Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16]2
Reactant: ICCCCCI
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)CCC1(CCC(N3CCCCC3)CC1)C2

Procedure:
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of 1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture after cooling is diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)].
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)[CH:12]=2)[C@@H:9]([O:27][C:28](=[O:30])[CH3:29])[C@H:8]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[C@@H:6]1[O:40][C:41](=[O:43])[CH3:42])(=[O:3])[CH3:2].C(O)(=[O:46])C>O>[C:1]([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:46])[CH3:26])=[CH:23][CH:24]=3)[CH:12]=2)[C@@H:9]([O:27][C:28](=[O:30])[CH3:29])[C@H:8]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[C@@H:6]1[O:40][C:41](=[O:43])[CH3:42])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)[C@@H]3OC(C)=O)ccc2Cl)cc1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H]1OC(C)=O
Temperature: 125 °C
Reaction time: 22 h

Procedure:
To a vigorously stirred solution of (1S,2R,3R,4S,5R,6R)-4-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (19) (300 mg, 48.7 μmol) in acetic acid (5 mL) was added K2Cr2O7 (172 mg, 0.58 mmol) and the mixture was stirred for 22 hours at 125° C. The mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with saturated NaHCO3 (3×10 mL) and then with brine (20 mL), dried (Na2SO4), filtered and concentrated. Preparative TLC (2:1 hexane:ethyl acetate) afforded 100 mg of the desired compound. MS (ESI+): 631 [M+H]+, 648 [M+H2O]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C1COCC1>[O:19]1[CH2:8][CH:12]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[S+](C)C
Reactant: O=Cc1cccnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1cncc(C2CO2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
The title compound was prepared by following general procedure 3. Sodium hydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 equiv.) was taken into DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added at the same temperature and heated for 10 min. The reaction mixture was cooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1 equiv.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1 equiv.) and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 3-(oxiran-2-yl)pyridine (1 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([N:67]([C:75]([O:77][CH2:78][C:79]3[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=3)=[O:76])[C:68](=[O:74])[CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:63]2)=[O:61])[CH2:43]1>>[N+:57]([C:54]1[CH:55]=[CH:56][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:39](=[O:40])[N:6]4[C:7]=3[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH2:43][C@H:44]2[C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([N:67]([C:75]([O:77][CH2:78][C:79]3[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=3)=[O:76])[C:68](=[O:74])[CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:63]2)=[O:61])=[O:48])=[CH:52][CH:53]=1)([O-:59])=[O:58]
Reactant: N=C(N)NCC(=O)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](N(C(=O)CNC(=N)N)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 49.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (697 mg) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(4-nitrobenzyloxycarbonyl)guanidinoacetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (751 mg), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(4-nitrobenzyloxycarbonyl)guanidinoacetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (563 mg) was obtained as a powder.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]2[C:20]3[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=3[O:18][C:17]3[C:11]=2[CH:12]=[CH:13][C:14]([CH:16]=3)=[O:15])=[C:3]([C:26]([OH:28])=[O:27])[CH:2]=1.[OH:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].[CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]3([O:27][C:26](=[O:28])[C:3]=2[CH:2]=1)[C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]3=1
