Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:29]3C=CC=CC=3)[CH2:27]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:29][CH:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:18](=[O:19])[C:17]2[CH:35]=[CH:36][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)[CH2:27][N:5]1[C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]2=[N:1][C:6]1=[O:7]
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(CO)c2ccccc2)CC1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Cn1c(=O)nc2n(c1=O)CCCC2)N1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione obtained in Example 1-1) and 4-(4-fluorobenzoyl)-1-(1-phenyl-2-hydroxyethyl)piperidine were condensed in N,N-dimmethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OC([O-])=O)([O-])=O.[K+].[K+]>CN(C=O)C.O>[Si:17]([O:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])OC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
The mixture of 4-hydroxy-2-methoxybenzaldehyde (10.0 g), (3-bromopropoxy)-tert-butyldimethylsilane (25.0 g), and potassium dicarbonate (13.6 g) in DMF (100 mL) was stirred at RT for 5 h. The mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give 21.3 g of the subtitle compound as a yellow oil [as a mixture with (3-bromopropoxy)-tert-butyldimethylsilane].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][N:14]3[C:17](=[O:34])[C@@H:18]([NH:26]C(=O)OC(C)(C)C)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[ClH:42]>ClCCl.CCOCC>[ClH:42].[NH2:26][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccc(F)cc3)cc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccc(F)cc3)cc21
Reaction time: 3 h
Yield: 89 %

Procedure:
The (S)-tert-butyl 1-(6-(4-fluorophenyl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (93.0 mg, 202 μmol) was dissolved in dichloromethane and TFA (1.0 mL, 13 mmol) was added. The resulting solution was stirred for three hours. The mixture was then concentrated and the residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate (1×30 mL). The organic layer was then dried over magnesium sulfate and concentrated to dryness and the residue was again dissolved in ethyl acetate and 2.0 equivalents of 1M HCl in ether solution was added. A precipitate formed and the slurry was filtered and washed with hexanes to give (2S)-2-amino-1-(6-(4-fluorophenyl)indolin-1-yl)-3-phenylpropan-1-one hydrochloride (65 mg, 89% yield). MS ESI (pos.) m/e: 361.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1F)(=O)[CH3:2].CO.O.[NH2:27][NH2:28]>C(Cl)(Cl)Cl>[CH3:2][C:1]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])[CH:5]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: CC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nc(C)c3c2)C1=O
Yield: 14 %

Procedure:
1-(3-Acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (160 mg, 0.513 mmol) in hydrazine hydrate (5 mL) was taken in a reaction flask and the flask was heated to reflux and maintained for 21 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (3% MeOH in CHCl3), followed by preparative HPLC afforded 22 mg of the product (14% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:20][CH3:30])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(OC)cccc21
Temperature: 60 °C
Reaction time: 13 h
Yield: 55.1 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)-7-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (65 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), methyl iodide (0.4 mL, 6.4 mmol) and dry acetone (5 mL) was stirred at 60° C. for 13 hours. The potassium carbonate solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (90:10) to give the title compound as a yellow solid (36 mg, 55%); 1H-NMR (CDCl3): δ 10.56 (1H, s), 7.98 (1H, s), 7.64-7.59 (2H, m), 7.18-7.12 (3H, m), 7.03 (1H, t), 6.64 (1H, d), 4.28-4.19 (4H, m), 3.96 (3H, s), 3.26-3.24 (2H, m), 1.24 (3H, t); MS (ES): 409 (MH+).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1>C(O)C>[C:4]([C:3]1[CH:10]=[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][N:12]2[CH:2]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ncnc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cc2c3ccccc3ncn2c1

