Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].ClCCl.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>O>[CH3:28][S:25]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)(=[O:27])=[O:26]
Reactant: CN(CCO)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
To a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) and dichloromethane (20 mL), triethylamine (0.66 mL) and mesyl chloride (0.37 mL) were added sequentially under ice cooling and stirred for 3 hours. Water was added to the reaction liquid, and the organic layer was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (1.0 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])[CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1>[F:30][CH:8]1[C:7](=[O:10])[N:6]2[C:2]([CH3:11])([CH3:1])[O:3][CH2:4][C@H:5]2[CH2:9]1
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H]2CC(F)C(=O)N21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution consisting of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 4, 18.5 g, 119 mmol) in dry THF (400 mL) at −75° C. was added lithium diisopropylamide (74.5 mL, 149 mmol, 2 M in heptanes/THF/ethylbenzene from Sigma Aldrich) dropwise over 20 minutes, then stirred for one hour. The reaction mixture was then treated with a solution consisting of N-fluorobenzenesulfonimide (56.6 g, 167 mmol, NFSi, from Oakwood Chemical) in THF (300 mL) with steady addition over 30 minutes, and the resulting mixture was stirred for 16 hours, warming to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride. The organic material was extracted twice with ethyl acetate. The organic layer was washed with a 50% aqueous solution of sodium chloride, followed by a saturated solution of sodium chloride, and dried over sodium sulfate, filtered, and concentrated. The residue was redissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), causing the formation of a white precipitate. The precipitate was filtered and washed with 50% ethyl acetate in heptane. The combined filtrate was concentrated. The residue was dissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), forming a second precipitate. The second precipitate was filtered and washed with 50% ethyl acetate in heptane. The filtrate was concentrated and the residue (31 g) was purified by silica gel chromatography. Elution with ethyl acetate-hexanes (1:3 v/v) afforded pure samples of each of the two diastereomers of the title compound as tan solids (4.1 g of each) and a portion of mixed diastereomers (3.8 g of an approximately 1:1 ratio). The total mass of the two diastereomer products isolated was 12.0 g (65% total yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N′,N′-dimethylethane-1,2-diamine (7.3 mg, 0.12 mmol). The title compound was obtained as a solid (5.8 mg, 14.8% yield). MS m/z: 421.90, 423.90 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Product: COC(=O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Reaction time: 24 h

Procedure:
(S)-3-Phenoxymandelic acid (13.0 g) was added to a solution of dry hydrogen chloride (15.0 g) in methanol (100 ml) and the solution thus obtained kept at the ambient temperature for 24 hours after which period the volatile portion was evaporated yielding methyl (S)-3-phenoxymandelate as a residual oil. This was then added to liquid ammonia (20 ml) in a pressure vessel which was then sealed and temperature of the mixture allowed to rise to the ambient temperature over a period of 24 hours. The vessel was then opened and the excess of ammonia allowed to evaporate. The residual material was stirred with water and the solid collected by filtration, and recrystallised from benzene (70 ml) to yield impure(S)-3-phenoxymandelamide, m.p. 93° C. [α]D25 +25.4° (C, 2.0, methanol), (approximately 80% optically pure).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[CH3:13]>C(Cl)(Cl)Cl>[Cl:3][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[F:5])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccccc1F
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1ccccc1F
Temperature: 20 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
767 mg of thionyl chloride are added to a solution of 1 g of commercial 1-(2-fluorophenyl)ethanol in 20 ml of chloroform. After stirring overnight at a temperature in the region of 20° C., the reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 780 mg of 1-(1-chloroethyl)-2-fluorobenzene are thus obtained, said product being used as it is in the next stage.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[C@@:18]3([CH2:27][C:26]3([CH3:29])[CH3:28])[C:17]2=[O:30])[CH:5]=1.Cl>O1CCCC1.[OH-].