Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:21]2[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=2)([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step D above (0.080 g, 0.17 mmol) and N-methylmorpholine (0.035 g, 0.35 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (0.019 g, 0.17 mmol) at 0° C. After stirring at RT for 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=504.1[M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:17][CH2:18][CH2:19][C:20](OCC)=[O:21].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:2]([S:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CCS
Reactant: CCCCCCCCCCCCCCCBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCSCCCO
Yield: 84 %

Procedure:
1-Bromopentadecane is reacted in the usual way with ethyl β-mercaptopropionate and the syrup obtained reduced with lithium aluminium hydride to give a yield of 84% of theory of 3-pentadecylthiopropanol; m.p. 36°-39° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)=[O:36])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)NC(=O)c2ccc(F)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.38 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (263 mg, 1.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (397 mg, 2.08 mmol) and 1-hydroxy-1H-benzotriazole (212 mg, 1.38 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (558 mg, 81%).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.Cl.[CH:39]12[O:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][NH2+:41][CH2:40]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:41]4[CH2:40][CH:39]5[O:46][CH:43]([CH2:44][CH2:45]5)[CH2:42]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CC2C[NH2+]CC1O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CC4CCC(C3)O4)CC2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.9 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol), 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (209 mg, 1.40 mmol), and DIPEA (0.49 mL, 2.80 mmol) in 1,4-dioxane was stirred at room temperature for 2.5 days. Additional 8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (84 mg, 0.561 mmol) was added and the mixture refluxed for 1 hr. The solvent was removed under vacuum, and the residue was diluted with water. The resulting precipitate was dissolved in CH2Cl2 and dried (Na2SO4). The solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexanes gave 3-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane (118 mg, 87%): mp 219-221° C.; 1H NMR (CDCl3) δ7.85 (dd, J=8.4, 0.5 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.07 (dd, J=8.1, 6.3 Hz, 2H), 2.79 (dd, J=8.1, 6.3 Hz, 2H), 2.55 (d, J=10.6 Hz, 2H), 2.38 (dd, J=10.9, 2.0 Hz, 2H), 1.83 (m, 4H); Anal. Calcd. for C28H37F2N9O5S: C, 51.8; H, 5.7; N, 19.4. Found: C, 51.8; H, 5.9; N, 19.3%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.CN(C)C=O>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]4)[CH2:19][CH2:20]2)=[CH:36][CH:35]=1
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc(CN2CCC(Oc3ccc4c(=O)[nH]ccc4c3)CC2)cc1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) was added to a solution of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (2 drops) and 4-methylbenzaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (700 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and the product semi-purified using an SCX cartridge. The product was further purified by prep-HPLC to afford 6-[1-(4-Methylbenzyl)piperidin4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=349.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CCOCC.[Br:16]Br>O1CCOCC1>[CH:5]1[C:4]([C:2]([CH2:1][Br:16])=[O:3])=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1

Procedure:
To a stirred, cooled solution of 4-chloroacetophenone (100 g, 0.65 mole), anhydrous ether (650 ml) and dioxane (325 ml) was added bromine (35 ml, 0.65 mole) dropwise over a period of 1.25 hours, keeping the temperature at 20° C. (±5° C.). The solution was then washed with water (3 × 1 l). The collected ether layer was dried over magnesium sulfate and the ether solution was evaporated under reduced pressure to give a solid. The solid was washed with water, collected by filtration, and air-dried to give the α-bromo-4-chloroacetophenone.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:17]1(N2C=CC(=O)NC2=O)[O:24][C@H:22]([CH3:23])[C@@H:20]([OH:21])[C@H:18]1[OH:19].[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:17]3[O:24][C@H:22]([CH3:23])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Reactant: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Product: C[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ccnc32)[C@H](O)[C@@H]1O
Yield: 77 %

