Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: NCCCO
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCCCO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) and 3-amino-1-propanol (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (73 mg, 70%) which was obtained as a white solid. MS: m/e=374.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.[CH3:28][O:29][C:30]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12].[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:30]=2[O:29][CH3:28])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Product: COc1ccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1OC
Product: COc1cccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)c1OC

Procedure:
Similarly, equimolar amounts of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 3,4-dimethoxybenzaldehyde or 2,3-dimethoxybenzaldehyde are reacted as above to yield the products, 5-acetyl-3-(3,4-dimethoxycinnamoyl)-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 223°-225° C., and 5-acetyl-3-(2,3-dimethoxycinnamoyl)-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 175°-176° C., respectively.
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)C(C)C)(C)C>C(O)C.C(Cl)(Cl)Cl.[Pd]>[C:15]1([N:13]2[C:12](=[O:21])[N:11]3[CH2:2][NH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1n(-c2ccccc2)nc2n1CNc1ccccc1-2
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-phenyl-1,2,4triazolo[4,3-c]-quinazolin-3-one (1g, 3.4 mmol), N,N-diisopropylethylamine (1 ml, 6.7 mmol) and 10% Pd-C (200 mg) in ethanol was shaken under hydrogen at 50 psi overnight. The reaction was diluted with CHCl3 and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water, dried over Na2SO4 and evaporated under reduced pressure to yield 2-phenyl-5,6-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-one (Compound 2) as a white solid. m.p. 202-204° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=[C:2]=[S:3].C(N(C(C)C)CC)(C)C.Cl.[NH:23]([CH2:25][C:26](OCC)=[O:27])[NH2:24]>ClCCl>[NH2:24][N:23]1[CH2:25][C:26](=[O:27])[N:1]([C:4]2[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=2)[C:2]1=[S:3]
Reactant: CCOC(=O)CNN
Reactant: O=C(O)c1cccc(N=C=S)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Yield: 22.2 %

Procedure:
179 mg (1 mmol) of 3-isothiocyanatobenzoic acid and 523 μl (3 mmol) of diisopropylethylamine were stirred in 8 ml of dichloromethane and then with 155 mg (1 mmol) of ethyl hydrazinoacetate hydrochloride at room temperature for 96 hours. After the solvent was concentrated, the mixture was partitioned between ethyl acetate and 30% acetic acid. The aqueous layer was extracted with ethyl acetate again, and the organic layers were combined, washed with water and then with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting solid was mixed with a 190:10:0.8 liquid mixture of ethyl acetate, methanol and acetic acid, and the insoluble was dried to obtain 55.7 mg of the desired product (yield 22%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>CCCCCC.C(OCC)C>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:10]=1[CH:24]=[O:25]
Reactant: COCOCc1coc(-c2ccccc2)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOCc1nc(-c2ccccc2)oc1C=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a mixture of 4-methoxymethoxymethyl-2-phenyloxazole (10.86 g) and diethyl ether (300 mL) was dropwise added a solution (1.6 M, 37 mL) of n-butyl lithium in hexane at −78° C., and the mixture was stirred at −78° C. for 1.5 hrs. A solution (10 mL) of N,N-dimethylformamide (6.50 g) in diethyl ether was added to the reaction mixture and the reaction mixture was allowed to warm to room temperature with stirring for 2 hrs. Dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (6.45 g, 53%) of 4-methoxymethoxymethyl-2-phenyl-5-oxazolecarbaldehyde from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 51-52° C.
Reaction SMILES: COC(=O)CSCC1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C3C=CC=CC=3OC)[CH:15]=2)[NH:10]C(C)(C)C=1.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OC)(=O)CS>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]acetic acid methyl ester 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 52 μL of methyl thioglycolate reacted to give 4 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:27]=[CH:28][CH:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6ncccc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and quinoline-6-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.64 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][C:28]([O:32][CH3:33])([O:30][CH3:31])C>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([NH:26][CH2:27][CH:28]([O:32][CH3:33])[O:30][CH3:31])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(C)(CN)OC
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C., i-butylchlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxypropane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aqueous HCl (2×2 L), washed with sat. NaHCO3 (2 L) and Na2CO3 (2 L), and washed with brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+. 1H NMR (CD3OD 300 MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:29](=[O:31])[CH3:30])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(=O)Cl
Reactant: Cc1cc(S(=O)(=O)N(C)C)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(S(=O)(=O)N(C)C)cc1C)S(=O)(=O)C(F)(F)F
Yield: 76.7 %

