Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH:32]O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-vinylpiperazine (16.2 g, 55.5 mmol) in tetrahydrofuran (370 mL), add 9-BBN (0.56 L of a 0.5 M solution in tetrahydrofuran) via addition funnel, stir at room temperature overnight. Cool to 0° C. and treat with 30% aqueous hydrogen peroxide (195 mL), followed by 3N aqueous sodium hydroxide (195 mL). Allow to reach room temperature and stir for 24 h. Pour into separatory funnel, separate organic layer and remove solvent in vacuo. Take up residue in dichloromethane, add water and recombine with aqueous layer from before. Pour into separatory funnel, separate organic layer and extract aqueous layer with several portions of dichloromethane. Combine all organic layers, remove solvent in vacuo. Take up residue in 1 L of methanol, add 185 g of SCX resin. Filter slurry through Büchner funnel, washing well with methanol. To elute product, wash cake thoroughly with 50% 7N ammonia-methanol in dichloromethane. Concentrate filtrate in vacuo to obtain the title compound (16.6 g, 96%) as a thick brownish oil: mass spectrum (APCI): m/z=311.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(C)cc23)cc(OC)c1OC
Yield: 33 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-methylindole-3-carboxaldehyde (1.59 g) except that the reaction solution was concentrated under reduced pressure, that the residue was purified by silica gel column chromatography, and that the obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane, to give Compound 20 (1.16 g).
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Solvent: CO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1

Procedure:
2.53 g (5 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 20 ml of methanol/water 1:1, about 100 mg of cation exchanger Amberlyst 15 is added and warmed to boiling temperature in 1 hour. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.94 g (4.18 mmol)=83.5% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].B(Br)(Br)Br.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)c(C(F)(F)F)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)Nc2ccc(-c3nc4ccc(O)cc4s3)cc2)cc1C(F)(F)F
Yield: 21.9 %

Procedure:
Prepared as described in the Demethylation section using 4-amino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.30 g, 0.68 mmol) in dry DCM (10 ml) and BBr3 (1.0 M solution in DCM, 5.42 ml, 5.42 mmol) to give the title compound (0.064 g, 22%) as an orange solid after work-up and flash chromatography (3:1 DCM/EtOAc).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]([C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M251) (0.23 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 83%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])=[N+]=[N-].[H][H]>C(OCC)(=O)C.O=[Pt]=O>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:5]=1[CH2:4][NH2:1]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN=[N+]=[N-]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN
Yield: 84.2 %

Procedure:
A mixture of 4-azidomethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (1.70 g) and PtO2 (0.106 g) in ethyl acetate (50 mL) at room temperature under 60 psi of hydrogen for 5 hrs, the reaction mixture is filtered through celite and filtrate is concentrated giving the title compound (1.3 g, 84.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.C(Cl)Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
10 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.04 mmol) at room temperature. And then 8.5 μl of benzoyl chloride (0.07 mmol) and 19.1 μl of diisopropylamine (0.11 mmol) were added thereto and the mixture was stirred for 2 hrs at 0° C. The reaction was quenched with methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with ethyl acetate and hexane (1:2) as an eluant to give 12 mg of 3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (i) (yield: 87%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])=[N:6][CH:5]=1.C1COCC1.O.Cl>O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Aqueous lithium hydroxide solution (1M, 0.47 ml, 0.473 mmol) was added to a solution of ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetate (112 mg, 0.237 mmol) in 3:1, THF/water (0.95 mL) and stirred for 18 h at room temperature. After concentrating, the crude reaction mixture was acidified with aqueous HCl solution (1M 1.2 mL), diluted with water (10 mL), stirred to break up solids, and filtered to afford 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetic acid as an off-white solid (99 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C([OH:13])C.[OH-].[Na+]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:13])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(C=O)cc1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a 1-liter flask were added 66.7 g (0.487 mol) of p-nitrotoluene, 223 g of ethanol and 2.7 g (4.1% by weight of the p-nitrotoluene) of N,N-dimethylformamide to form a mixture which was dissolved, maintained at 80° C. and then incorporated dropwise over a period of time of 2 hours with an aqueous alkali solution prepared by adding 51.5 g of a 50% aqueous solution of sodium hydroxide to said aqueous solution of sodium polysulphide. After the end of the incorporation with the aqueous alkali solution, the whole mass was refluxed for an additional two hours thereby completing the reaction. The resulting reaction mixture was subjected to steam distillation to obtain 42.3 g (0.350 mol) of p-aminobenzaldehyde in purified form. The yield of the p-aminobenzaldehyde so obtained was 71.8%, based on the weight of p-nitrotoluene used.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([O:13][Si](C)(C)C)[C:11]#N)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:13])[CH2:11][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(C#N)O[Si](C)(C)C)cc1F
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
The 3-fluoro-4-(methylthio)-a-[(trimethylsilyl)-oxy]-benzeneacetonitrile (40.1 g, 149 mmol) was cooled to −78° C. in tetrahydrofuran(400 mL). Lithium hexamethydisilazide (175 mL of 1.0 M in Hexanes, 175 mmol) was added dropwise over 1 hour. The solution was stirred for 1 additional hour at −78° C. Benzylbromide (24.5 g 149 mmol) was added as a solution in tetrahydrofuran (100 mL) over 25 minutes. The solution was kept at −78° C. for 1 hour, warmed to room temperature, and kept at room temperature for six hours. The solution was poured into ethyl acetate (300 mL). Aqueous 1 N hydrochloric acid (200 mL) was added and the solution stirred for 48 hours at room temperature. The layers were separated and the organic layer collected. The organic layer was mixed with aqueous 15% sodium hydroxide and stirred for 30 minutes. The organic layer was collected washed with saturated ammounium chloride(200 mL) and solution was dried over sodium sulfate and solvent removed at reduced pressure to afford a yellow oil. The product was isolated by preparative silica chromatography followed by crystallization from 2% ethyl acetate and hexanes (400 mL). 1-[3-fluoro-4-(methylthio)phenyl]-2-phenylethanone (21.5 grams, 82.0 mmol) was obtained as white crystals. (55% yield): Mp 77.1-77.2° C. 1H NMR (CDCl3/300 MHz) 7.77, (dd, 1H, J=8.0, 1.8 Hz), 7.64 (dd, 1H, J=10.7, 1.8 Hz), 7.20-7.40 (m, 6H), 4.22 (s, 3H), 2.51 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN)cc3)c(F)c2)C(=O)O1
Temperature: 52.5 °C
Yield: 87.1 %

