Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[C:3](#[N:5])[CH3:4].C[O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O.Cl>O1CCCC1>[CH:10]1([C:8](=[O:7])[CH2:4][C:3]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of sodium amide (1.87 g) in tetrahydrofuran (1.87 g) was added acetonitrile (2.72 ml) at −50˜−40° C. dropwise and then was added cyclohexanecarboxylic acid methyl ester (2.86 ml) and the mixture was stirred for 1 hour at −20° C. The reaction mixture was poured into cool hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride successively, and was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (0.91 g) having the following physical data.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:11]4[C:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[C:17]([C:25]([O:27][CH3:28])=[O:26])[S:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH:4]2[N:9]([C:10]3[C:11]4[C:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[C:17]([C:25]([O:27][CH3:28])=[O:26])[S:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: COC(=O)c1sc2ncnc(N3C4CCC3CC(O)C4)c2c1-c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(N3C4CCC3CC(=O)C4)c2c1-c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.940 g, 2.38 mmol) in DCM (100 mL) at room temperature was added Dess-Martin Periodinane (1.310 g, 3.094 mmol) in one portion and the reaction left to stir overnight. The reaction was filtered and the filtrate washed with saturated sodium bicarbonate and brine, the organic layer dried over sodium sulphate, filtered and concentrated under reduced pressure to afford methyl 4-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate which was used without further purification (0.935 g, 100%). LCMS: Rt=4.46, 394 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(C)c1

Procedure:
24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. The mixture was heated at reflux for 12 hours, the reaction medium evaporated, taken up in ethyl acetate and water, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in methanol, filtered and 21.9 g (85%) of the expected methyl ester of melting point 58-9° C. were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O.BrN1C(=O)CCC1=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(Cl)cc1O
Agent: O=C1CCC(=O)N1Br
Product: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example 6, Step 2, using 1-(4,5-dichloro-2-hydroxyphenyl)ethanone and N-iodosuccinimide (instead of N-bromosuccinimide) as the starting materials in 71% yield. LCMS for C8H6Cl2IO2 (M+H)+: m/z=330.9, 332.9. Found: 330.8, 332.9.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[C:24]([F:23])([F:33])[F:34])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (577 mg) in DMF (6 mL) was added potassium carbonate powder (890 mg) and 2-(trifluoromethyl)benzyl bromide (1.54 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with hexanes to yield the title compound as an orange-brown solid.
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][N:26]=[C:27]5[C:32]=4[N:31]=[CH:30][C:29]([OH:33])=[CH:28]5)=[N:19][N:20]=3)[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:39][CH:35]([F:40])[O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:22][CH2:21][C:18]3[N:16]4[N:17]=[C:12]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH:13]=[CH:14][C:15]4=[N:20][N:19]=3)=[CH:24][CH:25]=[N:26]2)=[N:31][CH:30]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 μmol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311 μmol), cesium carbonate (62 mg, 190 μmol). The reaction mixture was stirred at 100° C. for 18 h, cooled to RT and concentrated in vacuo. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z=420.1 [M+H]+. Calc'd for C, 21; H, 15; F, 2; N, 7O, : 419.40.
Reaction SMILES: [ClH:1].[S:2]1[C:6]([CH2:7][O:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:5][N:4]=[CH:3]1>C(OCC)C>[ClH:1].[NH:11]1[CH2:12][CH:9]([O:8][CH2:7][C:6]2[S:2][CH:3]=[N:4][CH:5]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2cncs2)C1
Agent: Cl
Solvent: CCOCC
Product: c1ncc(COC2CNC2)s1
Reaction time: 0.5 h

Procedure:
A solution of HCl in diethylether (2N, 5.5 mL) was added to a solution of tert-butyl 3-(thiazol-5-ylmethoxy)-azetidine-1-carboxylate (150 mg, 0.55 mmol) in diethylether (2 mL) at room temperature. The reaction mixture was stirred 30 minutes then concentrated to dryness. After trituration in diethyl ether (10 mL), the title compound was obtained as a yellow solid (113 mg, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23]C)=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[OH-].[K+:26].O>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1.[K+:26]
Reactant: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1

Procedure:
9.2 g (27.5 mmol) of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate was dissolved in 30 ml of methanol, and 1.55 g (27.5 mmol) of 10% potassium hydroxide was added thereto. Furthermore, 20 ml of water was added thereto, and the resultant mixture was stirred at room temperature. The reaction liquor was concentrated under reduced pressure, and acetone was added thereto to precipitate a crystal. The crystal thus obtained was separated by filtration and was washed with hexane to obtain an aimed compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[O:16][CH3:17]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: OCCCCl
Reactant: COc1cc(F)c(F)cc1CCl
Product: COc1cc(F)c(F)cc1COCCCCl

