Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]2.[CH3:15][O:16]C(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]([CH:15]=[O:16])=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7]2
Reactant: Cc1cc(Cl)c2c(c1C)CC(C)(C)C2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c2c(c(Cl)c1C=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 17.0 g of the 7-chloro-2,2,4,5-tetramethylindane in 100 ml of dry dichloromethane was continuously added 18.5 ml of α,α-dichloromethyl methyl ether and 11 ml of TiCl2 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 14.7 g of the title compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7](Cl)=[N:6][C:5]2=[C:10]([C:13]#[N:14])[C:11]=1[CH3:12].[CH:16]([N:19](C(C)C)[CH2:20]C)(C)C.CNC>ClCCl>[Br:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([N:19]([CH3:20])[CH3:16])=[N:6][C:5]2=[C:10]([C:13]#[N:14])[C:11]=1[CH3:12]
Reactant: Cc1c(Br)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: Cc1c(Br)c(F)c2oc(N(C)C)nc2c1C#N
Yield: 56.3 %

Procedure:
6-Bromo-2-chloro-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-167) (1.93 g, 6.67 mmol) was dissolved in dichloromethane (40 ml), then diisopropylethylamine (1.20 ml, 7.06 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 5.00 ml, 10.0 mmol) were added. After stirring with heating under reflux overnight, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, then the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a yellow solid (1.12 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:26]3[CH2:25][CH2:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=4)([OH:29])[CH2:28][CH2:27]3)[C:6]=2[CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 5.6 parts of 6-chloro-1-(3-chloro-propyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.2 parts of 4-(4-chloropheny)-4-piperidinol, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 3.5 parts of 6-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 180.6° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl>CC(O)(C)C.C1C=CC=CC=1>[CH2:15]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][C:7]2=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: O=C1CCCCC12CCCC2
Temperature: 120 °C

Procedure:
In a flask containing potassium tert-butoxide (45.7 g, 407.6 mmol) in t-BuOH (200 mL) and Benzene (150 mL) was added cyclohexanone (20.0 g, 203.8 mmol) and 1,4-dibromobutane (44.0 g, 203.8 mmol). The solution was heated at 120° C. for 6 hrs. The mixture was cooled to room temperature and neutralized with HCl (1N). The solution was extracted with ether, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (1% EtOAc/hexanes) to afford the title compound: GCMS ES+=153.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Cl:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Cl:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Cl)cc4Cl)cc3n2C)c1
Yield: 51.5 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (7.81 g, 25.0 mmol), 3,5-dichloro-2-fluoropyridine (4.57 g, 27.5 mmol), copper iodide (0.48 g, 2.50 mmol), 1,10-phenanthroline (0.45 g, 2.50 mmol), cesium carbonate (24.44 g, 75.0 mmol) and DMF (100 mL) to obtain the title compound (5.90 g, 53%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14])(C)(C)C>Cl.CC(O)C>[ClH:14].[NH2:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cccc(O)c2)ccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(-c2cccc(O)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (4-chloro-3′-hydroxy-biphenyl-3-yl)-carbamic acid tert-butyl ester (1.8 g, 5.64 mmol) was dissolved in a solution of HCl in i-PrOH (5-6M, 20 mL). The resulting solution was stirred at RT for 6 hrs then concentrated to provided 3′-amino-4′-chloro-biphenyl-3-ol hydrochloride.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][O:4][C:5]1[C:6]([C:22]([C:25]2[N:29](COCC[Si](C)(C)C)[C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)([OH:24])[CH3:23])=[C:7]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10](C(OC(C)(C)C)=O)[CH:9]=[CH:8]2.NC(=O)COC1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C)=C2C(=C(C)C=1)N(C(OC(C)(C)C)=O)C=C2>>[C:42]([C:40]1[CH:39]=[CH:38][C:28]2[NH:29][C:25]([C:22]([C:6]3[C:5]([O:4][CH2:3][C:2]([NH2:1])=[O:44])=[CH:13][C:12]([CH3:14])=[C:11]4[C:7]=3[CH:8]=[CH:9][NH:10]4)([OH:24])[CH3:23])=[N:26][C:27]=2[CH:41]=1)#[N:43]
Reactant: Cc1cc(OCC(N)=O)c(C(C)(O)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: Cc1cc(OCC(N)=O)c(C(C)(O)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Product: Cc1cc(OCC(N)=O)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 5-(2-amino-2-oxoethoxy)-4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 5-(2-amino-2-oxoethoxy)-4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate as described in Example 24-B. 1H NMR (TFA salt, 400 MHz, MeOH-d4) δ ppm 8.04 (s, 1H) 7.63-7.85 (m, 2H) 7.31 (d, J=3.28 Hz, 1H) 7.01 (d, J=3.28 Hz, 1H) 6.69 (s, 1H) 4.37-4.49 (m, 1H) 4.24-4.35 (m, 1H) 2.49 (s, 3H) 2.31 (s, 3H). HRMS calcd. for C21H19N5O3 (M+H)+ 390.1561. found 390.1561.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=O)C.[H-].CO.O>C1(C)C=CC=CC=1>[F:23][C:20]([F:21])([F:22])[S:17]([O:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH:4]=[O:3])[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2n1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=Cc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 4-trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid ethyl ester (4.5 g, 12.88 g) in toluene (80 mL) was added slowly under argon at −78° C. diisobuthylaluminum hydride (1.5M in toluene, 12.88 mL, 19.33 mmol). The reaction mixture was stirred at −78° C. for 1 hour. Methanol (13 mL) was added slowly followed by water (26 mL). The reaction mixture was slowly warmed up to room temperature extracted with ethylacetate and washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (5–10% ethylacetate in hexane) to give 2.9 g of 4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (74%). 1H NMR (300 MHz; DMSO-d6): 8–8.2 (m, 4 H), 8.43 (m, 1 H), 10.05 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([C:32]#[N:33])[N:23]=1>CN1C(=O)CCC1>[C:32]([C:24]1[N:23]=[C:22]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:31]2[C:26]([CH:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2)#[N:33]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (444 mg, 2.206 mmol) and Cs2CO3 (719 mg, 2.206 mmol) in NMP (4 mL) were stirred at 0° C. for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (400 mg, 2.121 mmol) was added and the reaction mixture was heated at 140° C. for 15 minutes in a microwave reactor. Additional Cs2CO3 (719 mg, 2.206 mmol) was added. The reaction mixture heated at 140° C. for 1 hour to give the title compound, which was used directly in the next step.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9]>C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2]1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=C1C=CCCC1
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCC(NC(=O)OCc2ccccc2)C1
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of 2-cyclohexen-1-one (1.442 g, 15.0 mmol) in anhydrous methylene chloride (15 mL) was added bis(acetonitrile)dichloro-palladium(II) (0.231 g, 1.0 mmol) and benzyl carbamate (1.497 g, 9.9 mmol) and stirred under nitrogen for 24 hrs. The reaction mixture was filtered through a pad of silica gel, washing with ethyl acetate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-65% ethyl acetate/hexanes) to give a pale yellow low melting solid (1.9 g). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 4.81 (br s, 1H), 3.99 (br s, 1H), 2.73 (m, 1H), 2.36-2.26 (m, 3H), 2.11-1.97 (m, 2H), 1.67-1.64 (m, 2H). ESI m/z: 248.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C)C=O>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1](=[O:3])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccnc1
Yield: 72 %

