Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+].C(Cl)Cl>C(O)(C)C>[CH:10]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)=[CH2:11]
Reactant: OCc1ccc(Cl)nc1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)O
Solvent: ClCCl
Product: C=Cc1ccc(CO)cn1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
A 100 mL sealed tube was charged with a solution of (6-chloropyridin-3-yl)methanol (0.5 g, 3.4 mmol, Org. Lett. 2005, p 2965-2967) dissolved in isopropanol (10 mL), potassium vinyltrifluoroborate (1 g, 7.63 mmol, Aldrich), [1,1,-bis(diphenyl phosphino)ferrocine]dichloro palladium(II) complex with DCM (0.277 g, 0.34 mmol, Aldrich) and TEA (0.92 mL, 6.8 mmol). The mixture was degassed with nitrogen then heated at about 80° C. for about 12 h. The reaction mixture was cooled to RT, filtered and washed with isopropanol (10 mL). The filtrate was evaporated to dryness under reduced pressure and the crude material obtained was purified by silica gel column chromatography using 30 to 40% of EtOAc in hexane as an eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford (6-vinylpyridin-3-yl)methanol as a dark brown liquid 0.25 g (53%), 1H NMR (400 MHz, DMSO): δ 8.479 (s, 1H), 7.704-7.688 (d, J=6.4 Hz, 1H), 7.471-7.456 (d, J=6.0 Hz, 1H), 6.827-6.806 (m, 1H), 6.212-6.177 (d, J=14 Hz, 1H), 5.439-5.417 (d, J=8.8 Hz, 1H), 5.300 (m, 1H), 4.524 (d, J=4.4 Hz, 2H), MS m/z: 136 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[N:3]1.[Xe](F)[F:20]>C(#N)C.C(OCC)(=O)C>[F:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]([C@@H:11]1[CH2:13][C@H:12]1[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:7][CH:6]=[CH:5]2
Reactant: F[Xe]F
Reactant: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)c(F)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.9 %

Procedure:
To a solution of N-{[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (100 mg, 0.411 mmol) in acetonitrile (4.1 mL) was added xenon difluoride (76.5 mg, 0.452 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate is solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0) and preparative TLC (methanol/ethyl acetate=10/90) to give the title compound (13.9 mg, yield 11%).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:26])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:14])[CH3:15]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminium (2M in toluene) (0.795 mL, 1.59 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (178 mg, 1.38 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (680 mg, 1.38 mmol) in toluene (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at reflux for 18 hours. The reaction mixture was allowed to cool to r.t. and concentrated. The residue was diluted with ethyl acetate and treated with 1M citric acid (2ml). The layers were separated and the organics were washed with water and brine, dried (MgSO4) and concentrated to a yellow foam, (2S)-5-(tert-butyldimethylsilyloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanamide (693 mg, 85%). m/z (ES+) (M+H)+=588.46; HPLC tR=3.54 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]3[CH2:15][O:14][C:13](=[O:16])[C:9]3=[CH:10][CH:11]=2)[CH2:6][CH2:5][O:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[O:16]=[C:13]1[C:9]2[C:8](=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:4][CH2:5][CH2:6]3)[CH2:15][O:14]1
Reactant: O=C1OCc2c1ccc1c2CCOC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2OCCc3c2ccc2c3COC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-(Hydroxymethyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one, in DCM (10 mL) was treated with p-Toluenesulfonyl chloride (0.40 g, 2.3 mmol); to the mixture was added pyridine (2 mL) and the resulting mixture stirred at room temperature for 12 h. TLC (hexanes/EtOAc=1/0.5) and LC indicated the consumption of starting material and formation of the desired product. Dichloromethane was added to the reaction mixture and it was washed with NaCl, water and dried over Na2SO4, filtered and concentrated to dryness, absorbed onto silica gel and was then subjected to purification over silica gel; the title compound was isolated with the solvent system of hexanes/EtOAc (1/0.5). 1H-NMR (400 MHz, CDCl3) δ ppm 7.781 (d, J=8 Hz, 1H), 7.727 (d, J=8 Hz, 1H), 7.367 (d, J=8 Hz, 1H), 7.257 (d, J=8.5 Hz, 1H), 7.206 (d, J=8 Hz, 1H), 5.253 (s, 2H), 5.110 (s, 1H), 4.481-4.452 (m, 2H), 4.419-4.385 (m, 2H), 4.196-4.153 (m, 2H), 2.495 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].O.[OH-].[Na+]>CCOCC>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH3:7]
Reactant: ClCC1CO1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCN(CC)CC1CO1
Yield: 59.6 %

