Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:26])[CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:34]([O:26][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Reactant: CCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Temperature: 63 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
To a stirred solution of 3,5-diphenyl-4-[(2-methoxyethoxy)methoxy]-phenol (0.946 g, 2.7 mmol) in DMF (15 ml) was added K2CO3 (0.746 g, 5.4 mmol) and iododecane (1.632 g, 5.4 mmol). The reaction mixture was warmed to ˜63° C. After ˜20 h, additional K2CO3 (0.373 g, 2.7 mmol) and iododecane (0.816 g, 2.7 mmol) were added. Heating was continued for an additional 20 h followed by stirring at room temperature for ˜20 h. The reaction mixture was concentrated in vac and the residue taken up in EtOAc (50 ml) and water (20 ml). The layers were shaken and separated and the organic layer was washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (hexane and 5% EtOAc/Hex) to give the product as a brown oil (0.897 g, 68%); 1H NMR (400 MHz, DMSO-d6) δ 0.83–0.88 (m, 3H), 1.20–1.37 (m, 12H), 1.37–1.46 (m, 2H), 1.68–1.76 (m, 2H), 2.71–2.75 (m, 2H), 2.86–2.88 (m, 2H), 3.01 (s, 3H), 4.03 (t, J=6.4 Hz, 2H), 4.22 (s, 2H), 6.87 (s, 2H), 7.34–7.39 (m, 2H), 7.42–7.48 (m, 4H), 7.56–7.60 (m, 4H); IR (film) 2940, 1590, 1460, 1190 cm−1; mass spectrum [(+)ESI], m/z 508 (M+NH4)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[C:18]([Br:27])=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(OCOC)c(C(=O)O)c(COCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
2-(Benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (60 mg, 0.17 mmol) obtained in Step 6 of Example 22 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (62 mg, 0.35 mmol) was added thereto followed by stirring at a room temperature for 2 hours. The reaction mixture was added with water and extracted with chloroform 3 times. The organic layers were combined and sequentially washed with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 2-(benzyloxymethyl)-3-bromo-4,6-bis(methoxymethoxy)benzoic acid (16 mg, 22%).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].CC(C)([O-])C.[K+].[C:13]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:21][C:22](=[O:25])[CH2:23][CH2:24][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:14])[CH3:15]
Reactant: CCN(O)CC
Reactant: C=CC(=O)NC(C)(C)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)OCCC(=O)NC(C)(C)CC(C)(C)C

Procedure:
The procedure of Example I is repeated using diethylhydroxylamine, potassium-tert-butoxide and N-tert-octylacrylamide in tetrahydrofuran to afford the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O-:15])=[O:14].[Na+].[CH2:18](O)[CH3:19]>>[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: CC1(C)NCC(=O)N1CC(=O)[O-]
Reactant: CCO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN1C(=O)CNC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice-cold solution of thionyl chloride (5 ml) in dry ethanol (50 ml) a solution of sodium 2,2-dimethyl-5-oxo-1-imidazolidineacetate (4 g) in dry ethanol (50 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour, then at room temperature overnight. After evaporation under reduced pressure, the residue was taken up with a saturated solution of sodium hydrogen carbonate and extracted with 3×100 ml of dichloromethane. The organic layer was dried and evaporated, to yield ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2.57 g) as a colorless oil (Rf. 0.49, methanol/acetone 1:1; silica gel plates). Oxalate salt m.p. 109°-113° C. (ethanol/diethyl ether).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:23][NH:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:26][C@H:25]1[C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[Si:1]([O:18][CH2:19][CH:20]1[CH2:23][N:22]([CH2:26][C@H:25]([OH:24])[C:27]([O:29][CH3:30])=[O:28])[CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H]1CO1
Reactant: CC(C)(C)[Si](OCC1CNC1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)[C@@H](O)CN1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 85 °C
Yield: 98 %

