Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][C:8]=2[F:21])[CH2:5][CH:6]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][C:8]=2[F:21])[N:3]=1
Reactant: NC1=CCN(c2ccc(OCc3ccccc3)cc2F)N1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1ccn(-c2ccc(OCc3ccccc3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.1 %

Procedure:
MnO2 (2.66 g) was added to a solution of 3-amino-1-(4-benzyloxy-2-fluorophenyl) pyrazoline (3.86 g) in CH2Cl2 (40 mL), and the mixture was stirred at room temperature for 4 hours. The precipitate (MnO2) was filtered off, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 1/9, 1/4, 1/2 and 1/1) and crystallization from EtOAc/hexane to yield 1.04 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCOCC5)CC4)c3c2)cc(Cl)c1O
Yield: 57.4 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(morpholinomethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (20 mg, 57%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.33 (d, J=1.7 Hz, 1H), 8.07-7.97 (m, 2H), 7.33 (d, J=2.1 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.75-3.68 (m, 4H), 3.55 (d, J=12.7 Hz, 2H), 3.25-3.15 (m, 2H), 2.61-2.41 (m, 5H), 2.36 (d, J=6.9 Hz, 2H), 2.07-1.90 (m, 3H), 1.68-1.54 (m, 2H), 1.37-1.27 (m, 2H), 1.26-1.20 (m, 2H); ESI MS m/z 536 [C30H34ClN3O4+H]+; HPLC>99% (AUC), tR=10.57 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][CH2:16][CH2:17][OH:18]>O1CCOCC1>[N:1]1([CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: OCCCBr
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCCCn1ccnn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
1,2,3-triazole (2 g, 28.96 mmol) was dissolved in 1,4-dioxane (40 mL), and potassium carbonate (8 g, 57.92 mmol), potassium iodide (962 mg, 5.79 mmol) and 3-bromopropanol (3.3 mL, 43.43 mmol) were added thereto, followed by stirring at 100° C. for 3 hours. After the reaction was completed, the reactants were cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (2.5 g, 68%).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1N=C=S.FC(F)(F)C1C=CC=CC=1NC(=S)NN.ClC(OCC)=O.[OH:35][C:36]1[N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[C:39]([SH:51])=[N:38][N:37]=1.Br[C:53]1[S:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][N:57]=1>>[OH:35][C:36]1[N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:48])([F:50])[F:49])[C:39]([S:51][C:53]2[S:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][N:57]=2)=[N:38][N:37]=1
Reactant: Oc1nnc(S)n1-c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: CCOC(=O)Cl
Agent: FC(F)(F)c1ccccc1N=C=S
Agent: NNC(=S)Nc1ccccc1C(F)(F)F
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2-c2ccccc2C(F)(F)F)s1
Yield: 25.8 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 5 starting with 2-(trifluoromethyl) phenyl isothiocyanate. The intermediate 4-[2-(trifluoromethyl)phenyl]-3-thiosemicarbazide (2.04 g) was treated with ethyl chloroformate (1.09 g) as in example 5. The reaction product 3-hydroxy-5-mercapto-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole (0.78 g) was reacted with 0.63 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole, a yellow solid, MP 183-185° C.
Reaction SMILES: C(Cl)(Cl)=O.[Cl:5][C:6]([N:8]([CH2:16][CH2:17][C:18](Cl)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:5][C:6]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:18](=[O:19])[CH2:17][CH2:16]1)=[O:7]
Reactant: O=C(Cl)CCN(C(=O)Cl)c1cccc(Cl)c1
Agent: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCN(C(=O)Cl)c2cc(Cl)ccc21
Yield: 86.2 %

