Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:16][CH2:15][C:14]#[N:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2CCCN2)cc1Cl
Reactant: C=CC#N
Solvent: CO
Product: N#CCCN1CCCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
To the solution of 2.4 g (11.2 mmol) 2-(3,4-dichlorophenyl)pyrrolidine in 13 ml abs. methanol dropwise under stirring at room temperature 2.21 ml (33.6 mmol) acrylonitrile is added. The reaction mixture is stirred for 3 days at room temperature, then evaporated. The residue is purified by column chromatography using at first chloroform, then chloroform:methanol 100:1 ratio mixture as eluent, to obtain 2.1 g title compound in the form of an oil. LC-MS[MH+]=269 (C13H14Cl2N2 269.14).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>ClCCl>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2ncc(SCCN3CCC(NS(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (318 μL, 1.82 mmol, 2.5 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (237 mg, 0.73 mmol, 1.0 eq) in dichloromethane (4 mL), followed by 2-nitro-benzenesulfonyl chloride (183 mg, 0.80 mmol, 1.1 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate 100%) to afford N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide as a yellow waxy solid (307 mg, 82% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)=O.[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>>[CH2:12]([O:14][C:15]([CH2:16][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])=[O:18])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccnc1O
Agent: O=C=O
Product: CCOC(=O)Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-Dihydroxypyridine (5 g) is suspended in ethylbromoacetate (20 ml) and the mixture heated in a sealed tube for 24 hours at 140° C. The tube is then cooled in solid CO2 and opened. The contents are subjected to rotary evaporation at 50° C. to yield a yellow solid. Recrystallisation of this solid from water yields 1-ethoxycarbonylmethyl-3-hydroxypyrid-2-one as white crystals (5.4 g), m.p. 141°-151° C.; νmax (nujol) 1645, 1720 cm-1 ; δ(d6DMSO), 1.0 (t, 3H), 4.0 (q, 2H), 4.55 (s, 2H), 5.95 (t, 1H), 6.6(d, 1H), 7.05 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: COc1ccccc1/C=C/C(=O)O
Product: COc1ccccc1/C=C/C(=O)Nc1cnn(CCCCC(C)=O)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:28]N1C(=O)CCC1=O>O1CCCC1>[I:28][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I

Procedure:
5-Amino-2-nitrobenzotrifluoride (16.25 g, 78.8 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (100 mL) and to this solution was added p-toluenesulfonic acid (0.18 g, 0.95 mmol) and N-iodosuccinimide (17.8 g, 78.8 mmol). The solution was stirred all day. N-iodosuccinimide (0.78 g, 3.47 mmol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) were then added and the solution stirred overnight at room temperature under nitrogen. The solution was concentrated under vacuum to a small volume. Water (200 mL) was added to the reaction mixture and and a brown solid precipitated out. The solid was filtered- and washed with water, then dissolved in ethyl acetate (100 mL) and diethyl ether (60 mL). The organic solution was washed with 10% sodium thiosulfate solution (50 mL). This created an emulsion which was alleviated by adding diethy! ether and water and filtering undissolved material. The layers were separated and the organic layer was washed with 10% sodium thiosulfate solution (50 mL), water was then added to the aqueous layer and the layers separated. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound as a brown solid that was dried under vacuum.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.O>CN(C=O)C>[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2c(SCc3ccc(CBr)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
In 25 mL round-bottomed flask 25 mL 7-trifluoromethyl-quinoline-4-thiol (1.0 g, 4.37 mmol) was dissolved in 8 mL DMF anhydrous and NaH (60% dispersion in oil, 184 mg) was added slowly. The reaction was stirred at RT for 10 min. In a 50 mL round-bottomed flask 1,4-bis-bromomethyl-benzene (1.27 g, 4.80 mmol) was dissolved in DMF anhydrous (10 mL) and the solution was stirred at 0° C. for 10 min. The first solution was added via syringe to this solution and the reaction was stirred at 0° C. for 15 min. The solution orange became pale yellow and the mixture stirred 2 h at RT. Water (50 mL) was added and the product extracted with diethyl ether (5×100 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL), dried with MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent cyclohexane:diethyl ether=7:3. 4-(4-(Bromomethyl)benzylthio)-7-(trifluoromethyl)quinoline 29 was obtained (265 mg, 15% yield) as white solid.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.[CH:27]1([CH2:39][NH2:40])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1>C(O)C>[CH:27]1([CH2:39][NH:40][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1
Reactant: NCC1Cc2cccc3cccc1c23
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4Cc5cccc6cccc4c56)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 85 %

