Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3-(phenyl)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-aminopropylbenzene, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:19])[C:15]([F:17])([F:18])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCCCI
Reactant: CC(C)(C)C(=O)OCc1cc(=O)c(O)c(CO)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1c(CO)oc(COC(=O)C(C)(C)C)cc1=O
Yield: 27 %

Procedure:
To a solution of 1.84 g (0.028 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 6.76 g (0.026 mole) of 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone, and the resulting mixture heated to 50°. An 8.3 g (0.03 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 2.9 g (27%) of oily product, 2-hydroxy-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J = 7 Hz), 1.23 (9H, s), 2.30 (2H, t, J = 5.5 Hz), 6.32 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH3:22]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[N:11]([CH3:22])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCC1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (17.01 g, 69.1 mmol) in methyl sulfoxide (60 ml) was added sodium hydride (2.76 g as a 60% dispersion in oil, 69 mmol). The reaction mixture was stirred for 30 minutes prior to the dropwise addition of iodomethane (4.3 ml, 69.1 mmol). The reaction was stirred for 1 hour, was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.76 g of 1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=[O:7].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C.CCOCC>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:5][C:6](=[O:7])[CH:8]([CH3:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A sodium ethoxide solution (21% by weight in EtOH, 4.86 gm, 15 mmol) was added to a mixture of methylisopropylketone (8.61 gm, 100 mmol, from Aldrich) and 4-fluorobenzaldehyde (12.411 gm, 100 mmol, from Aldrich) in ethanol (150 ml). The solution was allowed to stir at room temperature for 3 hours. The solvent was evaporated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to give an orange oil. The oil was purified by distillation (bp=106° C. at 1.3 mm Hg) to afford the title compound as a pale yellow oil (10.118 gm, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]([C:16]1([OH:19])[CH2:18][CH2:17]1)=[O:15].[H-].[Na+]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1([O:19][C:4]2[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)C1(O)CC1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2nc(Cl)nc(Cl)c2OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4,6-trichloro-5-methoxy-pyrimidine (213 mg, 1.00 mmol) and 1-hydroxy-cyclopropanecarboxylic acid methyl ester (139 mg, 1.20 mmol) in THF (4 mL) was added sodium hydride (48 mg, 1.20 mmol, 60% dispersion in mineral oil) at −78° C. The resulting mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropanecarboxylic acid methyl ester as a white solid (300 mg, quantitative). LCMS: RT=3.49 min, [M+H]+=341/343/345.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:23]([OH:25])=[O:24])[C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
To a solution of sodium (0.95 g) in ethanol (80 ml) are added diethyl malonate (7.2 g) and 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate (13.7 g). The mixture is refluxed for 2 hours with stirring. After the further addition of a mixture of sodium (0.25 g), ethanol (25 ml) and diethyl malonate (1.8 g), the reflux is continued for further 2 hours. After evaporation of ethanol, the residue is diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract is dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oil. To a mixture of this ester and ethanol (30 ml) is added dropwise a solution of sodium hydroxide (6 g) in water (50 ml). After the addition is complete, the mixture is diluted with water (150 ml) and extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml). The organic extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oil. This acid is heated for 1 hour at 160°-165° C. with stirring. The resulting oil is purified by silica gel column chromatography using hexane-ethyl acetate (3:1-1:1) as an eluent to yield 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23]OS([O-])=O.[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.9 %

Procedure:
190 mg (0.59 mmole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide [prepared as described in Preparation 4(a)] were dissolved in 30 ml of methanol, and 10 ml of an aqueous solution containing 270 mg (1.77 mmole) of Oxone (trade mark) were added. The reaction mixture was stirred at room temperature for 5 days, after which it was poured into water and then extracted twice with chloroform. The organic extract was separated and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by thin-layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 175 mg (yield 88%) of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19](O)=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl.Cl>[C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19]([F:31])=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC1(C(=O)O)CC2(C#N)c3ccccc3C1c1ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C(=O)F)CC2(C#N)c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 9-cyano-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core A) (5.26 g, 18.2 mmol) and pyridine (2.2 mL, 27.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (2.14 g, 27.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 4.8 g (91%) of 9-cyano-9,10-dihydro-11-methyl-9,10-ethano-anthracene-11-carboxylic acid fluoride, Core B. MS found: (M+H)+=292.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[F-].[K+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1>[O:28]1[CH2:29][C@H:27]1[CH2:26][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (10 g, 0.15 mol) in THF (100 mL) was cooled to 0° C. and potassium fluoride (22 g, 0.3 mol) was added. After 1 h, (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.4 g, 0.17 mol) was added; the mixture was warmed to 25° C. and stirred for 16 h. The solution was filtered, washed with THF and concentrated. The crude product was used in next step without further purification. (15 g, yield 53%) MS (ESI+) e/z: 190.1 [M+1]+.
Reaction SMILES: C(O)C.[NH3:4].[Cl:5][C:6]1[C:11]([C:12](OC)=[O:13])=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[Cl:5][C:6]1[C:11]2[C:12](=[O:13])[NH:4][S:16](=[O:18])(=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(Cl)cccc1S(=O)(=O)Cl
Reactant: N
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Temperature: 60 °C