Procedure:
In an apparatus idenntical to that used in Example 1, methylene chloride (25 cc) is introduced. A stream of phosgene is then passed through for 10 minutes at a temperature in the region of 20° C., in order to remove the water and ethanol present in the solvent used. The phosgene dissolved is removed by passing a stream of argon through the solution for 20 minutes at a temperature in the region of 40° C. N-Chloroformyl-3-(m-chloroanilino)propionic acid chloride (2 g; 7.13 mmol) is then added, while working under an atmosphere of argon at a temperature of 26° C. Anhydrous aluminum chloride (2.09 g) is then added in the course of 10 minutes, the temperature changing from 26° to 32° C. The reaction mixture then consists of a yellow liquid phase and a suspension. The mixture is left to react for 15 hours at a temperature in the region of 20° C., and the reaction mixture is then poured onto ice (25 g). The organic phase is separated by decantation. The aqueous phase is extracted with methylene chloride (4×25 cc). The combined organic extracts are washed with water (4×25 cc) and then dried over sodium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 1-Chloroformyl-7-chloro-1,2,3,4-tetrahydro-4-quinolinone (1.5 g), m.p. 150°-153° C., is thus obtained which, after recrystallisation in ethyl acetate, melts at 156° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH2:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])CCC.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.[OH-].[Na+]>O1CCCC1>[CH3:10][CH:9]([CH3:11])[CH2:8][O:7][CH2:6][B:25]([OH:30])[OH:26]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)COCC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)COCB(O)O
Reaction time: 0.58 h
Yield: 28.9 %

