Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[F:14][C:15]1[C:16]([O:25][CH3:26])=[C:17]([C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][CH:15]1[CH2:22][CH:18]([C:17]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:15]([F:14])[C:16]=2[O:25][CH3:26])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:16]1=[O:25]
Reactant: COc1ccc(F)c(OC)c1C=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: COc1ccc(F)c(OC)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3-fluoro-2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 431.90 g/mol.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>C(OCC)C>[Br:12][CH:13]([CH3:17])[C:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:15]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)COC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of iso-butanol and 1.0 equivalent of pyridine in dry diethyl ether was added dropwise 1.3 equivalents of 2-bromopropionyl bromide at 0° C. After stirring at room temperature for 16 hours, the reaction was diluted with diethyl ether, washed with 1N HCl, water, aqueous NaHCO3, brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvents at reduced pressure gave the title compound as a clear oil.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=O.Cl.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Reactant: CNC
Agent: Cl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)N(C)C

Procedure:
The carboxylic acid from Example 6 (0.07 g, 0.18 mmol) was reacted with dimethylamine hydrochloride (0.072 g, 0.88 mmol) according to the procedure in Example 7. The product was purified by flash chromatography on silica (eluant chloroform:methanol:acetic acid 98:1:1) to give a white solid; yield 0.08 g (11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:3]=1.BrC1C=C(Cl)C=CC=1OCO[CH2:32][CH2:33][O:34]C.FC(F)(F)C1C=CC=CC=1C=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:32]([C:33]([OH:34])=[O:41])=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COCCOCOc1ccc(Cl)cc1Br
Reactant: O=C(c1cc(Cl)ccc1O)c1ccccc1C(F)(F)F
Product: O=C(O)c1oc2ccc(Cl)cc2c1-c1ccccc1C(F)(F)F

Procedure:
Using 4-chloro-2-(2-trifluoromethylbenzoyl)phenol [prepared from 2-bromo-4-chloro-(2-methoxyethoxy)methoxybenzene and ortho-(trifluoromethyl)benzaldehyde as the starting materials: m.p. 71-72° C. (recrystallized from hexane-isopropyl ether)] in place of 4-chloro-2-benzoylphenol in Reference Example 1, substantially the same reations as in Step 1 to Step 3 of Reference Example 1 were conducted to give the title compound. The compounds obtained in the respective steps and their physico-chemical data are shown below.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:15]([CH3:14])[CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 1.6 g of 4-(1-methyl-2-isopropoxyethoxy)-benzyl bromide, and thereto was added 1.0 g of anhydrous potassium carbonate. The mixture was heated under stirring on an oil bath at 100° to 120° C. for 2 hours. Then, procedures similar to those in Preparation Example 2 were conducted to give 1.2 g of the aimed compound, m.p. 60.0°~62.0° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#[N:9])C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.NOS(O)(=O)=O>O>[NH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: CC#N
Reactant: c1ccc2c(c1)CCN2
Agent: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NN1CCc2ccccc21
Reaction time: 0.17 h
Yield: 37 %

Procedure:
In 40 ml of water was dissolved 2.76 g(20 mmol) of potassium carbonate thoroughly, and 10 ml of acetonitrile and 2.24 ml(20 mmol) of indoline were added thereto in this order. After stirring the reaction mixture for 10 min, 2.26 g(20 mmol) of hydroxylamine-O-sulfonic acid was added thereto. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under the reduced pressure. The concentrate was extracted with dichloromethane and treated with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the resulting concentrate was subjected to chromatography over silica gel using dichloromethane as an eluent. The fractions were concentrated to give 0.99 g of the desired compound(37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH3:26][O:27][CH:28]([CH2:31][O:32][CH3:33])[CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:29][CH:28]([O:27][CH3:26])[CH2:31][O:32][CH3:33]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: COCC(C=O)OC
Product: COCC(C=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21)OC

