Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].Br[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C>[CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:41]4[N:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: Brc1ncccn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ncccn4)cc3)oc2C)cc1
Temperature: 86 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
A 50 mL flask was charged with 2-methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionic acid ethyl ester (198 mg, 0.371 mmol), 2-bromopyrimidine (54 mg, 338 mmol), and 5 mL of isopropanol. The flask was purged with N2 three times. After 20 min, palladium acetate (3.0 mg, 0.04 mmol) and triphenylphosphine (3.5 mg, 0.04 mmol) were added. Following addition of a solution of sodium carbonate (43 mg in 1 mL H2O), the mixture was heated to 86° C. for 4 h. The solvent was removed under reduced pressure and the remaining residue taken up in CH2Cl2 (25 mL) and extracted with 0.5 N NaOH (25 mL). The aqueous layer was back extracted with an additional 25 mL CH2Cl2 and the organic layers combined. The organic layer was washed with 1 N NaOH (25 mL) and H2O (25 mL) and then dried and concentrated in vacuo. Flash chromatography provided 45.7 mg (28%) of desired product as a clear oil: 1H NMR (400 MHz, CDCl3) δ8.76 (d, 1 H), 8.45 (d, 2H), 8.06 (d, 2 H), 7.15 (t, 2 H), 6.76 (d, 2 H), 6.71 (d, 2 H), 4.18 (q, 2 H), 4.14 (t, 2 H), 2.93 (t, 2 H), 2.33 (s, 3 H), 1.45 (s, 6 H), 1.21 (t, 3 H); MS (EI) 488.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2nc(C)cs2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc(-c2ccc(C(=O)O)cc2C)n1

Procedure:
To a solution of methyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate (Step A, 6.0 g, 22.96 mmol) in 1,4-dioxane (5 mL) was added lithium hydroxide (1.65 g, 68.9 mmol) in water (5 mL). Once the reaction was deemed complete by LCMS, it was concentrated in vacuo. The residual white solid was washed with a mixture of dichloromethane/methanol (1/1), and filtered. The filtrate was concentrated to give the title compound as a white solid which was used in the next step without further purification. LCMS (M+H)+: 234.1
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[C@H:6]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:9]([F:12])([F:11])[F:10])#[N:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:45]2N=CC=C[C:44]=2N=N1.Cl.C1(N)CC1.[NH4+]>CN(C=O)C.C(OCC)C.C(N(CC)CC)C>[C:1]([C:3]1([NH:4][C:5](=[O:33])[C@H:6]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:7][C@@H:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:9]([F:10])([F:12])[F:11])[CH2:45][CH2:44]1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NCC#N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reaction time: 48 h

Procedure:
To a mixture of N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine from Example 8 (0.83 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.78 g), cyclopropylamine hydrochloride (0.466 g) in DMF (18 mL) at 0° C. was added triethylamine (0.9 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium cholride and diethyl ether. The ether layer was separated and the aqueous further extracted with diethylether. The combined ether extracts were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo. The residue was purified in SiO2 using ethyl acetate and hexanes (1:1) as eluant, followed by a swish in diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]#[CH:4].C[O:13][C:14]([CH3:16])=[CH2:15]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCCCCCC>[CH3:1][C:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[C:3]=[CH:4][CH2:15][C:14](=[O:13])[CH3:16]
Reactant: C#CC(C)(O)CCCC(C)C
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Product: CC(=O)CC=C=C(C)CCCC(C)C
Yield: 82 %

