Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[C:5]([F:16])=[CH:4][CH:3]=1.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]=[C:18]2B(O)O>C(O)C.C([O-])([O-])=O.[Cs+].[Cs+].[Pd]>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]=[C:18]2[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[C:5]([F:16])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](CO)NCc1nc(Br)ccc1F
Reactant: OB(O)C1=CC2CCC1C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC(C)[C@H](CO)NCc1nc(C2=CC3CCC2C3)ccc1F
Temperature: 120 °C

Procedure:
A microwave vial was charged with SiliaCat DPP-Pd (0.10 equivalent, 127 mg, purchased from Silicycle). A solution of Example 73A (100 mg, 0.30 mmol) in ethanol (1.0 mL) was added, followed by a solution of bicyclo[2.2.1]hept-2-en-2-ylboronic acid (41 mg, 0.30 mmol) in ethanol (1.0 mL) and 1 M aqueous Cs2CO3 (1.03 mL). The resulting mixture was heated in a microwave for 20 minutes at 120° C., filtered, and concentrated to provide (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol. (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) then purified by reverse phase HPLC to provide the title compound. MS (ESI+) m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([NH:15][CH:16]3[CH2:20][C:19](=[O:21])[O:18][CH:17]3[O:22]CC3C=CC=CC=3)=[O:14])[C:10](=[O:11])[C:5]=2[NH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([NH:15][C@H:16]([CH:17]=[O:22])[CH2:20][C:19]([OH:21])=[O:18])=[O:14])[C:10](=[O:11])[C:5]=2[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2c(=O)n(CC(=O)NC3CC(=O)OC3OCc3ccccc3)cnc12
Agent: [Pd]
Solvent: CO
Product: Cc1c[nH]c2c(=O)n(CC(=O)N[C@H](C=O)CC(=O)O)cnc12
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 42 (131 mg, 0.33 mmol), in methanol (50 ml) and 10% palladium on carbon (100 mg) was stirred vigorously under an atmosphere of hydrogen for 2 h. An additional quantity of catalyst (100 mg) was added and the mixture hydrogenated for a further 2 h. The mixture was filtered through a 0.2 μM nylon membrane, and concentrated. The residue was recrystallised from methanol/diethyl ether to afford 79 mg (78%) of 43 as a hygroscopic white solid: mp. 222°-226° C.; (decomp.); [α]D32 +0.5 (c 0.02, MeOH); IR (KBr) 3282, 1680, 1558, 1425 1275; 1H NMR (CD3OD) δ 8.03 (1H, s), 7.18 (1H, d, J=0.7), 4.79-4.74 (2H, m), 4.63-4.59 (1H, 2×d, J=3.6), 4.36-4.25 (1H, m), 2.78-2.39 (2H, m), 2.24 (3H, d, J=0.7). Anal. Calcd for C13H14N4O5. 1.4H2O: C, 47.10; H, 5.12; N, 16.90. Found: C, 47.00; H, 4.79; N, 16.59. FABMS m/e 307, 306 (M+), 244, 207, 190, 152, 115 (100%). ##STR101##
Reaction SMILES: [I-].[OH:2][C@H:3]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][N+:5](C)([CH2:15]C2C=CC=CC=2)[CH2:4]1>[Ag]=O.C(O)C>[CH3:15][N:5]1[CH2:6][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:3]([OH:2])[CH2:4]1
Reactant: C[N+]1(Cc2ccccc2)C[C@@H](O)[C@H](Oc2ccccc2)C1
Agent: O=[Ag]
Agent: [I-]
Solvent: CCO
Product: CN1C[C@@H](O)[C@H](Oc2ccccc2)C1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
A solution of 9.3 g. (22.6 mmol.) of trans-3-hydroxy-1-methyl-4-phenoxy-1-phenylmethylpyrrolidinium iodide in 200 ml. of absolute ethanol and 100 ml. of 190 ethanol was stirred at ambient temperature for 0.5 hr. with 2.6 g. (11.3 mmol.) of silver oxide. After 0.2 g. more silver oxide was added, the mixture was warmed to 45° C. and stirred for an additional 15 min. The mixture was separated by filtration through Celite, and the volume of the filtrate was reduced to 200 ml. This solution was treated with ca. 0.5 g. of 10% Pd/C catalyst and was shaken with H2 in the Parr reduction apparatus for 3 hr. The suspension was filtered through Celite and the filtrate was concentrated to give 4.3 g. of crystalline solid. This material, when recrystallized from cyclohexane, gave 3.66 g. (84%) of off-white crystals, m.p. 89.0°-90.0° C.
Reaction SMILES: O1CCCC1.C([Sn](CCCC)(CCCC)[C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1)CCC.[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[I:39][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Ic1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a tetrahydrofuran solution (15 mL) of 2-(4-(5-tri-n-butylstannyl-isoxazol-3-ylmethyl)-benzyloxy)-pyridine (5.1 g) described in Manufacturing Example 1-8-1 was added iodine (2.5 g) at 0° C. This mixture was stirred at this temperature for 20 minutes. A 10% sodium thiosulfate aqueous solution and ethyl acetate were added to this mixture. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1 to 4:1) to obtain the title compound (2.4 g).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH3:21]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC1=C(C)OC(C)C1=O
Yield: 29.3 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 44.0 g, 0.33 mole) and triethylamine (50.5 g, 0.5 mole) in methylene chloride (220 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.0 hours, a solution of methyl chloroformate (38.6 g, 0.41 mole) in methylene chloride (200 g), which is then stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 18 g of methyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product, b.p. 105° C.; IR (neat film) 2960(M), 1770(S), 1710(S), 1640(S), 1250(S), 1200(S) cm-1 ; 'H NMR δ 1.55(d, J=8 Hz,3), 2.28 (s,3), 3.95 (s,3), 4.70 (q, J=8 Hz,1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][N:18]=1>CC(O)=O>[C:7]1([CH:5]2[CH2:4][CH:3]([C:2]([F:15])([F:14])[F:1])[N:18]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[NH:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2C(F)(F)F
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3-aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH (100 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated and precipitated crystals were collected by filtration to give 8.63 g (79%) of the title compound as yellow crystals. 1H NMR (CDCl3, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s).
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH:12]([CH2:13][CH3:14])[CH2:11]1.S(=O)(=O)(O)O>O>[CH2:2]([O:9][CH2:11][CH:12]([OH:10])[CH2:13][CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC1CO1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: CCC(O)COCc1ccccc1
Yield: 90 %