Procedure:
To a solution of tributyl-(2-methylpropoxy)methyl-tin (1.00 g, 2.65 mmol) in tetrahydrofuran (20 ml) was added dropwise n-butyllithium (1.54M n-hexane solution, 1.72 ml, 2.65 mmol) at −78° C. (external temperature) under the nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 35 minutes. Then, to the reaction mixture was added triisopropyl borate (1.10 ml, 4.74 mmol) at −78° C. (external temperature) under the nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added a 1N aqueous sodium hydroxide solution at room temperature. The resultant was extracted three times, and the resulting aqueous layer was washed with diethyl ether. Then, to the resulting aqueous layer was added 5N aqueous hydrochloric acid solution to make the solution acidic, followed by extraction with diethyl ether three times. The resulting organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off from the filtrate to obtain the title compound (101 mg, 0.765 mmol, 29%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:20][CH:21]=1)(=[O:32])=[O:31]
Reactant: COC(=O)c1ccccc1COc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Methyl 2-{[4-(2-hydroxyethyl)phenoxy]methyl}benzoate (1.2 g, 4.19 mmol) was dissolved in dichloromethane (20 ml) and the solution was cooled to −20° C. Triethylamine (0.64 g, 6.29 mmol) was added dropwise, and then methylsulfonyl chloride (0.53 g, 4.61 mmol) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for one hour. Diethyl ether (5 ml) was added and the precipitate was filtered off. The organic phase was washed with 2 portions of brine, dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). This gave 0.703 g of methyl 2-[(4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)-methyl]benzoate (yield 46%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(Cl)Cl.[CH2:21](O)[CH3:22]>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:21][CH3:22])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4 g of the product of Step A, 3.4 g of dicyclohexylcarbodiiumide and 6 mg of 4-dimethylamino-pyridine were added to 30 ml of methylene chloride followed by the addition of 1.5 ml of ethanol and the mixture was stirred at 20° C. for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 4.25 g of tert.butyl (1R, cis)2,2-dimethyl-3-(ethoxycarbonyl-ethynyl)-cyclopropane-carboxylate.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([Si:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.C(=O)=O.CC(O)C.C([Li])CCC.CCCCCC.[I:51]I>C1COCC1.CCOCC>[I:51][C:13]1[C:7]2[O:6][C:5]3[C:4]([Si:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: II
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2cccc3c2oc2ccccc23)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1cccc2c1oc1c([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
Dibenzo[b,d]furan-4-yltriphenylsilane (9.80 g, 22.97 mmol) was dissolved in dry THF (100 mL) and cooled in the CO2/i-PrOH bath. n-Butyllithium in hexane (2.5 M, 12.87 mL, 32.2 mmol) was added dropwise. It was warmed to room temperature, stirred for 4 hours, and cooled again in the CO2/i-PrOH bath, and a solution of I2 (8.63 g, 34 mmol) in ether (50 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 1 hour, and quenched with an aqueous solution of NaHSO3 (10 wt %, 100 ml). It was diluted with saturated aqueous NaCl solution, extracted with EtOAc (50 mL×3 times). The organic extracts were combined, dried over anhydrous Na2SO4, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/EtOAc (95/5 to 90/10, v/v) as eluent to yield (6-iododibenzo[b,d]furan-4-yl)triphenylsilane (7.8 g, 62%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10](Cl)([Cl:12])=[O:11]>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:10]([Cl:12])=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cl)Cl
Reactant: c1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)n1nnc2ccccc21
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1H-benzo[d][1,2,3]triazole (0.5 g, 4.20 mmol) in tetrahydrofuran (25 ml) was added dropwise to a stirred 20% solution of phosgene (5.30 ml, 10.1 mmol) in toluene at 0-5° C. The reaction mixture was allowed to stir at 20-25° C. for 2 h (reaction complete by TLC). Argon was bubbled through the solution for 15 min. Then the solvent was evaporated in vacuum to give 1H-benzo[d][1,2,3]triazole-1-carbonyl chloride (0.763 g, 4.20 mmol) as a clear oil. The product was used without further purification. Pyridine (0.357 ml, 4.41 mmol) was added dropwise to a stirred solution of the oil in Tetrahydrofuran (25 ml) at 0-5° C. This was followed by a dropwise addition of N-methylcyclohexanamine (0.499 g, 4.41 mmol) at 0-5° C. The reaction mixture was allowed to stir overnight at 20-25° C. Water and EtOAc were added and the organic layer was separated, washed with 1M HCl, water and brine. The organic layer was dried (MgSO4) and evaporated in vacuum to give a clear oil. The oil was recrystallised from 2-propanol/DCM, the solid was collected, dried in vacuum at 40-45° C. Yield 230 mg (21%).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[C:27]#[C:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a mixture of triethylamine (60 mL) and tetrahydrofuran (20 mL) were added 1-iodo-2-methoxy-4-nitrobenzene (10 g, 35.8 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.503 g, 0.717 mmol). Phenylacetylene (4.48 g, 43.0 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture and the mixture was stirred for 5 minutes. Copper iodide (0.068 g, 0.358 mmol) was added, and the reaction mixture was stirred and purged with nitrogen for 10 minutes. The reaction flask was sealed and stirred for 2 hours at room temperature. The reaction mixture was treated with 200 mL of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo leaving a solid. The crude solid was recrystallized from absolute ethanol. The solid was collected by filtration and washed with cold ethanol and dried in vacuo to give the title compound as a tan solid (8.87 g, 98%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][C:12]([O:14][N:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[C:17]([OH:19])=O)=[O:13].[NH2:27][CH:28]1[C:46](=[O:47])[N:30]2[C:31]([C:43]([OH:45])=[O:44])=[C:32]([CH2:35][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.C(Cl)Cl.CN(C)C=O>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][C:12]([O:14][N:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[C:17]([NH:27][CH:28]1[C:46](=[O:47])[N:30]2[C:31]([C:43]([OH:45])=[O:44])=[C:32]([CH2:35][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12)=[O:19])=[O:13]
Reactant: O=C(Cc1cccs1)ON=C(C(=O)O)c1cccc(O)c1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)Cc3cccs3)c3cccc(O)c3)[C@H]2SC1
Temperature: -20 °C
Yield: 71.5 %

