazole (5.0 g).