Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11](O)=[O:12])=[O:8])=[O:4].C(OC(Cl)=O)C(C)C.C([N:28](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:28])=[O:12])=[O:8])=[O:4]
Reactant: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1-(3-Methoxycarbonyl-2-methylpropanoyl)-L-proline (2.4 g.) is dissolved in a mixture of dichloromethane (50 ml.) and triethylamine (1.4 ml.). The solution is chilled in an ice water bath and isobutylchloroformate (1.36 g.) is added while the mixture is stirred. After 10 minutes ammonia (gas) is bubbled through the solution, still in the ice bath, for 15 minutes. The reaction mixture is stirred for one hour at room temperature, diluted with methylene chloride (100 ml.) and washed with water, 0.1 N hydrochloric acid, water, and dried over magnesium sulfate. The solvent is removed in vacuo to yield 1-(3-methoxycarbonyl-2-methylpropanoyl)-L-prolineamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]([OH:8])[CH2:9][N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1cccc(OCC2CO2)c1
Solvent: CO
Product: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1

Procedure:
To a solution of 2-((3-bromophenoxy)methyl)oxirane (1.5 g, 6.55 mmol) in MeOH (15 mL) was added 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.86 mmol) at 20° C. The mixture was heated at reflux temperature for 16 h, until the reaction was shown to be complete. The mixture then was concentrated to provide the crude which was purified using column chromatography on silica gel producing the desired 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (1.8 g, 78.3%) as colorless oil. LCMS (m/z): 362.1 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:19])[NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[C:1]1([NH:7][C:8](=[O:19])[NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[O:16])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Yield: 67.1 %

Procedure:
To a solution of 4-(3-phenylureido)benzoic acid (13.5 g, 52.68 mmol) in acetonitrile (250 mL) at room temperature was added tert-butyl piperazine-1-carboxylate (11.8 g, 63.22 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.1 g, 156.5 mmol, HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 g, 156.5 mmol, EDCl). The mixture was stirred at reflux temperature for 16 hours and was then concentrated under vacuum. The residue was submitted to silica chromatography (0-5% ethyl acetate in n-hexanes as eluant) to give the title compound (15.0 g). MS (ESI) m/z 425.1 [M+H]+
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)C(C)C)(C)C.[F:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][CH2:19][C:20]2[C:21]([CH2:31][OH:32])=[C:22]([OH:30])[C:23]([C:26](OC)=[O:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>CO.CCOC(C)=O>[OH:3][NH:2][C:26]([C:23]1[C:22]([OH:30])=[C:21]([CH2:31][OH:32])[C:20]([CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:25][N:24]=1)=[O:27]
Reactant: COC(=O)c1ncc(COc2ccc(F)cc2)c(CO)c1O
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NO)c1ncc(COc2ccc(F)cc2)c(CO)c1O
Temperature: 70 °C
Yield: 97.3 %

Procedure:
Hydroxylamine hydrochloride (0.045 g, 0.65 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol) were added to a solution of methyl 5-((4-fluorophenoxy)methyl)-3-hydroxy-4-(hydroxymethyl)picolinate 28b (0.050 g, 0.16 mmol) in MeOH (3 mL) and heated to 70° C. for 5 h. The crude mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride solution and brine. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.048 g, 96%): LC-MS (M+H)+ m/z 309.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=[O:29].[NH4+].[Ce].[CH3:34][C:35]1([CH3:48])[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[C:41]2[CH:40]=[C:39]([CH3:47])[CH:38]=[CH:37][C:36]1=2>C(O)(=O)C>[CH3:34][C:35]1([CH3:48])[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[C:41]2[CH:40]=[C:39]([CH:47]=[O:29])[CH:38]=[CH:37][C:36]1=2
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The CAN in the reaction path stands for cerium ammonium nitrate. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-methylnaphthalene (b) (202 mg, 1.00 mol) were added acetic acid (8.2 mL) and cerium ammonium nitrate (2.40 g, 4.37 mol) followed by stirring at 100° C. for 1 hour. The reaction solution was poured into ice water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (15/1) as an elution solvent. The yield was 106 mg (49%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CC(C)=C1C=CC=C1>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CC(C)=C1C=CC=C1
Product: Brc1ccc2c(c1)Cc1ccccc1-2