Procedure:
To a solution of N,N-dimethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (1.5 g) and triethylamine (0.65 g) in tetrahydrofuran (40 ml), acetyl chloride (0.51 g) was added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and solidified with water. The solidified product was recrystallized from a mixture of ethanol and toluene to give 1.29 g of N,N-dimethyl-3-methyl-4-(N-acetyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 21). M.P., 148°-148.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl.O>[Si:16]([O:6][CH:4]1[CH2:5][NH:2][CH2:3]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1CNC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (5.11 g, 46.7 mmol, 1.0 equiv) and 1H-imidazole (9.52 g, 140 mmol, 3.0 equiv) in DCM (100 mL) at 0° C. was added TBDPSCl (19.18 g, 70 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at rt overnight and then diluted with water, and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was eluted over a silica gel with DCM/MeOH=1001 to 101 to give 12 g of 3-(tert-butyldiphenylsilyloxy)azetidine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1O.O(C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)C1.C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC)(=O)C.[C:42]([Si](C)(C)Cl)([CH3:45])([CH3:44])[CH3:43].N1[CH:54]=[CH:53]N=C1>CN(C=O)C>[C:42]([O:10][CH2:9][C@H:7]1[O:8][C@:3]([CH3:4])([O:2][CH3:1])[C@H:53]([CH3:54])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])([CH3:45])([CH3:44])[CH3:43]
Reactant: c1c[nH]cn1
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CO[C@@H]1C[C@@H](O)[C@H](O)[C@@H](CO)O1
Agent: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Solvent: CN(C)C=O
Product: CO[C@@]1(C)O[C@H](COC(C)(C)C)[C@@H](O)[C@H](O)[C@H]1C

Procedure:
This compound was prepared from the corresponding methyl glucoside, Methyl 2-deoxy-α-D-glucopyranoside. (Carbohydrates, Ed. Collins, P. M., Chapman and Hall, New York, 1987, p. 352) by treatment with t-butyldimethylchlorosilane in DMF and imidazole. 1H NMR δ4.73 (d, 1, J=3 Hz), 3.85-3.78 (m, 4), 3.55-3.46 (m, 2), 3.35 (m, 1), 3.29 (s, 3), 2.05 (m, 1), 1.61 (m, 1), 0.88 (m, 9), 0.07 (m, 6).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2>O1CCCC1.[OH-].[Li+]>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH:17]([CH3:18])[CH3:19])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:8]2[CH3:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(OCC(=O)O)c12
Yield: 71.1 %

Procedure:
A solution of [8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.087 g) in tetrahydrofuran (3.0 mL) and 1.0M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for three hours. The mixture was concentrated under reduced pressure and the pH adjusted to 4 by the addition of 0.1M aqueous hydrochloric acid (3 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane, ethyl acetate and formic acid (1:0:0:0.001 to 0:1:0.001 by volume) to afford title compound as pale yellow solid (0.06 g).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]1[CH:58]=[CH:59][C:60]([CH2:64][CH3:65])=[C:61]([OH:63])[CH:62]=1>C(Cl)(Cl)Cl>[Br:1][C:58]1[C:57]([O:56][CH3:55])=[CH:62][C:61]([OH:63])=[C:60]([CH2:64][CH3:65])[CH:59]=1
Reactant: CCc1ccc(OC)cc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1O
Reaction time: 4 h
Yield: 104.1 %