Procedure:
15.4 Grams (0.67 mole) of sodium are poured into a flask containing 3.500 g. (35.2 mole) of benzyl alcohol under nitrogen atmosphere. After the sodium is dissolved, the temperature is brought to 160°C, then 481 g. (6.7 mole) of 1,2-epoxybutane are added dropwise. The temperature is kept at 160°C during the approximately 2 hours addition period. The temperature is subsequently lowered to 120°C and the excess of the starting 1,2-epoxybutane is distilled off; then 33.8 g (0.335 mole) of concentrated sulfuric acid and 36 ml. of water are added to the reaction mixture and the resulting solid sodium sulfate is removed by filtration. The filtrate is distilled under reduced pressure, thus recovering pure 1-benzyloxy-2-butanol in a yield of 90%. B.p. 128-132/6 mmHg.
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)[NH2:8].C(O)(=O)C>C(O)C>[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:8]=1
Reactant: C/C=C(\N)C#N
Reactant: Cc1cccc(NN)n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(-n2nc(C)cc2N)n1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To an ice-cold solution of aminocrotononitrile (20.5 g, 0.25 mol) and 2-hydrazino-6-methylpyridine (31.0 g, 0.252 mol) in ethanol (200 mL), acetic acid (30 g, 0.5 mol) was added and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the reaction solvent was concentrated and evaporated under reduced pressure, and water was added to the residue. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to give the title compound (41.3 g, 88% yield).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:42]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([CH:34]([F:36])[F:35])[CH:31]=[CH:30][C:29]=5[O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:41][CH:39]([F:40])[CH2:38][O:37][C:29]1[CH:30]=[CH:31][C:32]([CH:34]([F:36])[F:35])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:42]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.111 g). MP=92-93° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.05 (m, 2H), 7.02 (br m, 1H), 6.30 (br m, 1H), 4.42 (m, 2H), 2.76 (br m, 9H). MS=486 (MH)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9]2)C=CC=CC=1.Cl.O1CCOCC1.[H][H]>CO>[NH:8]1[CH2:11][CH:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9]1
Reactant: [H][H]
Reactant: CS(=O)(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)NC1CNC1

Procedure:
A solution of N-[1-(diphenylmethyl)-3-azetidinyl]-methanesulfonamide (185 mg, 0.585 mmol) in MeOH (10 mL) was treated with 1 mL of 4.0 N HCl/dioxane and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[O:12][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methyl 3,5-dichloro-4-hydroxybenzoate (1) (1.00 g, 4.52 mmol) was dissolved in DMF (8 mL) and treated with bromocyclopentane (534 μL, 4.98 mmol), followed by potassium carbonate (937 mg, 6.79 mmol). The mixture was stirred at 80° C. for 3 h and then partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases washed successively with water (5×50 mL) and brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo to afford methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.10 g, 84%): 1H NMR (400 MHz, CDCl3) δ: 7.97 (2H, s), 5.04 (1H, m), 3.90 (3H, s), 2.04-1.91 (4H, m), 1.82-1.75 (2H, m), 1.69-1.60 (2H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=CC(B(O)O)=CC=1)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]#[N:39])=[CH:7][CH:6]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20].[ClH:23]>CO.O.[Pd]>[ClH:23].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20]
Reactant: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC(OC)c1c(O)c(=O)cc(C)n1C
Yield: 79.3 %

