Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:46][C:47]([CH3:51])([CH3:50])[CH:48]=[O:49]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:48]([OH:49])[C:47]([CH3:51])([CH3:50])[CH3:46])=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C=O
Reactant: Cc1cc(Br)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(C)(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: -78 °C

Procedure:
2 g (3 mmol) of 3′-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-4-bromo-2-methylbiphenyl are dissolved in 30 mL of anhydrous THF and the mixture is cooled to −78° C. 1.4 mL (3.5 mmol) of 2.5 M butyllithium are added slowly and the mixture is maintained at −78° C. for 1 hour. 400 mL (3.7 mmol) of 2,2-dimethylpropionaldehyde are added dropwise and the medium is warmed slowly to room temperature and then treated according to the usual treatment. The desired product is obtained in the form of a colourless oil (m=2 g; Y=100%).
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12](COC)[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=2)(=[O:14])=[O:15])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1Br)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of N-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.167 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (30% ethyl acetate in hexane) to afford 50 mg of title compound as an off white solid. MS: (M+H)/z=555.3, (M+Na)/z=575.3.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)=O>[CH2:23]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:11]1=[O:19])[CH2:24][CH2:25][CH3:26]
Reactant: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 2.6 g. (0.01 mole) of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]-pyridin-2-one in 150 ml. of acetone, was added 1.12 g. (0.02 mole) of powdered potassium hydroxide. The mixture was stirred at room temperature for 20 minutes and 2.74 g. (0.02 mole) of 1-bromobutane was added. The mixture was stirred at reflux for 16 hours and then evaporated in vacuo. The residue was extracted with a solution of 20 ml. of 2.5 N sodium hydroxide and 50 ml. of water. The product was separated by filtration and was purified by crystallization from ether-petroleum ether giving 2.4 g. of white needles melting at 74°-75° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:67]([O:69][CH:70]1[O:74][C@@H:73]([CH2:75]O)[C@H:72]([CH2:77][OH:78])[O:71]1)[CH3:68]>C1COCC1>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:75][C@H:73]3[C@H:72]([CH2:77][OH:78])[O:71][CH:70]([O:69][CH2:67][CH3:68])[O:74]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC1O[C@@H](CO)[C@H](CO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1O[C@@H](CO)[C@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Yield: 39 %

Procedure:
To a solution of probucol (5.16 g, 10 mmol) in THF (20 mL) cooled to 0° C. were added triphenylphosphine (1.3 g, 5 mmol), diethyl azodicarboxylate (0.8 mL g, 5 mmol) and 2-ethoxy-1,3-dioxolane-4(S),5(S)-dimethanol (0.89 g, 5 mmol; Nicolaou, K. C. et al.: J. Org. Chem. 1985, 50, 1440–1456). The resultant mixture was stirred at reflux for 3 hours and then evaporated. Silica gel chromatography (hexanes/ethyl acetate 4:1) gave 2,6-di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(2-ethoxy-5(S)-hydroxymethyl[1,3]dioxolan-4(S)-yl-methoxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenol in three parts: diasteroisomer A (0.36 g), diastereoisomer B (0.22 g) and a mixture of the two (0.72 g) all as viscous residues (total yield: 39%). Diastereoisomer A: 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.44 (s, 2H, Ph-H), 5.89 [s, 1H, CH(O) 3], 5.37 (s, 1H, PhOH), 4.7{tilde over (3)}4.81 (m, 1H, PhOCH2CH), 4.1{tilde over (9)}4.25 (m, 1H, CHCH2OH), 3.8{tilde over (0)}4.01 (m, 3H, CH2O), 3.6{tilde over (2)}3.96 (m, 3H, CH2O), 2.80 (dd, J=9, 3, 1H, OH), 1.45 (s, 6H, S,S′-isopropylidene), 1.44 (s, 18H, tert-butyls), 1.43 (s, 18H, tert-butyls), 1.25 (t, 3H, OCH2CH3). Diasteroisomer B: 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.44 (s, 2H, Ph-H), 5.92 [s, 1H, CH(O) 3], 5.36 (s, 1H, PhOH), 4.5{tilde over (0)}4.59 (m, 1H, PhOCH2CH), 4.1{tilde over (3)}4.30 (m, 3H, CHCH2OH, CH2O), 3.8{tilde over (9)}4.00 (m, 3H, CH2O), 3.61 (quad, J=7, 2H, OCH2CH3), 1.86 (dd, J=6, 8, 1H, OH), 1.4{tilde over (1)}1.46 (m, 42H, S,S′-isopropylidene, tert-butyls), 1.21 (t, 3H, OCH2CH3).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([O-:7])=[O:6].[N-:15]=[N+:16]=[N-].[Na+]>O.FC(F)(F)C(O)=O>[N:12]([C:11]1[CH:13]=[CH:14][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)=[N+:15]=[N-:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
A solution of sodium nitrite (761 mg, 11 mmol) in water (5 mL) was added dropwise to a 0° C. solution of 4-nitroaniline (508 mg, 3.68 mmol) in trifluoroacetic acid (5 mL). After stirring for 10 minutes, a solution of sodium azide (1.55 g, 23.9 mmol) was added slowly. The resulting yellow suspension was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-azido-4-nitrobenzene (600 mg, 99%). 1H NMR (400 MHz, CDCl3, δ): 8.16-8.19 (m, 2H), 7.05-7.09 (m, 2H).
Reaction SMILES: C(OC([CH:6]1[CH2:11][C:10]([C:17]#[N:18])([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:19])=O)C.O.[OH-].[Na+]>Cl.C(O)(=O)C>[O:19]=[C:7]1[CH2:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)([C:17]#[N:18])[CH2:11][CH2:6]1
Reactant: CCOC(=O)C1CC(C#N)(c2ccsc2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccsc2)CCC(=O)CC1
Reaction time: 4 h
Yield: 43.5 %