Procedure:
2-Bromoethylbenzene was obtained from 2-ethylaniline (Acros) as described in Hansch, C.; Geiger, C. J. Org. Chen. 1959, 24, 1025. Cyclopentadiene was obtained by thermal cracking of dicyclopentadiene (Acros). 2,7-Dibromo-9H-fluorene [Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Tanaka, T.; Fujisaki, S.; Okamoto, T. Bull. Chem. Soc. Jap. 1989, 62, 439], 6,6-dimethylfulvene [Buttrus, N. H.; Comforth, J.; Hitchcock, P. B.; Kumar, A.; Stuart, A. S. J. Chem. Soc., Perkin Trans. 1 1987, 851], and 2-bromo-9H-fluorene [Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Tanaka, T.; Fujisaki, S.; Okamoto, T. Bull. Chem. Soc. Jap. 1989, 62, 439] were prepared according to the published methods.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38].C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(C)(=O)=O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 425.9 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-chloro-5-hydroxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (62.5 mg, 0.0950 mmol) was dissolved in dichloromethane (2.4 mL), and the solution was treated with triethylamine (0.053 mL, 0.38 mmol) and methanesulfonyl chloride (0.015 mL, 0.019 mmol), followed by purification by slurry using hexane to obtain 4-chloro-5-methanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (50.1 mg, yield 72%).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[Br:14]Br.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[Br:14][CH2:5][C:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:1](=[O:6])[CH:2]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=c1cc(CBr)c2ccccc2[nH]1
Temperature: 25 °C

Procedure:
30 Grams of acetoacetanilide was dissolved in 30 ml of chloroform, then a solution containing 27 g of bromine in 30 ml of chloroform was added dropwise thereto at a room temperature with stirring. After completion of the addition of bromine, the reaction mixture was refluxed for 30 minutes. The reaction mixture was concentrated under a reduced pressure, the residue obtained was added to 70 ml of a concentrated sulfuric acid with stirring. The addition operation was conducted by keeping the inside of the vessel within 70°-75° C., then the whole mixture was poured into ice-water and the crystals precipitated were collected by filtration. Recrystallized from methanol-chloroform to obtain 20 g of 4-bromomethylcarbostyril in the form of colorless needel-like crystals.
Reaction SMILES: [Cl-].[NH4+].O1CCOCC1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][CH:20]=[O:21])=[C:14]([OH:22])[CH:13]=1)([O-])=O>[Fe].O>[NH2:9][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][CH:20]=[O:21])=[C:14]([OH:22])[CH:13]=1
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(NNC=O)c(O)c1
Yield: 77.3 %

Procedure:
A mixture of 120 g of iron powder, 5 g of ammonium chloride, 2 liters of dioxane, and 800 ml of water was heated on a steam bath with stirring and after adding thereto 61 g of 2-(4-nitro-2-hydroxyphenyl)-1-formylhydrazine with stirring, the resultant mixture was refluxed for 40 minutes. Then, insoluble matters were distilled off the filtrate was concentrated under reduced pressure, and water was added to the residue. Crystals thus formed were collected by filtration and washed with acetonitrile to provide 40 g of the desired compound with a yield of 79%.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[C:15](OCC)(OCC)(OCC)[CH3:16].N12CCCN=C1CCCCC2>C(O)CCC>[Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:15]([CH3:16])=[N:14][N:13]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc2occ(Br)c2n1
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Yield: 22.9 %

Procedure:
A solution of 3-bromofuro[3,2-b]pyridine-5-carbohydrazide (0.16 g, 0.64 mmol) and triethyl orthoacetate (0.26 mL, 1.40 mmol) in n-butanol (3 mL) was heated under reflux for 1 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.096 mL, 0.64 mmol) was added to the reaction mixture, and the resulting mixture was heated under reflux overnight. After cooling, the precipitate was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=3/1), and recrystallized from hexane/ethyl acetate to give the title compound (41 mg, yield 23%) as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][CH3:12]>C1C=CC=CC=1>[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8].[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: C=CC
Solvent: c1ccccc1
Solvent: CC(C)c1ccccc1
Product: CC(C)c1ccccc1C(C)C

Procedure:
In these experiments, cumene was manufactured by contacting 5.55 parts by weight benzene and 1 part by weight propylene in the batch slurry reactor using the procedure detailed above for Test Sequence for Cumene Manufacture in a Batch Test over catalyst comprising the 0.127 cm MCM-49 quadrulobal catalyst (Material 1) and the 250 to 297 micron catalyst prepared from it by crushing and sieving (Material 2). Cumene (isopropylbenzene, IPB) and diisopropylbenzene (DIPB) products were collected from each experiment and it was found that Material 2 again provided a 30% reduction in the DIPB/IPB ratio.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(C(F)(F)F)c3Cl)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-chloro-3-trifluoromethyl-benzylamine (124 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-3-trifluoromethyl-benzylamino)-2H-phthalazin-1-one: 38 mg (17.6%): m/z (M+H)=372. 1H-NMR (DMSO-d6) δ: 12.38 (s, 1H), 7.95 (d, 1H), 7.71 (m, 3H), 7.39 (m, 1H), 7.19 (dd, 1H), 6.85 (s, 1H), 4.57 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
127 mg (0.23 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 72 mg (63% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1N2CCN(CC2)C1.CN(C=O)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Yield: 989.4 %

