Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1.N1C(C)=CC=CC=1C>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine, whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.1 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[F:24]>CCOC(C)=O>[F:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of piperidine (5.88 g, 69 mmol) and Et3N (6.98 g, 69 mmol) in EtOAc (60 mL) was added 1,2-difluoro-4-nitrobenzene (10.00 g, 63 mmol) dropwise. The mixture was stirred at rt overnight. The resulting mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (14.00 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][N:28]1[CH:29]=[CH:30][N:31]=[C:27]1[CH3:26])=[O:22])[CH3:25]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1ccnc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (4.18 g, 10.0 mmol) and 2-methylimidazole (1.8 g, 22.0 mmol) in acetonitrile (200 ml) was stirred at 80° C. for 4 h. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1). The purified product was washed with water to give 2.6 g (62%) of the title compound. M.p. >250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15](=[NH:16])[O:18][CH3:17])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reaction time: 2 h
Yield: 1331.1 %

Procedure:
A mixture of 5-(2-nitrophenyl)-2-furonitrile (92 g, 0.43 mole) and anhydrous methanol (1000 ml) was heated to 55° and sodium methoxide (1.5 g) was added. The steam bath was removed, the solution was stirred for two hours and stored overnight at room temperature. The solution was poured into ice water (1000 ml) and stirred for one hour. The product was collected by filtration and air dried to yield 91 g (86%) of methyl 5-(2-nitrophenyl)-2-furancarboximidate. A sample was recrystallized from isopropanol, m.p. 107°-108°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.C(N(CC)CC)C.[C:32]([O:35][CH2:36]C)(=[O:34])C>CO.ClCCl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:36][O:35][C:32]([C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1)=[O:34]
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OC)n1
Reaction time: 20 h
Yield: 55 %

Procedure:
A solution of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (0.35 g, 1.0 mmol) in a mixture of 7 ml methanol and 3.5 ml ethyl acetate was treated with triethylamine (0.21 ml, 1.5 mmol) and tris(dibenzylideneacetone) dipalladium dichloromethane-complex (70 mg, 0.09 mmol). The mixture was transferred to an autoclave, flushed with carbon monoxide and hold 20 hours at 80° C. under a pressure of 5 bar of carbon monoxide. After cooling and evacuating the carbon monoxide, the mixture was concentrated to about 2 ml and diluted again with a mixture of ethyl acetate/methanol 9:1 v/v. The title compound precipitated as an intensely yellow solid after cooling in the refrigerator for 17 hours. Yield=55%.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH2:20]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:21][CH3:22].Br[CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36].Cl>C1COCC1.O>[CH2:20]([O:23][C:24]([C:26]1([CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:21][CH3:22]
Reactant: CCCOC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCOC(=O)C1(CC(CC)CC)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 77.4 %

Procedure:
To a solution of dicyclohexylamine (4.281 g, 23.6 mmol) in THF (27 mL) 1.6 M n-BuLi in hexane (13.22 mL, 21.14 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid n-propyl ester (3.0 g, 17.62 mmol) in THF (9 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (4.072 g, 24.67 mmol) in THF (11.25 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (5.1 g) was distilled at 60° C. (0.05 mbar) to give 3.47 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid n-propyl ester as a colorless oil, purity 97% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.79 (t, 6H), 0.96 (t, 3H), 1.15-1.42 (m, 10H), 1.41-1.43 (m, 2H), 1.52-1.61 (m, 3H), 1.63-1.70 (m, 2H), 2.06-2.14 (m, 2H), 4.0 (t, 2H).
Reaction SMILES: FC(F)(F)C1C=C(S([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=3)[CH2:14][CH2:13]2)(=O)=O)C=CC=1.[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>C(O)C>[CH:43]1([CH2:46][NH:47][C:24]([C:20]2[N:19]=[C:18]([C:15]3[CH2:14][CH2:13][N:12]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][C:29]([F:42])([F:41])[F:28])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH2:17][CH:16]=3)[CH:23]=[CH:22][CH:21]=2)=[NH:25])[CH2:45][CH2:44]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cccc(C2=CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)n1
Reactant: NCC1CC1
Solvent: CCO
Product: N=C(NCC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)n1
Temperature: 55 °C
Yield: 4 %

