Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:32]([CH2:31][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:33]
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(CC#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), 2-bromoacetonitrile (8 uL, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-(cyanomethyl)piperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 175. MS m/z 427.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.37(d, 1H), 7.94(s, 1H), 7.87(d, 1H), 7.68(d, 2H), 7.55(s, 1H), 7.48-7.44(m, 3H), 7.36(dd, 1H), 3.74(s, 2H), 3.67(s, 2H), 3.17(t, 4H), 2.69(t, 4H), 2.54(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[CH:22]=[CH:21][CH:20]=2)=[C:8]([CH2:17][CH2:18][CH3:19])[C:9]=1[OH:16])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 100 °C
Yield: 67.8 %

Procedure:
Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.65 g, 5.51 mmol), 3-bromo-benzonitrile (912 mg, 5.01 mmol), cesium carbonate (2.29 g, 7.01 mmol), and 18-crown-6 (132 mg, 0.501 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl] (468 mg, 0.752 mmol), and palladium acetate (112 mg, 0.501 mmol). Purge reaction vessel with argon. Heat to 100° C. for 18 hours and cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with 30% ethyl acetate:hexanes to yield a yellow oil (1.36 g, 68%): 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 5.86 (bs, 1H), 6.49 (d, 1H), 7.06 (m, 2H), 7.15-7.21 (m, 3H), 7.27-7.37 (m, 3H), 7.59 (d, 1H), 12.75 (s, 1H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CSC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A 21.56 g (86.55 mmol) sample of the compound from step 24a above was dissolved in 200 mL of THF, and the solution was cooled to 0° C. BH3 -dimethyl sulfide (86.5 mL, 2N) was added dropwise under a nitrogen atmosphere. The reaction was stirred at room temperature for 16 hr, then cooled to 0° C. and quenched by careful addition of 10% acetic acid in methanol. The mixture was reduced in volume on a rotary evaporator, and the concentrate was dissolved in ethyl acetate, which was washed successively with 1N HCl, water and sodium bicarbonate solution. The organic extract was dried over Na2SO4 and concentrated to afford the title product, 19.94 g (98% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O:11][C:12](=[O:16])[C:13]#[C:14][CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:10][O:11][C:12](=[O:16])/[CH:13]=[C:14](/[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)\[CH3:15]
Reactant: N#Cc1cccc(O)c1
Reactant: CC#CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)Oc1cccc(C#N)c1
Yield: 75.6 %

Procedure:
To a stirred mixture of 3-hydroxy-benzonitrile (3.30 g, 0.028 mol) and methyl-2-butynoate (5.40 g, 0.055 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.20 g, 0.028 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(3-cyano-phenoxy)-but-2-enoic acid methyl ester as an oil (4.60 g, 76%) and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCBr

Procedure:
A mixture of 4.13 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 7.6 ml of 1,3-dibromopropane and 3.0 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone was stirred at reflux for 73 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 19 hours at which time 1.0 g of potassium carbonate was added. After 16 hours reflux, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was chromatographed on 200 g of silica gel and eluted with 15% ethyl acetate-toluene to give 4.82 g of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:36]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:17](=[O:35])[N:18]([CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[C:11]([F:54])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(NCC)C>C(OCC)(=O)C>[NH2:36][C@@H:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[F:54])[C:17]([N:18]([CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:35]
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1F)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1F)OCC
Yield: 93 %