Procedure:
A solution of 53 (7.16 g, 18.69 mmol) in tetrahydrofaran (THF) (100 mL) was treated with triphenylphosphine (PPh3, 5.88 g, 22.43 mmol, 1.2 equiv) and H2O (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 50-55° C. for 12 h. When TLC and HPLC showed the reduction reaction was complete, the reaction mixture was cooled to room temperature before the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (0-15% MeOH-CH2Cl2 gradient elution) to afford the desired N-[3-(4′-Aminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 54 (5.82 g, 87% yield) as off-white crystals, which were of sufficient purity to be directly used in subsequent reactions. 1 H NMR (300 MHz, DMSO-d6) δ1.85 (s, 3H, COCH3), 3.04 (br. s, 2 H, NH2), 3.44 (t, 2 H, J=5.4 Hz), 3.78 (m, 3 H), 4.18 (t, 1 H, J=9.1 Hz), 4.77 (m, 1 H), 7.25-7.60 (m, 7 H, aromatic-H), 8.20 (t, 1 H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+2 H)2+.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[NH:5][C:4]1=[O:15]>C(O)C.C(O)(=O)C>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:3]([S:2][CH3:1])[C:4](=[O:15])[NH:5]2
Reactant: CSC1C(=O)Nc2cccc([N+](=O)[O-])c21
Solvent: CCO
Solvent: CC(=O)O
Product: CSC1C(=O)Nc2cccc(N)c21
Temperature: 70 °C

Procedure:
A mixture of compound D1 (1 g), stannous chloride dihydrate (5.03 g) in 36 mL of ethanol and acetic acid (EtOH:AcOH:5:1) was heated at 70° C. under argon. Reaction was monitored using TLC and terminated after 7 hrs on disappearance of the starting material. The reaction mixture was cooled, solvent evaporated to give a sticky solid, water added, then extracted with chloroform. Saturated sodium bicarbonate was added stepwise to water layer, extracted with chloroform. Organic layers were combined, washed with saturated sodium bicarbonate and brine solution, dried over MgSO4, filtered and concentrated to give crude product, which was washed with toluene to give the title compound D2. YD: 95.85%. 1H NMR (DMSO-d6) 400 MHz. δ: 1.888 (s, 3H) 4.303 (s, 1H), 5.121 (s, 2H), 6.050 (d, J=7.6 Hz, 1H), 6.250 (d, J=8.4, 1H), 6.889 (dd, J=7.6 & 8.0 Hz, 1H), 10.231 (s, 1H). MS (ESI): m/z 217.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH2:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][O:23]2)[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2
Reactant: C=Cc1cc(F)c2c(c1C)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)cc(F)c2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-fluoro-4-methyl-5-vinyl-3H-isobenzofuran-1-one (420 mg, 1.71 mmol) in 10 mL of DCM was slowly added mCPBA (741 mg, 85% purity, 3.43 mmol) in 10 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred overnight. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers was washed with brine and then concentrated. The residue was purified by column chromatography to give product 7-fluoro-4-methyl-5-oxiranyl-3H-isobenzofuran-1-one. The enantiomers of the product were resolved via SFC (Column: Chiralpak AD-H 250*4.6 mm ID, 5 um; Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL/min; Wavelength: 220 nm). MS m/z 209 (M+1)−.
Reaction SMILES: Br[CH:2]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O-])=[O:19].[Na+]>CO>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([CH:2]([OH:19])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:17]
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1Cl
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(O)C(=O)c1ccccc1Cl
Yield: 100.2 %