Procedure:
3-((tert-Butyldiphenylsilyloxy)methyl)azetidine (Intermediate BG3) (7.461 g, 22.92 mmol) and (S)-methyl oxirane-2-carboxylate (2.340 g, 22.92 mmol) were dissolved in acetonitrile (50 mL) and heated to 85° C. for 90 minutes. The resulting mixture was cooled and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM to afford the product (9.6 g, 56%).
Reaction SMILES: O[C:2]1([C:23]2[O:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27]=2[CH3:28])[CH2:7][CH2:6][N:5]([C:8](=[O:22])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[N:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+]>Cl>[CH3:28][C:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][C:23]=1[C:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:22])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[N:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:4][CH:3]=1
Reactant: Cc1c(C2(O)CCN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)CC2)oc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C2=CCN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)CC2)oc2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
A solution of 3d (50 mg, 0.11 mmol) in 10% HCl solution (5 ml) was stirred at 100° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 0° C. and basified with NaHCO3 solution. The resultant solid was filtered, washed with water and dried under vacuum for 16 h. The crude compound was purified by column chromatography using a mixture of 1% methanol/chloroform as an eluent to get the desired compound-3 as a pale brown solid (15 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.38 (s, 1H), 8.11 (d, J=16.7 Hz, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.53-7.47 (m, 2H), 7.38-7.22 (m, 3H), 6.42-6.34 (m, 1H), 4.56-4.44 (m, 1H), 4.38-4.24 (m, 1H), 3.98-3.90 (m, 1H), 3.89-3.77 (m, 1H), 2.93 (t, J=7.5 Hz, 2H), 2.78-2.70 (m, 1H), 2.67-2.64 (m, 1H), 2.57-2.54 (m, 2H), 2.35 (s, 3H); MS (ES) m/e 414.1 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH:11]([Br:1])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1

Procedure:
Bromine (2 ml.) was added dropwise to a solution of p-chloro-2-(p-chlorophenyl)acetophenone (10 g.; 0.038 mole), chloroform (50 ml.) and diethyl ether (25 ml.). The mixture was heated at reflux for 0.5 hours and cooled (ca. 20°). Following a thorough washing with saturated sodium bicarbonate, the organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 mesh (230-400) with 5% ethyl acetate in hexane. Recrystallization from hexane afforded 2.69 g.; m.p. 81.5°-83°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1Cn1cc(N)cn1
Yield: 99 %

Procedure:
Tert-butyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylcarbamate (Example 4-1b) (592 mg, 2 mmol) was stirred in a solution of 4N HCl in dioxane (20 mL) at ambient temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in a 1/1 mixture of ethyl acetate/hexanes (30 mL) and concentrated (twice). The solid was triturated with hexanes and collected by filtration providing 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (500 mg, 99%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): 2.11 (s, 3H), 2.38 (s, 3H), 5.16 (s, 2H), 7.51 (s, 1H), 8.03 (s, 1H), 10.27 (bs, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH3:8])[O:6][CH:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][C:3]=1[O:18][Si](CC)(CC)CC.[N-:26]=[N+:27]=[N-:28].[Na+].[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[N:26]([C:2]1([CH3:1])[C:3](=[O:18])[CH2:4][CH:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:6][CH:7]1[CH3:8])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)OC1=C(C)C(C)OC(c2c([N+](=O)[O-])cnn2C)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CC1OC(c2c([N+](=O)[O-])cnn2C)CC(=O)C1(C)N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole (507 mg, 1.38 mmol, intermediate 85) in dry MeCN (3.5 mL) cooled to −20° C. was added sodium azide (404 mg, 6.22 mmol) followed by a solution of cerium ammonium nitrate (2.27 g, 4.15 mmol) in CH3CN (10.4 mL) dropwise. The reaction mixture was stirred at −20° C. for 1 hr, slowly warmed to 0° C. over 1 hr then quenched with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-azido-2,3-dimethyl-6-(1-methyl-4-nitro-1H-pyrazol-5-yl)dihydro-2H-pyran-4(3H)-one as a white solid (187 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.78 (dd, J=12.3, 3.2 Hz, 1H), 4.21 (s, 3H), 3.73 (dd, J=12.3, 6.2 Hz, 1H), 3.13 (dd, J=14.6, 12.3 Hz, 1H), 2.73 (dd, J=14.6, 3.2 Hz, 1H), 1.44 (s, 3H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26]>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:28][Si:27]([C:25]#[C:26][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][S:18]([C:21]([F:23])([F:22])[F:24])(=[O:20])=[O:19])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To 4.2 g (10 mmol) Trifluoro-methanesulfonic acid 1-(4-bromo-phenyl)-1H-indol-5-yl ester in 30 ml piperidine, 580 mg (0.5 mmol) tetrakis-(triphenylphosphine)-palladium and 100 mg (0.625 mmol) CuI were added. The solution was evaporated and purged with argon three times, before 1.4 ml (10 mmol) ethynyltrimethylsilane were added. The solution was stirred at RT for 48 h. Additional 0.38 ml (3.3 mmol) ethynyltrimethylsilane were added and the mixture was stirred at 50° C. for 1 h. The solution was concentrated and the residue redissolved in 0.5M HCl and ether. The inorganic phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Purification on silica gel with hexane/EtOAc 19:1 yielded 1.7 g (38%) Trifluoro-methanesulfonic acid 1-(4-trimethylsilanylethynyl-phenyl)-1H-indol-5-yl ester as orange oil, MS: 437 (M).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=O)[CH3:2].[CH2:8]([NH:13][NH2:14])[CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH:5]=[N:14][NH:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)C=O
Reactant: CCCCCNN
Solvent: CCO
Product: CCCCCNN=CC(=O)OCC
Temperature: 80 °C
Yield: 97.7 %