Procedure:
Six chloropurine riboside (1.7 g, 6 mmol), triethyl amine (1.5 g, 15 mmol) and the N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine, B, as prepared in the following Example B (1.4 g, 6.4 mmol) were stirred at reflux in ethanol (100 ml) overnight. The solution was cooled to room temperature and filtered free of solid. The solution was washed with ethanol (50 ml) and dried at 65° C. in vacuo for four hours, to give 2.2 g (85%) of a white solid, mp 173°-175° C. Anal. (C23H23N5O4); calc: C=63.73, H=5.35, N=16.16; found: C=63.55, H=5.49, N=16.00.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:15]1([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:16][CH2:17][C:12]([F:11])([F:30])[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=434.1, tR (minutes, Method F)=3.04
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=[O:14]>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([OH:15])=[O:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sccc1Cl

Procedure:
52.1 g. of phosphorus pentachloride are dissolved in 600 ml. of absolute carbon tetrachloride and heated to boiling, whereupon a solution of 15.8 g. of 3-hydroxy-2-methoxycarbonyl-thiophene in 200 ml. of carbon tetrachloride is added dropwise during 3 hours. The mixture is boiled to reflux for 13 hours, the carbon tetrachloride is distilled off and the mixture is evaporated almost to dryness in vacuo. 450 Ml. of water are added dropwise while cooling, whereupon the mixture is heated to boiling and then allowed to cool. The resulting precipitate is filtered off under suction and boiled up with 10 g. of active carbon in a solution of 25 g. of sodium bicarbonate. The active carbon is then filtered off under suction and the cooled solution is acidified with hydrochloric acid. There is obtained 3-chlorothiophene-2-carboxylic acid of melting point 185°-186° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: Cc1nc2c(C=O)cccn2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccn2nc(C)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.42 g, 35.5 mmol) in tetrahydrofuran (35 mL) was added a solution of ethyl diethylphosphonoacetate (7.10 mL, 35.5 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde (5.20 g, 32.3 mmol) in tetrahydrofuran (60 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.30 g, yield 84%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Br:6])C.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13](Br)[N:12]=1.C(OCC)(=O)C>O>[Br:6][C:5]1[N:12]2[CH:13]=[CH:14][N:10]=[C:11]2[CH:16]=[C:15]([CH3:17])[CH:4]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(N)nc(Br)c1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)n2ccnc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (20 mL), concentrated hydrobomic acid (5 mL) and water (20 mL) is heated at 90° C. for 1.5 h. The reaction mixture is poured into 250 mL of water and 50 g sodium bicarbonate is gradually added. 2-Amino-6-bromo-4-methylpyridine (3 g, 0.016 mol) is then added and the mixture is stirred at room temperature for 3 h. Ethyl acetate (100 mL) and water (50 mL) are added. The organic layer is separated and extracted with hydrochloric acid (1N, 3×100 mL). The combined aqueous layer is neutralized with ammonium hydroxide at 0° C. and extracted with dichloromethane (3×200 mL). The combined organic layer is dried over sodium sulfate. Evaporation of the solvent gave 5-bromo-7-methylimidazo[1,2-a]pyridine (2.95 g, 76%) as a white solid, m.p. 53-54° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:16]([Cu])#[N:17]>CN(C=O)C.[C-]#N.[Na+]>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:16]#[N:17])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(Br)c1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)c(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
Methyl 3-bromo-4-tert-butyl-benzoate (2.26 g, 4.17 mmol) was dissolved in dry DMF (2.1 mL) before CuCN (821 mg, 9.17 mmol) and NaCN (1.0 mg, 0.021 mmol) were added. The mixture was flushed with nitrogen and was stirred at 110° C. for 24 h. The reaction mixture was diluted with ethyl acetate (70 mL) and was washed with water. The organics were dried over sodium sulfate and were evaporated to dryness. The crude material was purified by column chromatography eluting with 0-10% ethyl acetate in hexanes to give methyl 4-tert-butyl-3-cyano-benzoate (390 mg, 43%). ESI-MS m/z calc. 217.1. found 218.5 (M+1)+; Retention time: 2.07 minutes (3 min run). NMR (400 MHz, CD3CN) δ 8.31 (d, J=1.8 Hz, 1H), 8.16 (dd, J=8.4, 2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu].C(O)(=O)C>[NH2:20][C:16]1[CH:15]=[C:14]([NH:21][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1cccc(N)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 6.25 h