Procedure:
150 ml of ethanol saturated with ammonia were added dropwise over a period of 30 minutes to a solution of 38.2 gm (0.141 mol) of methyl 6-chloro-2-chlorosulfonyl-benzoate in 150 ml of dioxane at 30°-50° C. Subsequently, the reaction mixture was heated for 2 hours at 40° C. and for 2 hours more at 60° C. After cooling, the reaction mixture was evaporated, treated with ether and filtered. The filter cake was boiled with water, filtered while hot, and the filtrate was acidified with hydrochloric acid. Yield: 19.8 gm (64.5% of theory) of 4-chloro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O-])(O)=[O:10].[Na+].C=O.Cl>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OCc1ccc(O)c(Cl)n1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO3 (19.5 g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask. The flask is placed in an oil bath at 90° C., and after 5 min, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3×8 mL, then 2.2 mL all at 90-min intervals and then the final 2.3 mL after the reaction stirs for 15 h at 90° C. The reaction is stirred at 90° C. for another 4 h and then cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stirred for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc. The combined organic extracts are concentrated in vacuo, toluene is added to the flask and removed in vacuo to azeotrope water, and then CH2Cl2 is added and removed in vacuo to obtain 2-chloro-6-(hydroxymethyl)-3-pyridinol (C1) as a pale yellow solid (81% yield) sufficiently pure for subsequent reaction. MS (EI) for C6H6ClNO2, m/z: 159 (M)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:21][S:22][CH2:23]Cl>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][S:22][CH3:23])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CSCCl
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
6 G. of 1-acetamido-4-hydroxy-2-nitrobenzene is added to 200 ml. acetone containing 25 g. potassium carbonate and 6 ml. chloromethyl methyl sulfide. The mixture is heated at reflux for four hours and is filtered. The acetone is evaporated leaving 1-acetamido-4-methylthiomethoxy-2-nitrobenzene as a gum. This is purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:31]([CH3:32])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:22]4[CH2:21][CH2:20][N:19]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@@H:18]([CH3:17])[CH2:23]4)=[CH:30][CH:29]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCN(c2ccc(F)cc2)CC1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)C3CCN(c4ccc(F)cc4)CC3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The acid chloride from step 1 was taken up in DCM (2.5 mL) and added drop-wise to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.121 g, 0.38 mmol) in DCM (2.5 mL), followed by triethylamine (0.080 mL, 0.57 mmol). The reaction mixture was stirred for 3 h under argon, then the solvent was removed by evaporation. The residue was partitioned between DCM (30 mL) and water (30 mL). The aqueous was re-extracted with DCM (30 mL) and the combined organic layers were dried and concentrated to yield the title compound as a yellow oil. δH (CDCl3, 400 MHz) 7.40 (2H, d), 7.15 (2H, d), 6.89 (2H, m), 6.80 (2H, m), 4.20 (1H, br.s), 3.82 (1H, d), 3.50 (4H, m), 3.27 (3H, s), 3.10 (1H, m), 2.76 (1H, d), 2.58 (1H, d), 2.35 (3H, m), 2.17 (1H, m), 2.00 (3H, m), 1.70 (2H, d), 1.46 (9H, s), 1.22 (3H, d). MS (ES): MH+ 525.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[CH3:49][S:50]([N:8]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:10]2([CH2:11][CH2:12][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(S(C)(=O)=O)c1ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.134 g the intermediate from Step B in 5 mL of dichloromethane was added 0.080 mL of N-methylmorpholine, and 0.022 mL of methanesulfonylchloride and stirred at 0° C. for 30 min. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 20 g of silica gel gave 0.101 g of the desired product.
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC=O)=[O:12])([CH3:9])[CH3:8]>ClCCl>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)I
Reactant: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCOC=O)CS[C@H]12
Solvent: ClCCl
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12
Reaction time: 2 h

Procedure:
2.5 ml of iodotrimethylsilane are added at 0° to the solution of 7-trimethylsilylamino-3-(3-formyloxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester obtained in Example 2a) in dichloromethane, and the solution is stirred for 41/2 hours at 0°. The NMR-spectroscopic data are identical to the data given in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:29][CH2:30]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17][C@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]2[CH2:54][CH2:55]2)[CH:42]=1)[CH2:38][C:37]1[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=1[Cl:31])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A mixture of 2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoyloxy)acetic acid (0.215 g, 0.485 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (204 g, 0.485 mmol), EDC (0.279 g, 1.454 mmol), and DMAP (0.059 g, 0.485 mmol) in DCM (25 mL) was stirred at RT overnight. The mixture was diluted with DCM and washed with 1N HCl and 5% NaHCO3. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.326 g, 0.385 mmol, 80% yield, MS/ESI+ 845.1 [MH]+).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][S:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:3]>O>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]2[C:16]=1[C:2](=[O:3])[CH2:4][CH2:5][S:6]2
Reactant: COC(=O)c1ccc(Cl)cc1SCCC(=O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c2c1SCCC2=O
Reaction time: 0.5 h

Procedure:
At 70° C., 50 g (0.18 mol) of methyl 2-(2-hydroxycarbonyleth-1-yl)thio-4-chlorobenzoate were added to 500 g of polyphosphoric acid, and the mixture was stirred for a further 30 minutes. The reaction mixture was then stirred into water and the resulting precipitate was filtered off with suction and dried. This gave 41.1 g (88%) of methyl 5-chloro-4-oxothiochromane-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[N:8]2)=[CH:4][CH:3]=1>O1CCCC1.NN.[Ni]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccn(Cc2ccc(Cl)cc2)n1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccc(Cl)cc2)n1
Reaction time: 0.08 h

Procedure:
To a solution containing 1-(4-chloro-benzyl)-3-nitro-1H-pyrazole (101 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine as a yellow oil which was used in the following step with no further purification.