Procedure:
30.9 g 3,7-dimethyl-1-octin-3-ol, 28.9 g isopropenyl methyl ether and 60 ml n-heptane were initially introduced into a 250 ml flask and 25 mg pyridinium toluene-4-sulfonate were then added. The reaction mixture was stirred under reflux for 7 hours. During this period of time, 14.4 g isopropenyl methyl ether and 25 mg pyridinium toluene-4-sulfonate were added in two portions. When the reaction had ended, the solution was evaporated. The residue was distilled in vacuo. 31.9 g 6,10-dimethyl-4,5-undecadien-2-one were obtained, which corresponds to a yield of 82%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>>[Cl:13][C:14]1[C:15]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:25])([F:24])[F:26])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:32]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(OC(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethoxy)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 198.0-199.2° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.43 (d, 2H, J=9.1 Hz), 7.25 (d, 2H, J=9.1 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −59.4 (s, 3F), −79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 453 (M−H). ESHRMS m/z 452.9950 (M−H, Calc'd 452.9964). Anal. Calc'd for C18H9ClF6O5: C, 47.55; H, 2.00; Cl, 7.80. Found: C, 47.47; H, 1.89; Cl, 8.02.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=1.[CH3:13][NH2:14]>O1CCCC1.CO>[I:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([NH:14][CH3:13])=[N:3][CH:4]=1
Reactant: CN
Reactant: CCCNc1nc(Cl)ncc1I
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1nc(NC)ncc1I
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 46.3 mg) in tetrahydrofuran (0.5 mL), a 9.8 mol/L solution of methylamine in methanol (0.5 mL) was added at room temperature, the reaction vessel was sealed, and then by using a microwave reaction system, the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 27% hexane in ethyl acetate) to obtain 5-iodo-N2-methyl-N4-propylpyrimidine-2,4-diamine (F222, 32.4 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([N+:22]([O-])=O)[C:12](=[O:21])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:14]=1[CH3:15].Cl.[H][H]>CO.[Pt](=O)=O>[NH2:22][C@H:11]1[CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[F:1])[C@@H:14]([CH3:15])[N:13]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]1=[O:21]
Reactant: [H][H]
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])c(=O)n(CC(F)(F)F)c2C)c1F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Cc1cccc([C@@H]2C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F

Procedure:
A mixture of 5-(2-fluoro-3-methylphenyl)-6-methyl-3-nitro-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (1.95 g, 5.66 mmol), platinum(IV) oxide (0.643 g, 2.83 mmol), and concentrated aqueous hydrochloric acid solution (12 M, 4.72 mL, 56.6 mmol) in methanol (57 mL) was shaken under 50 psi of hydrogen at 23° C. for 5 h. The catalyst was removed by filtration through Celite® and washed thoroughly with methanol. The filtrate was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane initially, grading to 5% MeOH (basified 0.1% concentrated aqueous ammonium hydroxide solution) in dichloromethane to give the title compound as a racemate. The enantiomers were separated by normal-phase HPLC using a ChiralCel® OD column, eluting with 40% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second enantiomer to elute. MS: m/z=319.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11](O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:40][CH2:41][CH2:42][C:43]1[N:47]=[CH:46][NH:45][CH:44]=1>O1CCCC1.CO>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11]([NH:40][CH2:41][CH2:42][C:43]2[N:47]=[CH:46][NH:45][CH:44]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]cn1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To stirred solution of the product of step 1 (1.50 g, 4.34 mmol) in tetrahydrofuran (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.210 g, 5.25 mmol). After gas evolution ceased, p-toluenesulfonyl chloride (0.990 g, 5.20 mmol) was added and the mixture was stirred for 2 hours. At this time, histamine (1.93 g, 17.4 mmol) was added followed by methanol (10 mL). The reaction was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a pasty white solid. Flash chromatography over silica (methylene chloride/methanolic ammonia solution) provided 1.08 g (57%) of product as a colorless tacky foam: 1H NMR (CDCl3) δ 7.52-7.43 (m, 1H), 7.40-7.00 (m, 15H), 6.78-6.69 (m, 1H), 4.36-3.97 (m, 4H), 2.92-2.20 (m, 7H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>CO>[OH:14][C:15]1[C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: COc1c(Nc2cccc(C(=O)N3CCOCC3)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCOCC4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 72 h
Yield: 63.7 %

