Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(NCc1cccnc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1cccnc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 17.4 %

Procedure:
To a stirred solution of (3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-N-(3-pyridylmethyl)carboxamide (0.242 g, 0.335 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (5–70% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0230 g, 17% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.60 (m, 1H), 8.49 (m, 1H), 8.44 (dd, 1H), 8.22 (dt, 1H), 8.10 (d, 1H), 7.93 (m, 2H), 7.69 (m, 2H), 7.43 (m, 1H), 4.67 (s, 1H). ES-MS (m/z) 396 [M+1]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2C[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:7]12)[CH3:2].CC(NN(CC)NC(C)C)C>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:7]12)[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Agent: CCN(NC(C)C)NC(C)C
Product: CCOC(=O)CN1C(=O)C[C@@H]2CCCCC[C@@H]21

Procedure:
A solution of 5-n-butyloctahydro-2-oxo-1H-indoleacetic acid ethyl ester (3aα, 7aα) (VI) (5.0 g, 0.0178 mole) in N,N-bis-(1-methylethyl)aminoethylamine (4.49 g, 0.0267 mole) is heated at 100° C. for 18 hours. The solution is concentrated at reduced pressure to an oil. The oil is dissolved in 2-propanol and the solution is treated with a saturated solution of hydrogen chloride in 2-propanol. The solution is diluted with anhydrous diethyl ether and allowed to crystallize. The crystals are filtered. Recrystalliztion from acetonitrile-diethyl ether yields pure 5-n-butyloctahydro-2-oxo-1H-indoleacetamide N-[bis[1-methylethyl]amino]ethyl]·hydrochloride (3aα, 7aα) (VII) with mp 116°-118° C.
Reaction SMILES: S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[C:11]([O:14][C:15]1[CH:20]2[C:21]([CH3:27])([CH3:26])[CH:22]3[CH2:25][C:19]2([CH2:24][CH2:23]3)[C:18]([CH3:29])([CH3:28])[CH2:17][CH:16]=1)(=[O:13])[CH3:12]>C(OC(C)=C)(=O)C>[C:11]([O:14][C:15]1[CH2:16][CH2:17][C:18]([CH3:29])([CH3:28])[C:19]23[CH2:25][CH:22]([CH2:23][CH2:24]2)[C:21]([CH3:27])([CH3:26])[C:20]=13)(=[O:13])[CH3:12]
Reactant: CC(=O)OC1=CCC(C)(C)C23CCC(C2)C(C)(C)C13
Agent: C=C(C)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Yield: 90 %