Procedure:
In an analogous manner to that described in (δ) 1-chloromethyl-4,5-difluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene as a colorless liquid; MS: 250 (M)+.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].[C:27]([O-:30])(=[O:29])[CH3:28].[Na+]>CN(C=O)C>[C:27]([O:30][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CCl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC/C=C/Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
To a solution of 187 mg (0.5 mmol) of the compound obtained from Example 9 in 5 ml of DMF was added 410 mg (5 mmol) of sodium acetate. The reaction mixture was then stirred for about 48 hours at 100° C., and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 140 mg (yield 70%) of the title compound as a colorless syrup.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>>[N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:16])=[O:6])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NC(C(=O)O)c1ccccc1
Product: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1

Procedure:
A solution of 1.61 grams (9.1 mmole) of 2-azido-2-phenylacetic acid [Forster and Mueller, J. Chem. Soc., 97, 138 (1910)] and 5 ml. of thionyl chloride is heated under reflux for hour. The reaction solution is evaporated under reduced pressure to furnish a residue of 2-azido-2-phenylacetyl chloride which is dissolved in 10 ml. of dichloromethane and is added over 5 minutes to a stirred ice-bath cooled solution of 2.4 grams (10 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) of triethylamine and 50 ml. of dichloromethane. After 30 minutes the reaction solution is allowed to warm to room temperature. After a further 3 hours, the more volatile components of the solution are evaporated under reduceed pressure and the residue is taken up in 50 ml. of water. The aqueous solution is washed twice with 25 ml. portions of ethyl acetate, and it is then adjusted to pH 2.5 by the careful addition of 6N hydrochloric acid. The resulting cloudy mixture is extracted twice with 30 ml. portions of ethyl acetate. After being dried using anhydrous sodium sulfate, the combined extracts are filtered and solvent is evaporated in vacuo. The residue is dissolved in 10 ml. of dichloromethane; 1.0 ml. of triethylamine is added, and the resulting solution is poured into 350 ml. of rapidly stirred diethyl ether. The solid which precipitates is filtered off giving 1.62 g. (38% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1792 cm-1 (β-lactam) and 1693 cm-1 (amide I). NMR (in D2O/NaHCO3): 7.40 ppm (s,5H, aromatic hyddrogens), 5.60 and 5.80 ppm (m and m, 2H, C-5 and C-6 hydrogens), 5.30 ppm (m,2H, C-3 hydrogen and side-chain methine hydrogen), 3.20 (q,6H, NCH2CH3 (1.60 ppm (s,3H, C-2 methyl hydrogens), 1.30 ppm (t,9H, NCH2CH3), 1.10 ppm (s,3H, C-2 -methyl hydrogens).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:14][N:15]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:16](=[O:21])[C:17]=3[CH:18]=2)[N:10]=1.[NH2:29][CH2:30][CH2:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Br:42])(=[O:35])=[O:34].CCN(CC)CC>CCO>[Br:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[S:33]([NH:32][CH2:31][CH2:30][NH:29][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:20][C:19]2[C:11]([N:10]=1)=[CH:12][C:13]1[CH2:14][N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:16](=[O:21])[C:17]=1[CH:18]=2)(=[O:35])=[O:34]
Reactant: CN1CCC(N2Cc3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: NCCNS(=O)(=O)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCC(N2Cc3cc4nc(-c5c(NCCNS(=O)(=O)c6ccccc6Br)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 95 °C
Yield: 11.4 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.1 mmol) and N-(2-amino-ethyl)-2-bromo-benzenesulfonamide (56 mg, 0.20 mmol) in EtOH (4 mL) was added Et3N (500 μL, 3.6 mmol) and the reaction was heated at 95° C. for 16 h. The solvent was evaporated in vacuo and the residue was purified by flash chromatography with CH2Cl2/MeOH/28% aqueous NH4OH (100:10:1) afforded the title compound (7.3 mg, 11%). 1H NMR (DMSO-d6) δ 1.70 (m, 2H), 1.85 (m, 2H), 2.15 (m, 2H), 2.29 (s, 3H, CH3), 2.96 (m, 2H), 3.19 (m, 1H), 3.50 (m, 2H), 4.05 (m, 1H), 4.48 (s, 1H), 6.05 (d, J=7 Hz, 1H), 7.32 (br s, 1H), 7.38-7.50 (1.5H), 7.62-7.70 (1.5H), 7.82 (s, 0.5H), 7.87 (s, 0.5H), 7.96-7.99 (2H), 8.20) br S, 1H, NH), 11.02 (br s, 1H, NH), 11.26 (br s, 1H, NH); ESI-MS m/z 640.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH2:30]([SH:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1[S:32][CH2:30][CH3:31]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSc1cnn(-c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)c(=O)c1Cl
Yield: 46 %