Procedure:
A mixture of methyl 4-bromo-4-(chlorobenzoyl)butyrate (89.5 g), sodium formate (76.2 g) and methanol (400 ml) was stirred under reflux for 12 hours. The reaction mixture was concentrated, and water was added to the resulting residue and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The solvent was evaporated to give methyl 4-(chlorobenzoyl)-4-hydroxybutyrate (72.0 g, 100%) as an oily substance. This oily substance (72.0 g) was dissolved in tetrahydrofuran (400 ml), pyridine (22.2 g) was added thereto, and thereafter phenyl chlorocarbonate (43.8 g) was dropwise added thereto with cooling with ice. After the reaction mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture and then extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid and then with water, and dried (MgSO4). The solvent was evaporated, and the crystals thus precipitated were collected by filtration to obtain methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g, 58%). This was recrystallized from methanol to give colorless prisms. mp 97-98° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][C:15]2[CH:16]=[C:17]3[C:21]4=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]4[C@H:19]4[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]34)[CH:23]=2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 154. 1H NMR(CDCl3) δ: 9.30 (broad s, 1H), 9.15 (broad s, 1H), 7.60-7.52 (m, 1H), 7.38-7.25 (m, 1H), 7.13 (broad t, 1H, J=8.0 Hz), 6.30-6.15 (broad m, 2H), 4.45-4.25 (broad m, 2H), 4.17-3.98 (broad m, 2H)1 3.70-3.30 (m, 4H), 3.30-2.70 (broad m, 5H), 2.60-2.47 (m, 1H), 2.20-2.00 (m, 2H). LRMS (ES)+: 438.4 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br.C(O)C(N)(CO)CO>CN(C)C=O>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1ccccc1CBr
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccccc1CN1CCN(c2cccc3nc(N)nc(N)c23)CC1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) was shaken for 96 hours at 47° C. in the presence of 3-(Morphonlino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and o-methylbenzyl bromide (68.5 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated 1N NaOH with ethanol. Solids were collected by filtration to yield 47.9 mg of title compound. (69% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:23])[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:25][C:26]([NH:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]([CH3:40])[CH3:39])=[O:27]>C(C(C)=O)C>[CH:38]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH:35]([CH3:36])[CH3:37])[C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:15]1[C:16](=[O:23])[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)([CH3:39])[CH3:40]
Reactant: O=C1NCN(c2ccccc2)C12CCCCC2
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
72 mg (0.52 mmol) of potassium carbonate are added to a solution of 120 mg (0.52 mmol) of 1-phenyl-1,3-diazaspiro[4.5]decan-4-one and 132 mg (0.52 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide (described in Example 1 a) in 20 ml of methyl ethyl ketone. The reaction medium is stirred at room temperature for 12 hours and then for 6 h at reflux. The medium is then filtered and then the residue is chromatographed on silica gel (heptane then heptane/ethyl acetate 50/50, v/v). 135 mg of N-(2,6-diisopropylphenyl)-2-(4-oxo-1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid. Yield=58%, m.p.=251-3° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[CH:13]=[CH:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[CH:19][C:14]=2[CH:13]=[CH:12]1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc2occc2c1
Product: O=C(O)c1ccccc1NCc1ccc2occc2c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 1-benzofuran-5-carbaldehyde (Maybridge). 13C-NMR (DMSO-d6) δ 169.9, 153.5, 150.6, 146.3, 134.3, 133.9, 131.6, 127.3, 123.6, 119.5, 114.4, 111.6, 111.2, 110.2, 106.6, 45.8.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N:16]=[C:17]=[S:18])=[CH:10][N:9]=2)[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([NH:16][C:17]([NH2:1])=[S:18])=[CH:12][C:13]=2[O:14][CH3:15])[CH:7]=1
Reactant: N
Reactant: COc1cc(N=C=S)cnc1-n1cnc(Cl)c1
Product: COc1cc(NC(N)=S)cnc1-n1cnc(Cl)c1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Step O (4): Methanolic ammonia (2.0 M, 25 mL, 50 mmol) was added to a flask charged with 2-(4-chloro-1H-imidazol-1-yl)-5-isothiocyanato-3-methoxypyridine (2.5 g, 9.37 mmol). After 16 h, the reaction mixture was concentrated in vacuo to afford 1-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)thiourea (2.24 g, 7.89 mmol, 84% yield). LC-MS (M+H)+ 283.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.24 (d, J=1.83 Hz, 1 H) 8.12 (d, J=2.14 Hz, 1 H) 8.09 (d, J=2.14 Hz, 1 H) 7.79-7.82 (m, 1 H) 3.90-3.95 (m, 3 H).