Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:22]([CH3:21])[O:23][CH3:24])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 8042.2 %

Procedure:
The title compound was synthesized from tert-butyloxycarbonyl-L-phenylalanine (2.65 g, 0.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.07 g, 11 mmol) according to the procedure given for 1. The synthesis yielded compound 5 as an oil (2.48 g, 81%): Rf 0.40 (ethyl acetate/hexane, 1:1), Rf 0.78 (chloroform/methanol/acetic acid, 85:10:5); 1H-NMR (CDCl3, 17° C.)δ 1.38 (9H, s, C(CH3)3, 3.05 (2H, m, CH2), 3.18 (3H, s, N--CH3),3.66 (3 H, s, O--CH3), 4.97 (1H, m, CH), 5.18 (1H, d (br.),NH), 7.17-7.28 (5H, m, C6H5).
Reaction SMILES: [K+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred bright orange solution of N-(4'-chloro-5'-methyl-2'-nitrophenyl)glycine potassium salt (0.097 g, 0.36 mmol) in water (5.0 mL) at 80° C., sodium dithionite (0.500 g, 2.87 mmol) was added in two equal portions. It instantly formed a white suspension, which was stirred at 80° C. for 1 h. It was then cooled at room temperature and the solid was vacuum filtered, washed with water (5.0 mL), and dried in vacuo to yield 0.062 g (86%) of the title compound as a white powder; 1H NMR (DMSO-d6): δ 2.10 (s, 3H), 3.66 (s, 2H, J=1.2 Hz), 5.98 (s, 1H), 6.53 (s, 1H), 6.67 (s, 1H), 10.20 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:28]Br.BrC1N(COCC[Si](C)(C)C)C2C=NNC(=[O:39])C=2C=1CBr>>[Br:1][C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:9](=[O:10])[C:4]=2[C:3]=1[CH:28]=[O:39]
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Product: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(Br)n2COCC[Si](C)(C)C)c1=O
Yield: 67 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 24-(g) except for using 5.70 g (10.0 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) in place of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 3.38 g of the title compound was obtained as a white solid. (Yield: 67%)
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38]([C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[C:6]2[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:39]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
To a stirred solution of 66.6I (1.1209 g, 2.962 mmol) in dry DMF (10 mL) at 23° C. was added potassium carbonate (1.2262 g, 8.872 mmol) and then tetrakis(triphenylphosphine)palladium (0.3408 g, 0.2949 mmol). The mixture was purged with argon and placed under vacuum and the purging and vacuum process repeated three times. Before heating, 66.50A (1.6019 g, 5.888 mmol) was added via syringe and then the mixture was heated to 90° C. After 19 hours, LC-MS showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.50B as a clear oil (994.4 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, dd, J=8.0, 1.8 Hz), 7.94 (1H, d, J=1.6 Hz), 7.50 (3H, m), 7.16 (1H, t, J=9.0 Hz), 6.63 (1H, t), 5.53 (1H, s), 3.96 (3H, s), 2.25 (2H, td, J=7.0, 2.3 Hz), 1.65 (2H, t, J=7.0 Hz), 0.85 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:29])[C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:29])[C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(C(O)C(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1cccc(C(O)C(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionate (5.878 g, 13.59 mmol), sodium hydroxide (1.09 g, 27.2 mmol), methanol (20 ml), water (30 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionic acid as a liquid.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH2:14][C:15](=[O:17])[CH3:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:13][CH2:14][C:15](=[O:17])[CH3:16])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(=O)CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monohydroxyacetone was distilled prior to use. Chloroform was distilled from phosphorus pentoxide prior to use. Decanoyl chloride (65 cm3, 0.3146 mole) was added dropwise to stirred solution of monohydroxyacetone (21.8 cm3, 0.3146 mole) and anydrous pyridine (25.4 cm3, 0.3146 mole) in anhydrous chloroform (500 cm3). During the addition the solution was maintained in an ice bath. The mixture was then stirred at room temperature overnight. The solution was washed with water (4×200 cm3) and saturated sodium chloride solution (200 cm3). The organic phase was dried over sodium sulphate and evaporated in vacuo. The resulting oil was distilled to yield 1-decanoyloxypropan-2-one as a mobile liquid, bp 154°-60° (1 mm) (52.4 g, 0.230 mole, 73%),ir (neat) 2860, 1700, 1400, 1340, 1150, 1110 and 1050 cm-1 ; pmr (CDCI3) δ 4.6 (s, 2 H), 2.4 (t, 2 H), 2.1 (s, 3 H), 1.8-1.0 (bm, 14 H) and 0.9 (t, 3 H) ppm.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]#[N:19])=[CH:6][N:5]=1.[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].[I-].C[N+]1C=CN(C)C=1>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.O>[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]#[N:19])=[CH:6][N:5]=1)=[O:28]
Reactant: COc1cc2c(C#N)cnc(Br)c2cc1OC
Reactant: O=Cc1cccc(OCCO)c1
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(C#N)cnc(C(=O)c3cccc(OCCO)c3)c2cc1OC
Reaction time: 1 h
Yield: 48.2 %

