Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C[C:21](C)([O-:23])C.[K+].[CH3:26][CH:27]([CH3:31])[C:28](=[O:30])[CH3:29]>C1COCC1>[C:11]([C:6]1[CH:5]=[CH:10][C:9]([C:21](=[O:23])[CH2:29][C:28](=[O:30])[CH:27]([CH3:31])[CH3:26])=[CH:8][CH:7]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)C(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(=O)CC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
10 g (39 mmol) of benzoylbenzoic ethylester are added to a suspension of 3.94 g (35 mmol) of potassium-tert-butoxid in 60 ml of THF at 0° C. under argon. 2.82 g (33 mmol) of 3-methyl-2-butanone are added in 1 h while the temperature rises to 25° C. After 2 h at 40° C. the reaction mixture is poured into 500 ml of ice water containing 10 ml conc. HCl. Extraction with toluene and evaporation gives the crude product (8.5 g) which is purified by crystallisation in heptane yielding 3.7 g of a white solid. The structure is confirmed by 1H-NMR and 13C-NMR spectra. mp: 76.5-78° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[CH2:6][N:7]1[C:11]2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[NH:9][C:8]1=O)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:26])=O>>[CH:1]([O:4][C:5](=[O:23])[CH2:6][N:7]1[C:11]2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]=[C:8]1[Cl:26])([CH3:3])[CH3:2]
Reactant: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
A mixture of isopropyl[4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (3.73 g, 11.0 mmol) and phosphorus oxychloride (20 mL) was stirred at 100° C. for 48 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-15% ethyl acetate/hexane gradient mixture to give 3.82 g (10.7 mmol, 97.2%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][Br:12])[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[Br-:12].[C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 230 g (1.0 mole) of methyl-α-bromo-m-toluate and 300 g (1.2 mole) of triphenyl phosphine in 1 l of dry benzene was refluxed for 2 hr. After 15 minutes, the phosphonium bromide started precipitating from the solution. After cooling the flask to room temperature, the solid was filtered, washed with plenty of petroleum ether and dried. The yield 487 g was quantitative. m.p. 234°-236° C. The infrared spectrum showed absorption of 1720 cm-1 (COOCH3). NMR (CDCl3) showed 3.8 (S, --COOCH3, 3), 5.5-5.8 (d, --CH2 -P, 2), and 7-8.4 (m, aromatic, 19). Anal. calcd. for C27H24O2P Br: C, 65.98%, H, 4.88%, Br. 16.29%. Found: C, 65.88%, H, 4.82%, Br, 16.49%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[CH3:22][O:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:22][O:23][CH3:24]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: C#CCC(C(=COC)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-4-pentyn-1-one and methoxymethyltriphenylphosphonium chloride there is obtained 3-[2,4-dichloro-α-methoxymethylene-β-(2-propynyl)-phenethyl]-pyridine
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[NH2:13][CH2:14][C:15]([OH:17])=[O:16].S([O-])(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:22][O:16][C:15](=[O:17])[CH2:14][N:13]1[C:5](=[O:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCC(=O)O
Reactant: COS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CN1C(=O)c2ccc(F)cc2C1=O
Temperature: 210 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
A solid mixture of 5-fluoro-isobenzofuran-1,3-dione (3.68 g, 22.15 mmol) and glycine (1.66 g, 22.15 mmol) was stirred at 200-220° C. for 5 min. After cooling, it was dissolved in 25 ml of acetone. Methyl sulfate (4.19 g, 33.23 mmol) and potassium carbonate (4.59 g, 33.23 mmol) was added. The mixture was stirred at reflux for 2 h. After cooling, it was diluted with 100 ml of ethyl acetate. Insoluble was filtered off and filtrate was concentrated. Residue was taken into 200 ml of ethyl acetate and washed with water and brine. Ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give 5.1 g of product. 1H NMR (200 MHz, CDCl3) δ 7.88 (dd, J=8.2, 4.3 Hz, 1H), 7.54 (dd, J=6.8, 2.2 Hz, 1H), 7.40 (m, 1H), 4.44 (s, 2 H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[N:6]=1)[CH3:3].C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22]([Cl:24])=[O:23].[ClH:26]>C1C=CC=CC=1>[OH2:23].[ClH:24].[CH3:20][N:21]([CH3:25])[C:22]([N:11]([CH3:12])[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:6]=1)=[O:23].[CH3:20][N:21]([CH3:25])[C:22]([N:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[N:6]=1)[CH3:12])=[O:23].[ClH:26]
Reactant: CNc1cccc(CN(C)C)n1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1cccc(N(C)C(=O)N(C)C)n1
Product: O
Temperature: 25 °C

