Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1.Cl.[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33](O)=[O:34])[CH3:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:15](=[O:16])[NH:17][CH2:18][CH3:19])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1)=[O:34])[CH3:29]
Reactant: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CCN(CC)CCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCN(CC)CC)cc2F)CC1
Reaction time: 18 h
Yield: 58.6 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N-ethyl-2-phenyl-acetamide (22 mg, 0.06 mmol), 3-diethylaminopropionic acid hydrochloride (13 mg, 0.07 mmol) and PyBroP (34 mg, 0.07 mmol) in DCM (2 mL) was treated with iPr2NEt (0.032 mL, 0.19 mmol). After 18 h, the mixture was washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give an oil, which was purified by PTLC to give a beige solid (17 mg, 56%). MS (ESI): mass calcd. for C27H38FN5O2, 483.62. m/z found, 484.4 [M+H]+. 1H NMR (CDCl3): 11.15 (s, 1H), 7.38-7.37 (m, 1H), 7.36-7.35 (m, 1H), 7.33-7.32 (m, 3H), 7.31-7.28 (m, 1H), 7.13-7.09 (m, 2H), 6.85 (t, J=9.0, 1H), 3.88 (s, 1H), 3.38-3.33 (m, 2H), 3.06-3.04 (m, 4H), 2.79-2.76 (m, 1H), 2.69-2.65 (m, 4H), 2.59-2.58 (m, 4H), 2.50-2.47 (m, 1H), 1.40-1.38 (m, 1H), 1.35-1.32 (t, J=7.3, 1H), 1.77-1.22 (m, 9H).
Reaction SMILES: O[C@@H](C1C=CC=CC=1)[C@@H](N(C)[C:6](=[O:18])[C@H:7]([NH2:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[OH2:26]>>[NH2:17][C@H:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:18])=[O:26]
Reactant: O
Reactant: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Product: N[C@H](CCCc1ccccc1)C(=O)O

Procedure:
A solution of the compound of Example 199, Step A (400 mg, 1.18 mmol) in water (10 mL) was heated to reflux for 20 h. The reaction was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were back extracted with water (2×20 mL) and the combined aqueous extracts were concentrated down to a white solid. The solid was triturated with EtOH to remove residual pseudoephedrine and deliver Example 199, Step B (135 mg, 60%): +APcl MS (M+1)+ 194.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>CCOCC>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CCOCC
Product: NNC(=O)c1ccc(F)cc1

Procedure:
The p-fluorobenzoic acid hydrazide is prepared as follows. Ethyl p-fluorobenzoate (8.4 g) is refluxed with hydrazine hydrate (3.75 g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration, washed with ether and desiccated, m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[NH4+].[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].Cl>ClCCl>[C:11]([N:14]1[CH2:15][CH2:16][CH:17]([C:20](=[O:21])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:18][CH2:19]1)(=[O:13])[CH3:12]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
1,3-difluorobenzene (6.7 g, 58.7 mmol) and ammonium chloride (13.3 g, 250 mmol) are added to 15 ml of dichloromethane and cooled to room temperature; thereto is drop-added 50 ml of dichloromethane wherein 1-acetyl-4-piperidinyl carboxylic acid chloride (9.8 g, 51.8 mmol) is dissolved. A reaction is carried out at reflux for 3 hours and the resulting mixture is poured into a mixture of ice and hydrochloric acid after completion of reaction. The mixture is extracted with dichloromethane (20 ml×3). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 5.01 g of a product, with a yield of 36%.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 65 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (200 mg, 0.51 mmol), DMF (2.55 mL), ethanol (0.45 mL), 1M Na2S2O4 (3 eq, 1.53 mmol, 1.53 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 46 mg). After 18 h, filtration of the precipitate and washing with cold water (1 mL) gave the product (79 mg, 27%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 2.63-2.76 (m, 2H, piperazine NCH2), 2.89 (s, 2H, piperazine NCH2), 3.71-3.77 (m, 6H, piperazine N(CH2)2 & NCH2Ar), 4.19 (d, J=5.8 Hz, 2H, CH2NH—BOC), 7.39 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 7.40-7.44 (m, 1H, pyridine H-5), 7.82 (s, br, 1H, pyridine H-4), 7.95 (s, br, 1H, NH—BOC), 8.12 (d, J=8.1 Hz, 2H, phenyl H-3 & H-5), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.53 (br s, 1H, pyridine H-6), 8.60 (s, br, 1H, pyridine H-2), 13.49 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A mixture of 10 g (42.4 mmol) of 1,3-dibromobenzene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 7.4 g (49%) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].C(OCC)C.[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[NH4+]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH2:1][CH2:2][CH3:3]
Reactant: CCC[Mg]Cl
Reactant: O=Cc1cccc(Cl)c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(O)c1cccc(Cl)c1Br
Temperature: 25 °C
Yield: 62 %