Procedure:
To a mixed solution of 9H-fluoren-9-ylmethyl N-((1S)-2-(4-(benzyloxy)-2-fluorophenyl)-1-((2,2-diethoxyethyl)((6-fluoropyridin-2-yl)methyl)carbamoyl)ethyl)carbamate described in Production Example 1-1-2 (14.4 g) and THF (30 mL) was added diethylamine (5.27 mL, 50.4 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under a reduced pressure, methanol, water and heptane were added to the residue, and the resultant mixture was partitioned. An aqueous layer was washed with heptane, and was then concentrated under a reduced pressure. Water was added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, and then ethyl acetate) to give the title compound (6.87 g, yield: 93%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH2:11][CH3:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=1)=[O:4].C(O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(N(CC)CC)C>[CH2:11]([N:10]1[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9]1)[CH3:12]
Reactant: CCn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1CC
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a 25 ml flask was added (S)-2-amino-N-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-phenylpropanamide 101.1.B (132 mg, 0.39 mmole), 3 ml of ethanol and 0.08 ml of triethylamine. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (48 μl, 0.43 mmole) was added to the mixture. The reaction was stirred at 50° C. for 1 hour and at room temperature overnight. After then, the solution was concentrated, and dissolved in ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 101.1.C (45 mg, 27% yield) as colorless amorphous. 1H NMR (400 MHz, CDCl3) δ ppm 9.73 (s, 1H), 8.61 (d, J=5.9 Hz, 2H), 7.69 (d, J=6.3 Hz, 2H), 7.38-7.26 (m, 5H), 6.87 (s, 1H), 4.19-4.04 (m, 4H), 3.54 (dd, J=8.4, 4.5 Hz, 1H), 3.42 (d, J=17.6 Hz, 1H), 3.32 (d, J=17.6 Hz, 1H), 3.35 (dd, J=14.1, 4.5 Hz, 1H), 3.00 (dd, J=14.1, 8.2 Hz, 1H), 2.05 (brs, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14]>[Pd].C(OCC)(=O)C>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[C:3](=[O:14])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Nc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Palladium on activated carbon (10%, 129 mg, 121 μmol) was added to a solution of 3,3-dimethyl-6-nitroindolin-2-one (J.-P. Hölck et al., 1987, U.S. Pat. No. 4,666,923 A1; 500 mg, 2.42 mmol) in ethyl acetate (100 ml). The mixture was stirred at 70° C. under an hydrogen atmosphere (balloon) for 48 hours. The catalyst was filtered off, washed with ethyl acetate and the solvent was evaporated. The title compound was obtained as orange powder (427 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:28])[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:15]1[NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[N:17][CH:16]=1)[CH:27]=[CH:26]2
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.03 g) was dissolved in dichloromethane (75 mL), and trifluoroacetic acid (25 mL) was added. The reaction mixture was stirred at ambient temperature for 5 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (50 mL) and extracted with saturated NaHCO3 solution (50 mL). Solid was collected by vacuum filtration, washed with dichloromethane, and dried under vacuum, giving 5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl-1H-imidazole (98%) as an off-white solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCSc2ccccc2)c1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCS(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.8 gm (0.0074 mol) of 2-[2-(2-phenylthioethoxy)-4-methoxyphenyl]imidazo[4,5-b]pyridine in 40 ml of glacial acetic acid was admixed with 0.84 gm of hydrogen peroxide (30%), and the mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was diluted with 20 ml of water, neutralized with potassium carbonate, extracted three times with 50 ml each of methylene chloride, and dried over magnesium sulfate. The purification was carried out on 70 gm of silicagel with methylene chloride/acetone (100:0 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(O)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl

Procedure:
A mixture of 2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoic acid (50 mg) in thionyl chloride (1 ml) was stirred at reflux for 1 hour. The mixture was concentrated under vacuum to provide 50 mg of the title intermediate as an amorphous amber solid that was used immediately in the next step.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:36]>C1COCC1.CCOC(C)=O>[NH2:36][CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:23][N:22]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Temperature: 40 °C
Yield: 94 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (1.2 g, 2.37 mmol) in THF (40 ml) was treated with concentrated ammonia solution and heated in a bomb at 40° C. for 18 hours. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 solution followed by brine. The organic extract was dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. The colourless oil was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (4:1) gradually changing to (1:1) and then changing to DCM:MeOH:NH3 (95:5:0.5) to afford the title compound as a colourless oil (782 mg, 94%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:17]([CH:20]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C=O.O1CCC[CH2:64]1.C(OCC)(=O)C>C(OCC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:41])=[C:17]([CH:20]=[CH2:64])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: C1CCOC1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
A mixture of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (syn isomer) (2.2 g), 36% aqueous formaldehyde (20 ml) and tetrahydrofuran (60 ml) were stirred at ambient temperature for 12.5 hours. After addition of ethyl acetate (100 ml) to the reaction mixture, the organic layer was separated out, washed with 10% hydrochloric acid and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether, and chromatographed on silica gel using chloroform and then a mixture of chloroform and acetone (19:1 and 9:1 by volume) as an eluent. The fractions containing the desired compound were collected and evaporated to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.25 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: OCCCSc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Hydroxy-propylsulfanyl)-phenol (CAB02029, 3.686 g, 20 mmol) was dissolved in ethanol (50 mL) and potassium tert-Butoxide (2.80 g, 25 mmol) and benzyl bromide (3.0 mL, ca. 25 mmol) were added. The mixture was stirred overnight at room temperature, the precipitated potassium bromide was filtered off and the filtrate was concentrated under reduced pressure. The resulting yellow solid was dissolved in ethyl acetate (100 mL), the solution was washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (ca. 10 mL) and the product was precipitated by addition of hexane (ca. 200 mL). The crystalline product was collected and dried under high vacuum. Yield: 4.481 g (82%) colourless, small plates. 1H-NMR (400 MHz, CDCl3) δ=1.45 (br s, 1H, —OH), 1.82-1.87 (m, 2H), 2.84 (t, J=7.4 Hz, 2H), 3.74-3.78 (m, 2H), 5.05 (s, 2H, —OCH2Ph), 6.90-6.93 (m, 2H), 7.31-7.44 (m, 7H).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:26][C:27]1[N:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:26][C:27]1[N:35]=[CH:34][C:33]([I:1])=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CCCOc1ncccc1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 ml) and trifluoroacetic anhydride (25 ml) were added to 2-propoxynicotinic acid (0.054 mol). The mixture was refluxed for 2.5h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a solid; 1H NMR (300 MHz, CDCl3): δ=1.05 (t, 3H), 1.85-2.0 (m, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s, 1H), Analysis: found C, 35.16; H, 3.19; N, 4.46. Calcd for C9H10INO3: C, 35.19; H, 3.28; N, 4.56%; LRMS (TSP): 529.5 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>C1COCC1>[Cl:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate 116 (85.0 g, 379 mmol) and diisopropylethylamine (296 g, 2.27 mol) in THF (850 mL) was added methanesulfonyl chloride (130 g, 1.14 mol) over a period of 30 min at 0° C. The mixture was stirred for 12 h at room temperature then washed with H2O (2×100 mL) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give 117 (30 g, 63% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[CH:7]=[CH:6][CH2:5]1>C(O)(=O)C>[Br:1][C:7]1[C:8]([OH:14])=[C:9]([C:4]([CH3:3])=[CH:5][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1C(=O)C=CCC1C
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1c(C)ccc(Br)c1O

Procedure:
A solution of bromine (16.8 ml) in acetic acid (150 ml) was added dropwise to a stirred and cooled solution of methyl 6-methyl-2-oxocyclohex-3-enecarboxylate (prepared according to Hauser et al, Synthesis 1980 814, 28.2 g) in acetic acid at 0° C. The resultant mixture was stirred and heated at reflux for 24 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with sodium bicarbonate (saturated aqueous solution) and brine, then dried (MgSO4 and activated charcoal) and filtered through Celite. The filtrate was evaporated to dryness to give methyl 3-bromo-2-hydroxy-6-methylbenzoate (30.8 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].CCN=C=NCCCN(C)C.Cl.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:10]([F:11])([F:13])[F:12])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 73.8 %

Procedure:
To a solution of 4-(5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-ylamino)benzoic acid (Preparation 259, 116 mg, 0.27 mmol) in dichloromethane (5 mL) was added 4-dimethylaminopyridine (50 mg, 0.41 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (77 mg, 0.41 mmol). The solution was stirred for 25 minutes at room temperature and methanesulfonamide (39 mg, 0.41 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature. The solution was concentrated in vacuo and the material was purified by reverse phase chromatography eluting with acetonitrile:water (from 5:95 to 95:5, 30 minutes gradient followed by 5 minutes isocratic) to afford the title compound as a white solid (98 mg, 74%).