Procedure:
Dimethylformamide (0.4 g.), phosphorus oxychloride (0.81 g.), methylene chloride (20 ml.), ethyl acetate (10 ml.) and 2-[2-(2-thienyl)acetoxyimino]-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.68 g.) were treated in a manner as in example 1(B) to give an ethyl acetate solution. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.64 g.) and bis(trimethylsilyl)acetamide (3.55 g.) were dissolved in ethyl acetate (20 ml.) and stirred at -20° C., to which was added the above obtained solution. Then the reaction mixture was stirred for 1 hour at the same temperature. Water was added thereto and the mixture was stirred for 10 minutes. The ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. Two ethyl acetate layers were combined. The extract was washed with a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The residue was pulverized with a mixed solution of diisopropylether and ether, collected by filtration and washed to give 7-[2-{2-(2-thienyl)acetoxyimino}-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.2 g.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:32]([F:33])=[C:31]([NH2:34])[C:9]2[C:10](=[O:30])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[C:16]([F:29])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:35])(=O)C.[OH-].[Na+].O>CO>[NH2:34][C:31]1[C:9]2[C:10](=[O:30])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[C:16]([F:29])[CH:15]=3)[O:13][C:8]=2[C:7]([F:35])=[C:6]([CH2:5][OH:4])[C:32]=1[F:33]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCCN(C)C)c(F)c3)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCCC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of 1j (363 mg, 0.739 mmol) in methanol (36 mL) was added 1 mol/L sodium hydroxide (4 mL), and the mixture was stirred at room temperature for 20 minutes. Water was added thereto and the crystals precipitated were collected by filtration. Purification by silica gel column chromatography gave a free base of 1k (299 mg, 69%), which was converted into a hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:25]([C:32]1[S:33][C:34]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][C:35]=2[N:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:39]3[CH:38]=[CH:37][C:35]4[N:36]=[C:32]([CH2:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[S:33][C:34]=4[CH:40]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3nc(Cc4ccccc4)sc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c3c(N)ncnn23)CC1
Yield: 87 %

Procedure:
In a manner similar to the procedure described for step 7 of the preparation of Example 330 and using tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole as starting material, 510 mg (87%) of the desired product was isolated. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.97 (d, 1H), 7.81 (s, 1H), 7.51 (d, 1H), 7.38-7.32 (m, 5H), 7.56 (s, 1H), 4.41 (s, 2H), 4.12-4.04 (m, 2H), 3.81 (s, 2H), 3.32-3.28 (m, 1H), 2.88-2.82 (m, 2H), 2.01-1.96 (m, 2H), 1.60-1.52 (m, 2H), 1.38 (s, 9H); LC-MS m/z [M+H]+ 541.1, RT 3.40 min.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]1[O:14][CH:13]1[CH2:15][OH:16]>CO>[CH2:1]([NH:11][CH2:12][CH:13]([OH:14])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: OCC1CO1
Solvent: CO
Product: CCCCCCCCCCNCC(O)CO
Yield: 100 %

Procedure:
The procedures of Ulsperger et al., J. Prakt. Chemie, Vol. 27, pp. 195-212 (1965), the disclosures of which are hereby incorporated herein by reference in their entirety, were substantially followed. Specifically, 15.8 g decylamine (0.1M) and 7.4 g glycidol (0.1M) were mixed in 250 ml methanol at 60°-80° C. and refluxed for 10 hours. The methanol was rotary evaporated. The product was a semisolid, 23.2 g (yield 100%). After recrystallization with hexane, pure white solid DDP, m.p. 65°-67° C. (m.p.70°-70.5° C., lit.), was recovered.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1.C1COCC1.CO.[Li+].[OH-].Cl>CO>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN)n3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCCCOc1cccc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)n1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a solution of (R)-ethyl 5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (70 mg, 0.17 mmol) in 3:1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol) and the reaction mixture was heated at 70° C. for 20 hours. After cooling, the reaction mixture was diluted with MeOH, acidified with 1 N HCl (1.5 mL), and concentrated to afford the desired product (65 mg, 100% yield). MS (apci) m/z=383.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=S)[CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]#[N:10]>[Ni].CCO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]#[N:10]
Reactant: CN1C(=S)CC[C@H]1CC#N
Agent: [Ni]
Solvent: CCO
Product: CN1CCC[C@H]1CC#N

Procedure:
Raney-Ni (1.5 ml) was added to an EtOH (30 ml) solution of the 2-((2S)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (940 mg, 6.1 mmols), and the mixture was heated for 24 hours under reflux (upon TCL, the starting materials had not completely disappeared). The inorganic matter was filtered off, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (SiO2 40 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2S)-1-methylpyrrolidin-2-yl)ethanenitrile as a mixture (195 mg) with impurities difficult to separate.