Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:44]1([CH:54]([NH2:56])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CC(N(C)C)=O>[C:44]1([CH:54]([NH:56][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (40.0 mg, 0.156 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (89 mg, 0.23 mmol) were combined in a 20 mL vial and dimethylacetamide (DMA) (1 mL) was added. The yellow solution was stirred at room temperature for 10 minutes and then a solution of 1-(1-napthyl)ethylamine (40.1 mg, 0.234 mmol) and N-methylmorpholine (NMM) (0.086 mL, 0.78 mmol) in DMA (0.20 mL) was added. The mixture was shaken at room temperature for 16 hours then the solution was evaporated in vacuo. The crude product was purified by preparative reversed-phase HPLC to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[CH:31][N:30]=[N:29][CH:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[CH:31][N:30]=[N:29][CH:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnnc1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1ccnnc1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-chlorophenylcarbamate (Example B5; 1 mmol) and tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (Example C1; 1 mmol) according to the general procedure D. Obtained as a yellow solid (83%), MS (EI) 391 [(M+1)+].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a stirred solution of 4-iodophenol (11.0 g, 50 mmol) in CH2Cl2 (50 ml) cooled with an ice bath, dihydropyran (5.0 g, 60 mmol) was added dropwise over 10 min at 0° C. to 5° C. After the solution became clear, toluenesulfonic acid, TsOH (10 mg) was added. The solution was stirred at 20° C. for 15 min. Then it was quenched by addition of NaHCO3 (1 g) and 3 drops of water, and after stirring for 5 min at 20° C., the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether as eluent to give 14.0 g (92%) of 1 as colorless crystal; mp 66° C.; δH(CDCl3, 300 MHz): 7.55 (d, J=8.3, 2H, Ar—H), 6.83 (d, J=8.4, 2H, Ar—H), 5.37 (t, J=3.1, 1H, OCHO), 3.86 (m, 1H, THP), 3.59 (m, 1H, THP), 1.87˜1.58 (m, 6H, THP).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[C:7]([O:13][CH3:14])[CH:6]=1.[OH:15]O>OS(O)(=O)=O.CO.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([OH:15])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cc(OCCO)ccc1C=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1cc(OCCO)ccc1O

Procedure:
A solution of 4-(2-hydroxyethoxy)-2-methoxybenzaldehyde (465.6 mg, 2.373 mmol) and 30 wt % hydrogen peroxide (0.313 mL, 3.04 mmol) in conc. H2SO4 (0.0475 mL) and MeOH (4.75 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 55% EtOAc in hexanes over 2394 mL, gradient to 100% EtOAc over 999 mL) to afford 4-(2-hydroxyethoxy)-2-methoxyphenol, as a colorless oil. Rf=0.30 (50% EtOAc/hexanes). LCMS calc.=207.1; found=206.9 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 6.77 (d, J=8.6 Hz, 1 H); 6.47 (d, J=2.8 Hz, 1 H); 6.34 (dd, J=8.7, 2.8 Hz, 1 H); 5.82 (s, 1 H); 3.98 (t, J=4.6 Hz, 2 H); 3.90 (t, J=4.5 Hz, 2 H); 3.76 (s, 3 H); 2.96 (s, 1 H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1)=[O:6].[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:5]([NH:7][C:8]4[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=4)=[O:6])[CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)o1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)o1
Yield: 21.4 %