Procedure:
Concentrated sulphuric acid (0.7 ml) was added to a stirred solution of isolongifolan-8-one (1, 30.0 g, 90% pure, 0.12 mol) in isopropenyl acetate (150 ml). The reaction mixture was heated at reflux for 45 minutes, basified with saturated aqueous solution of sodium bicarbonate (200 ml) and extracted with MTBE (200 ml). The filtrate was washed with water (2×200 ml), dried (Na2SO4), concentrated in vacuo and distilled under reduced pressure to give (at 95° C./<1 mbar) a mixture of 2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undec-4-en-5-yl acetate and 2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undec-5-en-5-yl acetate (2a+2b: 70+25.5%, 30.5 g, 90% yield, pale yellow oil).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=O)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH2:15]([N:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]
Reactant: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide (282 mg, 0.80 mmol) in anhydrous THF (5 mL) was added LiAlH4 (1.2 mL of a 1M solution in Et2O, 1.2 mmol). After 18 hours, the reaction was quenched by addition of a mixture of H2O (2 mL), 2N NaOH (4 mL), and saturated NaCl (2 mL). The resulting mixture was diluted with Et2O (100 mL) and the resulting mixture was filtered. The filtrate was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (90:9:1 CH2Cl2:MeOH:NH4OH) gave trans-4-{4-[N-ethyl-N-(3-phenylpropyl)-amino]cyclohexyl}phenol (130 mg, 48%) as a white solid: mp 192-194° C.; IR (KBr): 3197, 2939, 1614, 1516 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.16 (br s, 1H), 7.35-7.23 (m, 5H), 7.02 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 2H), 3.35-3.12 (m, 5H), 2.68 (q, J=5, 2 Hz, 2H), 2.42 (tt, J=9, 2 Hz, 1H), 2.12 (br d, J=9 Hz, 2H), 2.10 (m, 2H), 1.87 (br d, J=9 Hz, 2H), 1.63 (dddd, J=9, 9, 9, 2 Hz, 2H), 1.53 (dddd, J=9, 9, 9, 2 Hz, 2H), 1.27 (t, J=5 Hz, 3H); CI-MS (methane) (m/z): 338 [M+H]+; HPLC: method A, 8.80 minutes (97.8%); method B, 10.66 minutes (99.9%); Anal. Calcd for C23H31NO.HCl.0.125H2O: C, 73.43; H, 8.64; N, 3.72. Found: C, 73.36; H, 8.75; N, 3.56.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH:36][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: CCOC(=O)c1noc(Cc2cc(C(F)(F)F)ccc2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cc(C(F)(F)F)ccc2F)n1
Yield: 7 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.111 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (3 mL). The crude mixture was purified by flash column chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.0113 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:18]=1.O>O1CCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:25]=2)[CH:18]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
In 6 ml of anhydrous tetrahydrofuran was suspended 700 mg of sodium hydride (purity: 50%), and into the suspension was dropped a mixture of 3.65 g of ethyl diethylphosphonoacetate and 3 ml of anhydrous tetrahydrofuran at a temperature of 30° to 35° C., after which the resulting mixture was subjected to reaction at room temperature for one hour. To the reaction mixture was added dropwise a mixture of 3.0 g of 4-(pyridin-3-yloxy)benzaldehyde and 3 ml of anhydrous tetrahydrofuran at room temperature, and the temperature thereof was gradually elevated. The mixture was subjected to reaction at 60° C. for 15 minutes. Subsequently, the reaction mixture was cooled to room temperature, and 20 ml of water was added to the mixture, after which the resulting mixture was subjected to extraction with 20 ml of ethyl acetate. The extract was washed with 10 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform], to obtain 3.64 g (yield 89.8%) of colorless, oily ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Nc1cnccn1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(Nc2cnccn2)ncn1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 2-aminopyrazine (230 mg, 2.42 mmol), sodium tert-butoxide (232 mg, 2.42 mmol) and bis(tri-t-butylphosphine)palladium (0) (51 mg, 0.1 mmol) in toluene (2 mL) was degassed under a stream of nitrogen over 10 min. 4,6-Dichloropyrimidine (300 mg, 2.01 mmol) was added to the mixture and the reaction was heated at 80° C. for 2 h. After cooling, the solution was passed through a PS-SH cartridge and the solvent removed in vacuo. The residue was triturated with dichloromethane and the resulting solid was collected and dried by vacuum filtration to give crude 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (333 mg) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1>CCOCC>[C:17]([C:8]1[C:9]2[O:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Methylisocyanate (0.14 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 2.28 mmol) in Et2O (5 mL). A solid forms over 0.5 h and the reaction is quenched with H2O (10 mL) after 1 h. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid (550 mg). This solid is recrystallized from EtOAc to give the product as white prisms (350 mg, 56%), mp=193°-194° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[C:6]([O:15][CH3:16])[C:5]([O:17][CH:18]([F:20])[F:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[C:40](=[O:44])[NH:39][CH2:38]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][CH:18]([F:20])[O:17][C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[C:40](=[O:44])[NH:39][CH2:38]3)=[C:7]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[C:6]=1[O:15][CH3:16]
Reactant: COc1c(OC(F)F)ccc(Br)c1OCC(C)(C)CO
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCC(C)(C)CO
Temperature: 85 °C

Procedure:
To a stirring solution of 3-(6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)-2,2-dimethylpropan-1-ol (200 mg, 0.563 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (548 mg, 1.689 mmol), tetrakis(triphenylphosphine) palladium(0) (32 mg, 0.028 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (175 mg, 0.675 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a (50 mg, 22%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](=[O:44])[CH3:43])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](=[O:44])[CH3:43])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 47.6 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}ethanone (3.30 g) and pyridine hydrochloride (870 mg), the title compound (910 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
(6-Fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (Example 103) (1.5304 g, 6.1387 mmol) was dissolved in DCM (60 mL) and manganese(IV) oxide (Aldrich less than 5 micron, activated, 2.546 g, 29.28 mmol) was added. The reaction was stirred at room temperature for 90 minutes, and then more activated manganese (IV) oxide (2.736 g, 31.47 mmol) was added. The reaction was stirred overnight and then was filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM. The filtrate was concentrated, and dried under high vacuum to give (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanone (1.334 g). 1H NMR (CDCl3, 400 MHz) δ 8.64 (d, J=2.35 Hz, 1H), 8.26 (td, J=8.07 Hz, 2.45 Hz, 1H), 7.75 (d, J=8.61 Hz, 2H), 7.33 (d, J=8.41 Hz, 2H), 7.09 (dd, J=8.41 Hz, 2.54 Hz, 1H), 2.56 (s, 3H). m/z (ESI, pos. ion) 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N[C@@H]2CCCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidine obtained in Example 14 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g) was added. The pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (0.28 g, yield: 66%).
Reaction SMILES: [N:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.NN>C(O)COCCO>[N:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ncccc2-c2cccnc21
Agent: NN
Solvent: OCCOCCO
Product: c1cnc2c(c1)-c1cccnc1C2
Reaction time: 1 h

Procedure:
A quantity of 3.62 g (20 moles) of 1,8-diazafluoren-9-one and 3.2 g (0.1 mole) of hydrazine was heated in 30 ml of diethyleneglycol at 100° for 1 hour, then heated rapidly to 200 and kept there for one hour (or until TLC showed the complete disappearance of starting material). Yield 2.6 g.
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][C:23]#[CH:24])[CH3:20]>>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][C:23]#[C:24][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1)[CH3:20]
Reactant: C#CCN(CC)CC
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)cc1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3)c2s1

