Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:51])/[C:16](/[N:24]2[CH:27]([S:28]S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:25]2=[O:50])=[C:17](\N2CCCC2)/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:61])C>C(#N)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:16]2[N:24]3[C:25](=[O:50])[C@@H:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@H:27]3[S:28][CH2:18][CH:17]2[OH:61])=[O:51])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C(=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N1CCCC1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 139.32 g (160 mmol) of a mixture consisting of the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidinyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 1350 ml of dry acetonitrile is heated at 80° for approximately 6 hours under nitrogen until it is no longer possible to detect any starting material by thin layer-chromatography (silica gel; toluene/ethyl acetate 1:1). The heating bath is removed, the reaction mixture containing the 7β-phenoxyacetamido-3-(1-pyrrolidinyl)-3-cephem-4-carboxylic acid diphenylmethyl ester is left to cool for a further 11/2 hours, 550 ml of 0.1 N hydrochloric acid are added and the mixture is further stirred for 81/2 hours at room temperature. The reaction mixture is diluted with ethyl acetate, the water is separated off, the organic phase is washed twice with 2 N hydrochloric acid and three times with water, dried over sodium sulphate, concentrated by evaporation in vacuo and dried under a high vacuum. The residue, containing the 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, is used in the next step without further purification.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:35])[C:30]([CH3:34])([CH3:33])[CH2:31]O.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:31][C:30]([N:29]([CH3:35])[CH3:28])([CH3:34])[CH3:33])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CN(C)C(C)(C)CO
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCC(C)(C)N(C)C

Procedure:
2-Dimethylamino-2-Methyl-1-Propyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) bis(tributyltin) oxide and 23.4 gm (0.2 mole) 2-dimethylamino-2-methyl-1-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes water began to collect in the Dean-Starke tube and after 46 hours only 1.6 ml of water (theory 1.8 ml) had collected. Solvent is stripped off on a rotating evaporator to provide 78.3 gm of straw colored liquid. This is fractionated at reduced pressure to collect the desired product, 52.7 gm of water-white liquid (Percent yield - 65), at 132°-137° C. at 0.5 mm. Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([O:14][C:15]([C@@:17]12[CH2:32][C@H:31]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]([NH3+:33])[C:22](=[O:34])[N:21]1[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:37][C@H:20]1[C:19](=[O:50])[NH:18]2)=[O:16])[CH3:13].[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57](O)=[O:58])[CH:53]=1.CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57]([NH:33][C@@H:23]2[C:22](=[O:34])[N:21]3[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)[CH2:37][C@H:20]3[C:19](=[O:50])[NH:18][C@:17]3([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:32][C@H:31]3[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:58])[CH:53]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Temperature: 25 °C