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 83 mg (0.22 mmol) of 6-carboxyfluorescein dissolved in 2 ml of dimethylformamide was added 28 mg (0.24 mmol) of N-hydroxysuccinimide and 55 mg (0.27 mmol) of N,N'-dicyclohexylcarbodiimide. The reaction mixture was stirred at 0° C. under argon atmosphere for one hour and then maintained at 4° C. for 16 hours to yield a N-hydroxysuccinimide active ester of carboxyfluorescein having the formula: ##STR5##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of compound 10.4 (2.1 mmol), p-toluenesulfonic acid monohydrate (0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours. After quenching with saturated aqueous NaHCO3, MeOH was removed under reduced pressure. The residue was extracted with EtOAc, and the combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered through short plug of silica gel. Upon concentration, compound 10.3 was obtained. MS ESI (pos.) m/e 248.1 (M+1). 1H NMR (500 MHz) (DMSO-d6) δ 9.04 (s, 1H); 7.99 (s, 1H); 7.14 (s, 1H); 7.05(m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, 1H); 3.57 (s, 1H); 3.22-3.27(m, 1H); 2.89-2.94(m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1.C[O-].[Na+].[Cl-].[NH4+:25].[C:26]([OH:29])(=[O:28])[CH3:27]>CO>[C:26]([OH:29])(=[O:28])[CH3:27].[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:25])[NH2:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.1 g (41.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (Example 27A) were added to 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml), and the mixture was stirred at RT for 2 h. 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were then added, and the mixture was heated to reflux overnight. It was then concentrated to dryness and the residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to a pH of 10 using 2N aqueous sodium hydroxide solution. The mixture was stirred vigorously at RT for about 1 h. The resulting suspension was filtered with suction and washed through with ethyl acetate (100 ml), with water (100 ml) and once more with ethyl acetate (100 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1>[N+](C)([O-])=O>[CH3:15][C:16]1[N:20]([CH:2]([C:3](=[O:4])[NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])[CH3:14])[CH2:19][CH2:18][N:17]=1
Reactant: CC1=NCCN1
Reactant: Cc1cccc(C)c1NC(=O)C(C)Cl
Solvent: C[N+](=O)[O-]
Product: CC1=NCCN1C(C)C(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Example IA react 15.88 gm. (0.075 M) of 2-chloro-N-(2,6-dimethylphenyl)propionamide with 31.55 gm. (0.375 M) of lysidine in 150 ml. of nitromethane to obtain the title compound.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:24]([C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:27])[CH2:25][CH3:26]
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added butyric acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to to provide the title compound (53 mg, 56%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 0.94 (t, J=7.42 Hz, 3H), 1.25-1.48 (m, 6H), 1.51-1.65 (m, 3H), 1.68 (d, J=11.72 Hz, 1H), 1.74-2.01 (m, 7H), 2.19-2.32 (m, 3H), 2.35 (t, J=7.62 Hz, 2H), 2.55 (t, J=12.11 Hz, 2H), 2.89-3.11 (m, 5H), 3.56-3.69 (m, 1H), 4.01 (d, J=13.28 Hz, 1H), 4.57 (d, J=13.28 Hz, 1H). MS (M+1): 377.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])=[CH:4][C:3]=1[Cl:20].[Cl-].[NH4+]>O1CCCC1.O.[Fe]>[Cl:20][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A mixture of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene (60 g, 190.40 mmol, 1.00 equiv), Fe (53 g, 946.43 mmol, 4.97 equiv) and ammonium chloride (10 g, 188.68 mmol, 0.99 equiv) in tetrahydrofuran/water (1/2) (600 mL) was stirred overnight at 60° C. under an inert atmosphere of nitrogen. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum to give 40 g (74%) of 4-(3,4-dichlorophenoxy)-3-methoxyaniline as a light gray solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][CH3:9].CN(C=O)C.[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([OH:32])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1>O>[CH:15]1([C:19]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:32][CH2:8][CH3:9])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2CCC2)c(C2CC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.44 g) and iodoethane (0.55 mL) were added to a DMF (25 mL) solution of methyl 4-cyclobutyl-5-cyclopropyl-2-hydroxybenzoate (1.3 g) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, followed by extraction with ethyl acetate twice. Combined organic layers were washed with water and saturated saline in this order and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[Cu][C:33]#[N:34]>CN(C)C=O.[Cu]I>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]#[N:34])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C#N)cc3)oc2C)cc1
Temperature: 150 °C
Yield: 86.8 %