Procedure:
7-Anilino-3H-imidazo[4,5-b]pyridine (0.8 g, 3.77 mmol) and 5'-deoxyuridine (2 g, 0.87 mmol) were added to a 10 mL solution of 10 mM KxHxPO4, pH 7.4 and 0.04% potassium azide. After mixing, 180 units of uridine phosphorylase and 1800 units of purine nucleoside phosphorylase were added. The reaction was continuously mixed at 35° C. for 6 days. Solids were collected by filtration and recrystallized from boiling ethanol yielding 0.943 g of the 7-anilino-3-(5-deoxy-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine. This corresponded to a yield of 77%; m.p. 219° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[N:6][CH:7]=[N:8][C:9]=1F.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33]>CN(C)C=O>[F:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[N:6][CH:7]=[N:8][C:9]=1[O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:26]
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(F)c1F
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(Oc2ccccc2C)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
With cooling, 0.25 g (0.0062 mol) of sodium hydride (60%) are added to a mixture of 2 g (0.0062 mol) of 2-[2-(5,6-difluoropyrimidin-4-yloxy)-phenyl]-2-methoxyimino-N-methyl-acetamide and 0.67 g (0.0062 mol) of 2-methylphenol in 20 ml of dimethylformamide, and the mixture is stirred at 25° C. for 12 hours. The reaction mixture is poured onto water and extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 1.5 g (58.9%) of 2-[2-(5-fluoro-6-o-tolyloxy-pyrimidin-4-yloxy)-phenyl]-2-methoxyimino-N-methyl-acetamide are obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1>ClC(Cl)C.ClCCl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:1][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.4 %

Procedure:
N-Bromosuccinimide (58.62 g, 329.34 mmol) was added in portions over a period of 5-10 min to a well stirred solution of 4-methyl-2-methoxy-1-nitro benzene (50.0 g, 299.4 mmol) and 1,1′-Azobis(cyclohexane carbonitrile) (1.0 g, 4.1 mmol) in dichloroethane (600 mL) and the resulting mixture was heated to reflux under a UV light for a maximum 7-8 hr. After cooling to rt, the reaction mixture was diluted with dichloromethane (400 mL) and washed with aqueous Na2S2O4 solution, water and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid (102.0 g) which was triturated with diisopropyl ether to afford 43.0 g of the desired product. The diisopropyl ether filtrate was concentrated and purified by silica-gel column chromatography (5-40% EtOAc/Hexanes) to obtain an additional 5.5 g of the desired product (48.5 g, 66%). 1H NMR (CDCl3-300 MHz): δ=3.98 (s, 3H), 4.46 (s, 2H), 7.05 (dd, J=6.60 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[CH:15]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH:15]1([S:21][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: SC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)c2cc(SC3CCCCC3)ccc21
Yield: 114.7 %

