Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:57])[C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:44][NH:45]2)=[CH:41][CH:40]=1>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:37]=[C:38]([C:39]3[CH:47]=[C:46]4[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:44][NH:45]4)=[CH:41][CH:40]=3)[N:57]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CCc1c[nH]c2cc(C(=N)NO)ccc12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
EDCI (297 mg) and HOBT (237 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (277 mg) in DMF (10 mL) at RT. The resulting solution was stirred for 10 min. A solution of 1,1-Dimethylethyl 3-{6-[(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D16) (392 mg) in DMF (10 mL) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 8 hours, then standed at RT for overweekend. The reaction mixture was heated to 80° C. for 2 hours. Most of the DMF was evaporated. EtOAc (100 mL) was added and the organic solution was washed with saturated aqueous sodium bicarbonate solution (100 mL) and water (100 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D17) (314 mg) as a white solid. MS (ES): C26H28ClN3O4 requires 481; found 482.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH2:18]([O:25][CH2:26][C@H:27]([OH:30])[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@H:27]([OH:30])[CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H](O)COCc3ccccc3)ccc2c1

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[O:14][C@:15]3([CH2:23][N:24]=2)[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]3)[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[O:14][C@:15]3([CH2:23][N:24]=2)[CH:20]2[CH2:19][CH2:18][N+:17]([O-:33])([CH2:22][CH2:21]2)[CH2:16]3)[N:3]=1
Reactant: Fc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc4ccccc4c(F)n3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To (R)—N-(1-Fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.063 g, 0.193 mmol) in CHCl3 (15 mL) was added m-CPBA (0.034 g, 0.195 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. TLC showed lower spot and no starting material. The mixture was purified by chromatography (Biotage: 15-20% of 9:1 MeOH:NH4OH in CHCl3; ˜1.1 L) to yield the pure fractions. The fractions were combined and the solvent was removed to yield (S)-2-(1-fluoroisoquinolin-3-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.050 g, 0.146 mmol, 76% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12-8.42 (m, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.86 (br. s., 1H), 7.73 (br. s., 1H), 7.43-7.60 (m, 1H), 6.93-7.35 (m, 1H), 3.69-4.05 (m, 1H), 3.58 (br. s., 1H), 3.00-3.33 (m, 6H), 2.19 (br. s., 2H), 1.94 (d, J=10.1 Hz, 3H). LC/MS: retention time 1.78 (M+1=343.1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]([Mg]Br)#[CH:17]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[C:16]#[CH:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: -78 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.285 g, 1.07 mmol) was dissolved in THF (8 mL) and the solution was cooled to −78° C. Ethynylmagnesium bromide (0.5M in THF, 2.6 mL, 1.28 mmol) was added dropwise and the reaction was allowed to warm to room temperature. After 1 hour the reaction was quenched with aqueous ammonium chloride the submitted to standard workup to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH2:55])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]>C(Cl)Cl>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH:55][C:7]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: NCCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCCn2ccc(-c3ccc(Cl)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a stirred solution of 3-methyl-1H-pyrazole-5-carboxylic acid (104 mg, 0.83 mmol) in DCM (2.0 ml) was added DIPEA (0.144 mL 0.81 mmol). EDCI (159 mg, 0.83 mmol) and HOBt (112 mg, 0.83 mmol). After 10 min 2-(3-(3,4-dichloro-phenyl)-1H-pyrazol-1-yl)ethanamine (102 mg, 0.40 mmol) was added to the reaction mixture as a solution in DCM (2.0 ml). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM; 2nd column C-18 RP, eluent: 0-100% MeCN/water) to obtain 65 mg (45%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.24 (s, 3H), 3.64 (q, 2H), 4.31 (t, 2H), 6.36 (s, 1H), 6.81 (d, 1H), 7.65 (d, 1H), 7.77 (d, 1H), 7.80 (dd, 1H), 8.00 (d, 1H), 8.23 (s, 1H), 12.88 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:38][CH2:39]OC(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:38]=[CH2:39])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (16a) (9.5 g, 18.9 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol), (2-ethenyl)tri-n-butyltin (11.0 mL, 37.8 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (16b) (7.7 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2; found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01(2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)(C)C.[CH2:12]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13]1.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:18]2[CH2:19][CH2:20][C:15]3([O:21][CH2:12][CH2:13][O:14]3)[CH2:16][CH2:17]2)[CH:26]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc(N2CCC3(CC2)OCCO3)c1
Temperature: 120 °C
Reaction time: 0.03 h
Yield: 97.1 %

Procedure:
Procedure adopted from Tetrahedron Lett., 2007, 48, 2519. A thick-walled glass reaction vessel was charged with palladium(II)acetate (235 mg, 1.05 mmol), X-Phos (500 mg, 1.05 mmol, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), cesium carbonate (6.82 g, 20.95 mmol) and 5:1 (v/v) toluene:t-BuOH (20 mL). The stirred contents were purged with nitrogen and a solution of 4-piperidone ethylene ketal (2.70 mL, 20.95 mmol) and methyl-3-bromobenzoate (4.95 g, 23.02 mmol) in 5:1 (v/v) toluene:t-BuOH (100 mL) was added. After stirring for 2 minutes, the vessel was sealed and the reaction mixture was heated at 120° C. for 16 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc) followed by concentration gave the title compound as an oil (5.64 g, 97%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)=[C:4]([C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]2[N:22]3[CH2:23][CH2:24][CH2:25][CH:21]3[CH2:20][CH2:19][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:18]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1CCC1CCCN21
Temperature: 100 °C
Yield: 50.2 %