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-14a-(ethoxycarbonyl)-2-(4-nitrobenzoyloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-aminium 4-methylbenzenesulfonate (9.95 g), 5-methylisoxazole-3-carboxylic acid (2.12 g), and NMP (30.0 g) at 5° C. was added diisopropylethylamine (6.5 g). Propanephosphonic acid anhydride (5.3 g) was charged as a solution in EtOAc (5.3 g) and NMP (10 mL) to the reaction mixture. The reaction was warmed to rt over 14 h. The reaction solution was diluted with 2-Me-THF (150 mL). The diluted reaction solution was washed with water (150 mL), a 1.0 M aqueous solution of H3PO4 (2×50 mL), water (50 mL), a 5% aqueous solution of NaHCO3 (50 mL), and then a 10% aqueous solution of NaCl (2×50 mL). The organic solution was dried over MgSO4, filtered, and then concentrated under reduced pressure, and then co-distilled with THF (200 mL). THF was added and the product-containing solution was filtered and evaporated to an oil (8.5 g, 93% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([N:16]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:17]2[O:21][C:20]([C:22]([N:24]([C:33]3[CH:34]=[N:35][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[N:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1.[C:53]1(B(O)O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C.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>[C:10]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:17]2[O:21][C:20]([C:22]([N:24]([C:33]3[CH:34]=[N:35][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[N:19][N:18]=2)[CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(I)c2)o1)c1ccc(N2CCOCC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(-c3ccccc3)c2)o1)c1ccc(N2CCOCC2)nc1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
Potassium phosphate (214 mg, 1.01 mmol) was added to 5-((3-iodophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-N-(6-morpholin-4-ylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4-oxadiazole-2-carboxamide (190 mg, 0.25 mmol) and phenylboronic acid (37 mg, 0.30 mmol) in DMF (3 mL) and the mixture was degassed. Tetrakis(triphenylphosphine)palladium (29 mg, 0.03 mmol) was added and the mixture was heated to 80° C. for 90 minutes. Phenylboronic acid (8 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium (10 mg, 0.01 mmol) was added, the mixture degassed and heated to 80° C. for 240 minutes. The mixture was cooled, diluted with ether (60 mL) and washed with water (3×20 mL). The aqueous layers were re-extracted with ether (20 mL) and the organic layers were combined, dried and concentrated by evaporation. The residue was purified by chromatography, eluting with 0-20% ether/DCM to give the title compound (Intermediate 49, 149 mg, 84%) as a gum; 1H NMR δ 8.09 (1H, s), 7.83-7.66 (4H, m), 7.66-7.37 (6H, m), 6.86 (1H, d), 5.37 (2H, s), 5.19 (2H, s), 3.79-3.62 (8H, m), 3.55-3.49 (4H, m), 0.93 (4H, t), 0.06 (9H, s), 0.01 (9H, s).
Reaction SMILES: C([O:4][C:5]1[C:13]2[O:12][C@H:11]3[CH2:14][C@@H:15]([OH:27])[C@H:16]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].CO.[Cl-].[NH4+]>CO>[C:21]1([S:18]([NH:17][C@@H:16]2[C@@H:10]3[C@@H:11]([O:12][C:13]4[C:5]([OH:4])=[CH:6][CH:7]=[CH:8][C:9]=43)[CH2:14][C@H:15]2[OH:27])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)Oc1cccc2c1O[C@H]1C[C@@H](O)[C@H](NS(=O)(=O)c3ccccc3)[C@@H]21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: O=S(=O)(N[C@@H]1[C@H]2c3cccc(O)c3O[C@H]2C[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
The (1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl acetate (448 mg), produced according to the process described above, was dissolved in methanol followed by the addition of 0.61N potassium hydroxide/methanol solution (1.9 ml) and stirring for 20 minutes at room temperature. The reaction mixture was added to a 5% aqueous solution of ammonium chloride and extracted with ethyl acetate (50 ml+30 ml×2). The organic layer was washed with saturated brine (30 ml) and concentrated after drying with anhydrous sodium sulfate. The residue was purified with column chromatography (silica gel: methylene chloride/methanol 20:1-7:1) to obtain (1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta [b]benzofuran-5-ol (376 mg).
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([C:7]1[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:20]=1)[CH2:4][CH2:5][CH3:6].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[NH2:2][C:11]1[C:10]2[N:20]=[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:9]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1