Procedure:
A mixture of 5-nitro-isoindole-1,3-dione (10.0 g), cyclohexanethiol (9.1 g) and potassium carbonate (18.7 g) in acetone (260 ml) was heated to reflux overnight. After cooling, the mixture was diluted with water (250 ml) and then acidified by 6 N HCl to pH=4. Precipitate was collected and dried in vacuo to give the intermediate 5-cyclohexylsulfanyl-isoindole-1,3-dione (15.6 g). This intermediate was dissolved in acetone (170 ml) and to the mixture was added bromo ethylacetate (10.6 g) and potassium carbonate (23.8 g). The mixture was refluxed overnight. After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and purified by silica gel chromatography (10%-50% ethyl acetate in methylene chloride) to give the title compound (13.1 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (m, 2 H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 4.40 (s, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 3.37 (m, 1H), 2.07-1.28 (m, 13 H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].CCOCC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:7][C:4]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[C:2]([NH:1][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[O:6][N:5]=1
Reactant: Cc1noc(N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(5-amino-3-methylisoxazol-4-yl)phenyl]piperazine-1-carboxylate (900 mg, 2.51 mmol) and DMAP (1.02 g, 8.3 mmol) in CH2Cl2 (25 mL) at 0° C. under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) dropwise and the reaction was warned to rt and stirred for 1 hour. Additional aliquots of DMAP (1.02 g, 8.3 mmol) and 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) were added and the reaction mixture was stirred for 2½ hours. Et2O was added and the reaction was poured into aqueous 10% HCl, extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]([OH:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[C:3]1([C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
To a suspension of 0.78 g of sodium hydride (55% w/w dispersion in mineral oil) in 300 cc of dimethylformamide was added a solution of 2 g of 3,5-diphenyl-phenol in 10 cc of dimethylformamide. The mixture was stirred for 5 hours at room temperature until effervescence had stopped. 2.2 g of ethyl 6-bromohexanoate was then added and the resultant mixture stirred at room temperature overnight. The mixture was then heated for 20 hours to 40° C. After cooling, the resultant mixture was poured into 100 cc of cold water and extracted with ethyl acetate (3#100 cc). The combined extracts were washed with water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was flash chromatographed on silica gel (30-60 mm; eluent: 92:8 n-hexane/ethyl acetate) to give 1 g of ethyl 6-(3,5-diphenyl-phenoxy)hexanoate as a oil, used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 59.3 %

Procedure:
A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144° C.; 1H NMR (CDCl3) δ: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].C(Cl)(Cl)[Cl:45].ClCl>C(Cl)(Cl)(Cl)Cl>[Cl:45][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1
Reactant: ClC(Cl)Cl
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: ClCl
Agent: [Na]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Cl)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a cold solution (~3°) of 6.12 g. of the sodium salt of antibiotic X-537A in 50 ml. of chloroform/3 ml. of carbon tetrachloride was slowly added 34 ml. of arbon tetrachloride saturated with 10 millimoles of chlorine gas. The reaction was continued for one-half hour after which the solution was filtered and the filtrate treated with a saturated aqueous solution of Na2CO3. The solvent layer was dried over Na2SO4 and concentrated to a small volume from which after addition of hexane the crystalline product was recovered. The crystalline material which had a tendency to incorporate the solvent of crystallization was twice recrystallized from methylene chloride/ether and acetone/-hexane, m.p. 183°-185°, [α]D25 -44.31° (C, 0.99 percent CHCl3).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:52]([O:56][CH2:57][CH:58]([OH:60])[CH3:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:60][C:50](=[O:51])[NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([S:42][CH3:41])[CH:44]=1)[CH3:59])(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCC(C)O
Reactant: CSc1cccc(N=C=O)c1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(C)OC(=O)Nc1cccc(SC)c1
Temperature: 60 °C

Procedure:
0.05 g of 2,6-di-tert-butyl-4-methylphenol, 0.02 g of Desmorapid Z, 26.8 g of 3-(methylthio)phenyl isocyanate in 50 g of ethyl acetate were initially introduced into a 250 ml round-bottomed flask and heated to 60° C. Thereafter 21.1 g of 2-hydroxypropyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Cl)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:14]=[C:15]([NH2:17])[S:16][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Reaction time: 0.58 h
Yield: 68.5 %

Procedure:
Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at 40° to 45° C., the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), mp 161° to 162° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Yield: 45 %

Procedure:
3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol), 2,3-dichloropyrazine (1.3 mL, 12.5 mmol), and DMF (5.0 mL) were combined and heated to 100 C overnight with stirring. The reaction mixture was poured into H2O and extracted with EtOAc (3×). The combined EtOAc extractions were washed with sat'd NaHCO3 (2×), sat's NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc) to give 1.76 g (45%) of 3′-chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.08 (d, 1H), 7.86 (d, 1H), 4.22-3.76 (complex m, 3H), 3.48-3.17 (complex m, 4H), 1.48 (s, 9H), 1.19 (d, 3H) ppm. LC-MS (MH+)=257 (-t-butyl).