Procedure:
In a three neck flask was placed 102 g (1.1 mols) of epichlorohydrin and while stirring vigorously, 73 g (1 mol) of diethylamine was added dropwise to epichlorohydrin together with a small amount (1/10 mol of the amine) of water at temperatures below 25° C. Thereafter, the mixture was stirred for 5 hours at 30° to 35° C. Then, an aqueous 35 to 40% solution of 1.7 mols of sodium hydroxide was added dropwise to the mixture at 25° to 30° C. followed by stirring vigorously. Thereafter, the mixture was further stirred for 3 hours at the same temperature as above. Then, after cooling the mixture, 200 ml of water was added to the reaction mixture to dissolve the salts formed and after further adding 300 ml of ether to the mixture and shaking them, the resultant mixture was allowed to stand, thereby the reaction mixture was separated into two phases. The organic phase thus formed was collected and dried with the addition of granular potassium hydroxide. Then, ether was distilled away and the residue was distilled under reduced pressure in N2 stream to provide 77 g of diethylglycidylamine having a boiling point of 50° to 52° C./13 mmHg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ncc([N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To 2-amino-5-nitropyrimidine (0.42 g, 3.0 mmol) dissolved in toluene (2 ml) was added acetic anhydride (1.4 ml, 15 mmol). The reaction mixture was stirred at 90° C. for 15 hr, after which an additional amount of acetic anhydride was added (0.7 mL) and the mixture was stirred at reflux for another 16 h. The solvent was removed in vacuo and to the residue was added hexane (10 mL) and DCM (1 mL). The solid was collected by filtration, dried to give N-(5-nitropyrimidin-2-yl)acetamide as an off-white solid. MS (ESI, pos. ion) m/z: 183 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:27]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.02 h

Procedure:
4-(Hydroxymethyl)-1-(triphenylmethyl)imidazole, as described in Example 1, Step A, (1.97 g, 5.72 mmol) and 4-(dimethylamino) pyridine (280 mg, 2.29 mmol) were stirred in CH2Cl2 (15 mL) and tert-butyldimethylsilyl chloride (905 mg, 6.01 mmol) was added. After 1 min, triethylamine (0.88 mL, 6.31 mmol) was added dropwise over 3 min. The reaction mixture was stirred for 45 min, then CH2Cl2 (150 mL) was added and the solution was washed with 0.1 N HCl (50 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—30% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.B(O)(O)[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=1>COCCOC.C(=O)(O)[O-].[Na+].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>[C:18]([C:17]1[C:12]([NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]2[S:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:20][C:14]2=[N:15][CH:16]=1)#[N:19]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
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: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg, 2.12 mmol) and 100 mg of tetrakis(triphenylphosphine)palladium(0) in 50 mL of ethylene glycol dimethyl ether and 35 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of chloroform to 10% methanol in chloroform to provide 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzoic acid as yellow crystals, mp>300° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.78 (s, 1H), 7.86 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s, 1H); MS 470.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14](F)=[CH:13][N:12]=[C:11]([C:16]([NH:18][C:19]4[N:20]=[C:21]([C:24]5[N:28]([CH:29]6[CH2:31][CH2:30]6)[CH:27]=[N:26][N:25]=5)[S:22][CH:23]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:13][N:12]=[C:11]([C:16]([NH:18][C:19]4[N:20]=[C:21]([C:24]5[N:28]([CH:29]6[CH2:31][CH2:30]6)[CH:27]=[N:26][N:25]=5)[S:22][CH:23]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(N2CCOCC2)cn1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a mixture of intermediate D (450 mg, 1.03 mmol) and K2CO3 (430 mg, 3.09 mmol) in DMF (3 mL) was added morpholine (270 μl, 3.09 mmol) and the reaction was heated to 80° C. overnight. The reaction was concentrated and purified by RP-HPLC to afford 390 mg (75% y) of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-morpholinopicolinamide. All final compounds were isolated as the HCl salt from the preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][CH2:21][OH:22])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]2([NH:1][C:32]([NH:31][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[S:33])[CH2:20][CH2:21][OH:22])=[CH:7][CH:6]=1
Reactant: COc1cc(F)c2c(c1)C(N)(CCO)c1cc(Br)ccc1O2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A reaction mixture of 2-(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)ethanol (8.8 g, 23.90 mmol) and benzoyl isothiocyanate (3.22 ml, 23.90 mmol) in THF (200 ml) was stirred at RT for 1 hour. The reaction mixture was then concentrated under reduced pressure to afford N-((7-bromo-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)carbamothioyl)benzamide (12.7 g, 23.90 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:13][CH3:14].C(N(CC)CC)C>C1COCC1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)CCC3=O)cc1
Yield: 64 %

