Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[C:27]([CH2:28]C)=[CH:26][C:25]([NH:30][C:31]([C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=4)[C:37]=3[CH3:38])=[O:32])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[NH:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:23]=[CH:24][C:25]([NH:30][C:31]([C:33]3[CH:34]=[N:35][N:36]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:41][N:40]=4)[C:37]=3[CH3:38])=[O:32])=[CH:26][C:27]=2[CH3:28])[CH2:17][CH2:16]1
Reactant: CCc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCNCC1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (4.0 ml) was added at room temperature to a solution of 4-[3-ethyl-5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]azepan-1-carboxylic acid tert-butyl ester (1.1 g) described in Example D291 in dichloromethane (20 ml), and stirred at the same temperature for 4 hours. After completion of the reaction, 4N aqueous solution of sodium hydroxide was added to adjust the solution to pH 11 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated to give N-[6-(azepan-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 279.1 %

Procedure:
To a suspension of 4-fluorobenzaldehyde (24.8 g, 200 mmol) (6.75 g, 54 mmol) and hydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) and water (13 mL) was added ice (25 g). Then a solution of sodium hydroxide (5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (23.3 g, 84%) which was obtained as a white solid. MS: m/e=139.1 [M]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: Fc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccccc2F)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (4.61 g) in DMF (25 mL) and add slowly to a suspension of sodium hydride (95%) (1.11 g) in DMF (25 mL) at room temperature. Heat the mixture in an oil bath at 65° C. After 30 min., add 1,2-difluorobenzene (4.56 g) and stir at 65° C. After 2 hr., partition between water and ether, dry over anhydrous sodium sulfate, evaporate to give a yellow oil (5.88 g, 70% yield). Mass spectrum (electric spray) m/z=210 (M+1); 1H NMR (CDCl3): 7.05 (m, 3H), 6.92 (m, 1H), 4.29 (m, 1H), 2.71 (m, 2H), 2.30 (s, 3H), 2.27 (m, 2H), 1.99 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([O:24]CC)=[O:23])[CH:15]=1.O>Cl.C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([OH:24])=[O:23])[CH:15]=1
Reactant: CCCn1nc(C(=O)OCC)cc1CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCn1nc(C(=O)O)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 10 °C
Yield: 69.4 %

Procedure:
A stirred solution of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylate (45.1 g, 127 mmol) in 1 M aqueous hydrochloric acid (157 mL) and acetic acid (157 mL) was heated at 95° C. (internal temperature) for 10 hours and then cooled to 10° C. Water (300 mL) was added and a white solid was isolated by filtration, washed with water and diethyl ether, and dried. The solid was treated with toluene (150 mL) and heated at reflux for 3 hours with a Dean-Stark trap. The mixture was cooled in an ice bath to 10° C. and a solid was isolated by filtration and dried to provide 28.85 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(S)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(SN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 17.1 g. (128 mmole) of N-chlorosuccinimide and 700 ml. of benzene is treated with 15 g. (107 mmole) of p-methoxythiophenol dissolved in 125 ml. of benzene. After 75 minutes, the resulting orange solution is cooled to 15° and 13.0 g. (128 mmole) of triethylamine in 125 ml. of benzene is added over a period of 25 minutes. The cooling bath is removed and the reaction is stirred at room temperature for an additional 45 minutes. The reaction mixture is then filtered and the organic solution is rinsed with three 200 ml. portions of water, 200 ml. of brine and dried (MgSO4). Removal of the solvents in vacuo gives 27.0 g. of crude product. Recrystallization from chloroform-hexane gives 21.2 g. of
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][S:15]2(=[O:24])=[O:23])=[CH:10][CH:9]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[S:15]1(=[O:23])=[O:24]
Reactant: BrCCCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCCCBr)c2ccccc2N1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Cesium carbonate (0.29 g, 0.9 mmol) was added to a solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Made analogously as in general procedure I, 0.25 g, 0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6 mmol) in dry DMF (5.0 mL) under nitrogen. After 3 h, the reaction mixture was diluted with diethyl ether and washed with water and brine. The ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.41 g of crude product. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.22 g (59%) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[O:25])=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:38][N:35]1[CH2:34][CH2:33][CH:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16](/[CH:15]=[CH:14]/[C:13]([OH:39])=[O:12])=[CH:21][CH:20]=3)=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of trifluoroacetic acid were added to a solution of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid tert-butyl ester (270 mg, 0.63 mmol) in 10 ml of DCM. The solution was stirred at room temperature for 2 hours. The solvent was then removed until dryness and 300 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid trifluoro acetate were obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:29]>>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([Cl:29])[CH3:9])[CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared according to the procedure of Example 13 step 6, using tert-butyl 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate (racemic) and cyanuric chloride as the starting materials. 1H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 5.46 (m, 1H), 4.23 (bs, 2H), 3.73 (s, 3H), 3.29 (bs, 1H), 2.78 (bs, 2H), 2.40 (s, 3H), 2.27-2.09 (m, 2H), 1.78 (d, 3H), 1.63 (m, 2H), 1.43 (s, 9H) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.C(O)C.[C:15](=S)=[S:16].[OH-].[Na+]>O>[SH:16][C:15]1[NH:11][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: S=C=S
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(S)[nH]c2c1
Yield: 59 %