Procedure:
A solution of tetrabutyl ammonium tribromide (38.10 g, 79 mmol) in CHCl3 (100 mL) was added to a stirred solution of 5-methoxy-2-ethyl-phenol (12.0 g, 79 mmol) dissolved in CHCl3 (90 mL). The reaction mixture was stirred for 4 hrs and then quenched with 5% solution of sodium thiosulfate (90 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as an oil (19 g). LCMS: APCI−VE=230 M/E.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.COC(OC)N(C)C.[Cl:23]N1C(=O)CCC1=O>CC#N>[Cl:23][C:3]1[C:4]2[CH:8]=[C:7]([S:9](=[O:11])(=[O:12])[NH2:10])[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[OH:1]
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Reactant: O=C1CCC(=O)N1Cl
Agent: COC(OC)N(C)C
Solvent: CC#N
Product: NS(=O)(=O)c1cc2c(Cl)c(O)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (3.0 g, 0.013 mole) in CH3CN (60 ml) was treated with N,N-dimethylformamide dimethylacetal (1.75 ml, 0.013 mole). Within 5 minutes, the protected sulfonamide started to precipitate. After 10 minutes, this was redissolved by the addition of CH3CN (65 ml). N-Chlorosuccinimide, (1.91 g, 0.0143 mole) was added in one portion and the mixture was stirred at ambient temperature. After 2 days, another 175 mg of N-chlorosuccinimide was added and stirring was continued for another 3 days. The solvent was evaporated under reduced pressure and the residual solid was triturated with H2O (100 ml) and collected. This solid then was suspended in 6N HCl (70 ml) and heated on the steam bath for 61/2 hours. The resulting solid was extracted into ethyl acetate. Evaporation of the washed and dried extract under reduced pressure left 3.1 g (90%) of 4-chloro-5-hydroxy-2-sulfamoylbenzo[ b]thiophene, m.p. 198°-201° C. Recrystallization from H2O, decolorizing with charcoal, gave 2.6 g, m.p. 203°-205° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:11])=[O:10].NC1SC2CCCCC=2C=1C(OCC)=O.[Br:44]C1C=CC=CC=1S(Cl)(=O)=O>>[Br:44][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:10])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Br)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 27, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2.00 g) and 2-bromobenzenesulphonyl chloride (4.50 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CNC1(NC)CCCCC1>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[CH:10][C:6]([O:5][CH2:4][C:3]3[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=3[Br:1])=[N:7]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(I)cc1
Reactant: Brc1ccccc1COc1cc[nH]n1
Agent: CNC1(NC)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Clc1ccc(-n2ccc(OCc3ccccc3Br)n2)cc1
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A suspension consisting of 3-(2-bromobenzyloxy)-1H-pyrazole (0.20 g, 0.91 mmol), 4-chloroiodobenzene (0.17 g, 0.73 mmol), Cul (9 mg, 0.05 mmol), K2CO3 (0.05 mg, 0.38 mmol) and N,N′-dimethylcyclohexanediamine (72 μL, 0.46 mmol) in 2 mL of toluene was heated to 100° C. for 20 h. The mixture was then cooled to room temperature and directly subjected to column chromatography (SiO2, hexane/ethyl acetate=100:0 to 80:20). The product was obtained as a colorless solid (140 mg, 0.14 mmol, 53% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].[ClH:29].Cl.O>C(O)C>[ClH:29].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Yield: 64.1 %

Procedure:
A mixture of 1-benzyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.13 ml), water (0.13 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water and dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (1 ml), and the mixture was concentrated. The residue was recrystallized from ethanol to give 1-benzyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 10) (0.67 g) as colorless crystals.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CO>[CH3:3][N:14]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
0.7 ml of a 37% aqueous formaldehyde solution and 0.21 g of sodium cyanoborohydride were added to 30 ml of a solution of 0.82 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol, under ice-cooling. To the mixture was dropwise added 0.7 ml of acetic acid. The mixture was stirred at room temperature for 1 hour and then subjected to distillation to remove the solvent. The residue was extracted with methylene chloride. The extract was washed with a 1N aqueous sodium hydroxide solution and water, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloride-diethyl ether to obtain 0.28 g of 4-(N-methyl-N-benzylamino)-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1B(O)O.C[N+]1([O-])CC[O:29]CC1.CCCCCC>C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[OH:29]
Reactant: Cc1cc(F)c(B(O)O)cc1SCC(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(F)c(O)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To 300 ml of toluene were added 32.0 g (119 mmol) of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl boronic acid produced by the method described in PCT International Publication No. WO 2007/034755 and 15.4 g (131 mmol) of N-methylmorpholine-N-oxide, followed by refluxing for 1 hour under heating. The reaction mixture was allowed to cool to room temperature. The solvent was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic phase obtained was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=4:1), to obtain 25.5 g (yield: 89%) of an intended product.