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2,3-dimethoxypropanal by the method of Example 1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]([Cl:18])=[C:13]([Cl:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH3:21]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]([CH2:20][CH3:21])[C:23]=3[CH3:31])[O:19][C:14](=[O:16])[C:13]([Cl:17])=[C:12]1[Cl:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCn1c(C)cc2ccccc21
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(Cl)=C(Cl)C(=O)O
Product: CCn1c(C)c(C2(c3c(C)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21

Procedure:
Following a procedure similar to that described above in Example 25, part B, 5.0 g (0.017 mole) of 4-(2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 2.7 g (0.017 mole) of 1-ethyl-2-methylindole were interacted to obtain 5-(2-methyl-3-indolyl)-5-(1-ethyl-2-methyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=Y=Y1 =H; R1 =R3 =CH3 ; R2 =CH3CH2) as a red-blue solid which melted in the range of 282°-285° C.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][N:19]=1.Cl[CH2:22][S:23][C:24]#[N:25].Cl>CN(C)C=O>[S:23]([CH2:22][S:10][C:14]1[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][N:19]=1)[C:24]#[N:25]
Reactant: [O-][n+]1ccnc(Cl)c1
Reactant: N#CSCCl
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CSCSc1c[n+]([O-])ccn1
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of 9.6 grams (0.04 mole) of sodium sulfide nonahydrate in 100 milliliters of dimethylformamide was gradually added 5.2 grams (0.04 mole) of 3-chloropyrazine-1-oxide in 50 milliliters of dimethylformamide. The reaction mixture was stirred overnight at 45°-50° C. Thereafter, 4.3 grams (0.04 mole) of chloromethylthiocyanate were gradually added and the mixture stirred for 4 hours. At the completion of the reaction, the dimethylformamide was removed by evaporation under reduced pressure and the residue was dissolved in a mixture of water and chloroform. Two phases formed and the aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The organic portions were combined and washed with both a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. The chloroform was thereafter removed by evaporation leaving the 3-(thiocyanatomethylthio)pyrazine-1-oxide as a residue. The product was recrystallized from methanol and was recovered in a yield of 4.75 grams (60 percent of theoretical). The product melted at 104°-106° C and upon analysis was found to have carbon, hydrogen, nitrogen and sulfur contents of 36.40, 2.66, 20.59 and 32.20 percent, respectively, as compared with the theoretical contents of 36.18, 2.51, 21.11 and 32.16 percent, respectively, as calculated for the above-named compound.
Reaction SMILES: Cl[CH2:2]CCBr.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][NH:18][CH3:19])=[CH:15][C:10]=2[S:9](=[O:20])[CH2:8]1.C[N:22]1[C:26]2C=CC(CCNCCC)=C[C:25]=2S(=O)C1>>[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][N:18]([CH3:2])[CH2:19][CH2:25][CH2:26][NH2:22])=[CH:15][C:10]=2[S:9](=[O:20])[CH2:8]1
Reactant: CNCCc1ccc2c(c1)S(=O)CN2C
Reactant: CCCNCCc1ccc2c(c1)S(=O)CN2C
Reactant: ClCCCBr
Product: CN(CCCN)CCc1ccc2c(c1)S(=O)CN2C

Procedure:
Using the procedure described in Example 19, but replacing 1-chloro-2-bromoethane by 1-chloro-3-bromopropane and 3-methyl-6-[2-(N-methylamino)ethyl]benzothiazolinone by 3-methyl-6- [2-(N-n-propylamino)ethyl]-benzothiazolinone, 3-methyl-6-{2-[N-methyl-N-(3-aminopropyl)amino]ethyl} benzothiazolinone is obtained, which product is treated as in Example 20 with tosyl chloride to yield the product of the title.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>C1COCC1.CN(C=O)C>[CH2:13]([O:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCBr
Reactant: O=C1OCCN1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOCCN1CCOC1=O
Yield: 79.6 %