Procedure:
1,6-Dimethyl-2-(1-methoxypropyl)-3-benzyloxy-pyridin-4(1H)-one (1.65 g, 5.5 mmol) was dissolved in methanol (30 ml)/water (10 ml) and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.35 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from methanol/diethyl ether gave the pure title compound (1.08 g, 79.3%) as a white crystalline solid. m.p. 225-227° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[C:12]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:11]=2)=[N:5][N:4]=1)[CH3:2].[H-].[Na+].CS(O[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:18][C:17]([N:16]([C:14]1[CH:13]=[C:12]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:11]=[C:10]([CH2:9][S:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[N:15]=1)[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)s1
Reactant: Cc1cc(COS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(N(Cc3cc(C)cc([N+](=O)[O-])c3)C(=O)OC(C)(C)C)n2)s1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-pyridyl]carbamate (200 mg) obtained in Example 1-(5) in dimethylformamide (2 ml), 60% sodium hydride (30 mg) was added under cooling with ice, followed by stirring at the same temperature for 30 minutes. A solution of 3-methyl-5-nitrobenzyl methanesulfonate (283 mg) in dimethylformamide (1 ml), was added to the reaction solution, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium hydrogen carbonate aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=1:1) to obtain the above identified compound (314 mg) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23])[CH3:31]
Reactant: CCOCCN
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NCCOCC)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (50 mg) was treated with ethoxyethylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (18 mg) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>O1CCCC1.C(Cl)(Cl)Cl>[Br:29][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (1.0 g in a mixture of 10 mL dry tetrahydrofuran and 10 mL dry chloroform) at 0° C. was added pyridinium bromide perbromide (1.14 g) and the reaction stirred at 0° C. After 50 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3x) and 0.3M sodium bisulfate (3x) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) gave the title compound (1.2 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[C:2]=[S:3].C[N:34](C=O)C.N>C(O)C>[CH3:30][N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:20]2[C:19](=[O:31])[NH:18][C:17](=[O:32])[C:16]=2[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH2:34])=[S:3])[CH:8]=2)=[CH:22]1
Reactant: Cn1cc(C2=C(c3cn(CCCN=C=S)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=S)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h

Procedure:
A suspension of 100 mg of the product of Example 48 in 10 ml of ethanol was treated with 4 ml of DMF and then with 10 ml of a saturated solution of ammonia in ethanol. The mixture was left to stand at room temperature for 1 hour and the solvent was then evaporated. The residue was crystallized from ethanol to give 18 mg of 3-(1-methyl-3-indolyl)-4-[1-(3-thioureidopropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 166°-168° C. (decomposition).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH3:11][NH2:12].[BH4-].[Na+]>CO>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH2:1][NH:12][CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added methylamine (130 mL of 40% in water, 1.5 mol). The resulting solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added in batches. The reaction solution was stirred at 0° C. for 2 h, then warmed to room temperature, concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70%) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3×). The combined methylene chloride extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give additional benzylamine (66.7 g, 29%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)cc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc(CBr)c1
Yield: 67.9 %

Procedure:
A suspension of 3,5-dimethylanisole (13.60 g, 100 mmol), N-bromosuccinimide (18.35 g, 100 mmol) and 2,2′-azobis(2-methylpropionitrile) in CCl4 was heated under reflux for 1 h. The succinimide was filtered off, the filtrate was concentrated and the residue was chromatographed (SiO2, CH2Cl2/hexane 1:4). There were obtained 14.61 g (68%) of 1-bromomethyl-3-methoxy-5-methyl-benzene.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:21](=[O:22])[N:8]2[C:9]([C:18]([OH:20])=[O:19])=[C:10]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]12)=[O:4].C([O-])(O)=O.[Na+].O.[C:29]1([C:35]2[O:36][C:37]([SH:40])=[N:38][N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:29]1([C:35]2[O:36][C:37]([S:40][CH2:2][C:3]([NH:5][CH:6]3[C:21](=[O:22])[N:8]4[C:9]([C:18]([OH:20])=[O:19])=[C:10]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]34)=[O:4])=[N:38][N:39]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Reactant: Sc1nnc(-c2ccccc2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3nnc(-c4ccccc4)o3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
1.75 g. of 7-chloroacetylamino-3-acetylaminomethylceph-3-em-4-carboxylic acid and 0.42 g. of sodium hydrocarbonate were dissolved in 10 ml. of water. Thereafter 0.9 g. of 2-phenyl-5-mercapto-1,3,4-oxadiazole and 0.42 g. of sodium hydrocarbonate dissolved in a mixture of 10 ml. of water and 5 ml. of acetone were added. The reaction mixture was stirred at room temperature for 12 hours. The acetone was evaporated in vacuo. The pH of the residue was adjusted to 2 by adding some diluted sulphuric acid. The precipitate separated was removed by filtration and dried. Thus 1.83 g. of 7-(2-phenyl-1,3,4-oxadiazole-5-ylthio)acetylamino-3-acetylaminomethylceph-3-em-4-carboxylic acid were obtained.