Procedure:
A solution of ethyl bromopyruvate (3.2g, 0.016 m) and 4-methylquinazoline (2.0g, 0.014 m) in dry ethanol (150 ml) was heated at reflux for two hours. During this time, a tan solid formed. Excess ethyl bromopyruvate was added (1.0g) and the reaction mixture was allowed to reflux overnight. After this time, the reaction was complete. The alcohol was removed in vacuo and the residue diluted with H2O. Sodium bicarbonate was added until effervescence ceased and the aqueous mixture extracted with ether. The ether extracts were combined, dried over Na2SO4, filtered and the solvent removed in vacuo to yield a tan solid. Crystallization from MeOH afforded the product as a white solid; m.p. 138°-139° C.
Reaction SMILES: I.[NH2:2][C@@H:3]1[C:10](=[O:11])[N:9]2[C@@H:4]1[S:5][CH2:6][C:7](/[CH:15]=[CH:16]/[CH2:17][N+:18]([CH2:21][C:22](=[O:24])[NH2:23])([CH3:20])[CH3:19])=[C:8]2[C:12]([O-:14])=[O:13].[Br:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28].C(OCC)C.O>ClCCl.C(#N)C>[Br:25][C@H:26]([CH3:30])[C:27]([NH:2][C@@H:3]1[C:10](=[O:11])[N:9]2[C@@H:4]1[S:5][CH2:6][C:7](/[CH:15]=[CH:16]/[CH2:17][N+:18]([CH2:21][C:22](=[O:24])[NH2:23])([CH3:20])[CH3:19])=[C:8]2[C:12]([O-:14])=[O:13])=[O:28]
Reactant: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)CC(N)=O
Reactant: C[C@@H](Br)C(=O)Cl
Agent: I
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: C[C@@H](Br)C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+](C)(C)CC(N)=O)CS[C@H]12
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a suspension of 1.4 g (E)-(6R,7R)-7-amino-3-[3-(carbamoylmethyl-dimethyl-ammonio)-propenyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate monohydroiodide in 24 ml of dichloromethane/acetonitrile (1:1) was added 4 ml of N,O-Bis(trimethylsilanyl)trifluoroacetamide and the mixture was stirred at 20° for 0.5 h. After cooling of the reaction mixture to 0°, 2.05 g of (R)-2-bromo-propionyl chloride was added and stirring was continued for 5 min. The solution was dropped onto 0.5 l of diethyl ether containing 0.2 ml of water. The mixture was stirred for 0.5 h and subsequently, the precipitate was isolated by filtration, washed with 50 ml of diethyl ether, and dried. The brown solid was suspended in 5 ml of water. After adjusting the pH to 2.5 by the addition of 2N NaOH, 0.3 l of 2-propanol were added and the mixture was stirred at 20° for 0.5 h. The precipitate was filtered off, washed with 50 ml of diethyl ether and dried, to give 1.3 g of (E)-(6R,7R)-7-[(R)-2-bromo-propionylamino]-3-[3-(carbamoylmethyl-dimethyl-ammonio)-propenyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate as a light-brown powder.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][CH:24]=1)C1C=CC=CC=1.C(N1C(C2C=NC(C3C=CC=CC=3)=NC=2)=CN=C1C1C=CC=CC=1)C1C=CC=CC=1>>[C:25]1([C:22]2[N:21]=[CH:20][C:19]([C:9]3[NH:8][C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:11][N:10]=3)=[CH:24][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(Cn2c(-c3ccccc3)cnc2-c2cnc(-c3ccccc3)nc2)cc1
Agent: c1ccc(Cn2c(-c3cnc(-c4ccccc4)nc3)cnc2-c2ccccc2)cc1
Product: c1ccc(-c2ncc(-c3ncc(-c4ccccc4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, Step D, except that 5-(1-benzyl-5-phenyl-1H-imidazol-2-yl)-2-phenylpyrimidine (this Example, Step B) was used instead of 5-(1-benzyl-2-phenyl-1H-imidazol-5-yl)-2-phenylpyrimidine. The title compound was isolated as a white solid (0.044 g, 62% yield); Rf 0.26 with 95:5 v/v dichloromethane-methanol; melting point 238° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.40 (s, 2H), 8.43 (m, 2H), 7.99-7.84 (m, 2H), 7.58-7.20 (m, 8H); MS (ESI+) m/z 299.1 (M+1); H-PGDS FPBA IC50: 2.8 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2S[CH:8]=[CH:7][C:6]=2[CH:10]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:22]([O-:26])([O-])(=[O:24])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:22](=[O:26])(=[O:24])[CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=S([O-])([O-])=S
Reactant: Brc1ccc2sccc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S1(=O)C=Cc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
5-Bromo-1-benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][CH3:18])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(Br)cc1C(F)(F)F
Reaction time: 0.67 h

Procedure:
After to a solution of 4-bromo-2-trifluoromethylaniline (2.805 ml) in pyridine (15 ml) was added dropwise ethyl chloroformate (2.130 ml) during 15 minutes in an ice bath, the reaction mixture was stirred for 40 minutes. Then, to the solution was added dropwise ethyl chloroformate (1.000 ml) during 5 minutes in an ice bath again. The reaction mixture was stirred for 1 hour. After to the reaction solution was added water, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (6.4509 g, quantitative yield).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[N:11]([CH2:19]C)[S:10]2(=[O:22])=[O:21])C=CC=CC=1.S(Cl)([Cl:26])(=O)=O>C(Cl)Cl>[Cl:26][CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[N:11]([CH3:19])[S:10]1(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC1(C)C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Solvent: ClCCl
Product: CCCC1(C)C(=O)N(CCl)S(=O)(=O)N1C
Yield: 64.5 %

Procedure:
A solution of 2-Phenylthiomethyl-4-methyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.96 g) and sulfuryl chloride (0.28 ml) in 25 ml of dry methylene chloride was stirred for 1.75 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in 30 ml of hexane to afford 480 mg (64.5%) of 2-chloromethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =propyl; R2 =CH3 ; R3 =CH3 ; X'=Cl) as a solid, m.p. 99°-100° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1Cc1c(Cl)cccc1Cl
Temperature: 75 °C
Reaction time: 4 h

