Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>>[Cl-:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13])#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Product: [Cl-]

Procedure:
By reacting 5-cyanoisatin with phosphorous pentachloride, there is obtained 5-cyanoisatin chloride which, on reaction with 3(2H)-thianaphthenone, yields 5'-cyano-2'-indole-2-thianaphthenone indigo, which also is useful as a dyestuff.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CCC3)C4)nc2n(CCC)c1=O

Procedure:
3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-acrylic acid (150 mg) was hydrogenated in the presence of 10% Pd/C in THF:MeOH (2:1, 5 ml) @60 psi overnight. Catalyst was filtered through celite and the solvent was concentrated. Solid was purified by crystallizing from ether Yield 105 mg. Mass (ES+ 431)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[CH:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCCl>[CH:19]1([C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:13]3[C:7]4[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][C:8]=4[CH2:9][N:10]4[CH:16]=[CH:15][CH:14]=[C:11]4[CH2:12]3)=[O:30])=[CH:32][CH:33]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester of Step B (9.9 mmol) in 1,2-dichloroethane (25 mL) was added 4-cyclohexyl benzoyl chloride (1.1 equiv.) and triethylamine (2.5 equiv.) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with 5% ethyl acetate in petroleum ether to provide the title compound as a white crystalline solid, m.p. 174–176° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 6 h
Yield: 88.4 %

Procedure:
To a suspension of potassium carbonate (8.08 g, 58.5 mmol, 1.50 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (11.43 g, 38.98 mmol) in acetonitrile (100 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (15.8 g, 43.31 mmol, 1.10 equiv.) in acetonitrile (50 mL) at room temperature. After 6 h at this temperature, the solids were filtered off. The resulting filtrate was washed with water and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diisopropyl ether to yield the title compound (19.53 g, 88%).
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]C(=O)C)[CH2:5][CH2:4]1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([S:10][CH2:9][CH:6]1[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1)[CH3:21])[CH3:20]
Reactant: CC(=O)SCC1CCOCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A solution of 0.86 g (15.2 mmol) of potassium hydroxide in ethanol (78 mL, degassed and under nitrogen) was added to 0.81 g (4.66 mmol) of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester. The reaction was stirred at room temperature under nitrogen for 0.5 h. Then 2.1 mL (14.1 mmol) of ethyl α-bromoisobutyrate were added and the reaction stirred for 4 h. The resulting precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL) and dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure, followed by column chromatography of the residue (silica, eluent: heptanes, 0-20% ethyl acetate) afforded 0.76 g of 2-methyl-2-(tetrahydro-pyran-4-ylmethylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6.8 g, 26.5 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (8.69 g, 29.1 mmol), N,N-diisopropyl ethylamine (14 mL, 80 mmol) and Pybrop (18.52 g, 39.7 mmol) in dichloromethane (DCM) (100 mL). After stirring at RT for 1 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with (EtOAc/hexanes, 1:1) to give the title compound (6.1 g, 42.9%) as a white solid: LCMS (ES) m/z 537 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=[O:26].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:17]1[CH:18]=[CH:19][C:15]([C:10]2[N:11]=[C:12]([NH:14][C:25]([C:24]3[CH:28]=[CH:29][N:30]=[C:22]([CH3:21])[CH:23]=3)=[O:26])[S:13][C:9]=2[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[CH:16]1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2nc(-c3ccoc3)c(C(=O)C3CCOCC3)s2)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Compound 610 (100 mg, 0.359 mmol) was dissolved in DMF (3 mL), and 2-methylisonicotinic acid hydrochloride (249 mg, 1.44 mmol), EDC hydrochloride (558 mg, 2.91 mmol), 1-hydroxybenzotriazole monohydrate (463 mg, 3.02 mmol) and triethylamine (0.400 mL, 2.87 mmol) were added thereto, followed by stirring overnight at 80° C. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1), followed by recrystallizing from a mixed solvent of ethanol and water to afford the entitled Compound 615 (73.1 mg, 51%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:22]1[C:27]([F:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:28][C:27]1[C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=2)=[N:23][CH:24]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:26]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1

Procedure:
A 22 liter (L), 3-necked round-bottom flask with a bottom outlet was fitted with a mechanical stirrer, a condenser topped with a nitrogen inlet, and an addition funnel. Through the funnel, 6.546 kilograms (kg) (33.13 moles) of molten methyl 2-(4-hydroxyphenoxy)propionate, 6.571 kg (47.55 moles) of anhydrous K2CO3 and 319 g (0.99 moles) of tetra-n-butylammonium bromide were added to the reactor. Under constant agitation, the slurry was heated to 66° C. with a steam-water mixture controlled by a microprocessor and 6.026 kg (32.93 moles) of 2,3-difluoro-5-trifluoromethyl-pyridine was added over 15 min. The reaction mixture was heated for 13 hours (hr) at 70°-75° C. after which the product was washed 5 times using a total 37 L of hot water. The washed product was stripped of residual water using a rotary evaporator at 75° C. at a reduced pressure of 30 millimeters (mm) of mercury. A total 10.7 kg of product was collected having a purity of 97.9 percent.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][C:3]=1[O:19][CH3:20].[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C.Cl>C1COCC1>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([C:10]([CH3:18])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:17])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[B:26]([OH:29])[OH:27]
Reactant: COB(OC)OC
Reactant: CCCCCCC(C)(C)c1cc(OC)c(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1cc(OC)c(B(O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a stirred solution of 37.1 (2.78 g, 8.0 mmol) in anhydrous THF (20 ml) under an argon atmosphere at −78° C. was added n-BuLi (5.5 ml, 8.8 mmol using 1.6 M solution in hexane) over a 30 min period. Stirring was continued at −78° C. for 15 min and then trimethyl borate (2.7 ml, 24 mmol) was added. Following addition, the reaction mixture was allowed to warm to room temperature over 12 hours period. The pH was adjusted to 6.5 by addition of 5% aqueous HCl solution at 0° C., and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (12% acetone in hexane) to give 38.1 as colorless oil, in 83% yield (2.1 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CO.C(OCC)C>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO[Si](C)(C)C(C)(C)C)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CO
Product: CC(=O)O[C@@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Yield: 100.8 %

