Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][NH:8][C:7]2[CH:10]=[C:11]([Cl:18])[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:6]=2[S:5]1(=[O:20])=[O:19].[N-:21]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:21][CH2:2][CH2:3][N:4]1[CH2:9][NH:8][C:7]2[CH:10]=[C:11]([Cl:18])[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:6]=2[S:5]1(=[O:20])=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCBr)S2(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCN1CNc2cc(Cl)c(S(N)(=O)=O)cc2S1(=O)=O
Reaction time: 44 h

Procedure:
Combine the product of step A (12.2 g) with sodium azide (3.9 g) in DMF (200 ml). Stir 44 hours, extract with ethyl acetate, wash with water, dry the organic layer over MgSO4 and concentrate. Dissolve the resultant residue in ethanol (150 ml), add 5.0 g 10% Pd/C and hydrogenate at 3 atm for 4 hours. Filter and concentrate the filtrate to obtain 2-(2-aminoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine. C. Treat the product of step B with N-(t-butoxycarbonyl)-(S)-aspartic acid, o-ethyl ester as described in Example 5, step A, and continue the procedure described in Example 5, steps B through F to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]=CC)=O)[CH3:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13].[CH:21](O)(C)[CH3:22]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([CH3:8])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:11])=[C:21]([CH3:22])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CC=CC(=O)CC(=O)OCC
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1C
Yield: 59 %

Procedure:
Upon heating a solution of 15.6 g of ethylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 140°C (isopropanol) is obtained.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14](O)[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C(OCC)(=O)C>[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([Cl:8])[N:13]=1
Reactant: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nc(Cl)nc(N)c2cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
N,N-Dimethyl formamide (7.9 ml, 0.10 mol) was added dropwise to phosphorus oxychloride (47.9 ml, 0.52 mol) with stirring. After 10 minutes, 4-amino-6-benzyloxy-2-hydroxy-7-methoxyquinazoline (16.4 g, 0.055 mol) was added portionwise and the resulting mixture heated at 90° C. for 1.5 hours, then cooled and poured into ethyl acetate (750 ml). The mixture was neutralised by the portionwise addition of aqueous sodium carbonate and the phases were separated. The organic layer was evaporated to dryness and the residue combined with the organic phase which was then treated with aqueous sodium hydroxide to basify (pH10) and the mixture was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between dichloromethane (11) and water (11), the organic phase washed with water, dried over MgSO4 and evaporated to give a pale yellow solid. Trituration with isopropanol afforded the subtitle compound as a colourless solid (4.64 g, 27%). Rf 0.64 (ethyl acetate:methanol 95:5, v/v). MS m/z 316, 318 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:28][CH2:26][CH3:27])=[CH:10][N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1cc(Br)cc(N(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1=O
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1ccc(N(C(=O)OC(C)(C)C)c2cc(Br)cn(C)c2=O)nc1
Yield: 63.5 %

Procedure:
(5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (500 mg, 1.22 mmol), ethanamine (6.12 ml of a 2.0 M solution in THF), sodium triacetoxyborohydride (649 mg, 3.06 mmol), and acetic acid (147 mg, 2.45 mmol) were added to a 20 ml microwave vial. The vial was capped and heated in a sand bath at 40 degrees centigrade overnight. TLC and LCMS analysis showed the reaction to be incomplete. Another 6 ml of ethanamine was added to the vial and the reaction was heated again at 40 degrees centigrade overnight. The reaction was diluted with DCM and washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified by flash chromatography using 10% methanol in DCM to give 340 mg (63.5%) of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-ethylaminomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:12])=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(Cl)=NO)ccc1Br
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 ml of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added a dropwise with stirring under ice cooling over 45 minutes. Then, 220 ml of 8% sodium hypochlorite aqueous solution was carefully added dropwise over 75 minutes so that the temperature of the reaction mixture would not exceed 5° C., after the completion of the addition, continued to stir at 10° C. or less further for 90 minutes. After the completion of the reaction, nitrogen gas was blown through the reaction mixture for 45 minutes and precipitated insoluble material was filtered off, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with 240.0 g of ethyl acetate. The organic phase was washed with water (240 ml×2) and then insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:30])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11](=[O:30])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccc(F)cc1
Yield: 47 %