Procedure:
To a magnetically stirred solution of oxo-acetic acid ethyl ester (35.08 ml, 177 mmol; 50% solution in toluene) in ethanol (450 ml) was added n-pentylhydrazine (21.7 g, 212 mmol) and the resulting solution was heated at 80° C. for 16 hours. The obtained mixture was allowed to attain room temperature and concentrated. The resulting residue was taken up in ethylacetate and water. The organic layer was separated and subsequently dried over MgSO4, filtered and concentrated to give (pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (32.2 gram, 93% yield) as a purple colored oil. 1H-NMR (400 MHz, CDCl3) δ 0.87-0.94 (m, 3H), 1.25-1.42 (m, 7H), 1.55-1.68 (m, 2H), 3.17-3.23 (m, 1H), 3.35-3.45 (m, 1H), 4.28 (q, J=7, 2H), 6.51 (br s, 1H), 6.72 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)#[N:23]>>[C:22]([C:24]1([C:27]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)=[O:28])[CH2:26][CH2:25]1)#[N:23]
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCCc2ccccc2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCc3ccccc3)cc2)CC1
Yield: 98.4 %

Procedure:
General procedure E was used to convert 3.15 mmol of 17a and 4.73 mmol of 1-cyanocyclopropanecarboxylic acid to 3.10 mmol (98%) of the title compound.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([O:25][CH3:26])=[C:17]2[C:27](O)=[O:28])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:30]([N:32]([CH2:35][CH:36]([OH:39])[CH2:37][NH2:38])[CH2:33][CH3:34])[CH3:31].O>C(Cl)Cl.C(N(CC)CC)C>[CH2:30]([N:32]([CH2:35][CH:36]([OH:39])[CH2:37][NH:38][C:27]([C:17]1[N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:24]2[C:19]([C:18]=1[O:25][CH3:26])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:28])[CH2:33][CH3:34])[CH3:31]
Reactant: COc1c(C(=O)O)n(-c2ccccc2)c2ccccc12
Reactant: CCN(CC)CC(O)CN
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 g of 2-chloro-N-methyl-pyridinium iodide in 150 ml of methylene chloride and 14 ml of triethylamine are added to 13.3 g of N-phenyl-3-methoxyindole-2-carboxylic acid, dissolved in 100 ml of methylene chloride, and the mixture is stirred at room temperature for one hour. 7.5 g of 3-(N,N-diethylamino)-2-hydroxypropylamine are then added, and the mixture is stirred at room temperature for a further 3 hours. The reaction solution is added to water and the mixture is extracted with methylene chloride. The organic phase is washed with dilute sodium hydroxide solution and water, dried and evaporated. The resulting oily title compound is converted into its hydrochloride in a manner corresponding to that in Example 1. Melting point: 148°-150° C., yield: 12 g.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1>CN(C)C=O>[CH3:28][C:25]1[O:24][C:23]([CH2:22][O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:27][N:26]=1
Reactant: Cc1nnc(CCl)o1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(COc2ccc(Oc3ccccc3)cc2)o1
Temperature: 20 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
9.3 g of 4-phenoxyphenol and 9 g of potassium carbonate are stirred in 75 ml of anhydrous dimethylformamide for 1 hour at 80° C. Subsequently, 6.6 g of 2-chloromethyl-5-methyl-1,3,4-oxadiazole in 20 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 10 hours at 80° C. and at room temperature (approx. 20° C.) overnight. The mixture is then stirred into 500 ml of ice water and extracted three times with ethyl acetate. After drying over sodium sulfate and removal of the solvent, the residue is purified by chromatography over silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 12 g of 5-methyl-2-[(4-phenoxyphenoxy)-methyl]-1,3,4-oxadiazole; colorless crystals; m.p.: 78°-79° C.
Reaction SMILES: CS(O[C@H:6]([C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([Cl:35])=[CH:28][C:27]=1[F:36])[CH2:7][CH2:8][C@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:11]=1[F:20])(=O)=O.[F:37][C:38]1[CH:39]=[C:40]([CH:42]=[C:43]([F:51])[C:44]=1[N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[NH2:41].CCN(C(C)C)C(C)C>CC#N>[Cl:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:26]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([Cl:35])=[CH:28][C:27]=3[F:36])[N:41]2[C:40]2[CH:39]=[C:38]([F:37])[C:44]([N:45]3[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]3)=[C:43]([F:51])[CH:42]=2)=[C:11]([F:20])[CH:12]=1
Reactant: CS(=O)(=O)O[C@@H](CC[C@H](OS(C)(=O)=O)c1cc([N+](=O)[O-])c(Cl)cc1F)c1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: Nc1cc(F)c(N2CCCCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3cc([N+](=O)[O-])c(Cl)cc3F)N2c2cc(F)c(N3CCCCC3)c(F)c2)c(F)cc1Cl
Temperature: 75 °C