Procedure:
A solution of 125 g of 3-acetylpyridine and 138 g of N,N-dimethylformamide-dimethylacetal in dry dimethyl-formamide was refluxed for 3 h, after which the solution was evaporated to dryness and the product triturated with ether to give N,N-dimethyl-3-oxo-3-(3-pyridinyl)-prop-1-enamine in 72% yield. To a solution of 10.2 g of this product in 2-methoxyethanol 3.2 g of hydrazine were added under nitrogen and the mixture was heated. After 2 h the solvent was removed in vacuo to give quantitatively 3-(lH-pyrazol-3-yl)pyridine, which was dissolved in dimethylformamide. To this solution 22.8 g of N-bromosuccinimide were added in small portions over a period of 30 min, maintaining the temperature at 0°-5° C. The mixture was stirred for 3 h, poured into water, extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness, to obtain crude 3-(4-bromo-1H-pyrazol-3-yl)pyridine. To a solution of 13.5 g of this product in 190 ml of acetonitrile were added 17.5 g of methyl iodide under nitrogen, after which the solution was refluxed for 3 h. After cooling the crystalline material was filtered to give 3-(4-bromo-1H-pyrazol-3-yl)-1-methylpyridinium iodide in 71% yield. 15.6 g of this product was suspended in methanol and 5.7 g of sodium borohydride were added in small portions over 20 min at 0° C. After 1 h of stirring glacial acetic acid was added and the pH was adjusted to 6. The solvent was removed in vacuo, the residue suspended in brine and basified, and the product extracted with ethyl acetate. After drying over sodium sulfate and evaporation to dryness 3-(4-bromo-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine was obtained in 93% yield, and converted into its fumaric salt, which was recrystallized from methanol to give 3-(4-bromo-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (E)-2-butenedioate. mp 228° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[O:17]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([CH3:14])[C:11]([CH:19]1[C:20](=[O:22])[O:21][C:16]([CH3:24])([CH3:15])[O:17][C:18]1=[O:23])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(CNC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The 3-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (3.0 g, 14.76 mmol) was dissolved in CH2Cl2 (73.8 ml), cooled to 0° C. and treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (2.55 g, 17.71 mmol) and DMAP (2.71 g, 22.14 mmol) and EDC (3.40 g, 17.71 mmol) and allowed to stir at room temperature for 18 hrs. The reaction mixture was diluted with CH2Cl2, washed with 5% KHSO4 (×3), dried (Na2SO4), filtered and evaporated in vacuo to give the title compound: 1H NMR (400 MHz, CDCl3) δ 4.78 (bs, 1H), 4.23 (bs, 1H), 3.42 (m, 2H), 1.75 (s, 6H), 1.41 (s, 9H), 1.23 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.CO.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C:10](=[N:22][OH:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](c2ccc(Br)cc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: ON=C1CC[C@H](c2ccc(Br)cc2)C1
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A slurry of (S)-3-(4-bromophenyl)cyclopentanone (prepared according to J. Org. Chem., 2009, 74, 929; 10.9 g, 45.5 mmol), MeOH (110 mL), sodium acetate (5.59 g, 68.2 mmol), and hydroxylamine hydrochloride (4.74 g, 68.2 mmol) was stirred at room temperature. After 10 minutes, LCMS showed complete reaction. Diluted with MTBE (300 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution, 25-50% EtOAc/hexanes) to afford the title compound (11.0 g, 43.3 mmol, 95%). MS (DCI) m/z 254 (M+H)+.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]2=[O:33])=[CH:23][CH:22]=1>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH:32]=[CH:31][N:30]=[CH:29][C:28]3=[O:33])=[CH:25][CH:26]=2)[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(-n2ccncc2=O)cc1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccncc3=O)cc2)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-aminophenyl)-1H-pyrazin-2-one (CAS 444002-64-6) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[4-(2-oxo-2H-pyrazin-1-yl)-phenylcarbamoyl]-cyclopentyl}-amide. Light yellow solid. MS: 459.3 ([M+H]+)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:8](=[O:16])[O:7][CH:6]2[OH:17])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CN(C=O)C.Cl>[CH2:1]([C:3]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]([C:8]([O:7][CH2:25][CH3:26])=[O:16])=[C:5]([CH:6]=[O:17])[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(c(C(F)(F)F)c1)C(=O)OC2O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)cc(CC)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of (±)-5-ethyl-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1 (3H)-one (1.97 g, 8.0 mmol) in 20 mL of DMF was added potassium carbonate (4.42 g, 32.0 mmol) followed by iodoethane (1.92 mL, 24.0 mmol). The resulting mixture was allowed to stir at ambient temperature for 1 h. The reaction was diluted with 1N HCl to pH ˜4 and extracted with EtOAc. The organics were washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (elution with 10% EtOAc/hexane) to afford 1.8 g (83%) of the title compound. 1H NMR (CDCl3): δ 10.05 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 4.47 (q, 2H), 2.80 (q, 2H), 1.38 (t, 3H), 1.29 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:13]([O:15]CCC(C)C)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:13]([OH:15])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC(OCc2ccccc2)C1
Temperature: 0 °C

