Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:2].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13]>C(OCC)C.COCCOC.[Cu].[Zn]>[Cl:10][C:11]1([Cl:16])[C:12](=[O:13])[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCCC(=O)OCC
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)CCC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
A mixture of 4-pentenoic acid ethyl ester (7.07 g, 55.2 mmol) and zinc-copper couple (10.2 g, 140 mmol) in diethyl ether (170 mL) and 1,2-dimethoxyethane (25 mL) was treated dropwise with trichloroacetyl chloride (25 g, 140 mmol). The mixture was stirred at room temperature for 3 days. The reddish heterogeneous reaction mixture was filtered through a pad of celite and the pad was washed with 300 mL Et2O. The filtrate was concentrated to about one half the original volume and the organic phase was washed with two 150 mL portions of H2O and one 150 mL portion of sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to yield a brown liquid. The material was purified by vacuum distillation (90-100° C. @0.044 torr) to yield the title compound (10.49 g, 80%) as a light yellow liquid: GC purity 95.8% (ret. time, 4.92 min).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18](OCC)=[O:19].O>CC(C)=O>[C:1]1([C:7]2[NH:17][C:18](=[O:19])[O:10][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
Benzoin (31.8 g, 0.15 mol) and urethane (42.79 g, 0.45 mol) were heated to reflux for 3.0 hours. The hot mixture was poured into water (150 mL). Acetone (150 mL) was added and heat was applied until the mixture dissolved. The solution was cooled and filtered, producing a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:33](=[O:32])[CH2:34][OH:35])[CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)N1CCc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 88 (200 mg, 0.5 mmol), acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (200 mg, 83%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H), 7.3 (dt, J=2.4 and 7.2 Hz, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 5.1 (s, 2H), 4.8 (t, J=5.8 Hz, 1H), 4.1 (d, J=5.6 Hz, 2H), 3.9 (t, J=7.9 Hz, 2H), 3.1 (t, J=7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088 (M+H calcd for C23H20ClF2N2O4 requires 461.1074).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)=[O:5])C.[CH2:22]([NH2:24])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)=[O:5])[CH3:23]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cccnc2)cc2nc(N)nn12
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(-c2cccnc2)cc2nc(N)nn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product of Step 1 (0.69 g, 2.45 mmol) and ethylamine (15 mL of a 2.0 M solution in THF) was allowed to stir at room temperature for 72 h. The solid was filtered to give 2-amino-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-carboxylic acid ethyl amide) as a solid.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([F:17])[CH:10]=1.C1(C)C(S(O)(=O)=[O:25])=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)CO>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[O:25][CH2:1][CH2:7][O:14]2)=[C:11]([F:17])[CH:10]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: Fc1cc(Br)ccc1C1OCCO1

Procedure:
To a toluene (99 mL) solution of 4-bromo-2-fluorobenzaldehyde (10.00 g) was added ethylene glycol (3.30 mL) and toluenesulfonic acid (849 mg), then the resultant mixture was refluxed for 8 hours. The mixture was poured into saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=99/1 to 95/5) to afford 2-(4-bromo-2-fluorophenyl)-1,3-dioxolane as a colorless oil (11.046 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.3 %

Procedure:
A solution of ethyl isonipecotate (25 g; 0.165 mol) in dichloromethane (250 ml) and triethylamine (50 ml) was cooled in a water bath and triphenylmethyl chloride (48.7 g; 0.175 mol) was added portionwise. Shortly after the addition was completed a precipitate was formed. The mixture was stirred at room temperature for 24 h and the mixture was then washed with water, dried over sodium sulfate and evaporated to dryness to give a yellow oil (74.0 g). This oil was triturated with methanol to give the product as cream coloured crystals in 97% yield (61.9 g); m.p. 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]1=[O:20].S>[OH-].[NH4+].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13][C:12]1=[O:20]
Reactant: CC1(C)CC(=O)C(c2ccc([N+](=O)[O-])cc2Cl)C(=O)C1
Agent: S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of 20.0 g (0.067 mol) of 2-(2'-chloro-4'-nitrophenyl)-5,5-dimethyl-1, 3-cyclohexanedione in 150 ml of concentrated ammonium hydroxide and 150 ml of ethanol was stirred at room temperature while passing hydrogen sulfide gas through the solution at such a rate that all of the H2S was absorbed. When the solution was saturated with H2S, the temperature was raised to the reflux point and H2S continuously passed slowly through the refluxing solution for 24 hours. The reaction mixture was filtered to remove sulfur, and the filtrate evaporated under reduced pressure. To the residue was added 300 ml of 0.25 N NaOH, and the solution filtered once more. The filtrate ws cooled and carefully acidified to pH=4 with 6 N HCl. A white solid formed which was collected by suction filtration to give 13.3 g (74%) of 2-(2'-Chloro-4'-aminophenyl)-5,5-dimethyl-1, 3-cyclohexanedione, m.p. 218°-219° C.
Reaction SMILES: C1(C([NH:20][C:21]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=2[CH:23]=[O:24])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH:23]([OH:24])[C:31]([F:33])([F:32])[F:30]
Reactant: O=Cc1c(F)cccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1C(O)C(F)(F)F
Temperature: 25 °C
Yield: 175.3 %