Procedure:
To a solution of 5-bromoindole (1.0 g, 5.10 mmol) in DMC (10 mL), DABCO (0.057 g, 0.51 mmol) is added followed by DMF (1 mL). The resulting solution is heated to 90–95° C. for 5 h. The reaction is cooled to RT, and diluted with ethyl acetate (EtOAc, 50 mL) and H2O (50 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×50 mL) and H2O (4×50 mL). The organic layer is dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under vacuum to give 5-bromo-1-methylindole (about 1.06 g, 99%) as a golden colored solid: 1H NMR (CDCl3) δ 7.72 (d, 1H), 7.26 (dd, 1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.39 (d, 1H), 3.71 (s, 3H); 13C NMR (CDCl3) δ 135.3, 130.1, 129.9, 124.2, 123.2, 112.6, 110.6, 100.5, 32.9; MS m/z 209 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10](OC)=O)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH:26]1(Br)[CH2:30]C[CH2:28][CH2:27]1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:28][CH2:27][CH2:26][CH2:30]2)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOC(=O)Nc1cc(OC(=O)OC)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h

Procedure:
Ethyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate (1.45 g, 4.97 mmol) prepared by the process described in Reference Example 1 and a solution of potassium carbonate (1.03 g, 7.46 mmol) in ethanol (5.0 ml) were stirred for 1 hour while refluxing, and then cyclopentyl bromide (1.11 g, 7.46 mmol) was added thereto, followed by further stirring for 2 hours. After completion of the reaction, the mixture was poured into 1N hydrochloric acid (50 ml), and extracted with ethyl acetate (50 ml×3 times). The organic layer was dried, and concentrated under reduced pressure to obtain ethyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as grey white crystals (1.41 g, 4 69 mmol 94.4% yield) The spectral data and the like are as shown in Reference Example 1.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][CH2:30][OH:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:33].[Na+]>N([O-])=O.[Na+]>[OH:31][CH2:30][CH2:29][CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:33])[NH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: [OH-]
Agent: O=N[O-]
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl -1,3-oxazinan-2-one (40 mg, 0.09 mmol.) was dissolved in 3.5 MH2SO4 (10 mL), and 2 M NaNO2 (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 tR=1.66, min, m/z=433, 455; 1H NMR (CDCl3): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[C:26]1([C:32]2([CH2:36]O)[CH2:35][O:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:25])=[CH:17][C:18]=1[O:24][CH2:36][C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][O:34][CH2:35]1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: OCC1(c2ccccc2)COC1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCC1(c2ccccc2)COC1

Procedure:
The compound of step 2 of example 15 and (3-phenyl-oxetan-3-yl)-methanol (S. Kanoh et al., Tetrahedron 58 (2002), 7065-7074) were reacted in analogy to step 3 of example 15, and the obtained methyl ester was hydrolyzed in analogy to example 16.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(-c2cccnc2)c2snc(C)c2c1O
Product: Cc1nsc2c(-c3cccnc3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyridin-3-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 345.1 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[NH2:14][C:8]1[C:7]([O:15][CH2:16][CH3:17])=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][C:9]=1[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1cc(CO)cc(OCC)c1N
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (2.8 g, 11.05 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick, Helv. Chim. Acta 1977, 60, 3025-3034) in dichloromethane (50 mL) at 0° C. under Ar was slowly added diisobutylaluminum hydride (27.6 mL, 27.64 mmol, 2.5 equiv; 1.0 M solution in dichloromethane) over a time period of 15 min and the cooling bath removed on completion of addition. After stirring for 18 h, the excess of hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (10 mL). The solidified mixture was extracted with dichloromethane (5×200 mL) and THF (2×150 mL), the combined organic phases washed with water (3×100 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) providing 1.10 g (47%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.82 (br s, 2H), 4.05 (q, J=7.0 Hz, 2H), 4.54 (s, 2H), 6.50 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 15.03, 66.00 104.51, 125.44, 129.89, 146.71. MS (ISP): 211.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(S)(OCC)(OCC)=[S:11].C([O-])(O)=O.[Na+].C(=O)=O.[Na+].[Cl-]>C(Cl)Cl.CCOCC.O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[S:11])[NH2:5]
Reactant: N#Cc1ccccc1O
Reactant: CCOP(=S)(S)OCC
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: NC(=S)c1ccccc1O
Yield: 54.5 %

Procedure:
A stirred solution of 2-hydroxybenzonitrile (23.8 g, 200 mmol), (EtO)2P(S)SH (33.6 mL, 200 mmol) and water (40 mL) was heated at 80° C. for 12 hr under nitrogen. The mixture was cooled down to 0°-10° C., diluted with CH2Cl2 (200 mL)/Et2O (400 mL), then cautiously treated with saturated aq. NaHCO3 (60 mL), and followed by adding solid NaHCO3 in small portions until CO2 evolution ceased. Half-saturated aq. NaCl (40 mL) was added to the mixture. The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and filtered. After concentration in vacuo, the residue was chromatographed on silica gel (gradient EtOAc/CH2Cl2 :0-5%) to give 3a (16.7 g, 55%) as a pinkish solid, which had the same 1HNMR data as reported in the literature (Yousif, N. M. Tetrahedron 1989, 45, 4599).