Procedure:
To a solution of (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate (500 mg, 0.843 mmol) in CH3CN (4.5 ml) was added 3,5-difluoro-4-(piperidin-1-yl)aniline (358 mg, 1.685 mmol) and Hunig's base (0.736 mL, 4.21 mmol). The suspension was heated at 75° C. for 24 hours. Solvent was removed by rotary evaporation and the residue was dissolved in EtOAc, washed with 1 N HCl, H2O, brine, dried (MgSO4), filtered and concentrated. The crude product was chromatographed on an ISCO 24 g silica gel cartridge eluting with 20-70% CH2Cl2/hexane to provide the title compound with some of the corresponding cis-pyrrolidine isomer.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC1CCc2c(-n3cccc3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CC1CCc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 2 h

Procedure:
To a solution of 3.6 g of 6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 50 ml of trifluoroacetic acid was added 2.0 g ten percent palladium on charcoal. The mixture was hydrogenated on a Paar apparatus for two hours at 50 psi at 50° C. The mixture was filtered, and the filtrate was evaporated. The residue was mixed with 50 ml of water and the pH adjusted to 5 by the addition of ten percent sodium hydroxide solution and acetic acid. The precipitate obtained was recrystallized from aqueous N,N-dimethylformamide (80%) to provide tan crystals of 6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrrolidyl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 243°-245° C. Analysis: Calculated for C18H19FN2O3 : %C, 65.5; %H, 5.8; %N, 8.5; Found: %C, 65.8; %H, 5.8; %N, 8.5. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: S1C=CC=C1S([NH2:9])(=O)=O.[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16]([NH2:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NS(=O)(=O)c1cccs1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
5.2.3 4-biphenylsulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 642.2 mg (90.6%) as a white solid, m.p.: 223-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a stirred solution of 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (17.0 g, 54.3 mmol) in dichloromethane (700 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.3 g, 54.3 mmol) in one portion. After 1 h, the resulting black mixture was diluted with a saturated aqueous sodium bicarbonate solution and stirred vigorously for 30 min. The solids were filtered off and the filtrate was separated. The aqueous layer was extracted with ethyl acetate. The combined organic solutions were dried over anhydrous sodium sulfate, concentrated in vacuo to afford 5-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (16.5 g, 97%) which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ ppm 0.64 (s, 6H), 0.94 (s, 9H), 6.49 (d, J=3.4 Hz, 1H), 7.27 (d, J=3.4 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 8.31 (d, J=2.3 Hz, 1H).