Procedure:
Concentrated ammonium hydroxide (35 mL) was added with stirring to a solution of N-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea (2.25 g, 5.39 mmol) in dichloromethane (100 mL). Tosyl chloride (1.13 g,5.93 mmol) was added in small portions over a period of 30 minutes. After 1 hour the layers were separated. The aqueous layer was extracted with dichloromethane (2×25 mL). The organics were combined and extracted with water (3×50 mL). The aqueous layers were combined and filtered to provide 1.64 g of an off white solid. This material was recrystallized sequentially from 1,2-dichloroethane, isopropyl alcohol and methanol to provide 960 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea as light tan needles, m.p. 191-192° C. Analysis: Calculated for C24H28N6O: %C, 69.21; %H, 6.78; %N, 20.18; Found: %C; 68.94; %H, 6.77; %N, 19.90.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:36]2[CH2:41][C@H:40]([CH3:42])[O:39][C@H:38]([CH3:43])[CH2:37]2)=[C:22]([F:35])[C:23]2[O:27][N:26]=[C:25]([C:28]3[O:32][C:31](=[O:33])[NH:30][N:29]=3)[C:24]=2[CH:34]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:42][C@@H:40]1[CH2:41][N:36]([C:21]2[C:20]([CH2:19][OH:18])=[CH:34][C:24]3[C:25]([C:28]4[O:32][C:31](=[O:33])[NH:30][N:29]=4)=[N:26][O:27][C:23]=3[C:22]=2[F:35])[CH2:37][C@H:38]([CH3:43])[O:39]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(-c4n[nH]c(=O)o4)noc3c2F)C[C@H](C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO)cc3c(-c4n[nH]c(=O)o4)noc3c2F)C[C@H](C)O1
Yield: 79.6 %

Procedure:
5-(5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazol-3-yl)-1,3,4-oxadiazol-2(3H)-one (Intermediate 208, 490 mg, 0.81 mmol) in 10 ml of THF was treated with TBAF (1M in THF; 1626 μl, 1.63 mmol) at room temperature for 16 hours. Reaction quenched with aq ammonium chloride solution and Extracted with ethyl acetate. Crude product purified on column (50-80% etoac in hexanaes) to give 5-(6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-(hydroxymethyl)benzo[d]isoxazol-3-yl)-1,3,4-oxadiazol-2(3H)-one (235 mg, 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
100 mg of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (produced in Intermediate Production Example 1) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 42 mg of anhydrous potassium carbonate, and 46 mg of ethyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 2 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 85 mg of ethyl 2-[4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 1-2 of the present invention].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][C:3]=1[NH2:4].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][C:3]=1[NH:4][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Yield: 100 %

Procedure:
Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloroformate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated NaHCO3 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F-:15].[K+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [F-]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)F)cc1
Yield: 28.7 %

Procedure:
60 gm (.257 mole) of p-acetamidobenzenesulfonyl chloride was added to 15 ml water and stirred to form a thick paste. 20 gm (.416 mole) of potassium fluoride dissolved in 25 ml water was added and the resulting slurry was heated for one hour in an oil bath at reflux. After one hour the slurry was cooled, filtered, washed with ice water and dried by suction. The crude product was recrystallized from 95% ethanol to give 16 gm of p-acetamidobenzenesulfonyl fluoride mp 169°-171° C; literature value 171° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.[Cu]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]2)=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: Oc1ccncc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(-n2ccc(=O)cc2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 160 °C
Yield: 25 %

Procedure:
To a solution of 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (150.0 mg, 0.4715 mmol) in DMF (3.000 mL) was added copper (5.992 mg, 0.09430 mmol) and cesium carbonate (307.2 mg, 0.9430 mmol) followed by pyridin-4-ol (448.4 mg, 4.715 mmol) and the reaction mixture heated at 160° C. in the microwave for 1 h. The reaction mixture was filtered and washed with DMF (2 mL). Ethyl acetate and water were added to the filtrate and the layers separated. The aqueous layer was extracted further with ethyl acetate (3×5 mL) and the combined organic extracts were washed with water (3×5 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The material was triturated with a mixture of methanol and ether to leave the product. (42.6 mg, 25% yield); 1H NMR (400 MHz, DMSO) d 6.33 (d, 2H), 7.69 (s, 2H), 8.15-8.18 (m, 2H), 8.35 (d, 2H) and 8.78 (s, 1H) ppm; MS (ES+) 333.11
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[N:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15].[C-]#N.[Na+]>>[C:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[N:4][CH:3]=1)#[N:15]
Reactant: N#C[Cu]C#N
Reactant: Oc1ncc(Br)c2ccccc12
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1cnc(O)c2ccccc12
Temperature: 180 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
4-Bromo-1-hydroxyisoquinoline (1.56 g) was dissolved in N-methyl-2-pyrrolidine (25 mL), and copper cyanide (1.56 g) was added thereto. The mixture was stirred at 180° C. for 4 hr with heating. The reaction mixture was added to cool to 100° C. and added to an aqueous solution (125 mL) of sodium cyanide (31.25 g). The mixture was extracted with dichloromethane and the extract was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-cyano-1-hydroxyisoquinoline (0.62 g) as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H].C1(=O)CCCCCCCCCCC1>>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CCCC2OC2CCC=CCC1
Reactant: [H][H]
Agent: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1
Temperature: 70 °C