Procedure:
To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][N:15]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCOc1ccnc(CBr)c1OC
Reactant: Sc1nc2ccccc2[nH]1
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of potassium salt of 2-mercaptobenzimidazole (0.4 g) in dimethylformamide (5 ml), was added dropwise a solution of 2-bromomethyl-3-methoxy-4-propoxypyridine (0.4 g) in dimethylformamide, and stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform (50 ml), washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)) to give 2-[(3-methoxy-4-propoxypyrid-2-yl)methylthio]benzimidazole (0.35 g) as a light brown oil.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH3:15])[CH2:11][CH2:10]1)=[O:8]>C1COCC1>[CH3:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:7](=[O:8])[CH3:1])[CH2:10][CH2:11]1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeMgBr (352 mL, 1.1 mol, 3 mol/L) was added dropwise slowly to a stirred solution of trans-N-methoxy-N,4-dimethylcyclohexanecarboxamide (130 g, 0.7 mol) in THF (1.2 L) at 0° C. The mixture was stirred at room temperature for 2 hours. TLC showed no starting material (petroleum ether/ethyl acetate=5:1) left. The mixture was cooled to 0-5° C., and quenched by the addition of saturated NH4Cl (0.1 L) and H2O (2 L). The mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(trans-4-methylcyclohexyl)ethanone, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 2.27-2.19 (m, 1H), 2.10 (s, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.70 (d, J=12.8 Hz, 2H), 1.35-1.23 (m, 3H), 0.96-0.85 (m, 5H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 92 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(4-trifluoromethoxy-phenyl)cyclopropane (Example 11) (0.25 g), benzene (12 ml) and pyridine (0.09 ml) to yield the title compound (0.27 g, 92%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([I:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(OCC)C>ClCCl.C(=O)=O.CC(C)=O>[CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:11]=[C:12]([I:18])[CH:13]=[C:14]([OH:16])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(I)cc(C(=O)NCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(NCc1ccccc1)c1cc(O)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-benzyl-3-iodo-5-methoxy-benzamide (4.7 g) in anhydrous dichloromethane (100 mL) was cooled to −78° C. in dry ice/acetone bath under flow of argon and a BBr3 solution (38.4 mL of 1 M solution in dichloromethane) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and then quenched by a dropwise addition of methanol. Then it was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to remove the solvents. The title compound was obtained by trituration with diethyl ether and hexanes (4.1 g, 90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 65 °C
Yield: 73.4 %

Procedure:
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (1 L, 10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65° C. and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 80° C. The reaction was deemed complete (approximately 9.0 hours) when <2% of the starting material remained (in process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 10° C. and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30% NH4OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14° C., and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation with the removal of solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10° C., during which time the product crystallized out. The solids were recovered by centrifugation, washed with n-heptane (20.0 kg), and dried at approximately 40° C. to afford the title compound (8.0 kg).
Reaction SMILES: [NH2:1][C@H:2]([C:8](O)=O)[CH2:3]CC(=O)O.[CH3:11][C:12]1C=CC(P(C2C=CC(C)=CC=2)CCP(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=C[CH:13]=1.[CH:43]1C=CC2N(O)N=NC=2[CH:48]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:43][CH2:48][N:1]([CH:2]([CH3:3])[CH3:8])[CH:12]([CH3:13])[CH3:11]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(P(CCP(c2ccc(C)cc2)c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C

