Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+](C1C=CC(O[C@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1)([O-])=O.[H][H].Cl.[NH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][C@H]2CCNC[C@H]2C2C=CC=CC=2)=[CH:30][CH:29]=1>C(O)C.O.[Pd]>[ClH:1].[NH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][N:13]2[CH2:14][CH2:15][CH2:10][CH:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)=[CH:30][CH:29]=1
Reactant: [H][H]
Reactant: Nc1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(ON2CCCC(c3ccccc3)C2)cc1

Procedure:
A solution of 4.1 g of cis-4-(4-nitrophenoxy)-3-phenylpiperidine hydrochloride, of Example 10, in a mixture of 125 ml of 95% aqueous ethanol and 5 ml of water is hydrogenated at 45 psi of hydrogen at room temperature over 0.41 g of 10% palladium on carbon catalyst. After 18 hours the catalyst is filtered off and the filtrate concentrated in vacuo. The resulting solid is triturated with ether and filtered to afford a nearly white salt, m.p. s 221°, 223.5°-225.5° C., of cis-4-(4-aminophenoxy)-3-phenylpiperidine hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[CH3:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.13 h

Procedure:
A mixture of 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (7.0 mg, 0.019 mmol, from Example 206) and acetaldehyde (5.2 μL, 0.093 mmol, Aldrich) in DCM (2.4 mL) was treated with Na(OAc)3BH (5.2 mg, 0.024 mmol, Aldrich). After 8 minutes, the solvent was removed in vacuo, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (2.0 mg, 26%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.CCN(CC)CC.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([O:27][C:25]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)=[O:24])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred solution of 300 mg (1.4 mmol) of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (commercially available) in 15 ml of CH2Cl2 were added 34 mg (0.28 mmol, 0.2 eq.) of DMAP, 190 μl (1.4 mmol, 1 eq.) of Et3N and 301 mg (1.4 mmol, 1 eq.) of (BOC)2O. After stirring at RT overnight the reaction mixture was poured on water and extracted with CH2Cl2. Column chromatography (SiO2, EtOAc/Hept. 1:1) afforded 360 mg (82%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:16]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Reactant: OC1CCCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(O)CC2)c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of methyl 4-bromo-3-chlorosulfonyl-benzoate (7.22 g, 23.03 mmol, 1.00 Eq) in DCM (100 mL) was added azepan-4-ol (2.65 g, 23.03 mmol, 1.00 Eq) and TEA (2.33 g, 23.03 mmol, 1.00 Eq). The resulting mixture was stirred at 25° C. until the starting material was consumed. The solvent was removed and the residue was purified by silica gel chromatography (PE:EA=1:1) to give desired compound methyl 4-bromo-3-(4-hydroxyazepan-1-yl)sulfonyl-benzoate (7.00 g, 17.85 mmol, 77.49% yield). LCMS: 393/395 [M+1].
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:30][C:31]([F:39])([F:38])[C:32]([C:34]([F:37])([F:36])[Cl:35])=[O:33]>O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:32]([C:31]([Cl:30])([F:39])[F:38])([C:34]([Cl:35])([F:37])[F:36])[OH:33])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)N2CCc3ccccc32)cc1
Reactant: O=C(C(F)(F)Cl)C(F)(F)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1ccc2c(c1)CCN2C(c1ccccc1)c1ccccc1)(C(F)(F)Cl)C(F)(F)Cl
Reaction time: 13 h

Procedure:
A mixture of 14.5 g (0.05 mole) of 1-benzhydryl-indoline, 100 ml of toluene, 2 ml of water, and 10.9 g (0.055 mole) of 1,3-dichlorotetrafluoroacetone is refluxed for 3 hrs. Another 10.9 g portion of 1,3-dichlorotetrafluoroacetone is added, and refluxing is continued for 13 hrs. The moisture is then removed azeotropically, and the solvent is evaporated to give a crude, viscous residue of 1-benzhydryl-α,α-bis(chlorodifluoromethyl)-2,3-dihydro-1H-indole-5-methanol. This crude material is tedious to purify and is more conveniently used without further purification for conversion to the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:26][O:25][C:17]1[C:16]2[C:6]3[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: COc1ccc(CCCCc2cc(OC)c(OC)c(OC)c2)cc1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)-c1c(cc(OC)c(OC)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 1 ml of dichloromethane, 70 mg (0.194 mmol) of 1-(3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-butane were dissolved. The solution was added with 0.1 ml of trifluoroacetic acid and 180 mg (0.39 mmol) of ferric perchlorate, followed by stirring at room temperature for 40 minutes. The reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with 2N-HCl and then with saturated NaCl. The organic layer was dried over anhydrous magnesium sulfate and the solvent was thereafter distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by thin-film chromatography (silica gel: "MERCK #5744", eluent: 1:5 mixed solvent of ethyl acetate and hexane), whereby 17 mg of the title compound were obtained as colorless oil (yield: 24%). In addition, the starting material was recovered as colorless oil (15 mg, recovery: 21%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[C:16]1([CH3:26])[C:17]([S:22]([O:13][C@H:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-pyrrolidinol (44.32 g), 132.88 g of toluene and 166.95 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.0° C. Then, 104.94 g of toluenesulfonyl chloride was added in divided portions at an interval of about 5 g/10 minutes over 3 hours and 10 minutes at a flask inside temperature of 5 to 10° C. Water (37 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of (S)-1-benzyl-3-pyrrolidinol toluenesulfonate was thus obtained in a yield of 85.5 mole percent.