Procedure:
5-cyano-2-oxo-5-thiophen-3-yl-cyclohexanecarboxylic acid ethylester (40 g; 0.14 mole) dissolved in a mixture of concentrated hydrochloric acid (200 ml) and glacial acetic acid (400 ml) was heated with stirring for about 4 hours to reflux. On completion of the reaction (reaction monitored by thin layer chromatography), water (100 ml) was added and neutralized with aqueous sodium hydroxide solution (200 ml) and extracted with ethylacetate (2×400 ml). The organic phase was washed with sodium hydrogen carbonate solution (200 ml) and water (100 ml), dried (sodium sulfate) and concentrated under vacuum. Purification by column chromatography (silica gel, 25% ethylacetate in n-hexane) yielded 12.5 g 4-oxo-1-thiophen-3-yl-cyclohexanecarbonitrile (42%; pale yellow solid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)#[N:2].OO.C(=O)([O-])[O-:33].[K+].[K+]>O.CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)(=[O:33])[NH2:2]
Reactant: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedure to prepare 379, compound 366, hydrogen peroxide, potassium carbonate in water and DMSO were reacted to give 432. Yield 38% MS: (ESI+)=426.1
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][CH:6]=1
Reactant: C=CC(=O)OCC
Reactant: Oc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(O)cn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
The mixture of 6-bromopyridin-3-ol (5.22 g, 30.0 mmol), ethyl acrylate (4.51 g, 45.0 mmol), palladium acetate (175 mg, 0.78 mmol), tri-o-tolylphosphine (438 mg, 1.44 mmol), and triethylamine (4.55 g, 45.0 mmol) in N,N-dimethylformamide was placed in a sealed tube, and the mixture was stirred at 140° C. for 24 h. The mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×4), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 2.3 g (40%) of the title compound as a yellow oil. ((E), (Z) mixture)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCC1CCCCC1)C(=O)OCC

Procedure:
16.6 g of 6-cyclohexyl-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 26 g of (4-cyclohexylbutyl)-malonic acid ethyl ester, 3.1 g of paraformaldehyde, 19 ml of pyridine and 1.2 ml of piperidine.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:5])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Yield: 50.4 %

Procedure:
To (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (716 mg, 2.77 mmol) in THF (27.700 mL) at 0° C. was added (4-(benzyloxy)phenyl)magnesium bromide (8.32 mL, 16.63 mmol) dropwise. After complete addition, the solution was heated to 65° C. for 1 h. The reaction was cooled to 0° C., quench carefully with 1N HCl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (5%→60% ethyl acetate in hexanes) to afford (R)-tert-butyl 2-(4-(benzyloxy)benzoyl)pyrrolidine-1-carboxylate (533 mg, 1.397 mmol, 50.4% yield) as an amorphous yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.87-8.00 (m, 2H), 7.29-7.47 (m, 5H), 6.95-7.07 (m, 2H), 5.13-5.31 (m, 1H), 5.10-5.13 (m, J=3.78 Hz, 2H), 3.40-3.73 (m, 2H), 2.19-2.35 (m, 1H), 1.82-1.98 (m, 3H), 1.21-1.30 (m, 9H); LRMS (ESI) m/e 282.17 [(M-Boc+H)+, calcd for C18H20NO2 282.15]; m/e 404.11 [(M+Na)+, calcd for C23H27NNaO4 404.18].
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])C.Cl.[OH:15][S:16]([O-:18])=[O:17].[Na+:19].C(O)C>O>[CH2:7]([N:6]([CH2:9][CH3:10])[CH2:5][CH:4]([OH:3])[S:16]([O-:18])(=[O:17])=[O:15])[CH3:8].[Na+:19]
Reactant: O=S([O-])O
Reactant: CCOC(CN(CC)CC)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CC(O)S(=O)(=O)[O-]
Reaction time: 2 h