Procedure:
To 5.12 g of 60% NaH in 130 ml of THF and 30 ml of DMF was added 12.9 of 3-(2-hydroxyethyl)oxazolidin-2-one and the contents were refluxed for 2 hours. 17 g of 1-bromooctane was added and the reaction mixture was refluxed overnight. It was cooled, poured into water and extracted with ether. The combined organic extracts were dried, concentrated and the residue Was kugelrohr distilled (150°-155° C./0.5 mm) to give 16.87 g (79.6%) of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: N#CCCOc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: N#CCCOc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A mixture of 2.93 g (0.018 mol) 3-(4-hydroxyphenoxy)propionitrile, 3.2 g (0.18 mol) 2-chlormethylquinoline hydrochloride and 18 ml (2N, NaOH) in 25 ml DMF and 25 ml THF is heated over a steam bath for a period of 24 hours. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent to obtain the desired product which is used directly in the next step.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[OH2:9].[C:10]1([CH3:20])C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:8][CH:5]1[CH2:6][CH2:7][C:2]2([O:9][CH2:10][CH2:20][O:1]2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: O=C1CCC(O)CC1
Solvent: c1ccccc1
Product: OC1CCC2(CC1)OCCO2
Yield: 33478.6 %

Procedure:
A mixture of 4-hydroxycyclohexanone (228 g, 2.0 mol) ethylene glycol (124 g, 2.0 mol) and p-toluenesulfonic acid monohydrate (0.89 g) in 2.0 l of benzene was stirred at reflux in a 3-l, three-necked, round-bottomed flask equipped with a Dean-Stark trap. The mixture was refluxed until the required amount of water had been removed. Solvent was removed by distillation and the residue was fractionally distilled at 85°-88.5° C. (0.08 mm Hg.) to give 247.8 g of the sub-titled intermediate. (78%), Lit bp 90°-95° C. (0.2 mm Hg.). (M. I. Batuev, et al., Ixvest. Akad. Nauk S.S.S.R., Otdel, Khim Nauk, 1960, 538-549.) IR, OH (3420), C-O (1105, 1035, 920); mass spectrum, m/e 158 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])C[C@H]2C[C@H]21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of (1R,3S,5R)-3-(toluene-4-sulfonyloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.400 g, 1.08 mmol) and NaN3 (0.420 g, 6.47 mmol) in dry DMSO (8 mL) was stirred at 65° C. overnight. After cooling, the mixture was diluted with Et2O and washed with water (×3) and brine (×2). The organics were dried (phase separator) and concentrated in vaccuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M+H]+; tR (HPLC conditions k): 3.78 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]([NH:16][C:17]3[C:22](I)=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:30][O:31][CH2:32]/[CH:33]=[CH:34]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:16][C:17]3[C:22](/[CH:34]=[CH:33]/[CH2:32][O:31][CH3:30])=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A mixture of tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (318 mg, 0.63 mmol, 1.0 equiv.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.53 mmol, 4.0 equiv.), PdCl2(dppf2)′CH2Cl2 (155 mg, 0.19 mmol, 0.3 equiv.) and K2CO3 (348 mg, 2.53 mmol, 4.0 equiv.) in dry DMF (40 mL) was heated to 90° C. under a nitrogen atmosphere and stirred for 2 hours. Then, the reaction mixture was cooled down to room temperature and concentrated in vacuum. The residue was purified by Prep-HPLC to give the title compound (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(3-methoxyprop-1-enyl)-2-phenylpyrimidin-4-amine (Compound 39) (10 mg, 2%). LCMS: 348.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 0.72-0.78 (m, 2H), 0.96-0.98 (m, 2H), 1.94-2.02 (m, 1H), 3.30 (s, 3H), 4.06 (d, J=5.2 Hz, 2H), 6.33 (m, 1H), 6.46 (s, 1H), 7.02 (d, J=15.6 Hz, 1H), 7.48 (m, 3H), 8.29 (d, J=4.4 Hz, 2H), 8.53 (s, 1H), 9.26 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:34][CH:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.07 g, 0.173 mmol, 1.0 eq) and 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.023 g, 0.173 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.087 g, 0.861 mmol, 5.0 eq) and BOP reagent (0.114 g, 0.257 mmol, 1.5 eq). The reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.040 g (44.45%). 1H NMR (400 MHz, CD3OD): δ 9.03 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.8 Hz, 1H), 8.04-7.94 (m, 2H), 7.91-7.83 (m, 2H), 7.72-7.64 (m, 2H), 7.57-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.34-7.24 (m, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.90-1.81 (m, 2H), 1.57-1.49 (m, 2H). 19F NMR (376.51 MHz, CD3OD): δ−78.35 (TFA), −113.31. LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1>>[CH3:15][CH:13]1[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2[C:5]3[C:6]([N:8]([CH3:23])[C:9]=2[CH2:14]1)=[N:7][C:2]([N:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)=[CH:34][C:35]1=[O:39])=[CH:3][CH:4]=3
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Product: CC1Cc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 73.3 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg, 0.520 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (115 mg, 0.520 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (198 mg, 73%) as a yellow oil: ESI MS m/z 520 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])S[C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:10]([OH:12])=[O:11].C(OO)(=O)C.[S:19](=[O:22])(O)[O-:20].[Na+]>O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:13])[S:19](=[O:22])(=[O:20])[C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:10]([OH:12])=[O:11]
Reactant: O=S([O-])O
Reactant: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1.78 g. of penicillanic acid in water, at pH 7.5, was added 1.46 ml. of 40% peracetic acid, followed by an additional 2.94 ml. of 40% peracetic acid 30 minutes later. The reaction mixture was stirred for 3 days at room temperature and then it was diluted with ethyl acetate and water. Solid sodium bisulfite was added to decompose excess peracid, and then the pH was adjusted to 1.5. The ethyl acetate layer was removed, dried (Na2SO4) and evaporated in vacuo. The residue was a 3:2 mixture of penicillanic acid 1,1-dioxide and penicillanic acid 1-oxide.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[Br:20])(=O)C.F[C:22](F)(F)[C:23](O)=O.CO[CH2:30][N:31]([Si](C)(C)C)C.[OH-].[K+].Cl>C1(C)C=CC=CC=1.O>[CH3:30][N:31]1[CH2:23][CH2:22][C@@H:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Br:20])[C@@H:11]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1ccccc1/C=C/c1cc(Cl)ccc1Br
Reactant: COCN(C)[Si](C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](c2cc(Cl)ccc2Br)[C@@H]1c1ccccc1O
Reaction time: 0.5 h