Procedure:
Reaction of 5-amino-indan-1-one (75 mg, 0.50 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (108 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(1-oxo-indan-5-yl)-4-propyl-benzamide (94 mg, 0.32 mmol, 64% yield) as a white powder after purification on silica gel (eluent EtOAc/DCM 0/10 to 1/9).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.[CH3:7][N:8]([CH3:12])[C:9]([NH2:11])=[S:10]>>[CH3:7][N:8]([CH3:12])[C:9](=[NH:11])[S:10][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CN(C)C(N)=S
Reactant: CN(C)CCO
Product: CN(C)CCSC(=N)N(C)C
Yield: 128 %

Procedure:
A mixture of 2-dimethylaminoethanol (2.23 g), N,N1 -dimethylthiourea (2.6 g) and aqueous hybrobromic acid (48%, 20 ml) was boiled under reflux for 50 hours and evaporated to dryness. The residue was recrystallised from a mixture of methanol and ethanol to give the dihydrobromide of the title compound (5.6 g) m.p. 198°-199°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=4)[CH:10]=[N:9][CH:8]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Yield: 79.5 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (1.00 g, 2.38 mmol) and tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (998 mg, 2.57 mmol), the desired title compound (1.01 g, yield 79%) was obtained by the same method as in Example 4 (4a).
Reaction SMILES: [CH3:1][O:2]CCOC1C=C2C(=CC=1)NC=C2.[CH2:15]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([NH2:30])=[O:29])[CH:23]=[C:22]2[N:31]=[C:32]=[O:33])[CH:16]=C>>[N:31]([C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH2:15][CH2:16][O:2][CH3:1])[CH:20]=2)[N:24]([C:28]([NH2:30])=[O:29])[CH:23]=1)=[C:32]=[O:33]
Reactant: COCCOc1ccc2[nH]ccc2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: COCCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O

Procedure:
was prepared from 5-(2-methoxy-ethoxy)-1H-indole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzoyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 15 mg (23%) of the desired 4fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-phenyl]benzamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C25H21F8N2O3: 549.1424 [M+H]+, found: 549.1436. 1H NMR (CDCl3) δ 3.6 (dd, 1H), 3.8 (dd, 1H), 4.4 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.8 (d, 1H), 7.0-7.4 (m, 7H), 7.8 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>N1C=CC=CC=1>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:18]2[CH:17]=[CH:16][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH:7]=[CH:8]1
Reactant: Nc1cccc2cc[nH]c12
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(S(=O)(=O)Nc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
The synthesis of the present compound can be carried out according to the process disclosed in JP-A-7-165708. For example, the present compound can be synthesized as follows. After dissolving 264 mg (2 mmol) of 7-amino-1H-indole in pyridine, 767 mg (3 mmol) of 4-sulfamoylbenzenesulfonyl chloride is added thereto under stirring at room temperature. After the mixture is stirred overnight at room temperature, the solvent is evaporated under reduced pressure. Ethyl acetate and 0.2 N hydrochloric acid are added to the resulting residue. The organic layer is separated, washed with water, and dried over magnesium sulfate, followed by evaporation of the solvent. The resulting residue is purified by silica gel column chromatography to give 445 mg of N-(1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-hydroxy-phenyl)-propionic acid ethyl ester (9.02 g) in acetic acid (75 mL) was added nitric acid (60%, 5.24 g in AcOH) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow oil. (9.71 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2F)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
A solution of 3-chloro-5-[(2,6-difluoro-3-methylphenyl)oxy]benzonitrile (4.05 g, 14.48 mmol) and NBS (3.09 g, 17.38 mmol) in carbon tetrachloride (500 mL) was degassed and heated to 90° C. under a nitrogen atmosphere. After ca. 5 min, AIBN (0.119 g, 0.724 mmol) was added and the solution was heated for 6 h. The solution was cooled to 0° C. then filtered through Celite. The filtrate was concentrated and the crude material was purified on silica gel (hexanes/ethyl acetate) to give the title compound (2.9 g, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.40 (m, 2H), 7.21 (t, 1H), 7.04-7.11 (m, 2H), 4.51 (s, 2H).