Procedure:
A mixture of 2.6 g of 4-methoxy-o-phenylenediamine hydrochloride, 70 ml of ethanol, 15 ml of carbon disulfide and an aqueous solution containing 1.5 g of sodium hydroxide and 5 ml of water was refluxed for 4 hours. Then, the reaction mixture was condensed under reduced pressure. The residue was recrystallized from a mixture of water and methanol (70:30 by volume) to obtain 1.3 g of 2-mercapto-5-methoxybenzimidazole (Compound (III-15)) having a melting point of 254° to 255° C. (yield: 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COCCOCOc1cc(O)c(C(C)=O)c(OCOCCOC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(C(C)=O)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred suspension of 1-{2-hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone (3.53 g, 10 mmol), potassium carbonate (1.7 g, 14 mmol) in DMF (15 mL) was added benzylbromide (2.1 g, 12 mmol). After stirring overnight, the reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine. The organic phase was dried and evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 7/1, to provide the title compound (g 3.25, yield 73%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1)=O.[BH4-].[Li+].Cl>C1COCC1.CCOC(C)=O>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc([C@@H]2COCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(CO)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a solution of tert-butyl (3R)-3-(4-methoxycarbonylphenyl)morpholine-4-carboxylate 9 (6.91 g, 21.50 mmol) in THF (140 mL) was added lithium borohydride (1.873 g, 86.00 mmol) and the resulting mixture then heated under reflux overnight. Additional lithium borohydride (341 mg, 2 eq) was added and the reaction mixture heated under reflux for 2 h. The reaction mixture was cooled in an ice bath and then added ice-water, followed by 2M HCl (10 mL) and stirred until effervescence ceased then diluted with EtOAc (100 mL), mixed and the organic layer separated, washed sequentially with water (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo to leave the product as a colourless viscous oil (6.0 g, 95% yield); 1H NMR (400.0 MHz, DMSO) d 1.40 (9H, s), 3.01 (1H, m), 3.49 (1H, m), 3.71-3.83 (3H, m), 4.27 (1H, m), 4.47 (2H, m), 4.96 (1H, s), 5.17 (1H, m) and 7.30 (4H, m) ppm.
Reaction SMILES: C[Al](C)C.[NH2:5][C@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[CH3:14][O:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](OC)=[O:20]>C1(C)C=CC=CC=1>[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[C@H:6]([NH:5][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[C:17]=1[CH3:26])[CH2:7]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc(OC)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)N[C@@H]2CN3CCC2CC3)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminum (0.8 mmol) in toluene was slowly added to asolution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.1 g; 0.8 mmol) in toluene (5.0 mL) and the mixture stirred for 15 minutes. A solution of methyl 3-methoxy-2-methylbenzoate (0.1 g; 0.55 mmol) in toluene (2 mL) wasadded and the reaction mixture heated to reflux until, as indicated by thin-layer chromatography, the reaction had finished. The mixture was cooled to 0° C. and then carefully quenched with water (0.4 mL). The reaction mixture was stirred for an additional 30 minutes and then filtered washing with ethyl acetate (2×20 mL). Removal of the solvent from the combined filtrate gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide as a whitesolid (0.19 g, 0.686 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide hydrochloride, m.p. 259°-261° C., [α]D25 -13.8° (c=0.16, H2O).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:13]=1)=[N:7][CH:8]=[C:9]([CH2:11]O)[CH:10]=2.O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:11][C:9]1[CH:10]=[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:13][C:6]2=[N:7][CH:8]=1
Reactant: CSc1nc2ncc(CO)cc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1nc2ncc(CCl)cc2s1
Reaction time: 3 h
Yield: 107.7 %