Procedure:
A mixture of methyl 3-bromo-6-(2,2-dimethylpropionylamino)-2-(2-pyrrolidin-2-yl-ethyl)-benzoate (Intermediate 35, 2.05 g), palladium acetate (0.282 g), cesium carbonate (3.26 g) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.557 g) in toluene (40 mL) was stirred and heated at 100° C. under nitrogen for one hour. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl 7-(2,2-dimethylpropionylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (0.826 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCNc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (120 mg, 0.33 mmol), 2-methylbut-3-yn-2-ol (277.2 mg, 3.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (231.67 mg) and triethylamine (2.4 mL) in dimethylsulfoxide (1 mL) was stirred under nitrogen for 1 hr at 70° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 5 mL of water then extracted with 3×30 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to give 5.0 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol as a white solid: 1H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.16-7.12 (m, 3H), 6.91 (d, 1H), 5.40 (s, 1H), 3.63-3.57 (m, 4H), 3.35 (s, 3H), 1.47 (s, 6H); LC-MS: m/z=+367 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])cc3Cl)CC2)cc1

Procedure:
The title compound, m.p. 102°-4°, was prepared similarly to the procedure of Example 1(A) from 1-(2-chloro-4-nitrophenyl)piperazine (1.2 g), 4-nitrophenethyl bromide (1.15 g) and sodium bicarbonate (0.85 g). The yield of the title compound was 0.37 g (from ethyl acetate), m.p. 100°-102°. A second batch had an m.p. of 102°-4° (from ethyl acetate/methanol)
Reaction SMILES: C(NC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(N)=O)CCC.[CH2:26]([C:33]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:36]([C:37]([N:39]([CH3:41])[CH3:40])=O)=[CH:35][C:34]=1[O:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[C:43]([S:44](=[O:46])(=[O:47])[NH2:45])=[CH:42][C:36]([CH2:37][N:39]([CH3:41])[CH3:40])=[CH:35][C:34]=1[O:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCOc1cc(C(=O)N(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCOc1cc(CN(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide with an equimolar amount of 4-benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide and following the procedure described, (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine is obtained with a melting point of 110°-111° C. The material (IR, analysis) is identical with the material prepared as in Example 180.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH:26](=[O:28])[CH3:27].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:26]([CH3:27])[OH:28])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CC=O
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
To a solution of 25 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 145 ml of dried tetrahydrofuran at -25° to -30° is added 110 ml of 2.5 M n-butyllithium maintaining a temperature below -21°. After the addition, the carbon tetrachloride-dry ice bath is replaced with an ice-water bath and the mixture is stirred at 0°-5° for 4 hrs. A solution of 7.5 ml of freshly distilled acetaldehyde in 10 ml tetrahydrofuran is added dropwise. And additional 2 ml of acetaldehyde is added and the solution is stirred for 1 hr. The solution is poured onto 500 ml of a cold 5% hydrochloric acid solution and the mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and solvent is removed to give a solid. Recrystallization from ethyl acetate and hexane gives 20 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol, mp 173°-174°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][C:14]2[O:18][CH:17]=[CH:16][C:15]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C.O.Cl>O1CCCC1>[C:20]([C:19]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=1[OH:10])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc2occc2c(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Lithium aluminum hydride (1.31 g) was suspended in tetrahydrofuran (150 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-4,6-di-tert-butylbenzofuran (10 g) in tetrahydrofuran (100 ml) was added dropwise to the suspension under cooling with ice. After heating under reflux for 3 h, the mixture was cooled to room temperature and, after addition of water and 10% aqueous HCl (100 ml), the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-5-hydroxybenzofuran [8.3 g (yield, 98%)].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH3:9][CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[N:4]=1)[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 60-63° C.; 1H NMR (300 MHz, CDCl3) δ7.28-7.21 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 5.15 (d, J=16.2 Hz, 1H), 4.95 (d, J=16.2 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H), 3.37-3.22 (m, 1H), 1.39 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 178.5, 177.2, 155.2, 150.2, 144.6, 142.1, 138.3, 132.2, 128.8, 123.7, 123.4, 121.1, 114.1, 111.6, 109.7, 99.4, 80.1, 64.5, 63.9, 58.1, 40.6, 33.3, 23.1; MS (ES+) m/z 434.9 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C#N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-:25].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:25])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)c1cc(C(C#N)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 26.7 parts of intermediate 9, namely 3-(dimethoxymethyl)-4-nitro-α-phenylbenzeneacetonitrile, 12.3 parts of potassium carbonate and 360 parts of N,N-dimethylacetamide was stirred at room temperature while bubbling air through it. The reaction mixture was poured into water and the whole was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CHCl3 /hexane 80:20). The eluent of the desired fraction was evaporated, yielding 18.1 parts (67.3%) of [3-(dimethoxymethyl)-4-nitrophenyl]phenylmethanone (interm. 10).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]=[C:16]([CH3:25])[C:15]=2[CH3:26])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Reactant: COc1cc(Br)cc2[nH]ccc12
Product: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure U using 6-bromo-4-methoxy-1H-indole (0.05 g, 0.22 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.075 g, 0.33 mmol) to give 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline as a yellow solid: Mass Spectrum (ESI) m/e=415.0 [M+1 (79Br)] and 417.0 [M+1 (81Br)].