Procedure:
Prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 72, Step A; 130 mg, 0.353 mmol), and N,N-diethylprop-2-yn-1-amine (58.9 mg, 0.530 mmol), according to the procedure for Example 6, Step B. The product was purified by Biotage 40S column (EtOAc). Product was an orange oil which crystallized upon standing (40 mg, 31%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 6.96 (d, J=9 Hz, 2H), 6.72 (d, J=9 Hz, 2H), 6.52 (d, J=5 Hz, 1H), 3.77 (s, 2H), 3.71 (s, 2H), 2.64 (q, J=7, 14 Hz, 4H), 1.13 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 352 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([N:19]=[N+]=[N-])=[CH:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[CH3:2]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:4]([C:5]1[NH:19][C:8]2[C:7]([CH:6]=1)=[C:16]([O:17][CH3:18])[CH:15]=[C:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=21)([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C(=Cc1cc2c(cc1OC)CCCC2)N=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(OC)cc3c(c2[nH]1)CCCC3
Temperature: 25 °C
Yield: 83533.1 %

Procedure:
A solution of 3-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-azido-2-propenoic acid ethyl ester (34.2 g, 0.113 mmol) in toluene (200 mL) was treated with rhodium(II) acetate dimer (300 mg, 0.679 mmol) at 95° C. for 4 h then at reflux for 1 h. The mixture was cooled to room temperature and the resulting solids were collected via vacuum filtration. The filtrate was concentrated to give a further precipitate that was collected via vacuum filtration. The filtrate was filtered through a silica gel plug and concentrated to provide an additional portion of product to give a total of 25.8 g (83%) of the title compound: mp 202-203° C. 1H NMR (CDCl3) δ 8.65 (bs, 1H, —NH), 7.30 (d, J=2.2 Hz, 1H), 6.24 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 3.91 (s, 3H), 2.84 (t, J=5.9 Hz, 2H), 2.76 (t, J=5.5 Hz, 2H), 1.90 (m, 4H), 1.40 (t, J=7.0 Hz, 3H); MS ES+ m/e 274 (p+1); IR (CHCl3, cm−1) 3459, 2937, 1698.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].C([Li])CCC.[CH:18](=[O:22])[CH2:19][CH2:20][CH3:21].C(O)(=O)C>C1COCC1.O>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[CH:18]([OH:22])[CH2:19][CH2:20][CH3:21]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CCCC=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(F)(F)F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (0.30 mL, 2.1 mmol) in THF (6 mL) was added dropwise 1.5M butyllithium in THF (1.65 mL) at −78° C. The mixture was stirred at −78° C. for 15 minutes, to which was added a solution of butyraldehyde (0.18 mL, 2.5 mmol) in THF (2 ml) at −78° C. After stirring at −78° C. for 30 minutes, the mixture was treated with acetic acid (1 mL)/THF (2 mL), and then followed by water at room temperature. The organic layer was separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give 1-[2-fluoro-4-(trifluoromethyl)-phenyl]butanol. To a suspension of the product and powdered Molecular sieves 3A (750 mg) in dichloromethane was added pyridinium chlorochromate (887 mg, 4.12 mmol). The mixture was stirred for 16 hours at room temperature, to which was added ether (20 mL) and silica gel (Wakogel C-300HG, 2 g). The mixture was stirred for 10 minutes at room temperature, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1), to give the titled compound as a white crystal (323 mg, yield 67%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:38]1[N:42]=[C:41]([NH2:43])[S:40][N:39]=1)[C:19]([NH:21][CH:22]1[C:36](=[O:37])[N:24]2[C:25]([C:33]([OH:35])=[O:34])=[C:26]([CH2:29][N:30]=[N+:31]=[N-:32])[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:38]1[N:42]=[C:41]([NH2:43])[S:40][N:39]=1)[C:19]([NH:21][CH:22]1[C:36](=[O:37])[N:24]2[C:25]([C:33]([OH:35])=[O:34])=[C:26]([CH2:29][N:30]=[N+:31]=[N-:32])[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1nsc(N)n1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Trifluoroacetic acid (18 ml) was added to a suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-azidomethyl-3-cephem-4-carboxylic acid (syn isomer) (4.6 g) in methylene chloride (10 ml) and anisole (5 ml), and the mixture was stirred for 7 hours at ambient temperature. The reaction mixture was added dropwise to diisopropyl ether (200 ml) and precipitates were collected by filtration. The precipitates were added to a mixture of water and ethyl acetate, and the mixture was adjusted to pH 7.0 with saturated aqueous solution of sodium bicarbonate. The separated aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration and successively washed with water to give 7-[2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-azidomethyl-3-cephem-4-carboxylic acid (syn isomer). (2.7 g).