Procedure:
A mixed solution of methyl 5-{[(2,2,2-trichloroethoxy)carbonyl]amino}-2-furancarboxylate (321 mg, 1.01 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.177 ml, 1.01 mmol) in dimethyl sulfoxide (3.4 ml) was stirred at 70° C. for 5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 71.7 mg (17.1%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1C2C=[CH:12][O:13][C:9]=2[CH:8]=[C:7]([C:14]([O:16]CC)=O)[CH:6]=1)(=O)C.O.[CH:20]([Cl:23])(Cl)Cl.Cl[CH2:25]Cl>[O-2].[O-2].[Mn+4]>[Cl:23][C:20]1[C:9]([O:13][CH3:12])=[CH:8][C:7]([C:14](=[O:16])[CH3:25])=[CH:6][C:5]=1[O:4][CH3:1]
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccoc2c1
Reactant: ClC(Cl)Cl
Reactant: ClCCl
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Product: COc1cc(C(C)=O)cc(OC)c1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of the compound obtained in the above (1) (1.23 g) in dichloromethane 928 mL) was added 85% activated manganese dioxide (5.81 g), and the mixture was stirred at 40° C. for 4 hours. The reaction solution was cooled to room temperature, and then thereto was added water-chloroform, and an insoluble was filtered off through Celite, and then the organic layer was separated. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→1/1) to give 1-(4-chloro-3,5-dimethoxyphenyl)ethanone [REx(22-2)] (723 mg) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28].[H-].[Na+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH2:28][C:2]1[C:11]2[C:6](=[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1Cc1ccncc1
Yield: 41.4 %

Procedure:
Operating analogously to what described in example 15 starting from 1-chloro-6-methoxy-5-pyridin-4-ylmethyl-phthalazine (1.38 g, 4.66 mmoles), prepared as described in example 142, 3,5-dichloro-4-methylpyridine (1.887 mg, 11.65 mmoles), DMF (20 ml), NaH (466 mg, 11.65 mmoles), 793 mg of the title compound were obtained.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>ClCCl>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[O:21][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: Nc1cc(F)ccc1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)ccc2o1
Yield: 67 %

Procedure:
Carbonyl diimidazole (7.6 g) was added to a solution of 2-amino-4-fluorophenol (5 g, 39 mmol) in dichloromethane (0.100 ml). After 14 hours the solution was washed with 5M aqueous HCl, water, and dried over magnesium sulfate. The solution was filtered through a plug of silica and evaporated affording a white solid (4.0 g, 66%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:8][OH:9])[CH2:6][OH:7].[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=O)[CH2:11][CH3:12].C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:11]([C:10]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[O:9][CH2:8][C:2]2([O:3][CH2:4][CH2:5][O:1]2)[CH2:6][O:7]1)[CH3:12]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCC1(CO)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCC1(CC(=O)OC)OCC2(CO1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
The 1,3-dioxolan-2,2-diyldimethanol (4 g, 29.8 mmol), which was obtained at another time in the same manner as described in the steps (4a)-(4c), was mixed with methyl propionylacetate (5.6 ml, 44.6 mmol) and triethyl orthoformate (5.2 ml, 31.3 mmol), and p-toluenesulfonic acid monohydrate (163 mg, 0.856 mmol). The mixture was stirred at room temperature for 3 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water twice and with an aqueous saline solution, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-3/1-1/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (2.63 g, yield: 35.8%) as a colorless oil.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)C>[N:23]1([CH2:22][CH2:21][NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCN1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCN4CCCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The experiment of Example 1 was repeated in every essential detail except for the following. The suspension was prepared using 2.0 g (6.98 mmol) of the 6-chloropurine riboside in 30 ml of absolute ethanol. 1-(2-Aminoethyl) piperidine (commercially available) was added in an amount of 1.07 g (0.7 ml, 8.3 mmol). Also added to this suspension was 1.5 ml (10.5 mmol) of triethylamine. The reaction mixture was refluxed for 72 hours. The resulting residue was chromatographed on a silica gel column eluting with an eluent of 20 parts methanol, 79 parts dichloromethane and one part ammonium hydroxide. The title product was produced in a yield of 1.1 g (42%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: COc1cccc(OCCCl)c1
Reactant: c1cnc(N2CCNCC2)c(-c2ccncc2)c1
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3ccncc3)CC2)c1