Procedure:
205 mg (1.13 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in solution in 3 ml of methanol were added to a suspension of 249 mg (0.75 mmol) of 3-[2-hydroxy-3-(morpholine-4-carbonyl)phenylamino]-4-methoxycyclobut-3-ene-1,2-dione in 22 ml of methanol. The reaction medium was then heated at 50° C. for two hours and stirred at ambient temperature for 3 days. The reaction medium was concentrated. The residue was taken up with ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (25 g prepacked column: eluent heptane/ethyl acetate from 80% to 100% of ethyl acetate). 0.23 g of product were obtained in the form of a yellow solid. Yield=64%, HPLC purity=98.01%
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][OH:52])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>[Ag]=O.CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][O:52][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
0.5 g of silver oxide were added at 20° C. to a mixture of 0.074 g of the product of Step B, 0.7 ml of dimethylformamide and 0.5 ml of tert.-butyl bromoacetate and the mixture was stirred for 30 minutes and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was added to 10 ml of water. The mixture was decanted and the aqueous phase was extracted with 5 ml of ethyl acetate. The combined organic phases were washed with 5 ml of aqueous sodium chloride solution, dried over magnesium sulfate and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was evaporated to dryness. The residue was taken up in isopropyl ether and efflorescenced. The mixture was vacuum filtered and the product was rinsed with isopropyl ether and dried to obtain 0.02 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-(tert.-butoxycarbonylmethyloxyimino)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with Rf=0.34 (methylene chloride containing 5% ether). The product was identical to the product of Example 3.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Anisole (6.75 g, 62.4 mmol) was dissolved in dichloromethane (80 ml). The mixture was cooled to −5° C. and aluminum chloride (8.32 g, 62.4 mmol) was added. 4-Chlorobutyryl chloride (8.8 g, 62.4 mmol) was added dropwise to the mixture at −10° C. and stirred at −10° C. for 1 hour. The reaction mixture was poured into iced water (100 ml). After separation, the organic layer was washed with 1N hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml), and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (12.7 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from N-(tert-butyl)-4-chloro-3-nitrobenzenesulfonamide (step 1) and 4-aminophenylethyl alcohol.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=4[O:31][CH3:32])=[CH:19][CH:18]=3)[CH:13]=2)[CH:8]=[N:7]1)C.O.[OH-].[Li+].CCOC(C)=O.Cl>C1COCC1.O>[F:30][C:26]1[C:27]([F:29])=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[N:7][N:6]4[CH2:5][C:4]([OH:33])=[O:3])=[CH:10][CH:11]=3)=[CH:22][CH:21]=2)=[C:24]([O:31][CH3:32])[CH:25]=1
Reactant: CCOC(=O)Cn1ncc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cnn(CC(=O)O)c3c2)cc1

Procedure:
[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid ethyl ester (0.095 g, 0.204 mmol) and lithium hydroxide hydrate (10 mg, 0.245 mmol) in 5 mL THF/1 mL H2O was stirred at RT for 6 hrs. The reaction was distributed between EtOAc and H2O. The water layer was made acidic to pH 3 with 1N HCl and the organic layer was separated and concentrated in vacuo. The crude product was purified by trituration with Et2O to yield [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid as a white solid. LC-MS (ES) calculated for C23H18F2N2O4, 424.41; found m/z 425 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:30]C)=[C:15]3[C:20]=2[C:19]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:18][C:17]([C:27]([OH:29])=[O:28])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:30])=[C:15]3[C:20]=2[C:19]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[N:18][C:17]([C:27]([OH:29])=[O:28])=[CH:16]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccc(C(C)(C)C)cc2)c2c(CC3CCCC3)nc(C(=O)O)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2ccc(O)c3cc(C(=O)O)nc(CC4CCCC4)c23)cc1
Temperature: 120 °C
Yield: 88.1 %