Procedure:
trans-2-Acetoxy-2′-bromo-5′-chlorostilbene (1189 g, 3381 mmol) was dissolved in toluene (5350 ml) and trifluoroacetic acid (10.42 ml, 165 mmol) at 33° C. N-methoxymethyl-N-trimethylsilyl-N-methylamine (670 g, 4153 mmol) was added in the course of 1 hour. The organic layer was concentrated under vacuum to an oil. This oil was dissolved in methanol (4160 ml) at 30° C. Potassium hydroxide (209 g, 3725 mmol) in water (900 ml) was added. After 30 minutes, the pH was adjusted to 8-9 with 3N HCl (approx. 200 ml). The mixture was stirred for 30 minutes and filtered. The product was dried for 24 h under vacuum, yielding the title pyrrolidine in 1188 grams (96%). Purity according to HPLC is >99.0% a/a.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([N:13]([CH2:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=[O:30])[C:14]=2[C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.C(Cl)(=O)C([Cl:35])=O>ClCCl>[Cl-:35].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([C:15]=1[CH3:16])=[N+:13]([CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]1=[O:30])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[Cl:35]
Reactant: Cc1ccc2c(=O)c3ccccc3n(CCCN3C(=O)c4ccccc4C3=O)c2c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(Cl)c3ccccc3[n+](CCCN3C(=O)c4ccccc4C3=O)c2c1C
Product: [Cl-]

Procedure:
A mixture of 1.0 g of 3,4-dimethyl-10-(3-phthalimidopropyl)-9-acridone with 340 ml of oxalyl chloride was stirred at room temperature in 100 ml of dichloromethane for 30 min. After evaporating the excessive oxalyl chloride and dichloromethane under reduced pressure, 1.1 g of the title compound was obtained.