Procedure:
The title compound was prepared starting from 1-(2-chloroethoxy)-3-methoxybenzene and 1-[3-(4-pyridyl)-2-pyridyl]piperazine following the procedure outlined for Example 15. 1H NMR (CDCl3): δ 2.47-2.52 (m, 4H), 2.75 (t, 2H, J=5.9 Hz), 2.92 (br s, 4H), 3.77 (s, 3H), 4.05 (t, 2H, J=5.9 Hz), 6.47-6.54 (m, 3H), 7.01-7.09 (m, 2H), 7.56 (dd, 1H, J=1.9, 7.4 Hz), 7.60 (dd, 2H, J=1.7, 4.7 Hz), 8.29 (dd, 1H, J=1.9, 4.9 Hz), 8.66 (dd, 2H, J=1.7, 4.9 Hz). GC-MS m/z 391 (M+1, 1), 390 (M+, 8), 267 (35), 253 (100), 198 (10), 184 (40).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][C:13](O)=O.[NH4+].[OH-]>CO>[CH3:10][O:11][CH2:12][C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9]
Reactant: COCC(=O)O
Reactant: Cc1ccnc(N)c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COCc1nc2nccc(C)c2[nH]1
Temperature: 165 °C

Procedure:
A mixture of 2,3-diamino-4-picoline (0.1 g, 0.81 mmol) and methoxyacetic acid (0.16 ml, 2 mmol) was heated in a sealed tube at 165° C. for 24 hours. The reaction was cooled and neutralized with NH4OH. The crude material was dissolved in methanol (2 ml) and silica-gel (10 g) was added. The dried silica-gel was then loaded on a silica-gel flash-column and eluted initially with EtOAc and then with 2% methanol in EtOAc. The pure desired compound was obtained as a cream colored solid (0.067 g, 47%). 1H-NMR (CDCl3): 8.27 (d, 1H, J=5 Hz), 7.07 (d, 1H, J=5 Hz), 4.86 (s, 2H), 3.57 (s, 3H), 2.7 (s, 3H). FAB-MS: m/e 178 (M+H).
Reaction SMILES: [O:1]([C:8]1C=CC(O)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](C)([O-:18])[CH3:17].[K+].CI.[CH2:23]1[CH2:27]OC[CH2:24]1>>[O:18]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:27][CH:23]=[CH:24][CH:15]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: c1ccc(OCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Phenoxy)phenol (9.31 g, 50 mmol) in THF (100 mL) was treated with potassium t-butoxide (6.17 g, 55 mmol) at room temperature for 10 min. Methyl iodide (7.87 g, 55 mmol) was added by syringe. After stirring for 18 h at room temperature the reaction was quenched with saturated ammonium chloride solution and diluted with ethyl ether. The separated organic layer was washed with saturated ammonium chloride solution, dried with magnesium sulfate, filtered and concentrated to give 9.98 g of the title compound as a pale yellow oil. GS-MS (m/z, EI): 200 [M]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Reactant: O=C1CCCC(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (2.0 g, 5.1 mmol) and THF (200 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (6.1 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then glutaric anhydride (0.69 g in 10 mL THF, 6.0 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product Compound 11 (670 mg, 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.75 (d, J=7.0 Hz, 2H), 7.68 (m, 1H), 7.50 (d, J=6.9 Hz, 2H), 7.15 (t, J=6.9 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 1.80 (t, J=6.8 Hz, 2H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: N1C2C=CC=C[C:4]=2N=N1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:31]=1[CH:32]=O)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1>C(O)C>[F:48][C:45]([F:47])([F:46])[C:43]1[CH:42]=[C:20]([CH:19]=[C:18]([C:17]([F:49])([F:50])[F:16])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:31]=1[CH:32]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:4])[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: C1COCCN1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCO
Product: CC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCOCC1
Reaction time: 0.17 h
Yield: 14.1 %