Procedure:
Under an argon atmosphere, zinc chloride (0.68 g, 4.97 mmol) was added to a 2.0 M solution of n-propyl magnesium chloride in diethyl ether (12.42 mL, 24.93 mmol), and the mixture was stirred at room temperature. After stirring for 0.5 hours, a solution of 2-bromo-3-chlorobenzaldehyde (4.36 g, 19.87 mmol), which had been obtained in Reference example 7 (7b), in tetrahydrofuran (10 mL) was added dropwise thereto. After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution (20 mL) was added thereto. The mixture obtained was extracted with ethyl acetate (20 mL×2). After that, the organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=5/1) to give the title compound as a white solid (3.23 g, yield 62%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([O:10]CC)=[O:9])[CH:6]=1.CO.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: CCOC(=O)Cn1cc(C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 0.51 g (3.0 mmol) of ethyl [4-methyl-1H-1,2,3-triazole-1-yl]acetate from step B above in tetrahydrofuran (10 ml), methanol (6 ml) was added 6 mL (6 mmol) of an aqueous 1.0 M lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 8 mL of a 2 N hydrochloric acid solution which was then evaporated to remove all volatiles. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a white solid (0.40 g, 95%). LC/MS 142 (M+1).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[C:7]1([CH3:11])[CH:8]=[CH:9][CH:10]=[C:5]([PH:12](=[O:19])[C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1
Reactant: Cc1cccc(Br)c1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc([PH](=O)c2cccc(C)c2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Under a nitrogen stream, a solution of magnesium (3.60 g, 3.50 equivalents) and a small amount of iodine and 1,27 dibromoethane-in THF (25 mL)solution was stirred at room temperature for 30 min. A solution of m-bromotoluene (25.36 g, 3.51 equivalents) in THF (130 mL) was added at 24° C., and the mixture was stirred at 40° C. for 30 min. Then, a solution of diethyl phosphite (5.84 g, 42.3 mmol) in THF (10 mL) was added at 25° C., and the mixture was stirred at 24° C. for 1.5 hrs. 6M-HCl (20 mL) was added at 4° C., and then water (20 mL) and toluene (60 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with 10% aqueous NaHCO3 solution (20 mL), water (20 mL) and 10% aqueous NaCl solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and further passed through a membrane filter (0.2 μm) under reduced pressure. The filtrate was concentrated under reduced pressure to give the title compound (9.09 g, colorless oil). yield 93.3%
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 12 h

Procedure:
Combine 2-chloro-1H-benzimidazole (5.0 g, 33 mmol) and 1-benzyl-4-aminopiperidine (14.2 g, 75 mmol) and heat to about 150° C. After 12 hours, cool and partition between water and chloroform, warming if necessary. Separate the layers and add methanol and toluene to the organic layer. Evaporate the organic layer in vacuo to give a solid. Triturate the solid with ethyl acetate, collect by filtration, and dry to give (1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine: Rf=0.30 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:17])[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2