Procedure:
In an SUS-made autoclave having an inner volume of 100 ml and equipped with a stirrer, 20 g (0.112 mol) of 1,2-epoxy-5,9-cyclododecadiene and 0.08 g of a 5 mass % Pt/C catalyst (50% hydrous product, produced by N.E. Chemcat Corporation; 0.0102 mmol as platinum atom) were added and after pressurizing to 5 MPa with hydrogen at room temperature, heated to a temperature of 70° C. Under the same pressure, the contents were heated with stirring until the hydrogen absorption did not occur. After the completion of reaction, the reaction solution was cooled to room temperature, the catalyst was removed by filtration and the resulting reaction solution was analyzed. The analysis of the reaction solution was performed by gas chromatography. As a result, 1,2-epoxy-5,9-cyclododecadiene was 100% consumed and epoxycyclododecane (hereinafter referred to as “ECD”) was produced in a yield of 99.6 mol %. Also, as by-products, cyclododecanone (hereinafter referred to as “CDON”) was produced in 0.04 mol %, cyclododecanol (hereinafter referred to as “CDOL”) was produced in 0.20 mol % and cyclododecane (hereinafter referred to as “CDAN”) was produced in 0.04 mol %.
Reaction SMILES: [C:1](OC1C=CC=CC=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>ClC1C=CC(Cl)=CC=1Cl>[N:20]1[C:19]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: Nc1cccnc1Cl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1Nc2cccnc2Oc2ccccc21
Yield: 28.3 %

Procedure:
A mixture of 21.4 g of phenyl salicylate, 25.71 g 3-amino-2-chloropyridine and 20 ml of 1,2,4-trichlorobenzene is refluxed for 1 hour under argon and the liberated phenol and HCl simultaneously distilled (from the refluxing mixture) and collected in a solution of 1N NaOH. The hot mixture is poured into 200 ml of ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried Recrystallization from methanol--DMF (6:1) gives 6.0 g of product, m.p. 268°-270° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:21][NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(Oc1ccc(Cl)c2ccccc12)C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NNC(=O)C(C)(C)Oc1ccc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-[(4-chloro-1-naphthyl)oxy]-2-methylpropanoic acid (6.66 g), WSC•monohydrochloride (6.0 g) and N,N-dimethylaminopyridine (200 mg) were dissolved in acetonitrile (70 ml), tert-butyl carbazate (4.0 g) was added thereto, followed by stirring at room temperature overnight. The solvent was concentrated under reduced pressure, water was added thereto, followed by extraction portionwise with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol) to obtain tert-butyl 2-{2-[(4-chloro-1-naphthyl)oxy]-2-methylpropanoyl}hydrazinecarboxylate (6.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[N:23]#[C:24]Br>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:24]([NH2:23])=[N:16][C:11]=3[CH:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(N)c(N)c2)nc1N1CCOCC1
Reactant: N#CBr
Solvent: O
Solvent: CC#N
Product: COc1cnc(-c2ccc3[nH]c(N)nc3c2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine (0.58 g, 1.0 eq.) and ACN/H2O (5 ml/1 ml). In ice bath, cyanogen bromide (0.3 g, 1.5 eq) was added to mixture solution dropwisely. The solution was stirred overnight at room temperature, quenched with a NaHCO3(sat.) solution, and then filtered to give a light brown solid (0.32 g, 51.78%), which was dried in vacuo to give a product.