[Na+].O.C(OCC)(=O)C>[F:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[CH2:14][CH2:13][O:12][C:11]3=[O:15])[CH:7]=1)[C:3]([OH:31])=[O:2])[C:17](=[O:30])[C@@:18]12[CH2:27][C:26]1([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@]3(CC3(C)C)c3cc(F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A mixture of (R) and (S)-methyl-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate (850 mg, 2.4 mmol) in tetrahydrofuran (10 mL) and 30% sodium hydroxide in water (5 mL) was stirred at 25° C. for 16 hours. The mixture was neutralized with a 2N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound (410 mg, 50%) as a white solid: LC/MS m/e calcd. for C20H18FNO3: 340, observed (M+H)+: 340.; 1H NMR (400 MHz, MeOD) δppm 1.50 (s, 3 H) 1.57 (s, 3 H) 1.86 (d, J=4.29 Hz, 1 H) 1.93 (d, J=4.55 Hz, 1 H) 4.22 (t, J=7.96 Hz, 2 H) 4.56 (t, J=7.96 Hz, 2 H) 6.86-6.94 (m, 1 H) 6.94-7.02 (m, 1 H) 7.06 (d, J=8.59 Hz, 1 H) 7.84 (s, 1 H) 8.03 (br. s., 1 H) 8.25 (br. s., 1 H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27](=O)([O-])[O-:28].[K+].[K+]>CN(C=O)C>[CH2:6]([N:13]1[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][C:15]([C:22]2[O:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)nn1Cc1ccccc1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2cc(C(F)(F)F)n(Cc3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 ml of dry DMF were initially charged at 10° C., 1.9 g (12.4 mmol) of phosphorus oxychloride were added dropwise and the mixture was stirred for 30 min. A solution of 3 g (10.3 mmol) of 1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole in 10 ml of DMF was added dropwise, and the mixture was stirred at RT overnight. The mixture was poured into ice-water and adjusted to pH 9 using potassium carbonate solution. The precipitated product was filtered off with suction and dried in a vacuum drying cabinet at 50° C. This gave 3.3 g (100%) of the title compound. m.p.: 76.5-77.5° C.
Reaction SMILES: B(F)(F)F.[CH2:5]([O:7][P:8]([N:13]1[CH:19]2[CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:18]2)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6].[CH3:30][OH:31]>>[CH2:5]([O:7][P:8]([NH:13][C@H:19]1[C@H:14]([O:31][CH3:30])[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18]1)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: CO
Agent: FB(F)F
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OC)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
BF3 etherate (1.35 mL, 10.6 mmol) was added to a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.96 g, 5.32 mmol) in methanol (10 mL) at 0° C. and stirred at 0° C. for 2 hours. The solvent was removed in vacuo, ethyl acetate (30 mL) and saturated sodium bicarbonate (20 mL) were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo to give trans-benzyl 3-(diethoxyphosphorylamino)-4-methoxypiperidine-1-carboxylate (2.00 g, 94%) as an oil.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:7]1([N:6]2[C:2]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Yield: 36.8 %

Procedure:
A suspension of 5-chloro-1-phenyl-1H-tetrazole (2.80 g, 15.5 mmol), L-leucine (3.36 g, 25.6 mmol) and potassium carbonate (6.43 g, 46.5 mmol) in isopropanol (20 mL) was heated to reflux for 3 h. The mixture was cooled and partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with brine and concentrated. Purification by flash chromatography on silicic acid (50% ethyl acetate/hexanes) provided 1.57 g of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH:8]1[C:14](=[O:15])[N:13](OC(C)(C)C)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:10][CH2:9]1)=[O:5])[CH3:2].[ClH:25]>O1CCOCC1>[ClH:25].[C:4]([CH2:6][N:13]1[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:10][CH2:9][CH:8]([NH:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]1=[O:15])([OH:5])=[O:3]
Reactant: CCOC(=O)CNC1CSc2ccccc2N(OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CNC1CSc2ccccc2N(CC(=O)O)C1=O

Procedure:
1.25 g of the 3-ethoxycarbonylmethylamino- 5-t-butoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one obtained in Example 14 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane and then reacted at room temperature for an hour. After this solution was concentrated under reduced pressure, ether was added thereto so as to cause crystallization. Thus, there was obtained 720 mg of the desired compound. When heated to determine its melting point, this compound decomposed at 248° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CCCCO>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=2)[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Mechanically stir mixture of 6-chloro-2-methyl-3-nitro-pyridine (Asymchem, 25.00 g, 144.9 mmol), tert-butyl 1-piperazinecarboxylate (29.68 g, 159.4 mmol), and triethylamine (23.2 mL, 167 mmol) in n-BuOH (250 mL) at 50° C. under nitrogen for 4 hours, at 65° C. for 2 hours, then at room temperature overnight. Add additional tert-butyl 1-piperazinecarboxylate (1.5 g), and heat the reaction at 65° C. for 4 hours. Cool the resulting slurry to 30° C. then add hexanes (75 mL). Cool the slurry to room temperature over 1 hour, then add water (150 mL). Allow the slurry to stand for 45 min then filter. Wash the cake with water (4×100 mL) then hexanes (100 mL) and air-dry overnight to yield 4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as bright yellow crystals (46.30 g, 99% yield, MS(ES): m/z=267 [M+H—C4H8]).