Procedure:
1000 mg (5.4 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate together with 1426 mg (5.94 mmol) of 2,6-dichlorobenzyl bromide were dissolved in 37 ml of DMF, and 2112 mg (6.48 mmol) of cesium carbonate were added. The mixture was stirred at 75° C. for 4 h. After cooling to RT, the mixture was added to 100 ml of ice-water. The precipitated product was filtered off and washed with water. The beige solid was dried under high vacuum. This gave 1500 mg (81% of theory) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31]Br>CC(C)=O>[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[O:1][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=2[F:28])[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=1
Reactant: CCC(=O)Nc1cc(C(=O)O)cc(C2=C(c3cc(C)ccc3O)CCC2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)OCc2ccc(F)cc2F)cc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure 5 but using 5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid instead of 6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid, 2,4-difluorobenzyl bromide instead of 4-chlorobenzyl bromide and acetone instead of 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=2)[CH3:19])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][C:11](OCC)=[O:12])=[O:8].[CH3:37][NH2:38].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:34])[F:35])=[N:22][N:21]=2)[CH3:19])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][C:11]([NH:38][CH3:37])=[O:12])=[O:8]
Reactant: CN
Reactant: CCOC(=O)CNC(=O)c1cc(Cl)ccc1OC(C)(C)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=O)CNC(=O)c1cc(Cl)ccc1OC(C)(C)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoyl]glycinate (300 mg) was dissolved in ethanol (6 ml), and methylamine (2.86 ml) was added thereto, followed by stirring at room temperature for one hour. Potassium carbonate (240 mg) was added thereto, followed by stirring at 60° C. for one hour. Methylamine (2.86 ml) was added thereto, followed by stirring at 60° C. for 2 hours. The reaction solution was cooled to room temperature and water and a 1M aqueous sodium hydroxide solution were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-N-[2-(methylamino)-2-oxoethyl]-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (131 mg).
Reaction SMILES: [C:1]1([PH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[Br:68])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>C1(C)C=CC=CC=1>[Br:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[P:11]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Reactant: c1ccc2c(Pc3cccc4ccccc34)cccc2c1
Agent: CCCP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
Into a four-neck flask were weighed 16.89 g (59.0 mmol) of di(1-naphthyl)phosphine, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of diphenylphosphinopropane. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (10.68 g, a pale yellow solid). Yield 49.2%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55]C)=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.B(Br)(Br)Br.N>ClCCl>[OH:55][C:52]1[CH:51]=[CH:50][C:49]([S:46]([NH:45][C:4]2[CH:5]=[C:6]([C:8]3[C:16]4[C:15]([NH:17][C@H:18]([C:20]5[N:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:24](=[O:32])[C:23]6=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]6[N:21]=5)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=4[NH:10][CH:9]=3)[CH:7]=[C:2]([OH:1])[CH:3]=2)(=[O:48])=[O:47])=[CH:54][CH:53]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(O)cc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(=O)(=O)c6ccc(O)cc6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 11 %

Procedure:
(S)—N-(3-Hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-methoxybenzenesulfonamide (40 mg, 0.04 mmol) was treated with boron tribromide (1M in dichloromethane, 388 μl, 0.39 mmol) in dichloromethane (800 μl) and then with a solution of ammonia (7N in methanol, 800 μl, 5.60 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 10% dichloromethane-2-propanol) to obtain 3 mg (11% yield, 88% purity) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][N:31]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 89.7 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (250 mg, 0.75 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (148 mg, 0.82 mmol) and anhydrous NaOAc (67 mg, 0.82 mmol) in EtOH (15 mL) was stirred for 20 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2) and the solvent removed under reduced pressure. The residue was purified by recrystallization from CH2Cl2/PE to afford N-{2-[1-(4-chlorophenoxyimino)ethyl]-5-trifluoromethylphenyl}trifluoromethanesulfonamide 199 (310 mg, 90%), as a pale yellow solid. M.p. 89-90° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.41, br s, 1H, 8.02, s, 1H, 7.76, d, J=8.6 Hz, 1H, 7.56, m, 1H, 7.36, d, J=9.2 Hz, 2H, 7.12, d, J=9.2 Hz, 2H, 2.60, s, 3H.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:10]#[C:9][C:5]2[CH:4]=[C:3]([CH2:2][N:23]3[CH2:28][CH2:27][N:26]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[CH:4]=4)[CH2:25][CH2:24]3)[CH:8]=[CH:7][N:6]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C#Cc2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(C#Cc2cc(CN3CCN(Cc4ccnc(C#Cc5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-Trimethoxyphenylethynyl)-pyridine (254 mg) and piperazine (31 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.