Procedure:
To 2-dimethylaminomethyl-6-methylaminopyridine (2.14 g, 0.013 mol) in dry benzene (35 ml) is added triethylamine (1.77 g, 0.0175 mol) and dimethylcarbamoyl chloride (1.72 g, 0.016 mol). The solution is stirred under nitrogen at reflux for 16 hours overnight. The mixture is cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the residual oil is taken up in ether, filtered and again concentrated in vacuo. The residual oil is converted to the monohydrochloride salt with 6N ethanolic hydrochloric acid (1.7 ml, 0.0103 mol). The solid is recrystallized from ethanol-ether several times, affording 2.2 g of N,N,N'-trimethyl-N'-(6-dimethylaminomethyl-2-pyridyl)urea hydrochloride hemihydrate as a white solid, m.p. 154°-155° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.[C:15]1([N:21]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:26][C:23]2[CH:24]=[CH:25][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Reactant: O=c1ccn(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1ccn(-c2ccccc2)n1

Procedure:
A mixture of methyl (4-chloro-2,6-dimethyl-5-pyrimidinyl)-acetate (5.0 g, 23 mmol), 1-phenyl-1H-pyrazol-3-on (3.73 g, 23 mmol), potassium carbonate (5,5 g, 40 mmol) in dimethylformamide (30 ml) is heated at +120° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-phenyl-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=1[NH:1][S:21]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)(=[O:23])=[O:22]
Reactant: Nc1cc(CO)ccc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(CO)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-4-chloro-phenyl)-methanol (2.0 g, 12.7 mmol) in pyridine (26 mL) was treated with 3,4-dimethoxybenzenesulfonyl chloride (3.3 g, 1.1 eq). The solution was stirred at RT overnight. The mixture was then partitioned between EA and 3M HCl. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was recovered as a brownish foam.
Reaction SMILES: [N+:1]([C:4]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:5][N:6]([CH2:11][C:12]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[CH3:13])[CH2:7][C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:29]O>>[CH3:29][CH:7]([C:8]([OH:10])=[O:9])[N:6]([CH2:11][C:12]([N+:14]([O-:16])=[O:15])([N+:17]([O-:19])=[O:18])[CH3:13])[CH2:5][C:4]([N+:21]([O-:23])=[O:22])([N+:1]([O-:3])=[O:2])[CH3:20]
Reactant: CO
Reactant: CC(CN(CC(=O)O)CC(C)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(C(=O)O)N(CC(C)([N+](=O)[O-])[N+](=O)[O-])CC(C)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A mixture of 20 g. (0.059 mole) of bis-(2,2-dinitropropyl)-glycine, 100 ml. of methanol and 10.0 ml. of concentrated sulfuric acid was refluxed for 90 minutes. The solution was diluted with 250 ml. of methylene chloride and washed with water, 5% sodium carbonate solution and water. The solvent was evaporated to yield 14.0 g. (67.3%) of white solid. Recrystallization from methanol-ether gave crystals, m.p. 94°-95°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([CH2:20][CH2:21][OH:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl.O>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:22][CH2:21][CH2:20][N:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=[C:9]2[CH3:8])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1cc(-c2ccccc2)cn1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2cc(-c3ccccc3)cc2C)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
Triethylamine (2.1 mL, 15.22 mmol) was added to a solution of 2-(2-methyl-4-phenylpyrrol-1-yl)ethanol (1.53 g, 7.61 mmol) in dry dichloromethane (20 mL) at room temperature followed by the addition of p-toluene sulfonyl chloride (1.88 g, 9.89 mmol). The resulting reaction mixture was stirred for 16 h and then diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield the crude compound. Purification by column chromatography over silica gel (100-200 mesh) with gradient elution with 10-12% ethyl acetate in petroleum ether as eluent afforded 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 44%) as a brownish white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[O-][CH2:13]C.[Na+].BrC[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C(O)C>[CH2:10]([O:9][C:7]([C:4]1[C:3]([CH3:13])=[C:2]([CH3:1])[N:6]([C:18](=[O:19])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]=1)=[O:8])[CH3:11]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C(CBr)Nc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nn(C(=O)Nc2ccccc2)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a magnetically stirred mixture of ethyl 5-methyl-1H-pyrazole-3-carboxylate (0.02 mol) and sodium ethoxide (0.22 mol) in ethanol (20 mL) is added the title A compound, 2-bromo-N-phenyl-acetamide (0.02 mol). The resulting suspension is stirred at RT for 3 h. After concentration in vacuo, EtOAc is added and the resulting solution is washed twice with water and dried over anhydrous Na2SO4. After filtration and concentration, the residue is purified by flash chromatography (ethyl acetate/hexane) to afford 5-methyl-1-phenylcarbamoyl-methyl-1H-pyrazole-3-carboxylic acid ethyl ester: m.p. 139-140° C.; 1H-NMR (DMSO-d6) δ 1.26-1.29 (t, 3H J=72 Hz), 2.28 (s, 3H), 4.23-4.25 (q, 2H J=72 Hz), δ 06 (s, 2H), δ 6.56 (s, 1H), 7.07 (m, 1H), 7.32 (m, 2H), 7.57 (m, 2H), 10.41 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c(O)c(C(=O)O)cnc21