Procedure:
Sodium hydride (11 mg, 0.26 mmol) was added to a stirred mixture of 1-Bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (see example 82) (50 mg, 0.17 mmol), 3-(2-hydroxyethoxy)-benzaldehyde (43 mg, 0.26 mmol), 1,3-dimethylimidazolium iodide (16 mg, 0.26 mmol) in DMF (2 mL). The reaction mixture became dark color. After 1 h, water (4 mL) was added to the above mixture, and extracted with chloroform (6 mL). The extract was washed with water (4 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 0–40% EtOAc in methylenechloride in 30 min) afforded 1-(3-hydroxyethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (31 mg, 41%) as a white solid. LC-MS m/e calcd for C21H18N2O5 (MH+) 379, found 379.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1C=CC=CC=1C(O)=O.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1>CS(C)=O.[Cu]I>[F:40][C:39]([F:42])([F:41])[C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[C:19]([NH2:18])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Nc1ncccc1-c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Copper(I) iodide (61.4 mg) was added to a mixture of tripotassium phosphate (1026 mg), picolinic acid (39.7 mg), 4-(2-aminopyridin-3-yl)phenol (300 mg) and 1-iodo-3-(trifluoromethyl)benzene (526 mg) in DMSO (6 mL). The mixture was stirred at 120° C. under nitrogen for 2 hr. The mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (348 mg) as a pale yellow solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH:14]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18](O)[C@H:16]([OH:17])[C@H:15]1[NH:24][C:25]([CH3:27])=[O:26]>>[O:1]([C@@H:18]1[C@@H:20]([CH2:22][OH:23])[O:21][CH:14]([OH:13])[C@H:15]([NH:24][C:25]([CH3:27])=[O:26])[C@H:16]1[OH:17])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O

Procedure:
The 1H-NMR spectrum of the difucosylated product (FIG. 3C, Table 3) showed that two fucoses had been transferred to the acceptor, yielding the glycan 4. The H-1 signals of the fucoses resonated at 5.117 ppm and 4.078(α)/5.091(β) ppm (3FucH-1 and 6FucH-1, respectively). In glycan 4 also the H-1 signals of 3Gal and 6Gal were shifted (-0.027 and -0.028 ppm, respectively) compared to the corresponding signals in glycan 3. In contrast, the H-1 signal of the branching galactose was practically unaffected, showing that the GlcNAc in the reducing end was not fucosylated. This confirms and extends previous data showing that branch forming Galβ1-4GlcNAc residues of polylactosamines are not fucosylated under the conditions used (Niemela et al., Glycoconjugate J. 12: 36-44 (1995)).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1cc(F)cc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cc(F)cc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:42]=[CH:41][C:30]([CH:31](Cl)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:31]([N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])[C:30]2[CH:41]=[CH:42][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:37][CH:36]=1
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)[nH]1
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 83.7 %

Procedure:
To a suspension of 10.0 g (45 mmol) of 2-propyl-6-nitro-quinazolin-4(3H)-one in 160 ml of dry CH2Cl2 was added 9.5 ml (67 mmol) of triethylamine followed by 12.9 g (49 mmol) of 4,4'-dimethoxybenzhydryl chloride. The reaction mixture was stirred for 48 hours and then washed with 10% citric acid (2×20 ml), water (1×20 ml), saturated NaHCO3 (2×20 ml) and brine (1×20 ml). The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was recrystalised from EtOAc to give 17.3 g of white solid. 85% yield. 1H-NMR (CDCl3): 0.87 (t, 3H, J=7.3 Hz), 1.58 (bm, 2H), 2.72 (t, 2H, J=7.8 Hz), 3.80 (s, 6H), 6.88 (d, 4H, J=9 Hz), 7.19 (d, 4H, J=9.0 Hz), 7.73 (d, 1H, J=8.9 Hz), 8.48 (dd, 1H, J=2.8, 9.0 Hz), 9.08 (d, 1H, J=2.8 Hz).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:30])[C:13]2[O:19][C:18]3[C:20]([Cl:26])=[CH:21][C:22]([CH2:24][NH2:25])=[CH:23][C:17]=3[CH2:16][S:15](=[O:28])(=[O:27])[C:14]=2[CH:29]=1)=[O:9].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:30])[C:13]2[O:19][C:18]3[C:20]([Cl:26])=[CH:21][C:22]([CH2:24][NH:25][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:28])[C:14]=2[CH:29]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(CN)cc(Cl)c1O2
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(CNCc3ccccc3)cc(Cl)c1O2
Reaction time: 2.5 h