Procedure:
2,2-diethoxy-N,N-diethylethanamine (140 mg, 0.75 mmol) was added in 0.1 mL H2O. Concentrated HCl (190 mg) was added dropwise in an ice bath. The solution was stirred for 2 hours at 40 degree. NaHSO3 (350 mg, 3.36 mmol) in 0.6 mL H2O was added to the reaction solution in an ice bath and stirred for 1 hour at room temperature, then 0.6 ml ethanol was added and stirred for 1 hour at room temperature. This reaction solution was concentrated, the resulting residue was used directly for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 76%). 1H NMR (200 MHz, CDCl3): δ 3.22 (s, 4H), 3.79-3.85 (m, 12H), 4.13 (s, 4H), 6.19 (s, 2H), 7.20-7.34 (m, 1H), 7.35-7.36 (m, 1H), 7.44 (s, 1H), 7.67-7.70 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[C:23]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5][C:4]=2[CH:3]=1)([CH3:32])[CH3:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)NC1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCc2cc(OC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a suspension of N-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (0.439 g; 2.1 mmol) in DMF (6 mL) is added Cs2CO3 (1.7 g; 5.2 mmol) and tert-butyl 2-bromoisobutyrate (2.1 mL; 9.4 mmol) and the reaction mixture was stirred at 100° C. for 18 h. The reaction was cooled to RT, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide a crude oil, which was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 0.51 g (69%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy)-2-methylpropionic acid tert-butyl ester as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:20])[CH2:12][NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:7][CH:6]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C1CCN2C(=NCCC2)CC1>>[CH3:18][CH:17]([S:14]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:10][CH:9]=1)[CH3:20])(=[O:16])=[O:15])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCN)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNS(C)(=O)=O)cc1
Yield: 23.9 %

Procedure:
Scheme Vc, step C: {2-[4-(3-aminopropyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.5 g, 1.67 mmol), methanesulfonyl chloride (0.15 mL, 1.84 mmol) and DBU (0.29 mL, 1.93 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the final title compound, [(methylethyl)sulfonyl][2-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)propyl]amine, (0.15 g, 24%) as a white crystalline solid. Electron spray M.S. 377 (M*+H). Analysis for C16H28N2O4S2:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[N:14]1.[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[N:14]1
Reactant: CCOC(=O)c1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 63 %

Procedure:
To a solution of ethyl 1-(2,6-dichloro-4-trifluoromethylphenyl)indazol-6-yl carboxylate [Compound No. 62] (3 g) in conc. sulfuric acid (20 g), fuming nitric acid (0.7 g) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give ethyl 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitroindazol-6-yl carboxylate (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A suspension of 4-fluorophenylacetic acid (10.0 g, 64.9 mmol) in concentrated sulfuric acid (100 ml) was cooled to 0° C. Concentrated nitric acid (4.5 ml, 65 mmol) was added drop-wise, keeping the temperature at 0-5° C. At the end of the addition the mixture was poured into ice-water (400 ml). The precipitate was filtered off, washed thoroughly with water and dried with suction to yield 1i (9.11 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To an ice-cold solution of 3-bromo-5-nitro-phenol (21.0 g, 96.33 mmol) in acetone (420.0 mL) was added K2CO3 (40.0 g, 289.41 mmol) followed by addition of benzyl bromide (17.20 mL, 144.40 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×250.0 mL). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified over silica gel (100-200 M, 5% EtOAc-Hexane) to get the desired product (27.0 g, 91%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 55.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (17 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C@H:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][C:5]([O:6][C@H:7]4[CH:12]5[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]5)[CH2:8]4)=[CH:4][CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Brc1ccc(O[C@@H]2CN3CCC2CC3)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(O[C@@H]4CN5CCC4CC5)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from (S)-3-(4-bromo-phenoxy)-1-aza-bicyclo[2.2.2]octane (170 mg, 0.62 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (100 mg, 0.47 mmol).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]C)=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:19][NH2:20]>C(O)C>[CH3:1][C:2]1([C:15]([NH:20][CH3:19])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN
Reactant: COC(=O)C1(C)NCCc2c1[nH]c1ccccc21
Solvent: CCO
Product: CNC(=O)C1(C)NCCc2c1[nH]c1ccccc21
Reaction time: 48 h

Procedure:
4.8 g (0.02 mol) of methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate are dissolved in 100 ml of ethanol saturated with methylamine. The solution is left at ambient temperature for 48 hours. The solvent is removed and the residue is then taken up in 20 ml of ethanol. The product is filtered off and washed with ethanol.