Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][O:6][CH2:5]1)[CH:2]=C.[OH2:10]>C(#N)C>[O:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:10])[CH2:5]1
Reactant: O
Reactant: C=CC[C@H]1CCCOC1
Solvent: CC#N
Product: O=CC[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a magnetically stirred solution of (R)-3-allyl-tetrahydro-2H-pyran (18.7 g, 148 mmol) in acetonitrile (740 mL) at room temperature was added RuCl3.2H2O (1.43 g, 5.92 mmol) in one portion. The resulting dark brown solution was stirred at room temperature for 5 min and then NaIO4 (69 g, 326 mmol) was added in one portion. H2O was added in small portions (10×8 mL) at 5 min intervals. The reaction was stirred at room temperature for 30 min, at which time it was judged complete by TLC. The reaction mixture was quenched by addition of saturated aqueous Na2S2O3 (250 mL) and H2O (1000 mL). The phases were separated and the aqueous phase was extracted with Et2O (4×400 mL). The combined with organic layers were washed with H2O, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as a yellow oil. The crude material was purified by flash chromatography (ISCO; 120 g column; Hexane to 40% EtOAc/Hexane) to provide (R)-2-(tetrahydro-2H-pyran-3-yl)acetaldehyde as a yellow oil (14.3 g, 111 mmol, 60%); 1H NMR (400 MHz, CDCl3) δ 9.78 (t, J=2, 1H), 3.84-3.88 (m, 2H), 3.40-3.47 (m, 1H), 3.17 (dd, J=11.2, 8.8 Hz, 1H), 2.31-2.41 (m, 2H), 2.21-2.28 (m, 1H), 1.88-1.93 (m, 1H), 1.61-1.72 (m, 2H), 1.29-1.33 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-(+)-3-hydroxy-tetrahydrofuran (0.34 mL, 4.2 mmol) and dry THF (20 mL) was added NaH (0.17 g, 4.2 mmol, 60%) under N2 at RT. After 5 min, added 2,6-dibromopyridine. Stirred at RT for 4 h. Quenched with H2O and extracted with EtOAc. Washed organic layer with saturated NH4Cl, brine, dried (MgSO4) and concentrated in vacuo to give 2-bromo-6-(tetrahydro-furan-3-yloxy)-pyridine as a clear, colorless oil. MS m/z: 245.2 (M+H). Calc'd for C9H10BrNO2-244.09.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1.C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:3][CH:4]=1)#[N:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
4-Aminobenzonitrile (98%, 500.0 g (4.15 mol) was dissolved in a mixed solvent of pyridine (360 ml) and acetonitrile (900 ml). To this, p-toluenesulfonyl chloride (872.3 g (4.44 mol)) was added with stirring at room temperature. After stirring for 16 hours at room temperature, water (4000 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 1153 g (98%) of 4′-cyano-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: ClC1C=CC(NN=CC)=CC=1N[S:13]([CH3:16])(=[O:15])=[O:14].ClC1C=CC([N+]([O-])=O)=CC=1N.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[N:38]([S:13]([CH3:16])(=[O:15])=[O:14])[S:39]([CH3:42])(=[O:40])=[O:41]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC=NNc1ccc(Cl)c(NS(C)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Agent: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc([N+](=O)[O-])ccc1Cl)S(C)(=O)=O
Temperature: 0 °C

Procedure:
To prepare the starting material, acetaldehyde 4-chloro-3-methylsulfonylaminophenylhydrazone, a mixture of 20.0 5 (116 mmoles) of 2-chloro-5-nitroaniline (compound 4, FIG. 1), 24.6 g (243 mmoles) of triethylamine and 100 ml of methylene chloride was cooled in an ice bath, and a solution of 27.8 g (243 mmols) of methylsulfonyl chloride in 20 ml of methylene chloride was added dropwise. When the addition was about half complete the ice bath was removed. After completion of the addition, the mixture was allowed to stand for an hour and then filtered to remove undesired salts. The filtrate was evaporated under reduced pressure to give a yellow solid which was washed with 100 ml of water; the filter cake was then mixed with 100 ml of ethanol and then filtered rapidly, and the resulting off-white solid was dried in vacuo to give 32.7 g of 2-chloro-5-nitro-1-bis(methylsulfonyl)amino-benzene. The latter was then mixed with 50 ml of ethanol; 8 g of NaOH in 20 ml of water was added slowly with stirring, after which the mixture was diluted with 300 ml of water followed by the addition of 45 ml of 6N HCl, yielding a precipitate which was collected by filtration and dried in vacuo to give 24.3 g of 2-chloro-5-nitro-1-methylsulfonylaminobenzene (compound 4, FIG. 1). The latter material was reduced with iron powder to form 17.7 g of 4-chloro-3-methylsulfonylaminoiline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[N:36]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([NH:43][CH2:42][CH2:41][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 37.2 %