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid 16 (150.0 g, 744 mmol), 1,3-phenylenediamine 17 (150.0 g, 1.387 mol), anhydrous potassium carbonate (309.0 g, 2.236 mol ), copper powder (2.0 g, 31.5 mmol), cupric sulfate (10 mg) and water (2.0 L) was heated to reflux with stirring for 6.25 hr under argon. It was then allowed to stand overnight at room temperature. Glacial acetic acid was added to the reaction mixture with stirring until pH 5 and the flask cooled in ice water. The mustard yellow solid was collected, washed with ice-cold water (3×100 mL), and redissolved in hot dilute ammonia (300 mL 0.88 s.g. ammonia and 2.7 L water). Charcoal (2.0 g) was added, the mixture refluxed briefly, and then filtered through a fluted paper. On cooling to room temperature the mixture was acidified to pH 5 by adding glacial acetic acid and the flask cooled in ice-water. The product was collected and washed with ice-cold water (2×100 mL) followed by ice-cold ethanol (2×100 mL), dry ether (2×100 mL) and finally hexane (100 mL). The product was dried over P2O5 under vacuum to yield the product AR-ACO-06 (155.10 g, 76%) as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[Br:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([Br:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(Br)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
998 Milligrams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 30 ml of tetrahydrofuran with 3 ml of hexamethylphosphoric triamide, to this solution was added 1.03 ml of N,N,N',N'-tetramethylethylenediamine, was cooled to -78° C. on a dry ice-acetone mixture bath. 4.56 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.22 g of N-bromosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 50 ml of diethyl ether, and the diethyl ether layer was washed twice with 50 ml of water, and washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There were obtained 155 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy- 3,6-bis(methoxymethoxy)-4-bromophenyl]pentane, as well as 22 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-bromobenzene].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1>>[O:12]=[C:4]1[C:3](=[CH:2][NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(NS(N)(=O)=O)cc1
Product: NS(=O)(=O)Nc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Yield: 52 %

Procedure:
The title compound was prepared from 3-hydroxymethylene-1,3-dihydro-indol-2-one and 4-aminophenyisulfamide according to Procedure J in 52% yield: 1H NMR (DMSO-d6): δ 6.85 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 7.08 (s, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.5 Hz, 1H), 8.53 (d, J=12.7 Hz, 1H), 9.38 (s, 1H), 10.48 (s, 1H), 10.70 (d, J=12.7 Hz, 1H): APCI−MS m/z 329 (M−H)−. Anal. Calcd for C15H14N4O3S: C, 54.54, H, 4.27; N, 16.96; S, 9.71. Found C, 54.48, H, 4.30; N, 16.90; S, 9.63.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[C:12](I)[C:11]([O:15][CH2:16][C:17]([CH3:19])=[CH2:18])=[C:10](I)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)COc1c(I)cc(C2(C(=O)OC)CC2)cc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc3c(c2)C(C)(C)CO3)CC1
Yield: 60.9 %

Procedure:
To a solution of 1-[3,5-diiodo-4-(2-methyl-allyloxy)-phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu3SnH (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated at reflux overnight. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.07 (m, 2H), 6.71 (d, J=8 Hz, 1H), 4.23 (s, 2H), 3.62 (s, 3H), 1.58-1.54 (m, 2H), 1.34 (s, 6H), 1.17-1.12 (m, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C([O:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[CH:12]=1)=O)C>C(O)C>[OH:3][NH:2][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[CH:12]=1)=[O:8]
Reactant: NO
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2cc(C(=O)NO)sc2cc1OC
Reaction time: 72 h
Yield: 87.3 %

Procedure:
Hydroxylamine hydrochloride (5.3 g) was dissolved in warm ethanol (100 ml). The solution was stirred under an atmosphere of nitrogen and treated with a warm solution of potassium hydroxide (6.4 g) in ethanol (50 ml). After 10 min. a solution of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (10 g) in ethanol (250 ml) was added and the resultant mixture was allowed to stand at room temperature for 72 hours. The resultant suspension was filtered to remove the precipitated potassium chloride and the filtrate was evaporated to dryness. The resultant yellow residue was dissolved in water (250 ml), filtered and the filtrate was acidified with 5M hydrochloric acid. The precipitated product was filtered and dried at 65° C. under vacuum to give N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide (8.3 g). A portion crystallised from acetone had a melting point: 179°-180° C.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:3].[O:16]1CCOC[CH2:17]1.Cl>[Cl-].[Na+].O>[OH:16][CH2:17][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1
Reactant: C1COCCO1
Reactant: O=C(Cl)CCCCCCC1=CCCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCCCC1=CCCC1=O
Temperature: 80 °C

Procedure:
A mixture of 6.3 g. of 2-[6-(chloroformyl)hexyl]-cyclopent-2-en-1-one (Example 75) and 16 g. of tris-trimethylsilyloxyethylene (Example 74) are stirred at 90° to 100° C. under argon for one hour. To this mixture is added 25 ml. of dioxane and 10 ml. of 0.6N hydrochloric acid. The mixture is heated at 80° C. for 30 minutes. The mixture is poured into brine and extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether containing 2% acetic acid to give 1.7 g. of the title compound (Rf =0.45).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[H-].[Na+].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cncc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (250 mg, 0.819 mmol) in DMF (5 mL), sodium hydride (59.0 mg, 2.46 mmol) and 7-chloro-1-methyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one (152 mg, 0.819 mmol).