Procedure:
The peptide on resin was suspended in DMF (5-7 mL/100 mg resin). In a separate vial, 1.5-2 eq of Glu-DTPE acid was activated by addition of HOBt, and PyBOP in DMF (10% of the volume of peptide mixture) for 5-10 min at pH≈8 obtained by addition of DIEA (measured with wet pH paper). Activated DTPE acid mixture was added to the solution of peptide and the pH was adjusted to ˜8 with DIEA. The mixture was shaken at RT for 4-18 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([N:14]=[O:15])[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a solution of glacial acetic acid (2750 ml) and water (250 ml) was dissolved 150 g (0.75 mol) of 1-(4-chlorophenyl)-2-imidazolidinone with heating. The solution was cooled to room temperature, and sodium nitrite (70 g, 1.0 mol) in water (200 ml) was added dropwise over 1 hr. The mixture was stirred for another 6 hrs, diluted with water (1.5 l) and the product (137 g, 81%) was collected m.p. 154°-156°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:17])[C:10]([C:14]([OH:16])=O)=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:35][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C:52]1[CH:78]=[CH:77][C:55]([O:56][C:57]2[C:58]3[CH:59]=[C:60]4[O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][C:61]4=[CH:62][C:63]=3[N:64]=[CH:65][N:66]=2)=[C:54](C)[CH:53]=1.Cl>CN(C=O)C>[F:35][C:54]1[CH:53]=[C:52]([NH:51][C:14]([C:10]2[C:9](=[O:17])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][NH:12][CH:11]=2)=[O:16])[CH:78]=[CH:77][C:55]=1[O:56][C:57]1[C:58]2[CH:59]=[C:60]3[O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][C:61]3=[CH:62][C:63]=2[N:64]=[CH:65][N:66]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Cc1cc(N)ccc1Oc1ncnc2cc3c(cc12)OCCOCCOCCO3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ncnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a suspension of 5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8 d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) in anhydrous DMF (56 ml) were added HATU (15.65 g, 41.2 mmol) and i-Pr2NEt (18 mL, 104 mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5 min. To the solution was added 4-(4-Amino-2-Fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene 7a (7.9 g, 32.5 mmol) slowly. The reaction mixture was stirred for 3 h at room temperature and was poured into aqueous 1N HCl solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2Cl2 to obtain 9a as a light-yellow solid (5.9 g, 40%), mp 188-190° C. HPLC purity 97%; 1HNMR (400 MHz, DMSO) δ 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 6.89 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+616.6. found 616.5.
Reaction SMILES: C1CCCCC1.C1(C)C=C[C:10]([S:13](O)(=O)=O)=[CH:9][CH:8]=1.[CH2:18]([SH:21])[CH2:19][CH3:20].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:18]([S:21][CH:22]([S:13][CH2:10][CH2:9][CH3:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH3:20]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCS
Solvent: C1CCCCC1
Solvent: O
Product: CCCSC(SCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 cc reaction flask equipped with reflux condenser, magnetic stirring bar, and hot plate equipped with magnetic stirring apparatus is placed 10 ml cyclohexane, 0.5 grams of para-toluenesulfonic acid and 15.2 grams (0.2 moles) of n-propyl mercaptan. Over a period of 25 minutes with stirring is added 10.6 grams (0.1 moles) of benzaldehyde. The reaction mass is heated to reflux with stirring and refluxed for a period of 7 hours. During the refluxing, water of reaction is removed. At the end of the 7 hour period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following five fractions:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ncco1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
In a round-bottomed flask, oxazole-2-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 10 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 419 mg (68%) of 2-methyl-propane-2-sulfinic acid 1-oxazol-2-yl-meth-(E)-ylideneamide as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)([CH3:20])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:10]2([CH3:20])[CH:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)=[N:24][CH:25]=1
Reactant: CC1(COc2ccc(Cl)cn2)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(Cl)cn2)CNCC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To a stirred solution of 2-[(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-ylmethoxy]-5-chloro-pyridine (0.70 g, 1.64 mmol) in toluene (10 mL) at RT was added 1-chloroethyl chloroformate (0.229 mL, 2.12 mmol) and iPr2NEt (0.36 mL, 2.12 mmol). After 3 hours all volatiles were removed under high vacuum and the residue was dissolved in MeOH (10 mL). The reaction mixture was stirred at RT for 2 hours, and then concentrated under high vacuum. Column chromatography (SiO2, CH2Cl2/MeOH, 9:1) afforded 595 mg (97%) of the title product as white foam. ES-MS m/e: 337.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].CO.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:19]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.04 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 2.2 mmol methanol and 2.34 mmol triphenylphosphine in 10 ml THF was added 2.24 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane) to afford the title compound.