Procedure:
Following General Procedure R, the title compound (21 mg, 49%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid (48 mg, 0.085 mmol), 2-(pyrrolidin-1-yl)ethanamine (16 μl, 0.13 mmol), EDC (32 mg, 0.17 mmol) and DMAP (cat.) in DMF (2 ml).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].NN=CNC1C=C(C(NCC([NH:24][CH:25]([C:30]2[CH:42]=[CH:41][C:40]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C:32]=3[CH:31]=2)CC(O)=O)=O)=O)C=CC=1.Cl.[CH3:44][CH2:45]O>>[NH2:24][CH:25]([C:30]1[CH:42]=[CH:41][C:40]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C:32]=2[CH:31]=1)[CH2:2][C:3]([O:5][CH2:44][CH3:45])=[O:4]
Reactant: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3c(c2)Cc2ccccc2-3)c1
Reactant: O=C(O)C(F)(F)F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(N)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
The product from Step A was taken up in absolute EtOH, dry HCl gas was added to saturation, and the mixture refluxed overnight. Volatiles were removed and the resulting semi-solid partitioned between ethyl acetate and water. The aqueous layer was made basic by addition of 2.5N NaOH and extracted with EtOAc (2×200 mL). The organic layer was dried (anhydrous NaSO4) and dry HCl gas added until precipitation ceased. Volatiles were removed until a semisolid residue remained. This was triturated with diethyl ether to obtain a solid that was collected by filtration. NMR and MS were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](N2C=CN=C2)=[O:12])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:22][C:21](=[O:30])[NH:20]1.C1CCN2C(=NCCC2)CC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([N:20]2[C@@H:19]([CH3:18])[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]2=[O:30])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C([C@@H]1C[C@@H]1c1ccc(Br)cc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
A mixture of (cis)-1-{[2-(4-bromophenyl)cyclopropyl]carbonyl}-1H-imidazole (1 eq) from Step 1, (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.2 eq) or (−)-isomer and DBU (added at 0° C., 1.2 eq) in CH3CN (0.2M) was stirred at 0° C. for 4 h. The solvent evaporated and residue purified by flash chromatography (Hexane:EtOAc; 100:0 to 80:20) to afford each diastereoisomer.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([CH2:22][NH:23][C:24]2[C:25]([S:43][CH3:44])=[N:26][N:27]3[C:32]([C:33]4[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])=[CH:31][CH:30]=[CH:29][C:28]=23)[CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:19]1([CH2:22][N:23]([C:24]2[C:25]([S:43][CH3:44])=[N:26][N:27]3[C:32]([C:33]4[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])=[CH:31][CH:30]=[CH:29][C:28]=23)[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][CH:10]=2)[CH2:20][CH2:21]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C(=O)c3cccnc3)c(SC)nn12
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Triethylamine (0.038 mL) and chloronicotinic acid hydrochloride (20 mg) were added to a solution of N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (33 mg) in dichloromethane (0.8 mL) while cooling on ice, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added while cooling on ice, extraction was performed with ethyl acetate, and the extract washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:2) to obtain the title compound (36 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)([Cl:18])=O.[CH:20]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[ClH:18].[CH:20]([N:33]1[CH2:38][CH2:37][N:36]([C:7](=[O:9])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:3]=2[O:2][CH3:1])[CH2:35][CH2:34]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: O=S(Cl)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
In 100 ml of chloroform was suspended 25 g (120 millimoles) of 2,4-dimethoxycinnamic acid. At room temperature, 44 ml (about 600 millimoles) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for 1.5 hours, and the excess of thionyl chloride and chloroform were distilled off. The residue was diluted with 200 ml of chloroform, and added dropwise at room temperature to 300 ml of of a chloroform solution of 30.2 g (120 millimoles) of benzhydrylpiperazine and 24.3 g (240 millimoles) of triethylamine. The mixture was stirred at room temperature for 3 hours, and then a 10% aqueous solution of sodium bicarbonate was added. The mixture was shaken and the organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting oily product was diluted with 200 ml of ethanol, and 15 ml of concentrated hydrochloric acid was added. The crystals precipitated were collected by filtration. Recrystallization from hydrous methanol gave 22.7 g (yield 39.5%) of 1-benzhydryl-4-(2,4-dimethoxycinnamoyl)piperazine hydrochloride as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2](=[N:49]C(OCC(C)=C)=O)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:33][O:34][C:35]([O:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:36])[N:29]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.CN(C=O)C>[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.C(O)(=O)C>[C:18]([OH:20])(=[O:17])[CH3:19].[C:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:33][O:34][C:35]([O:37][CH:38]([CH2:39][CH3:40])[CH2:41][CH3:42])=[O:36])[N:29]([C:43]3[N:44]=[CH:45][CH:46]=[CH:47][N:48]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1)(=[NH:1])[NH2:49]
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(CC)CC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(CC)OC(=O)OCOc1nc([C@H](Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of acetic acid 2-(3-{(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-[5-(1-ethylpropoxycarbonyloxymethoxy)-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl]methyl}-2-fluoro-5-methoxyphenoxy)ethyl ester (Example 51, 266 mg), DMF (2 mL) and acetic acid (0.196 mL), tetrakis(triphenylphosphine) palladium (0) (20 mg) was added, and the resulting mixture was stirred overnight at an external temperature of 45° C. After cooling the mixture to room temperature, the reaction solution containing the captioned compound was divided into 4 equal lots, and used for the following reactions.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:26])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccc(C)cc3)c(O)cc21
Temperature: 25 °C