Procedure:
A solution of 48 g of 17β-acetoxy-7α-(5-tert-butyl-dimethylsilyloxypentyl)-estr-4-en-3-one in 350 ml of methanol is allowed to stand with 35 ml of 8 vol % sulfuric acid for 30 minutes at room temperature. The solution is diluted with diethyl ether, washed neutral with water, and dried. After the concentration by evaporation, 37.7 g of 17α-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl>[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[C:3]([Cl:13])[C:4]=34)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)c(Cl)c34)cn2)CC1
Temperature: 75 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (500 mg, 1.52 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (542 mg, 1.67 mmol) (1,1′-bis-(diphenylphosphine)-ferrocene) palladium dichloride (111 mg, 0.152 mmol) and potassium carbonate (525 mg, 3.80 mmol) in 1,4-dioxane (5.06 mL) and water (2.2 mL) was heated to 75° C. for 2 h. The reaction mixture was concentrated, suspended in ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated onto silica gel. Purification by ISCO chromatography (5 to 50% acetone:heptane) afforded 437 mg (51%) of the title compound as a red-brown solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1 H), 7.65 (d, J=0.5 Hz, 1 H), 7.57 (d, J=0.8 Hz, 1 H), 5.03 (br. s., 2 H), 3.99-4.41 (m, 1 H), 3.54-3.86 (m, 1 H), 2.14-2.42 (m, 2 H), 2.03 (dd, J=14.4, 3.5 Hz, 2 H), 1.81-1.96 (m, 2 H), 1.45-1.64 (m, 2 H), 0.91 (s, 9 H), 0.05-0.17 (m, 6 H); MS (APCl): 481.31, 483.37 [M+H]+; HPLC tR=3.99 min (ZQ3: nonpolar—4 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][NH:30][C:29]1=[O:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:31][C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:34])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1C(=O)CNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(=O)N(C)C3=O)cc2F)CC1
Yield: 59.4 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (107 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.C1(OC)C=CC=CC=1.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:31]([OH:33])=[O:32])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CSc2nnnn2-c2ccccc2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3ccccc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylate (1.0 g, purity 80%, 1.42 mmol) in dichloromethane (50 ml) and anisole (0.93 ml) was cooled to 0° C. Titanium tetrachloride (0.62 ml, 5.6 mmol) was added in 1 min. After stirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.60 g of (6R,7R)-7-phenylacetamido-3-(1-phenyl-1-H-tetrazol-5-yl)thiomethyl-ceph-3-em-4-carboxylic acid (purity 60%, yield 49.9%).
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15][CH3:16]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15]([CH3:16])=[O:5]
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CN(C(=O)CCS(C)=O)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
Sodium perborate tetrahydrate (52 mg, 0.34 mmol, 1.0 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23° C. The resulting suspension was stirred at 23° C. for 3 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (5×20 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as an off-white powder (82 mg, 78% yield): mp 138-140° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=2 Hz, 1H), 8.71 (dd, J=5, 2 Hz, 1H), 8.34 (m, 1H), 7.56 (dd, J=8, 5 Hz, 1H), 3.80 (s, 3H), 2.90-3.30 (m, 3H), 2.62 (s, 3H); ESIMS m/z 311 ([M+H]+). Compounds 32, 45, 51, and 77 were prepared as described in Example 10.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=CC1CCCCC1
Product: FC(F)(F)c1nnc2ccc(N3CCN(CC4CCCCC4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with cyclohexanecarbaldehyde was carried out according to General Synthetic Method 6. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(cyclohexylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][NH:22][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC2CC2)s1
Yield: 52 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using aminomethylcyclopropane instead of rac-2-amino-1-butanol, to the title compound (93 mg, 52%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:17])(Cl)Cl)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:18](C1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.Cl>>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([Cl:17])=[O:18])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC(Cl)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
P-phenoxybenzotrichloride (288 parts) was added to 182 parts of p-phenoxybenzoic acid, with mixing. The mixture was allowed to stand at ambient temperature for about 16 hours, then heated, over a period of about 4 hours, to a temperature of about 140° C., at which point HCl evolution was detected. The mixture was maintained at a temperature of between about 112° and 140° C. for an additional 21 hours, then cooled and analyzed by gas chromatographic techniques. Analysis indicated a 73% yield of p-phenoxybenzoylchloride based on the starting materials.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(C3=CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
5-(2,4-Difluoro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 213, triethylamine (28.0 uL, 0.20 mmol) and methanesulfonyl chloride (5.0 uL, 0.06 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.