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].C(Cl)(=O)C(C)(C)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][CH:27]([CH3:30])[CH2:28][OH:29])[CH:19]=[CH:20][C:13]1=2.[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C.O>[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:26]([CH:27]([CH3:30])[CH2:28][OH:29])[CH:1]=[O:2])[CH:19]=[CH:20][C:13]1=2
Reactant: CC(CO)NCCOCCc1ccc2sccc2c1
Reactant: O=C[O-]
Agent: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(CO)N(C=O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
In 2.4 mL of acetone is suspended 0.38 g of sodium formate, to which is added 0.37 mL of pivaloyl chloride. The mixture is stirred at ambient temperature for 2 hours. Then, at an ice-cooled temperature, 4 mL of a solution of 0.50 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-amino}-1-propanol in acetone is added, and the resulting mixture is stirred at ambient temperature for 2 hours. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 8.5 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform). Thus, 0.46 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-hydroxy-1-methylethyl)-formamide (is obtained as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39]Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:37][O:38][CH3:39])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), potassium carbonate (89 mg) and DMF (4.0 ml) was added methoxymethylchloride (39 μl) at room temperature with stirring, and the mixture was stirred at 50° C. for 12 hrs. After cooling the reaction mixture, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (75 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].[C:22](=[O:25])([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CN(C=O)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]([CH2:2][C:17]3[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[C:22]2=[O:25])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of benzimidazolinone (1.5 g, 11.2 mmol) in abs. DMF (25 mL) there were added 4-nitrobenzyl bromide (2.16 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol), and a catalytic amount of potassium iodide under a blanket of argon. The reaction mixture was heated to 100° C. over a period of 2 h. Following cooling, the reaction mixture was poured into a solution of H2O (200 mL) and 2N hydrochloric acid solution in H2O (10 mL). The resulting mixture was extracted with EtOAc (5×40 mL), the combined organic phases were washed with sat. NaCl solution (2×30 mL), dried over Na2SO4, and the solvent was removed in vacuo. The residue was taken up in hot toluene (100 mL), and the resulting solid matter was isolated by filtration. The filtrate was concentrated in vacuo. The residue was purified by means of column chromatography (SiO2, cyclohexane/EtOAc 1:1), and there were obtained 1,3-bis(4-nitrobenzyl)-1,3-dihydrobenzimidazol-2-one (W) (1.65 g, mp: 200-201° C.) and 1-(4-nitrobenzyl)-1,3-dihydrobenzimidazol-2-one (V) (600 mg, 22% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CO>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound of step P.i of Preparation P; 8.0 g, 39.5 mmol) in EtOH/H2O 9-1 (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 93.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64D) (136 mg, 0.455 mmol) using sodium carbonate (81 mg, 0.759 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (10/2/1 ml) to afford 200 mg (93.8% yield) of titled compound after purification by column (Silica gel 6/120) using 50% EtOAc/hexane as eluent. MS: m/z=703.2 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1C2C(COC([N:56]=[C:57]=[S:58])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:9][C:10]([C@H:12]1[CH2:17][N:16]([C:57](=[S:58])[NH2:56])[CH2:15][CH2:14][N:13]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(OCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: NC(=S)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of the compound (2.58 g) obtained in Step 3 in chloroform (26 ml) was added, with stirring at room temperature, triethylamine (896 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (1.66 g) was added. After stirring overnight at room temperature, piperidine (1.11 ml) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (5% methanol/chloroform) to give the title compound (2.12 g).
