Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)C.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][O:20][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: -20 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
22.7 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol was dissolved in 140 ml of pyridine. The solution was cooled to -20° C. To the solution was added 19 g of p-toluenesulfonyl chloride. The resulting mixture was heated to 0° C. and stirred for 15 hours at the same temperature. The rection mixture was added to a mixture of 300 ml of ice water and 200 ml of diethyl ether. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with 1N hydrochloric acid, water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain 20.5 g of oily 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyl)oxyethoxy]ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[O:13]1[CH2:16][CH:15]([NH2:17])[CH2:14]1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:17][CH:15]1[CH2:16][O:13][CH2:14]1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: NC1COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1COC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.3 %

Procedure:
3-Nitrobenzoic acid (0.50 g, 2.99 mmol), oxetan-3-amine (0.219 g, 2.99 mmol) were taken in pyridine (0.5 ml) and under nitrogen atmosphere and EDC.HCl (0.574 g, 2.99 mmol) was added. The reaction mixture was stirred at room temperature for 10 hrs. After completion of reaction, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×5 ml). Combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH:13]([CH3:16])[CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:19]S(O)(=O)=O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH:13]([CH3:16])[C:14]([OH:19])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(CO)c1cc(C(=O)c2ccc(Cl)cc2)no1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C(=O)O)c1cc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.0 g of 2-[3-(4-chlorobenzoyl)-isoxazol-5-yl]propan-1-ol in 1000 ml of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 150 ml of 9M H2SO4 was added 12.3 g of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 1.5 hour. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was separated and the organics were washed with water and brine, and dried over MgSO4. Concentration of the product gave 8.0 g of a solid. Recrystallization from toluene with norite for decolorizing gave 2.0 g of a solid, m.p. 119°-123°. A second recrystallization from toluene gave 1.6 g (13%) of a solid, m.p. 122.5°-124.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][N:15]([CH3:23])[CH:16]([CH2:21][CH3:22])[CH:17]([OH:20])[CH2:18][CH3:19])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:21]([CH:16]([N:15]([CH3:23])[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:17]([O:20][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[CH2:18][CH3:19])[CH3:22]
Reactant: CCC(O)C(CC)N(C)CCc1cc(OC)c(OC)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)C(CC)N(C)CCc1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 2, react 4-[[2-(3,4,5-trimethoxyphenyl)ethyl](methyl)amino]hexan-3-ol with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1ccccc1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and benzene boronic acid, gave 5-formyl-6-methoxy-biphenyl-3-sulfonic acid amide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([Cl:34])[CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:21]2[CH2:22][CH2:23][CH2:24][C@@:17]3([C:16](=[O:25])[N:15]([C@H:12]4[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10][CH2:11]4)[CH2:19][CH2:18]3)[CH2:20]2)=[C:29]([Cl:34])[CH:28]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (0.282 g, 0.000769 mol), 4-bromo-2-chloro-1-iodobenzene (0.293 g, 0.000922 mol) (Lancaster, cat #: 19245), copper(I) iodide (0.015 g, 0.000077 mol), potassium phosphate (0.490 g, 0.00231 mol) and 1,2-ethanediol (0.0857 mL, 0.00154 mol) in 1-butanol (0.75 mL) was heated at 100° C. under nitrogen for 2 d. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column (eluting with 0 to 50% ethyl acetate in hexanes) to afford the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[N:7]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: Clc1ccc2nc(-c3ccco3)cn2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(-c5ccco5)cn4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 6-chloro-2-(2-furyl)imidazo[1,2-b]pyridazine (61.9 mg, 0.282 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[C:20]([C:25]([F:27])([F:28])[F:26])=[N+:21]([O-:32])[CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(-c2ccnn2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Solvent: ClCCl