Procedure:
A solution of Compound 19 (5 g, 12.24 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.90 g (47%) of yellow solids. M.P. 206° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 5.52 (s, 2H), 7.12–7.15 (m, 2H), 7.30–7.33 (m, 2H), 7.46 (d, J=8.7 Hz, 1H), 7.64 (dd, J=1.2, 8.7 Hz, 2H), 7.89 (d, J=1.2 Hz, 1H). EIMS m/z 327 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:38][CH2:39][CH:40]([OH:44])[CH2:41][C:42]#[CH:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:29])[O:44][CH:40]([CH2:39][CH3:38])[CH2:41][C:42]#[CH:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: C#CCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Yield: 84.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-hexyn-3-ol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (115 mg, yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)CC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(CC(=O)c1cccc(Br)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-bromophenyl)-3-hydroxyhex-5-en-1-one (9.08 g, 33.7 mmol), 1H-imidazole (5.34 g, 77.6 mmol) and tert-butyldimethylchlorosilane (6.29 g, 40.5 mmol) in DMF (40 mL) is stirred at room temperature for 2 h. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 5% ethyl acetate in hexanes over 20 minutes to give the title compound as a racemic mixture (11.3 g, 88%). ES/MS m/e (79Br/81Br) 383, 385 (M+1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O.[C:29](Cl)(Cl)(Cl)Cl>>[C:9]([O:16][CH:17]([O:23][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:18]1[CH:29]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)OC(=O)CCCCC
Reactant: O=Cc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: CCCCCC(=O)OC(OC(=O)CCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzaldehyde (26.3 g, 0.25 mol) and hexanoic acid anhydride (53.3 g, 0.25 mol) were dissolved in carbontetrachloride (200 ml) under N2 -atrnosphere. Catalytic amounts of sulfuric acid was added and the reaction mixture stirred at room temperature for 1 hr. The reaction mixture was evaporated over night, the residue dissolved in hexane and the solution filtered through a bed of silica. The filtrate was purified on a silica column, eluting with hexane. The evaporated eluate was a colourless oil and the yield was 14.0 g, 18% of the theoretical. 1H- and 13C NMR (CDCl3) d (ppm) rel. to TMS: 7.72 (s, 1H, CH(OC5H11)2), 7.58-7.39 (m, 5H, Ar-H), 2.37 (double t, 4 H, COCH2), 1.64 (m, 4H, COCH2CH2), 1.30 (m, 4H,CH2CH2CH3) and 0.88 (t, 6H, CH3); 171.524 (C=O), 135.688, 129.523, 128.466 and 126.547 (Ar), 89.398 (CH(OC5H11)2), 33.965, 31.030, 24.235 and 22.179 (CH2) and 13.777 (CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[I:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[I:27])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCc1ccccc1I
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3I)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
To a solution of {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) in a mixture of CH2Cl2 (2 mL) and DMF (1 mL) were added 2-iodobenzylamine (192 mg, 0.82 mmol) and DIPEA (135 μL, 1.04 mmoL). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The resulting residue was diluted with EtOAc and washed with water (×3) and then with brine. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 97 mg (64%) of (4-{[2-(2-iodo-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2.ClCCl.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH:17]1([C:20]([N:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:13])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1CC[C@H](C)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1CC[C@H](C)N2C(=O)C1CC1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (47.41 g, 267.5 mmol), dichloromethane (500 mL), and pyridine (38 mL). Cyclopropanecarbonyl chloride (28.4 g, 271.7 mmol) was added dropwise with stirring at 0° C., and the resulting solution stirred for 3 h at 0° C. The reaction mixture was poured into 400 mL of water/ice, and then washed with 2 N hydrochloric acid (1×100 mL) and brine (3×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-15% ethyl acetate/petroleum ether) to afford (2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (64.6 g, 98%) as a yellow solid. MS (ES, m/z): 246 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14](C=O)[N:13]=[CH:12]1.[CH:18](OC)([O:21][CH3:22])[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O.S([O-])(O)(=O)=O.[Na+]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH:18]([O:21][CH3:22])[O:19][CH3:20])[N:13]=[CH:12]1
Reactant: O=Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Reactant: COC(OC)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(OC)c1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1-(2-Fluoro-4-nitrophenyl)-1H-imidazole-4-carboxaldehyde (Intermediate 30) (361.7 g, 1.538 mol) was suspended in dry methanol (1700 ml). Trimethyl orthoformate (340 g, 2 mol) and sodium hydrogen sulfate (8 g) were added and the mixture was heated to reflux for 3.5 hours. It was cooled to room temperature, a solution of sodium carbonate in water (10%, 200 ml) was added and it was stirred for 1 hour. It was diluted with water (4 L) and left for 2 hours. The precipitate was collected by filtration, washed with water and dried to give the title compound (402.4 g) as a solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[C@@H:14]([NH2:15])[C@@H:13]1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1>C(OCC)(=O)C>[CH2:12]1[C@@H:14]([NH3+:15])[C@H:13]1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1.[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([OH:11])[C:8]([O-:10])=[O:9])=[CH:5][CH:6]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C([O-])C(O)c1ccccc1
Product: [NH3+][C@@H]1C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 93.2 %