Procedure:
To a solution of benzotriazole (12.8 mg, 0.1075 mmoles) in ethanol (2 mL) was added morpholine (9.4 mg, 0.1075 mmoles) and the reaction was stirred for 10 minutes. A solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (50 mg, 0.0977 mmoles) in ethanol (1 mL) was added to the reaction mixture and it was further stirred for 16 hours. The imine fragment was observed MH+=581.4. Parent ion for the intermediate was not found. The ethanol was evaporated and the crude product was taken to the next step. Half of the crude was dissolved in toluene and methyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether) was added. The reaction mixture was heated at reflux for 2 hours. LC-MS indicated formation of product. The solvent was evaporated from the reaction mixture. 1N NaOH solution was added and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated and the residue was dissolved in DMSO and purified on prepHPLC (Shimadzu, 30×50 C18, Basic, 30-95%, 0.1% NaOH, 8 min gradient, 220 UV) to yield 8.2 mg (28%) of the title compound as clear oil. MS (ES+) Calc: 596.4, Found: 597.2 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH2:31][C:32]1[CH:36]=[CH:35][NH:34][N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:31][C:32]2[CH:36]=[CH:35][NH:34][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2cc[nH]n2)cc1)Cc1nc2ccccc2[nH]1
Yield: 22.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (199 mg, 0.50 mmol) and 3-aminopyrazole (60 mg, 0.72 mmol) in THF (5 mL) and acetic acid (0.2 mL) was added NaBH(OAc)3 (166 mg, 0.78 mmol) and the resultant mixture stirred at room temperature for 2.5 days. Purification of the crude material by radial chromatography on silica gel gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) afforded the desired amine (52 mg, 23%) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]1=[O:18]>[Pd].C(O)C>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]2[N:5]([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:18])=[CH:14][CH:13]=1
Reactant: CN1CCN(C)C(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 1j (200 mg, 0.80 mmol), ethanol (5 mL) and 10% palladium on carbon (50% wet, 4 mg dry weight). The reaction flask was purged with hydrogen gas and the reaction mixture stirred under a balloon pressure of hydrogen for 2 h. After this time the flask was purged with nitrogen. The catalyst was removed by filtration through a pad of Celite 521 and the filter cake washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure to afford a 94% yield of 1k (166 mg) as a colorless oil: 1H NMR (500 MHz, DMSO-d6) δ 6.89 (d, 2H, J=8.5 Hz), 6.47 (d, 2H, J=8.5 Hz), 4.94 (s, 2H), 3.53 (td, 1H, J=12.0, 4.0 Hz), 3.44 (m, 1H), 3.21 (dt, 1H, J=12.0, 4.0 Hz), 2.92 (dt, 1H, J=12.0, 4.0 Hz), 2.82 (s, 3H), 2.02 (s, 3H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: C12(C3C=CC(OCC(N[C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])=O)=CC=3)CC3CC(CC(C3)C1)C2.FC(F)(F)C1C=C([NH2:39])C=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([NH2:39])(=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Yield: 248.3 %

Procedure:
To a solution of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid (50.0 mg, 0.13 mmol), 3-trifluoromethyl-phenylamine (31.5 mg, 0.03 ml 0.20 mmol), EDC (37.4 mg, 0.20 mmol) and HOBt (30.0 mg, 0.20 mmol) in DMF 1.3 mL was added DIPEA (0.04 ml, 0.20 mmol). Reaction mixture was stirred, and separated by ethyl acetate and 10% HCl. It was sequentially washed with brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel flash column chromatography (EtoAC:Hexane=1:3) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-3-trifluoromethyl-phenyl)-benzamide as a white solid (39.1 mg, 54.9% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1O.[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH3:17]I>CC(C)=O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:17])=[C:3]([O:14][CH3:11])[C:2]=1[Cl:1]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)c(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(Cl)c1OC
Yield: 91.9 %

Procedure:
A suspension of 104 g of 3,4-dichloro-1,2-benzenediol, 240 g of potassium carbonate and 354 g of methyl iodide in 2 litters of acetone is refluxed for 2 hours. The reaction mixture is filtered and washed with acetone. The filtrate and the washings are combined and evaporated to remove solvent. Water is added to the residue and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is distilled under reduced pressure to give 110.5 g of 1,2-dichloro-3,4-dimethoxybenzene.