Product: COc1cc(-c2ccnn2-c2ccc[n+]([O-])c2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine (0.50 g, 1.27 mmol) in dichloromethane (10 mL) cooled in an ice-water bath was added urea-hydrogen peroxide complex (0.26 g, 2.76 mmol) in one portion followed by trifluoroacetic anhydride (0.53 g, 2.52 mmol) dropwise. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulphate, filtered and evaporated to leave an off-white solid. Recrystallisation from ethanol afforded 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine 1-oxide, 0.34 g (65%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:12]O>CO>[O:1]([CH3:12])[C@H:2]1[O:10][CH2:9][C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: Cl
Product: CO[C@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 201.4 %

Procedure:
To a suspension of L-arabinose (100 g, 667 mmol) in anhydrous MeOH (450 mL) was added a HCl /MeOH solution (7.3 g dry HCl in 50 mL MeOH) at room temperature under argon atmosphere. The mixture was refluxed for 2 h and cooled down to room temperature. The solution was concentrated to about 3/4 of its volume to give a suspension. The solid precipitated was filtered and washed with cold MeOH (20 mL) to give the first crop as a crystalline powder (35.23 g). The filtrate was concentrated (35° C.) to 1/4 of its volume. The solid precipitated was filtered, washed and dried as above to give the second crop (9.66 g) as a colorless crystalline powder. The concentration and filtration were repeated to afford additional 28.31 g of the product (total 73.2 g, 67%). 1H NMR (D2O) δ 3.30 (s, OCH3, 3H), 3.56 (dd, 1H, H5), 3.73 (m, 1H, H4), 3.77 (dd, 1H, H5), 3.82 (bs, 1H, H2), 4.73 (m, 1H, H1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH2:15]I)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][O:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][N:22]([O:23][CH3:24])[C:20](=[O:21])[C:19]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:18]=3[F:17])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CONC(=O)c1c(F)cccc1F
Reactant: FC(F)(F)c1cnc(C2(CI)CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CON(CC1(c2ncc(C(F)(F)F)cc2Cl)CC1)C(=O)c1c(F)cccc1F
Temperature: 70 °C
Yield: 15.3 %

Procedure:
169 mg of 3-chloro-2-[1-(iodomethyl)cyclopropyl]-5-(trifluoromethyl)pyridine (step 3) and 110 mg of 2,6-difluoro-N-methoxy-benzamide were dissolved in dry dimethylsulfoxide under argon and 90 mg of potassium carbonate was added. The mixture was heated at 70° C. for 1 hour. Then ice water was added and the mixture was extracted with ether. The concentrated organic phase was purified on 30 g of silica gel, eluent hexane/ethyl acetate (4:1). Thus, 30 mg of N-[[1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropyl]methyl]-2,6-difluoro-N-methoxy-benzamide was obtained as a colorless resin. 1H-NMR (CDCl3): 8.70 ppm (s, 1H), 7.90 ppm (s, 1H), 7.32 ppm (m, 1H), 6.87 ppm (m, 2H), 4.24 ppm (s, 2H), 3.40 ppm (s, 3H), 1.19 ppm (m, 4H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial cyclohexanecarboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.92 (m, 3 H) 1.10-1.39 (m, 8 H) 1.58-1.76 (m, 8 H) 2.23-2.31 (m, 1 H) 2.38-2.41 (s, 3 H) 4.04 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=1[C:33]#[N:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:1][C@@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[O:29])=[CH:26][C:25]=1[C:33]#[N:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C#N
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)O[C@@H]2CC[C@@H](CCCCCC)OC2=O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
In 1 ml of dehydrated benzene were suspended 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone synthesized in the same manner as described in Referential Example 2 and 120 mg of 4-octyloxy-3-cyanobenzoic acid, and 0.1 ml of diethyl azodicarboxylate was added to the suspension with stirring at room temperature. Then, 150 mg of triphenylphosphine was added to the mixture and reaction was carried out overnight with stirring. The reaction mixture was concentrated under a reduced pressure and the residue was separated and purified by the silica gel column chromatography using an n-hexane/benzene (1/4) mixed solvent as the developing solvent. Recrystallization from ethanol gave 90 mg of (2R,5R)-(4'-octyloxy-3'-cyanobenzoyloxy)-5-hexyl-δ-valerolactone. When the phase transition behavior of the obtained compound was measured by a differential thermal scanning calorimeter and a polarization microscope, the following results were obtained: ##STR88##