Procedure:
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in acetonitrile (10 mL) was added of 0.15 mL of ethylmercaptan and 0.280 mg of potassium carbonate. The mixture was heated to reflux for 2 h. The suspension was filtered and the solid was washed with ethyl acetate to gave the title compound (0.220 g, 46%). Mp 80–100° C., 1H NMR (DMSO-d6) 8.8 (1H, d, 3 Hz), 859 (1H, d, 6 Hz), 8.37 (1H, s, NH), 7.98 (1H, d, 6 Hz, 3 Hz), 7.92 (1H, t, 3 Hz), 7.86 (1H, s), 7.46 (1H, d, 9 Hz, 3 Hz), 7.40 (1H,s), 7.27(2H, m), 7.04(1H, d, 9 Hz), 3.12 (2H, q, 6 Hz), 1.47 (3H, t, 6 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([CH3:12])=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:8][C:7]=2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:22])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH2:16]([O:15][C:13]([C:9]1[O:8][C:7]2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=[C:3]([C:1]([OH:22])=[O:2])[C:11]=2[C:10]=1[CH3:12])=[O:14])[CH3:17]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1oc2c(OC)ccc(C=O)c2c1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2c(OC)ccc(C(=O)O)c2c1C

Procedure:
The solution of ethyl 4-formyl-7-methoxy-3-methylbenzo[b]furan-2-carboxylate (3.0 g, 11.4 mmol) in acetone (30 ml) was cooled to 10-20° C. Sulfamic acid (1.55 g, 17.1 mmol) was added at once to the reaction mixture at 10-20° C. Then solution of sodium chlorite (1.6 g, 17.1 mmol) in water (10 ml) was added dropwise at the same temp. Water (100 ml) was added to reaction mixture. Acetone was distilled off under vacuum. The solid obtained was filtered and suck dried. Yellow coloured solid (3.0 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11]C(=O)C(F)(F)F)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[NH2:11]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of N-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide (1.3 g, 3.97 mmol) in CH3OH (30 mL) was treated with potassium carbonate (1.099 g, 7.95 mmol), and the mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and poured into water, 1N aq HCl was added to adjust to pH 6, and the mixture was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4, and the drying agent was filtered off and solvent was removed in vacuo to give the title compound as a yellow solid (0.57 g, 62%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][N:27]([CH3:29])C)[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O[C@@H](C1C([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=C2C(=CC=1C)[N+]([O-])=C(C)C=C2)COC(=O)C(C)(C)C)(C)(C)C.CN>>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[C:15]1[C:16]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][NH:27][CH3:29])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: CN
Product: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1

Procedure:
Following the procedure used to prepare compound (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate of Example 9, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide, and methylamine solution was used instead of N,N-dimethylamine solution. LCMS-ESI+ (m/z): 497.3, 499.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.S(O)(O)(=O)=O.[NH2:16][OH:17]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:16][OH:17])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Cc1ncc(C=NO)c(N)n1
Yield: 148.3 %

Procedure:
To 8.6 g of 2-methyl-4-amino-5-formylpyrimidine, while stirring at room temperature in a mixture of 340 ml of methanol and 40 ml of water, was added dropwise gradually 10 ml of an aqueous solution containing 6.10 g of hydroxylamine sulfate. As the reaction proceeded, crystals precipitated out. Four hours later, the crystals were collected by filtration, followed by drying under reduced pressure to give 10.5 g (83.5%) of 2-methyl-4-amino-5-pyrimidine aldoxime 1/2 sulfate. The mother liquor was subjected to quantitative deterimination (by absolute calibration curve method) of 2-methyl-4-amino-5-pyrimidine aldoxime 1/2 sulfate by means of high performance liquid chromatography to thereby confirm the production of 1.67 g (13.3%) of the object compound. The total yield of the crystals thus obtained and the object compound in the mother liquor was 96.8%. Physical properties of 2-methyl-4-amino-5-pyrimidine aldoxime 1/2 sulfate first obtained were as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
1.0 g (0.00255 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 25 ml of dioxane and treated with 2.1 ml of pyrrolidine. The mixture was stirred at room temperature for 4 hrs., the solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.9 g (93%) of 4-(2-bromo-6-pyrrolidin-1-yl-pyridine-4-sulphonyl)- phenylamine as beige crystals; m.p.: 216° C. (dec).
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:41]1[CH:45]=CC(C(O)=O)=N1.[NH4+].[OH-].Cl>C(Cl)(Cl)Cl.CO>[ClH:1].[ClH:1].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]4[CH:34]=[CH:45][NH:41][N:31]=4)=[O:29])=[CH:25][CH:26]=3)=[CH:39][CH:40]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1cc[nH]n1
Yield: 48 %

Procedure:
By essentially following the conditions described in Example 16, Part E, the free base of the title compound was prepared as a solid from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 3-pyrazole carboxylic acid in 48% yield following radial chromatography (SiO2; 1% then 3% then 5% MeOH in CHCl3 sat'd with NH4OH). The solid was taken up in 5 mL MeOH, and the solution was treated with 1 mL of 1 N HCl. The solution was concentrated to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCCCC3)cc2C1

Procedure:
21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).