Procedure:
47 g of 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.2 mol) are saponified by means of 400 ml of aqueous sodium hydroxide (2.5 N) by refluxing the mixture for 11/2 hours. After cooling of the filtered solution and diluting with 300 ml of water, it is acidified with glacial acetic acid. The precipitated 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid is filtered under suction, washed with water and dried at 120°. Yield 37 g (89%), recrystallization from glacial acetic acid, and has a melting point of 201°-202°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21](O)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: CC(=O)Nc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 8 %

Procedure:
Reaction of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 64 (8% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.09-2.17 (m, 6H), 2.66 and 2.92 (2t, 2H), 3.49 and 4.06 (2t, 2H), 4.40 and 4.93 (2s, 2H), 6.30 and 6.74 (2d, 1H), 6.79 and 7.00 (2d, 1H), 7.64-7.95 (m, 4H), 8.02-8.13 (m, 2H), 8.39-8.50 (m, 3H), 10.22-10.24 (m, 1H); MS (ESI) m/z 453 ([M+H]+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>OS(O)(=O)=O>[Br:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccccc1Br
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A nitrating acid prepared at -10° C. by adding 55 ml of concentrated H2SO4 to 20 ml of 98 percent HNO3 was added dropwise, in the course of 60 minutes, to a solution of 63.4 g (0.34 mole) of 2-bromobenzaldehyde in 110 ml of concentrated H2SO4 at -5° C. Stirring was continued for a further 45 minutes, after which the reaction mixture was poured onto 550 g of ice, and the precipitated solid was filtered off under suction, washed with water, then with 10 percent strength Na2CO3 solution and again with water. Drying under reduced pressure at 50° C. gave 72 g (92% of theory) of product as a yellow solid of melting point 86°-88° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH3:8].[CH2:14]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Product: N