Procedure:
Sodium acetate (0.107 g, 1.30 mmol) was added to a solution of Example 198k (0.2 g, 0.52 mmol) in dry methanol (15 mL). Subsequently benzaldehyde (0.083 mL, 0.78 mmol) was added and the reaction mixture was stirred for 2.5 h. It was then chilled and treated with sodium borohydride (0.19 g, 0.52 mmol). The reaction mixture was stirred overnight at room temperature, then treated with an aqueous 10% sodium bicarbonate solution (2 mL), diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.095 g, (38.46%); 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.81 (s, 4H, 2CH2), 3.91 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.26-7.34 (m, 5H, Ar), 7.51 (s, 1H, Ar), 8.09 (s, 2H, Ar), 8.46 (s, 1H, Ar); MS: m/e (EI+) 472 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.[N+](C=C(SC)SC)([O-])=O.[N+:20]([CH:23]=[C:24](SC)[NH:25][CH2:26]CSCC1C=CON=1)([O-:22])=[O:21].CN>>[N+:20]([CH:23]=[C:24]([NH:25][CH3:26])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:22])=[O:21]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Reactant: NCCSCc1ccon1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole (from the dihydrobromide (3.8 g)) with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 4(i) and treatment of the resultant 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene with methylamine according to the procedure of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene.
Reaction SMILES: [CH:1]([NH:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)=O.[C:21](=O)([O-])[O-:22].[K+].[K+].CI>CN(C)C=O>[CH:21]([CH2:1][NH:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(NC=O)c2nc(C)ccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(NCC=O)c2nc(C)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-(formylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (11.8 g, 0.043 m) was added to a stirred mixture of 20.3 g (0.136 m) of anhydrous, milled potassium carbonate and 103 ml of dimethylformamide. The mixture was stirred for 30 minutes, and 20.3 ml (0.33 m) of methyl iodide was then added. The reaction mixture was stirred for five hours on a steam bath, then at room temperature overnight, and poured into 400 ml of ice-water. The solid product was collected by filtration, washed with water, and dried at 60° C. in vacuo to give 8.1 g of ethyl 1-(N-formylmethylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, beige solid, m.p. 210°-212° C.
Reaction SMILES: O[Li].O.O.C([O:7][C:8]([C:10]1([CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH2:13][CH2:12][CH2:11]1)=[O:9])C>CCO>[C:27]([C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14][C:10]2([C:8]([OH:9])=[O:7])[CH2:11][CH2:12][CH2:13]2)[CH2:26][CH2:25][CH2:24]1)([OH:29])=[O:28]
Reactant: CCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCC)CCC2)CCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(CCCCC1(C(=O)O)CCC1)CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
LiOH.H2O (3.94 g, 93.9 mmol) and H2O (30 mL) were added to a solution of ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate (9.20 g, 23.3 mmol) in EtOH (90 mL) and the resulting mixture was stirred at reflux temperature for 17 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (150 mL) was added and the resulting mixture was extracted with Et2O (50 mL), acidified with aqueous HCl (6 M, 25 mL) and extracted with Et2O (1×100 mL, 2×50 mL). The latter organic layers were combined, washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was recrystallized from a mixture of iPr2O and heptane to give 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (4.41 g, 56%) as small, white granules. mp 69–70° C. 13H NMR (CDCl3): δ=11.2 (br s, 2H), 2.50–2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96–1.84 (m, 8H), 1.81–1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26–1.12 (m, 4H). 13C NMR (CDCl3): δ=210.6, 183.4 (2×), 47.6 (2×), 42.7 (2×), 37.8 (2×), 30.1 (4×). 24.7 (2×), 24.1 (2×), 15.7 (2×). Anal. calcd for C19H30O5: C, 67.43; H, 8.93, found: C, 67.19; H, 8.97.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>CN(C)C=O.O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Nc1c2c(nc3cccc(O)c13)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc2nc3c(c(N)c12)CCCC3
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
8-Hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (18.07 g) was suspended in 500 ml of dry dimethylformamide. Potassium carbonate (22.6 g) was added, and the reaction mixture was stirred vigorously for 30 mins. Ethyl bromoacetate (18.0 g) was added dropwise, and the reaction was stirred vigorously overnight. The reaction mixture was distributed between ethyl acetate and water, and the organic layer was separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase was washed with water, dried, filtered, and the filtrate evaporate. The residue was purified by flash chromatography (ethyl acetate, then 5% triethylamine/ethyl acetate) to give 15.75 g (72.91%) of product, mp 141°-142° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[O:15][CH2:14][CH2:13][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Yield: 72.7 %

Procedure:
A mixture of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.35 g of rac.-4-[[2-(2-naphthalenyloxy) ethyl]sulfinyl]-alpha-oxobenzeneacetic acid as a yellow solid, mp 157°-158° C.