Procedure:
N-Cyclopropylmethyl-1′-(4-trifluoromethoxybenzenesulfonyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxamidine (34) was synthesized as follows. Compound 33 was prepared according to the procedure described above for preparing compound 32 using 4-(trifluoromethoxy)benzenesulfonyl chloride instead of 3-trifluoromethylbenzenesulfonyl chloride. To a solution of compound 33 (154 mg, 0.37 mmol) in ethanol was added cyclopropylmethylamine (52 mg, 0.75 mmol) and the resulting solution was heated at 55° C. for 12 hours. The mixture was purified, without an aqueous work-up, on CombiFlash® and further purified by Prep-TLC to obtain the title compound 34 (7 mg, yield 4%). 1H NMR (400 MHz, CD3OD): δ 7.97-7.85 (m, 4H), 7.77 (d, 1H, J=8 Hz), 7.43 (d, 2H, J=8.8 Hz), 6.76 (m, 1H), 3.81 (m, 2H), 3.32 (m, 4H), 2.71 (m, 2H), 1.14 (m, 1H), 0.58 (m, 2H), 0.31 (m, 2H); MS: 481 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:16].[K+].C(O)CO>O>[OH:16][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
4-Isopropylbenzoic acid (5.0 g, 30.5 mmol) was dissolved in a solution of potassium hydroxide (4.1 g, 2 mL, 73.1 mmol) in water (125 mL). To the reaction mixture was added a solution of potassium permanganate (9.6 g, 60.9 mmol) in water (125 mL). The combined mixture was allowed to stir at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. and treated with ethylene glycol (100 μL) and cooled to 0° C. The solid were removed by filtration and the filtrate was acidified to pH 1 by addition of 6 N HCl solution. The solid was removed by filtration, and the filtrate was extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(1-hydroxy-1-methyl-ethyl)benzoic acid (5.1 g, 93%) as a white solid. ESI-MS m/z calc. 180.1. found 181.2 (M+1)+; Retention time: 0.6 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.00-7.95 (m, 2H), 7.61-7.56 (m, 2H), 2.64 (s, 1H), 1.54 (s, 6H).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21](O)(=[O:39])[CH2:22]CCCCCC/C=C/CCCCCCCC.C(O)(=O)CCCCCCC/C=C\C/C=C\CCCCC.C(O)(=O)CCCCCCC/C=C\C[C@@H](CCCCCC)O.C(Cl)C(OC(N)=O)CCl>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:20][CH2:22][CH2:21][OH:39]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Agent: NC(=O)OC(CCl)CCl
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOCCO

Procedure:
Surface-active dispersing agents in the form of oxyalkylated esters of unsaturated higher fatty acids are preferred. Oxymethylated and/or oxyethylated esters are especially preferred. In this, case, a glyceride type ester is preferred. This ester can be a mono-, di- and tri-glyceride. The oxyalkylated forms of the esters which can be used in accordance with the invention are obtained, in particular, from esters of unsaturated higher fatty acids which can undergo an oxyalkylation, particularly an oxyethylation. Particularly useful fatty acids are oleic acid, elaidic acid, linoleic acid and ricinoleic acid. The oxyethylated glyceride of ricinoleic acid, which can be advantageously used in the form of ethoxylated castor oil is of particular value for the purposes of the present invention. Castor oil consists of 80 to 85% of the glyceride of ricinoleic acid, and in addition the glycerides of oleic (7%), linoleic (3%), palmitic (2%) and stearic (1%) acids. Ethoxylated castor oil is marked by a good solubility in fatty acids, polar solutions and water. The oxyethylated castor oil may be that produced commercially by BASF (trademark: Emulphor EL). This castor oil is a yellow oil, having a freezing point below +20° C., and which is soluble in fatty acids, waxes, castor oil, polar solvents (e.g., trichloroethylene, xylene) and water.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])[CH:19]=1
Reactant: Brc1c[nH]cn1
Reactant: COC(=O)c1ccc(F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(Br)c2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A mixture of methyl 4-fluoro-3-methoxybenzoate (2.13 g), 4-bromo-1H-imidazole (3.74 g) and potassium carbonate (4.80 g) in DMF (20 mL) was stirred at 100° C. overnight, and allowed to cool to room temperature, and ethyl acetate and water were added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.580 g).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]4[CH2:22][CH2:21][CH2:20][C:19]=4[C:12]=3[O:11]2)C=CC=C[CH:2]=1.C(#[N:26])C=C.[H][H]>C(O)C>[O:11]1[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][C:18]=3[CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][CH:10]1[CH2:9][NH:8][CH2:7][CH2:1][CH2:2][NH2:26]
Reactant: C=CC#N
Reactant: [H][H]
Reactant: c1ccc(CNCC2CCc3ccc4c(c3O2)CCC4)cc1
Solvent: CCO
Product: NCCCNCC1CCc2ccc3c(c2O1)CCC3
Yield: 99.9 %