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[NH2:6][C:7]1[CH:16]=[CH:15][C:10](C(OC)=O)=[CH:9][C:8]=1[Cl:17].C(N)=O.C[O-].[Na+]>CC(O)C>[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:4]([NH2:2])=[O:5])=[CH:9][C:8]=1[Cl:17]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: NC=O
Solvent: CC(C)O
Product: NC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An anhydrous DMF solution of 1.00 g (5.39 mmol) of methyl 4-amino-3-chlorobenzoate (17-1), 728 mg (16.16 mmol) of formamide and 204 mg (3.77 mmol) of 5.5M sodium methoxide was stirred for 1 hour at 100° C. and then stirred overnight at room temperature. The reaction was poured into 2-propanol (60 mL) and then evaporated off the solvent. The resultant crude oil was purified on a silica column and eluted with DCM:MeOH:NH4OH (95:5:0.5 to 9:1:0.1). Recovered the desired product 17-2. MS (M+1): measured 171.2; theoretical 170.0. 1H NMR (DMSO): 5.86 (s, 2H), 6.75 (d, 1H), 7.01 (bs, 1H), 7.56 (dd, 1H), 7.66 (bs, 1H), 7.75 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:17][NH:18][C:19](=[O:22])[CH2:20][Cl:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:21][CH2:20][C:19]([NH:18][CH2:17][C:6]1[C:7]([OH:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: O=C(CCl)NCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(O)c(CNC(=O)CCl)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A finely powdered mixture of 5.2 g (25 mmol) of 3,5-di-tert-butylphenol and 3.15 g (25 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 22.5 mL acetic acid and 2.5 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 16 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15-30-50% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][C:25]([O:27]C)=O)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH3:29]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][C:25]([NH2:29])=[O:27])[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Reactant: N
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2oc(CCC(N)=O)nc2-c2ccc(F)cc2)cc1

Procedure:
Part 20) 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-oxazolepropionic amide is prepared by treating 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-oxazolepropionic acid, methyl ester with excess ammonia in methanol for 5 days, mp 193°-195° C.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O>[CH3:22][S:23]([O:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(OS(C)(=O)=O)c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
tert-Butyl 4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylate (Prepared in Example 124; 8.00 g, 27.4 mmol) and TEA (11.4 ml, 82.1 mmol) were combined and cooled to 0° C. Methanesulfonyl chloride (2.65 ml, 34.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hours. Water was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried, filtered, and concentrated to give tert-butyl 4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate (9.9 g, 97.7% yield). 1H NMR (DMSO-d6) δ 10.88 (bs, 1H), 8.49 (d, 1H), 8.35 (d, 1H), 7.95 (m, 1H), 7.75 (s, 1H), 7.65 (t, 1H), 7.57 (d, 2H), 7.42 (m, 3H), 7.36 (m, 1H), 7.31 (s, 1H), 7.21 (m, 1H), 7.14 (d, 1H), 5.23 (s, 2H), 4.19 (d, 1H), 3.98 (m, 1H), 3.84 (m, 1H), 2.14 (m, 2H), 1.37 (m, 10H), 1.20 (m, 3H), 1.01 (m, 1H).