Procedure:
To a stirring solution of 8-(4-tert-butyl-phenyl)-1-cyclopentylmethyl-5-methoxy-isoquinoline-3-carboxylic acid (190 mg, 0.45 mmol) in 3 ml of DMF was added sodium ethane thiolate (383 mg, 4.5 mmol) and resulting mixture was heated at 120° C. for 4 h. Ethyl acetate was added (10 ml) to mixture and washed with 1 N HCl, water and brine and dried over Na2SO4. Evaporation of the solvent under vacuo gave 160 mg of the title compound as a thick liquid.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[S:11][CH2:12][C:13](/[CH:21]=[C:22]1/[C:23](=[O:46])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][N+:31]([CH2:34][C:35](=[O:45])[NH:36][C:37]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([F:44])[CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]/1)=[C:14]2[C:18]([OH:20])=[O:19].C[Si](N=C(O[Si](C)(C)C)C(F)(F)F)(C)C.[Br:62][CH2:63][C:64](Br)=[O:65].O>ClCCl.C(OCC)C>[Br:62][CH2:63][C:64]([NH:8][C@@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[S:11][CH2:12][C:13](/[CH:21]=[C:22]1/[C:23](=[O:46])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][N+:31]([CH2:34][C:35](=[O:45])[NH:36][C:37]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([F:44])[CH:38]=4)=[CH:32][CH:33]=3)[CH2:25][CH2:26]/1)=[C:14]2[C:18]([O-:20])=[O:19])=[O:65]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reactant: O=C(Br)CBr
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Reaction time: 3 h

Procedure:
To a suspension of 280.0 mg (0.42 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml dichloromethane were added 0.37 μl (1.40 mmol) N,O-bis-(trimethylsilyl)-trifluoroacetamide. After a clear solution had formed, 36.8 μl (0.42 mmol) bromoacetyl bromide were added and the reaction mixture was stirred for 3 h. To this solution 25.6 μl (1.42 mmol) water and 25 ml diethyl ether was added. The precipitate was filtered off and washed with diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: Oc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)Oc1cc(O)ccc1Br
Yield: 42 %

Procedure:
To a solution of 4-bromo-benzene-1,3-diol (1.50 g, 7.94 mmol) in acetone (10 mL) were added potassium carbonate (1.1 g, 7.94 mmol) and 2-iodopropane (1.58 mL, 15.87 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 4-bromo-3-isopropoxy-phenol (0.77 g, 42%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)([CH3:12])([CH3:11])[CH3:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][CH2:21][C:17]1[N:16]=[C:15]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)OC(C)(C)C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(CBr)n1
Yield: 17.2 %

Procedure:
N-bromosuccinimide (1.95 g, 10.99 mmol), 6-methylpicolinic acid tert-butyl ester (2.1175 g, 10.96 mmol), and benzoyl peroxide (0.27 g, 1.10 mmol, 0.1 eq.) were dissolved in CCl4 (150 mL) and refluxed for 6.5 hours while monitored by TLC (3:1 hexane: ethyl acetate, Rf=0.28). The reaction mixture was filtered and the solvent was removed in vacuo. The light orange oil was redissolved in DCM and extracted three times with an aqueous solution of saturated NaHCO3 (50 mL). The organic layer was dried with MgSO4 and the solvent was removed in vacuo. The crude product was recrystallised twice from a hexane/ethyl acetate mixture (3:1) in the freezer afford the mono-brominated product as small off-white crystals (0.511 g, 1.88 mmol, 17.1%). 1H NMR (300 MHz, CDCl3, δ): 7.92 (d, 1H, ortho-H), 7.82 (t, 1H, meta-H), 7.65 (d, 1H, ortho-H), 4.65 (s, 2H, CH2), 1.64 (s, 9H, tBu-CH3). 13C NMR (300 MHz, CDCl3, δ): 171.0, 161.0, 157.9, 138.4, 127.0, 124.4, 60.9, 33.9, 28.6.