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2C2C=CC=C(C(OCC)OCC)C=2)[CH:8]=[CH:9][CH:10]=1)C.[C:41](=[O:44])([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][C:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])([C:5]4[CH:10]=[C:9]([CH:8]=[CH:7][CH:6]=4)[CH:41]=[O:44])[CH2:12][C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Agent: Cl
Agent: [K+]
Product: O=Cc1cccc(C2(c3cccc(C=O)c3)Cc3n[nH]c(=O)c4cccc(c34)N2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 2 hr. Then the mixture was adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.57-4.59 (d, J=9.6 Hz, 1H), 4.98-5.00 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.42-7.52 (m, 5H), 7.60-7.77 (m, 5H), 7.89 (s, 1H), 9.90 (s, 1H), 9.93 (s, 1H), 12.08 (s, 1H); LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: [CH3:1][S:2][CH3:3].[K].ClC1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O>C(OCC)C>[CH3:1][S:2][C:3]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Cl)cc1C(=O)OCC
Reactant: CSC
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC)cc1C(=O)OCC

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:23][S:20]([CH2:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)(=[O:32])=[O:31])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:22])=[O:21]
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a mixture of ethyl 7-amino-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylate (4.8 g) and pyridine (50 mL) was added pyridine-2-sulfonyl chloride (3.0 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated, aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with diisopropyl ether, and recrystallized from acetone-hexane to give the title compound (4.68 g, yield 69%) as pale-brown prism crystals. melting point 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C1COCC1>[CH3:32][S:29]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(N)c2)CC1
Solvent: C1CCOC1
Product: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(NS(C)(=O)=O)c2)CC1
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a mixture of 77 mg (0.2 mmol) of 2-[4-(3-aminophenyl)piperazino]ethyl-N-(2-ethoxyphenyl)carbamate derivative and 56 μl (0.4 mmol, 2 eq) of TEA in 5 ml of THF, 31 μl (0.4 mmol, 2 eq) of mesyl chloride is added. Shaking is carried out at room temperature for about 20 hours. After concentration under reduced pressure, H2O is added and the aqueous phase is extracted with CH2Cl2. After drying on Na2SO4 and concentration of the organic phase, a brown oil is obtained which is purified by column chromatography (eluent AcOEt/petroleum ether 8:2) to produce 61 mg of the expected product as a brown oil (yield: 66%).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C:13]#[N:14].[F:21][C:22]1[CH:29]=[CH:28]C(C=O)=[CH:24][CH:23]=1.[Na+].[Cl-]>CN(C=O)C.O>[F:21][C:22]1[CH:29]=[CH:28][C:18]([CH:17]=[CH:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]#[N:14])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc(F)cc1C#N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
Sodium hydride (60% in mineral oil; 1.66 g [0.993 g NaH], 1.4 mmol, 1.10 equiv) was added to a solution of diethyl-2-cyano-4-fluorobenzyl phosphonate (10.2 g-equiv, 37.6 mmol, 1.0 equiv) in DMF (40 mL) over a period of 2 min. The reaction was stirred for 20 min at room temperature. 4-Fluorobenzaldehyde (4.67 g, 38 mmol, 1.0 equiv) was then added over a period of 2 min. After stirring for 18 h, H2O (200 mL) and satd. NaCl (50 mL) were added and the resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with 1N NaOH (1×100 mL) and H2O (2×100 mL), dried (anhyd. Na2SO4), and rotary evaporated (>100° C., heat gun). The crude, dark-red crystalline/oil (7.49 g, 82.7%) was chromatographed twice on silica gel (50×250 mm, dry pack), eluting first with hexane/EtOAc [4:1] and the second chromatography with [30:1] to provide a TLC-pure, yellow compound (2.1 g, 23.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23](=[O:24])[NH:15][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N:8]2[CH2:13][CH:12]3[CH:10]([O:11]3)[CH2:9]2)=[C:2]([F:1])[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(F)c(N2CC3OC3C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(F)c(N2CC3OC3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,5-Difluoro-4-(6-oxa-3-aza-bicyclo[3.1.0]hex-3-yl)-phenylamine (0.14 g, 0.66 mmol) was dissolved in dichloromethane (1.0 mL) and pyridine (0.11 mL, 1.32 mmol) and stirred at 0° C. Benzyl chloroformate (0.1 mL, 0.72 mmol) was added and the mixture was stirred at 0° C. for one hour. The reaction mixture was allowed to warm to room temperature, washed with water, brine and dried (MgSO4). The title compound was isolated by silica gel chromatography (0-1% MeOH-DCM) as a pale yellow solid.