Procedure:
A solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester in a little methylene chloride is first slowly added dropwise, at 0° C. to 10° C., to a suspension of 66.8 g of finely powdered aluminium chloride in 100 ml of methylene chloride, which is being stirred under anhydrous conditions; 46.3 g of p-methylbenzoyl chloride are then added dropwise under such conditions that the reaction mixture boils gently under reflux. After completion of the addition, the mixture is heated to the boil for a further 31/2 hours. It is then allowed to cool to room temperature, poured onto 500 g of ice and extracted with twice 500 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo (finally in a high vacuum). The evaporation residue, when crystallised from cold ether-petroleum ether, gives 5-(p-toluoyl)-6-hydroxyindane-1-carboxylic acid methyl ester which after a further crystallisation from ethanol-petroleum ether, melts at 74°-76° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]([CH3:73])[N:70]=[CH:71][N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]([CH3:73])[N:70]=[CH:71][N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1ncnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.73 g: 1.64 mMol.) in dimethylformamide (15 ml) is added at -20° C. phosphorus trichloride (0.41 ml: 4.08 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into cold two layers of aqueous sodium hydrogen carbonate and ethyl acetate and stirred. The organic layer is taken, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.60 g) as dark brown foam. Yield: 94%.
Reaction SMILES: C(O)(=O)C.[C:5]1([CH3:19])[CH:10]=[CH:9][C:8]([O:11][C:12]2[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:17]/[C:15]1[S:16][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH3:19])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)([O-:22])=[O:21]
Reactant: Cc1ccc(Oc2ccc(C=O)s2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
To an acetic acid (20.0 mL) solution of 5-p-tolyloxy-thiophene-2-carbaldehyde (2.30 g, 10.5 mmol) described in Manufacturing Example 48-1-2 were added nitromethane (3.20 g, 52.5 mmol) and ammonium acetate (1.62 g, 21.0 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure to obtain the title compound (2.50 g) as a crude product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[O:20][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)CCc1cc(Cl)c(O)c(OC)c1
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)OCC)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Yield: 102.2 %

Procedure:
To a stirring solution of (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (66 mg, 0.21 mmol) and ethyl 3-[3-chloro-4-hydroxy-5-(methyloxy)phenyl]propanoate (78 mg, 0.30 mmol) in THF (4 mL) at 0° C. under nitrogen was added ADDP (100 mg, 0.40 mmol) followed by nBu3P (0.10 mL, 0.40 mmol). The resulting mixture was then stirred at 0° C. with slow warming to ambient temperature over 19 h and then reduced under vacuum (Genevac). The residue was then purified by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) to afford the title compound (118 mg).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:18](OC)=O)=[C:16]([CH2:22][CH3:23])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1N=CN=C(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)C=1CO)C.C(N(S(F)(F)[F:51])CC)C>>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][F:51])=[C:16]([CH2:22][CH3:23])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(=O)OC
Agent: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1CO
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CF

Procedure:
This compound can be prepared starting from 5-carbomethoxy-4-(cis-4-tert-butylcyclohexylamino)-6-ethylpyrimidine (Example 5) by reduction to the 5-hydroxymethyl compound (in analogy to Example 37) and fluorination with diethylaminosulfur trifluoride (DAST).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:30])[C:15]([CH2:28][CH3:29])=[C:16]([C:26]#[N:27])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1)=[O:12])[CH3:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:30])[C:15]([CH2:28][CH3:29])=[C:16]([C:26]#[N:27])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(-c2ccc(CO)cc2)c(C#N)c(CC)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(COS(C)(=O)=O)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Add triethyl amine (0.053 g, 0.53 mmol) to a solution of 4-cyano-5-ethyl-3(4-hydroxymethyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.15 g, 0.48 mmol, prepared directly above) in dichloromethane (5 mL) at 0° C. under nitrogen, followed by drop-wise addition of methanesulfonyl chloride (0.06 g, 0.53 mmol). Stir at 0° C. for 1.5 h. Add ice-water and dichloromethane. Separate phases and wash organics with water. Combine aqueous layers and back-extract aqueous phase with more dichloromethane. Combine organic phases, wash with brine, dry (sodium sulfate), filter and concentrate in vacuo, to give 0.181 g of title compound for use without further purification. 1H NMR (CDCl3, δ (ppm)): 7.46-7.38 (m, 4H); 5.28 (s, 2H), 4.09 (q, J=7.1 Hz, 2H); 3.89 (s, 3H); 2.93 (s, 3H); 2.85 (q, J=7.5 Hz, 2H); 1.30 (t, J=7.7 Hz, 3H); 1.00 (t, J=7.1 Hz, 3H).