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](SC)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.O[O:35][S:36]([O-:38])=O.[K+].[C:40]([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([S:36]([CH3:40])(=[O:38])=[O:35])[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 100 ml dry round bottom flask was charged with 5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.82 g, 1.76 mmol) and sonicated in methanol (17.62 ml, 0.10 M) for 20 minutes. To this was added oxone (3.25 g, 5.29 mmol) and mixture stirred at RT for 2 days. The reaction mixture was cooled to 0° C. and basified with aq. NaHCO3. The resulting solids were filtered, washed with water, and dried under high vacuum to provide 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a light yellow solid. MS m/z=495.1 [M+H]+. Calc'd for C23H16F2N6O3S: 494.47.
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:1](=[O:5])[CH2:2][CH2:3][OH:4])=[CH:26][CH:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: O=C1CCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCO)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
Propiolactone (0.23 ml) was added to a mixture of 4-[3-(2-benzyloxyphenyl]propyl]benzeneamine hydrochloride (1.26 g) and triethylamine (0.5 ml) in methylene chloride (10 ml) and the mixture was stirred for 18 hours. A further equivalent of propiolactone (0.23 ml) was added and stirring continued for a further 24 hours. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica eluted with a stepwise gradient of methanol in methylene chloride. The fractions eluting with 5% methanol in methylene chloride were collected, concentrated and subjected to chromatography again, eluting with ethyl acetate to give, after crystallisation from dichloromethane/hexane (1:20 v/v) 4-[3-(2-benzyloxyphenyl)propyl]-N-(3-hydroxypropionyl]benzene amine m.p. 109°-110°, 0.22 g (15%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: CN(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)C1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-aminophenyl)-N,N-dimethylpiperidine-4-carboxamide (4.2 g, 16.98 mmol) in 25 mL HBr in 20 mL of water was added a solution of NaNO2 (1.17 g, 16.98 mmol) in water (2 mL) slowly. The mixture was stirred at −10° C.˜0° C. for 30 minutes, and added dropwise to a solution of CuBr (1.34 g, 9.34 mmol) in 12 mL HBr in water (10 mL). Then the mixture was stirred at reflux for 2 hours. The mixture was partitioned between 2N NaOH and EA, washed with EA, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (15:1˜2:1) to give 2.5 g of 1-(4-bromophenyl)-N,N-dimethylpiperidine-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[F:9])N.[ClH:12].N([O-])=O.[Na+]>Cl[Cu].O>[F:11][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[C:7]([Cl:10])=[CH:6][C:4]=1[Cl:12]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1c(Cl)cc(Cl)c(F)c1Cl
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
31.1 g of 3,5-dichloro-2,4-difluoroaniline (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70° C. The resulting mixture was stirred to be a slurry and cooled to 0-5° C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield.
Reaction SMILES: [N:1](=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CCOCC>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])=[O:14]
Reactant: CN=C=O
Reactant: N#CC(=NO)c1cccs1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C#N)c1cccs1

Procedure:
To a solution of 3.04 g. (0.02 mole) of alphaoximino-2-thienylacetonitrile and 2 drops of triethylamine in 50 ml. of ether was added 1.14 g. (0.02 mole) of methylisocyanate in 10 ml. of ether. After 1 hour the solid was filtered and crystallized from benzene to give 3.8 g. of product melting at 154°-155° C.