Procedure:
The title compound was prepared from (R)-(−)-N-boc-3-pyrrolidinol and benzyl bromide, using the same method as that described for preparation 5. The crude compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, to afford the desired product in 97% yield.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]3[O:6][CH:5]=[CH:4][C:12]=3[CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(COc1ccc(-c2ccccc2)cc1)OCC
Solvent: c1ccccc1
Product: c1ccc(-c2ccc3occc3c2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 1-(2,2-diethoxyethoxy)-4-phenylbenzene (3.52 g, 12.3 mmol) and polyphosphoric acid (2.95 g, 29.4 mmol) in benzene (60 mL) was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature, decanted from the PPA and filtered through a plug of silica gel, which was washed with hexanes. The filtrate and the wash were combined anc concentrated under reduced pressure to yield 2.00 g of the crude benzofuran: 1H NMR (400 MHz, CD3OD) δ 7.79 (dd, 1H), 7.66 (d, 1H), 7.63-7.60 (m, 2H), 7.58-7.51 (m, 2H), 7.45 (t, 2H), 7.36-7.33 (m, 1H), 6.82 (dd, 1H).
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:22]=1[CH3:35].S([O-])([O-])(=O)=S.[Na+].[Na+].[OH2:43]>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:22]=1[CH3:35])(=[O:9])=[O:43]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)c(Sc1c(Cl)cccc1Cl)c(C)n2CC(=O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc2c(c1)c(S(=O)(=O)c1c(Cl)cccc1Cl)c(C)n2CC(=O)O
Reaction time: 1 h

Procedure:
3-Chlorobenzenecarboperoxoic acid (0.34 g) was added to a solution of the product from example 24 step a) (0.18 g) in acetonitrile (5 ml) and water (0.5 ml). The reaction was stirred for 1 h, 1M aqueous sodium thiosulphate (2 ml) added and stirred for a further 15 min. The mixture was filtered, purified by reverse phase HPLC and evaporated in vacuo to yield the title compound as a white solid (40 mg).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[I:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH2:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28]>>[CH2:27]([C:29]1[CH:35]=[CH:34][C:32]([N:33]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[I:16])(=[O:25])=[O:24])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1I
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4I)CC3)C2=O)cc1

Procedure:
Amorphous brown solid. MS (ESI) 525.07 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-Iodo-benzenesulfonyl chloride and 4-(ethyl)-aniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH:16][C:23]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](N)C1
Reactant: O=C(O)c1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccncc2)C1
Temperature: 5 °C
Reaction time: 48 h

Procedure:
36.85 g of (3R,4S)-3-Amino-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester, 19.70 g 4-pyridinecarboxylic acid, and 9.76 g dimethylaminopyridine were dissolved in 500 mL CH2Cl2 and cooled to 5° C. 33.01 g DCC was dissolved in 250 mL CH2Cl2 and added to the above mixture within 2 h. The reaction mixture was stirred for 48 h at rt. 200 mL water was added and the mixture is stirred for 2 h at rt. The precipitate was filtered off and the organic phase was extracted two times with 500 mL water. The organic solvent was evaporated in vacuo. The crude product was then submitted to column chromatography (SiO2, ethyl acetate/methanol 99:1) to give 46.2 g (86%) of 1 g as a white solid. MS (ESI): m/z (%): 334 (MH+), 336 ([M−H]+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:38]=2)[CH2:33][C:32]1=[O:49].C([O-])([O-])=O.[K+].[K+].O.O1[CH2:62][CH2:61]OCC1>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:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:62]3[CH:61]=[CH:2][N:6]=[C:5]([C:35]4[CH:36]=[CH:37][CH:38]=[C:39]5[C:34]=4[CH2:33][C:32](=[O:49])[N:31]5[CH3:30])[CH:4]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccc5c4CC(=O)N5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.1 mmol) in dioxane (1.2 mL, degassed) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (30 mg, 1.1 eq.), Pd(PPh3)4 (17 mg, 0.05 eq.), K2CO3(42 mg, 2 eq.) and water (0.1 mL). The reaction mixture was heated at 110° C. for 2 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C31H32ClN2O4S: 563.2 (M+H+); Found: 563.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH3:46])=[C:40]([O:43][CH3:44])[CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH3:46])=[C:40]([O:43][CH3:44])[CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: COc1cc2c(cc1OC)C(N)CC2
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3cc(OC)c(OC)cc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5,6-dimethoxy-indane