Procedure:
2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (170 mg, 0.35 mmol), copper (I) cyanide (96 mg, 1.07 mmol), and copper (I) iodide (120 mg, 0.63 mmol) were dissolved in dimethylformamide (1.5 mL) and heated to 150° C. for 20 h. The mixture was cooled ambient temperature and partitioned between EtOAc (20 mL) and saturated aqueous FeCl3 (20 mL). The organic phase was washed with FeCl3 solution, H2O, brine and then dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (15 mL SiO2, 40% EtOAc/hexanes) and obtained as a clear, colorless oil (132 mg, 87%). Rf=0.32 in 35% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 6.81-6.76 (m, 4H), 4.21 (q, J=6.4 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.51 (s, 6H), 1.26 (t, J=7.2 Hz, 3H); MS (EI) 457.2 (M+Na)+; 435.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])[CH3:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:48]3[CH2:49][CH2:50][CH:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:46][CH2:47]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 99.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(ethoxycarbonyl)piperidine (28.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (97.0 mg, 100%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[N:8]([CH2:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=O)[N:7]=C(C(F)(F)F)O1>C(#N)C>[NH2:7][N:8]1[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:2]([CH3:1])[C:4]1=[O:3]
Reactant: CC(C)(C)C(=O)Cn1nc(C(F)(F)F)oc1=O
Reactant: CN
Solvent: CC#N
Product: Cn1c(C(C)(C)C)cn(N)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 ml of aqueous methylamine solution (40%) are added to a solution of 12.6 g of 2,3-dihydro-2-oxo-3-tert-butylcarbonylmethyl-5-trifluoromethyl-1,3,4-oxadiazole in 50 ml of acetonitrile. After the slightly exothermal reaction has subsided, the reaction mixture is stirred for 2 hours at room temperature and then for 14 hours at 80° and then evaporated the liquid residue is treated with ice-water, and the aqueous mixture is extracted three times by shaking with ethyl acetate. The combined ethyl acetate phases are dried and evaporated, and the oily orange residue is recrystallized from hexane. This gives the title compound in the form of pale yellow crystals which melt at 100°-105°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[O:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Yield: 54 %

Procedure:
3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (90 mg, 0.264 mmol) was reacted with phenyl 3-isopropylisoxazol-5-ylcarbamate as prepared in Example 122A (78 mg, 0.317 mmol) to afford 1-(3-isopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (70 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ 10.30 (brs, 1H), 9.14 (brs, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.38-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.32-4.35 (m, 2H), 3.99 (s, 3H), 3.77-3.78 (m, 2H), 3.35 (s, 3H), 2.90 (septet, J=9 Hz, 1H), 1.19 (d, J=9 Hz, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH2:32])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH:32][C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Reaction time: 15 h
Yield: 81.6 %

Procedure:
39 g calcium carbonate and 36.8 g phenyl chloroformate in 250 mL THF was added to a stirred solution of 50 g 2-amino-6,7-dihydro-4H-thiazolo (5,4-c)pyridine-5-carboxylic acid tert-butyl ester in 1 L THF. The reaction mixture was allowed to stir for 15 h. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was washed with 20% ethyl acetate in hexane to give 60 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]([C:13]1[N:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:12].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc(N)n1
Temperature: 160 °C

Procedure:
To a stirred mixture of 2-amino-4-chloro-6-methylpyrimidine (0.266 mmol, 1.62 eq) and compound 1 (0.164 mmol, 0.164 mmol, 1 eq) in NMP (1.5 ml), DIPEA (0.656 mmol, 4 eq) was added. The mixture was heated to 160° C. for 12 hours. Then the mixture was extracted with ethyl acetate and washed with water and brine. The product was purified by silica gel column chromatography eluting with DCM/methanol (from 0 to 10%) to afford the product (S)-3-(1-((2-amino-6-methylpyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 92. ESI-MS m/z: 406.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([OH:11])=O)=[O:7].[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([NH:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12)=[O:11])=[O:7]
Reactant: O=C(O)CS(=O)c1ccco1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccco3)[C@H]2SC1

Procedure:
348 mg. of 2-furylsulfinylacetic acid of the R form and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 163 mg. of 7-(2-furylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid of the R form were obtained.