Reaction SMILES: C1(C=CC2C=CC=CC=2)C=CC=CC=1.II.[C:17](C1C=CC=CC=1)(=[O:19])C.[CH3:26][O:27][C:28]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]2[C:38]3[C:33](=[CH:34][C:35](OC)=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH:29]=1>C1CCCCC1>[CH3:26][O:27][C:28]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]2[C:38]3[C:33](=[C:34]([O:19][CH3:17])[CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH:29]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc2c(ccc3cc(OC)c(OC)c(OC)c32)c1
Agent: C(=Cc1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCCCC1
Product: COc1cc2ccc3c(OC)cccc3c2c(OC)c1OC
Yield: 76 %

Procedure:
The stilbene mixture containing 30c and 31c (1010 mg, 3.36 mmol) in cyclohexane (500 mL) containing iodine (53 mg) and acetophenone (1.71 mmol, 0.5 eq) was irradiated as in the above synthesis of 32a and 32c to give 32d (760 mg, 76%): mp 80°-82° C.; IR (KBr) 846 (2H adjacent), 790 cm-1 (3H adjacent); 1H NMR (CDCl3, 200 Mhz) δ9.12 (d, 1H, J=10 Hz), 8.20 (d, 1H, J=10 Hz), 7.57 (m, 2H), 7.10 (s, 1H), 6.99 (d, 1H, J=8 Hz), 4.03 (s, 6H), 4.02 (s, 3H), 4.00 (s, 3H); EIMS m/e 298 (M+, 100), 283 (40). Anal. (C18H18O4) C, H.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([OH:13])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.CCOC(C)=O.O>CN(C=O)C>[OH:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH2:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1cc(O)c2ccc(O)cc2n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(O)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 2.05 g (10.4 mmol) of 2-methyl-quinoline-4,7-diol, 1.72 g (12.5 mmol) of potassium carbonate and 2.1 g (12.5 mmol) of 4-(bromomethyl)-benzonitrile in 100 ml of DMF were stirred at RT under an nitrogen atmosphere for 4 h until completion of the reaction according to HPLC analysis. The reaction mixture was cooled to RT and poured into EtOAc/water (300 ml/400 ml). The product that precipitated was filtered off by suction, washed with water, AcOEt and ether and dried in a high vacuum to give 2.23 g (73%) of 4-(4-hydroxy-2-methyl-quinolin-7-yloxymethyl)-benzonitrile as a white solid. ISP mass spectrum, m/e: 291.4 (M+1 calculated for C18H14N2O2: 291).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of Example 45A (6.6 g, 23.0 mmol) in tetrahydrofuran (31 mL) and methanol (20 mL) was added lithium hydroxide monohydrate (1.93 g, 46.1 mmol). The resulting mixture was heated at 60° C. for 2 hours. The heat was removed and the reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the solution was neutralized with 1M HCl. Ethyl acetate (200 mL) was added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the titled compound (4.5 g). MS (CI) m/z 259 (M+1)+
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C:9]1([S:12]([NH:15][C:16]2[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:20]([CH3:31])[C:19](=[O:32])[N:18]([CH3:33])[CH:17]=2)(=[O:14])=[O:13])[CH2:11][CH2:10]1)(C)(C)C.Cl>C1COCC1>[OH:6][CH2:7][CH2:8][C:9]1([S:12]([NH:15][C:16]2[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:20]([CH3:31])[C:19](=[O:32])[N:18]([CH3:33])[CH:17]=2)(=[O:14])=[O:13])[CH2:11][CH2:10]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO[Si](C)(C)C(C)(C)C)CC2)cn(C)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-[2-(tertbutyldimethylsilanyloxy)ethyl]-N-(4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)cyclopropanesulfonamide (20 mg, 0.032 mmol) in THF (2 mL) at 0° C. is added 1N HCl (0.128 mL. 0.128 mmol) The ice-bath is removed after 30 minutes and the solution stirred at room temperature for 45 minutes. Then the solution is cooled to 0° C., saturated NaHCO3 (3 mL) solution is added, and extracted with ethyl acetate (3×5 mL). The combined organic layers are concentrated under reduced pressure to give the title compound.