Procedure:
A mixture of intermediate (14-a) (0.02 mol) and 2-propenenitrile (0.2 mol) in ethanol (100 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was dissolved in methanol. Palladium on activated carbon (10%) (2 g) was added and the mixture was hydrogenated. After uptake of hydrogen (3 eq.), the catalyst was filtered off and the filtrate was evaporated, yielding 5.2 g of (±)-N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine (interm. 15-a).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]#[N:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]#[N:36])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(C)(C)C
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (943 mg) and 37% formalin (0.57 mL) in the same manner as in Example 1 was dissolved in chloroform (15 mL), and triethylamine (1.04 mL) and 3-t-butyl-5-cyano-4-methoxybenzoyl chloride (630 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (904 mg) as a yellow oily substance.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([O:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.9 %

Procedure:
A solution of methyl 2-bromo-2-(4-bromo-2-fluorophenyl)acetate (7.29 mmol) in N,N-dimethylformamide (30 mL) was treated with potassium carbonate (19.90 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (8.31 mmol). The reaction was stirred at room temperature for two days. The reaction solution was diluted with water (200 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed five times with water and three times with brine. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting semi-solid was diluted with dichloromethane (10 mL) and was concentrated to dryness in vacuo. This was repeated twice, at which point the resulting solid was dried under high vacuum overnight, affording the title compound as a white solid (3.05 g, 87% yield). MS(ES)+ m/e 454.8/456.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: C[C@@H](N)c1cccc(Cl)c1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(Cl)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,3-dichlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:26]([O:29][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:11])(=[O:28])[CH3:27]
Reactant: CC(=O)O
Reactant: Clc1ccccc1[C@H]1O[C@@H]1COCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Product: CC(=O)O[C@H](COCc1ccccc1)[C@@H](O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of (±)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane (Preparation example 373, 2.9 g, 10.55 mmole) in Acetic acid (55 mL) was added Cerium Ammonium Nitrate (1.15 g, 2.11 mmole) at room temperature. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with sat'NaHCO3 to pH7 at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (1.2 g, 34%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41]([N:45]=[C:46]=[O:47])[CH:42]=[CH:43][CH:44]=1.CO>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:46]([NH:45][C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:48])[F:49])[CH:40]=5)=[O:47])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CN)cc4)cnc3c2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CNC(=O)Nc5cccc(C(F)(F)F)c5)cc4)cnc3c2)cc1
Yield: 65.7 %

Procedure:
Dissolve 4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzylamine (2.37 g, 6.28 mmol) and diisopropylethylamine (2.44 g, 3.28 mL, 18.84 mmol) in dimethylsulfoxide under a nitrogen environment at room temperature. Add 3-trifluoromethylphenylisocyanate (1.17 g, 6.28 mmol) and stir the mixture for 2.5 hours. Pour the reaction contents onto a Varian SCX column (50 g) prewashed with methanol. Wash the column with dichloromethane, 1:1 methanol/dichloromethane and methanol (150 mL each). Elute the title compound with 2 N NH3/methanol (300 mL). Concentrate the methanolic solution to dryness and chromatograph on silica using 0→3→5→10% methanol/dichloromethane over 4, 15 and 30 minutes, respectively. Dissolve the product in heated CHCl3 (65 mL), followed by treatment with hexanes (5 mL) and cooling. Dry the resulting precipitate in vacuo to yield the product (2.33 g, 66%). MS(ES), m/z 565 (M+1).
Reaction SMILES: [H-].[Na+].[C@@H:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].[H][H].[Na].Br[CH2:15][C:16](OCC)=[O:17]>C1(C)C=CC=CC=1.O>[O:9]1[C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]2[O:10][CH2:15][C:16]1=[O:17]
Reactant: O[C@@H]1CCCC[C@H]1O
Reactant: CCOC(=O)CBr
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CO[C@@H]2CCCC[C@H]2O1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a slurry of 54 grams of 55% sodium hydride in 1000 mls of toluene is portionwise added 140 grams of trans-1,2-cyclohexanediol at 90° C. with concommitant release of hydrogen. The resulting mass, containing the monosodium salt of trans-1,2-cyclohexanediol is stirred at 100° C. for 30 minutes. Ethyl bromoacetate (203 grams) is added dropwise to the stirred reaction mass at 100° C. over a 30 minute period. After stirring for 30 minutes, the mass is cooled to 20° C. Water (100 ml) is added and the organic layer is distilled to afford 130 grams of trans-hexahydro-1,4-benzodioxan-2-one. The product is purified by distillation through a 1"×12" Goodloe® packed column to afford a semi solid (m.p. 20°-22° C., bp. 97° C. at 1.2 mm).