Procedure:
103 G. of 8-fluoro-2-methyl-dibenzo[b,f]-thiepin-10(11H)-one is suspended in 550 ml. of ethanol and mixed with 24.3 g. of sodium borohydride. The reaction mixture is heated for about 10 minutes under reflux conditions. The reaction mixture, after the addition of water, is extracted with chloroform. The organic phase is again washed with water, dried over sodium sulfate and evaporated, whereby there is obtained 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-ol as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1)[CH3:10].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([C:14]2[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[OH:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CCc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)cs2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-2-thiophenecarboxaldehyde (4.78 g) in tetrahydrofuran (40 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 M tetrahydrofuran solution, 50 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3-84:16) to give 4-bromo-2-thienyl-4-ethylphenylmethanol (5.37 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H−H2O).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([C:40]5[CH:52]=[CH:51][C:43]([C:44]([O:46]C(C)(C)C)=[O:45])=[CH:42][C:41]=5[CH3:53])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>ClCCl.C(O)(C(F)(F)F)=O>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([C:40]5[CH:52]=[CH:51][C:43]([C:44]([OH:46])=[O:45])=[CH:42][C:41]=5[CH3:53])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To tert-butyl 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoate (1 g, 1.28 mmol) was added dichloromethane:TFA (9:1, 10 mL). The reaction was stirred overnight at room temperature. Upon completion the solvent was removed under reduced pressure and the resultant residue was redissolved in acetonitrile for direct purification by reverse phase HPLC to yield 4-{5-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-4-(trifluoromethyl)phenyl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (0.674 g, 0.931 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ8.27 (s, 1H), 8.04 (m, 4H, peaks overlap for the two rotamers), 7.90 (s, 1H), 7.84 (s, 2H, minor rotamer), 7.83 (s, 2H, major rotamer), 7.75 (s, 1H, major rotamer), 7.67 (s, 1H, minor rotamer), 7.63 (d, J=8 Hz, 1H, major rotamer), 7.42 (m, 2H), 7.38 (d, J=7.9 Hz, 1H, major rotamer), 7.36 (d, J=7.9 Hz, 1H, minor rotamer), 6.11 (d, J=7.9 Hz, 1H, minor rotamer), 6.09 (d, J=7.9 Hz, 1H, major rotamer), 5.27 (t, J=7.9 Hz, 1H, major rotamer), 4.95 (t, J=7.9 Hz, 1H, minor rotamer), 4.62 (m, 1H, minor rotamer), 4.51 (m, 1H, major rotamer), 4.12 (s, 3H, minor rotamer), 3.94 (s, 3H, minor rotamer), 2.45 (s, 3H, minor rotamer), 2.45 (s, 3H, major rotamer), 2.37 (m, 1H), 2.2 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.4 (m, 1H), 1.1 (m, 2H). MS ESI calc'd. for C35H26F9N2O5 [M+H]+ 725.2. found 725.0. RTA (95% HS): 53.18 nM
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1.N1C=CC=CC=1.[C:34](Cl)(=[O:38])[C:35]([CH3:37])=[CH2:36]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:34](=[O:38])[C:35]([CH3:37])=[CH2:36])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]2=[N:18]1
Reactant: COc1ccc2nn(-c3cc(OCCCO)cc(C(C)(C)C)c3O)nc2c1
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCOc1cc(-n2nc3ccc(OC)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer, a thermometer and an addition funnel which was protected from moisture with a drying tube were placed 37.16 g (0.1 mol) of the benzotriazole of Example 3, 800 mL of dry toluene and 17 mL (0.21 mol) of dry pyridine. A solution of 13 mL (0.128 mol) of methacryloyl chloride (freshly distilled) in 10 mL of toluene was added to the mixture over 30 minutes. The reaction mixture was stirred overnight at room temperature (<25° C.). A white precipitate (pyridinium chloride) was separated by filtration and washed with toluene. The filtrate and washings were combined, washed with 1N hydrochloric acid, water, aqueous sodium bicarbonate and water successively, then dried with anhydrous sodium sulfate and evaporated. The residue (ca. 41 g) was dissolved in a mixture of 1 L of methanol and 500 mL of methylene chloride by heating in a water bath at 45° C. The resulting solution was filtered to remove a small amount of insoluble materials and diluted with 250 mL of methanol. The solution was cooled slowly at room temperature, in a refrigerator and finally then placed in a freezer where the temperature was reduced to about -5° C. The resulting crystals were separated by filtration, washed with 250 mL of cold methanol/methylene chloride (90/10 v/v) and dried in vacuo to give 38.4 g of 99.7% pure product m.p. 114°-116° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([C:27]3[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:36]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[ClH:36].[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([N:18]2[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:20][C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[N:17]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2ccccc2)cn1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccc2)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 4-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (332 mg) obtained in Example 64 in methylene chloride (2 mL), anisole (0.4 mL) and trifluoroacetic acid (1.6 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solvent was removed under reduced pressure, and the residue was partitioned between water and diethyl ether. The aqueous layer was alkalinized with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate four times. The organic layers were combined, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was dissolved in a solvent mixture of diethyl ether and a small amount of methanol. 1M HCl-ethanol (0.78 mL) was added thereto, and the precipitated crystals were collected through filtration. The thus-obtained matter was recrystallized from methanol-diethyl ether, to thereby give the title compound (229 mg, 76%).
Reaction SMILES: Br[CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:2][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1ccc(SCBr)cc1
Product: FC(F)(F)c1cccc(OCSc2ccc(Cl)cc2)c1
Yield: 71 %

Procedure:
The synthesis was effected by reaction of 1-bromomethylthio-4-chlorobenzene and 3-trifluoromethylphenol in the same manner as described in preparation 3(b); yield 71%, b.p. 118°-122° C./0,01 mmHg. 1H NMR (CDC13); δ 5.13 (CH2), 7.1-7.5 (2×Ph), MS [70 eV 70, m/z (% rel. int)]: 318. (2,M), 159 (37), 157 (100), 145 (21) 121 (7), 108 (8), 75 (14)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:28]O)=[C:6]([NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:7]=1.O=S(Cl)Cl.C([O-])([O-])=O.[K+].[K+].[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:46]([N:40]1[CH2:45][CH2:44][N:43]([CH2:28][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH2:42][CH2:41]1)(=[O:48])[CH3:47]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)Nc1cc(Br)ccc1CO
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 8.5 %

Procedure:
At room temperature, 3-(5-Bromo-2-hydroxymethyl-phenylamino)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.137 mmol) was dissolved in 2 ml dried CH2Cl2. Then SOCl2 (49 mg, 0.333 mmol) was added slowly. After stirred for about half an hour, K2CO3 (84 mg, 0.612 mmol) and 1-piperazin-1-yl-ethanone (32 mg, 0.245 mmol) were added. This solution was stirred for about 2 h, then the solution was concentrated and the crude product was purified by Prep-HPLC to obtain 7 mg white solid rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.