Procedure:
A 45.28 g (115.7 mmol) portion of 1-benzyloxy-3-(tert-butoxycarbonylamino)-3-isoamyloxycarbonylcyclobutane was dissolved in 300 ml of methanol to which, while cooling in an ice bath with stirring, was subsequently added dropwise 127 ml (127.2 mmol) of 1 N sodium hydroxide in 10 minutes. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 5 hours. This was mixed with 200 ml of water, and methanol was evaporated under a reduced pressure. The thus obtained residue was mixed with ether to effect separation of layers, the resulting aqueous layer was extracted with diethyl ether, and the ether layer was extracted with water. The aqueous layers were combined, acidified with 10% citric acid while cooling in an ice bath with stirring and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated brine, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to give 37.24 g (quantitative) of the title compound. This compound was used in the following reaction without purification.
Reaction SMILES: C([C:4]1[S:5](=[O:18])[C:6]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:7]=2[N+:8]=1[O-])(=O)N.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N+:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:6]2[S:5](=[O:18])[CH:4]=[N:8][C:7]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])cc2c1S(=O)C(C(N)=O)=[N+]2[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cc2c1S(=O)C=N2
Temperature: 100 °C
Yield: 75.2 %

Procedure:
25.3 g (0.1 mol) of 2-carbamyl-5-nitro-7-methylbenzothiazolone-N-oxide are suspended in 150 ml of anhydrous toluene. 16.8 g (0.11 mol) of phosphorus oxychloride are added dropwise to this suspension, with stirring, at an internal temperature of 100° C. and the reaction mixture is heated under reflux for a further 4 hours and allowed to cool. 15.8 g (75 % of theory) of 5-nitro-7-methyl-benzothiazolone of melting point >250° C. are obtained.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=1[F:34].Cl.[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH2:40].C(N(CC)CC)C>O.CN(C)C=O>[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH:40][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([Br:24])=[C:26]([F:34])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(Br)c(F)c1
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
1-Hydroxybenzotriazole monohydrate (839 mg, 5.48 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.05 g, 5.48 mmol) were added to an N,N-dimethylformamide (34 mL) solution of 4-bromo-3-fluorobenzoic acid (1.00 g, 4.57 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then L-serine methyl ester hydrochloride (1.42 g, 9.13 mmol) and triethylamine (1.27 mL, 9.13 mmol) were added to the mixture. The resulting mixture was further stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the crude title compound (1.63 g).