Procedure:
R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8](CO)[CH2:9][CH2:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.C(Cl)(Cl)Cl.CO>O>[NH:16]1[C:17](=[O:21])[C:18]2[N:19]=[CH:20][N:12]([CH2:11][CH2:10][CH2:9][CH:8]=[O:7])[C:13]=2[N:14]=[C:15]1[NH2:22]
Reactant: Nc1nc2c(ncn2CCCC(O)CO)c(=O)[nH]1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2c(ncn2CCCC=O)c(=O)[nH]1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a vigorously stirred solution of 113 mg (0.53 mmole) of sodium periodate in 1.1 ml of H2O at room temperature was added 101 mg (0.4 mmole) of (±)-9-(4,5-dihydroxypentyl)guanine. After 2 hours, TLC (silica gel, 70:30:3 CHCl3 --MeOH--H2O) showed complete conversion to a faster-moving product. The white solid was collected on a filter and washed with some H2O, then with diethyl ether, to give 79 mg of white solid. Recrystallization from H2O--MeOH yielded 29 mg (33%) of white solid, m.p. not less than 300° C. By 200 MHz NMR (DMSO-d6), the material consisted of a mixture of the free aldehyde and the covalent hydrate. A similar preparation showed only the free aldehyde by NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[C:9](C#CC3C=CC(C(O)=O)=CC=3)[CH:8]=[CH:7][C:6]=2[C:5]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:4][CH2:3]1.CC1(C)C2C=CC([C:40]#[C:41][C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)=CC=2C(SCC)=CC1>>[CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:40]#[C:41][C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)=[CH:7][C:6]=2[C:5]([S:23]([CH2:26][CH3:27])(=[O:24])=[O:25])=[CH:4][CH2:3]1
Reactant: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reactant: CCS(=O)(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CCS(=O)(=O)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4- (7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-2-ylethynyl)benzoic acid (Compound 150), 25 mg (0.07 mmol) of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152) was converted to the title compound (white solid, recrystallized from ethyl alcohol) using 95 mg (0.28 mmol) of 50% 3-chloroperoxybenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11]
Reactant: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C(C)=O
Temperature: 100 °C

Procedure:
Methyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.84 g, 2.51 mmol) was dissolved in 24 mL of a solvent mixture of acetone/water (v/v=5/1), and p-toluenesulfonic acid monohydrate (about 0.19 g) was then added to the obtained solution. The resulting mixture was refluxed at 100° C. for 2 days. After the reaction was completed, the reaction mixture was concentrated under a reduced pressure and then extracted with dichloromethane. The desired product was obtained (0.55 mg, 75%) by performing column chromatography (eluent: n-hexane/ethyl acetate=2/1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[N-:24]=[N+:25]=[N-:26].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C1C=CC=CC=1.C(OCC)(=O)C>[N:24]([CH:2]([CH2:3][OH:1])[CH2:4][O:5][CH:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+:25]=[N-:26]
Reactant: c1cc(CCC2CCC3(CC2)CCC(OCC2CO2)CC3)co1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: [N-]=[N+]=NC(CO)COC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 0.12 g of 9-(oxiranylmethoxy)-3-(2-(3-furyl)ethyl)-spiro[5.5]-undecane (prepared as intermediate in Ex. 21), 0.130 g of sodium azide and 0.030 g of tetrabutylammonium hydrogen sulfate in 1.5 ml of water and 1.5 ml of benzene was vigorously stirred at reflux temperature for 48 hrs. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, the organic phase washed with water several times, dried on sodium sulfate and evaporated to dryness. The residue was purified by chromatography (SiO2 ; n-hexane/diethylether 50/50), to give 0.110 g of 9-(2-azido-3-hydroxypropoxy)-3-(2-(3-furyl)ethyl)-spiro[5.5]-undecane as brown foam. [TLC: Rf=0.48 (SiO2 plates, diethylether/n-hexane 70/30). PG,28 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.35 (1H, m), 7.20 (1H, m), 6.23 (1H, m), 4.00-3.80 (1H, m), 3.55-3.20 (5H, m), 2.42 (2H, t), 1.90-0.80 (19H, m)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[C:16]1([C:22]2([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][CH2:26][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:27][CH2:28][OH:29])[CH2:23]1)=[O:6]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccccc3)C2)c(OC)c1OC

Procedure:
Combine 2,3,4-trimethoxybenzoyl chloride (10 mmol) and 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (2.1 g, 9.2 mmol) in acetone (70 mL). Add water (25 mL) and potassium carbonate (1.93 g, 14 mmol). Dilute the reaction mixture with ethyl acetate and extract with aqueous sodium bicarbonate solution and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.