Procedure:
To a stirred mixture of (2-(methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol (404 mg, 2 mmol) in anhydrous CH2Cl2 (20 mL) at rt was added SOCl2 (166 μL, 2.4 mmol). After 3 h, the mixture was concentrated under reduced pressure to afford 6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridine (497 mg) as a white solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=1.9 Hz, 1H), 8.60 (d, J=1.9 Hz, 1H), 4.95 (s, 2H), 2.83 (s, 3H); LCMS (ESI) m/z 231 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:31]1[C:36]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([NH2:44])[N:38]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[NH2:44][C:39]1[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:36]2[C:31]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:32][CH:33]=[CH:34][CH:35]=2)[N:38]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A solution of N-(5-amino-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.124 g, 0.409 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (1.706 mL, 1.706 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. 4-(2-Fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.070 g, 0.341 mmol) was added and the mixture was stirred at 0° C. for 10 min. The reaction mixture was then stirred at rt for 20 h. The reaction was quenched with sat. NH4Cl and the resulting mixture was partitioned between sat. NaHCO3 and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by prep HPLC. Fractions containing the product were combined and concentrated. The residue was basified using sat. NaHCO3 (10 mL). The aqueous layer was extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated to give the product as a yellow solid (0.050 g). m/z (ESI, +ve ion) 486.8 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.38 (s, 1H); 8.74-9.01 (m, 2H); 8.44 (d, J=3.22 Hz, 1H); 8.39 (d, J=2.34 Hz, 1H); 7.95 (dd, J=8.62, 5.12 Hz, 2H); 7.15 (t, J=8.48 Hz, 2H); 6.86-7.03 (m, 2H); 5.43 (br. s., 2H); 2.60 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:44])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:44][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:43]=[CH:42][C:18]=1[O:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)=[O:28])[N:23]=[CH:22][N:21]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)CC1
Reaction time: 3.5 h
Yield: 31 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 2.5 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyrimidine (134 mg) and (+)-10-camphorsulfonic acid (109 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated to provide the title compound (60.7 mg, 31%) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)=O.C[O:18][C:19](=O)[CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([C:11]3[CH:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:20][C:19](=[O:18])[O:1]2)=[CH:4][CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=O)c2cc(C)on2)c(O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(-c3cc(C)on3)cc(=O)oc2c1

Procedure:
A solution of (2-hydroxy-4-methylphenyl)(5-methylisoxazol-3-yl)methanone from step 3 (0.93 g, 4.28 mmol) and methyl(triphenylphosphoranylidene)acetate (1.86 g, 5.57 mmol) in toluene (30 mL) was heated to 90° C. for 2 h, concentrated in vacuo, and the residue washed with Et2O and hot acetone to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.18 (d, 1H), 7.27-7.19 (m, 2H), 6.77 (s, 1H), 6.67 (s, 1H), 2.60 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:39]([N:41]([CH2:50][CH3:51])[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:40].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:47]1[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][N:41]([CH2:50][CH3:51])[CH2:39][CH3:40])[CH2:45][CH2:46]1)=[O:6]
Reactant: CCN(CC)CCN1CCNCC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC)cn4S(=O)(=O)c3ccc(C)cc3)cc(F)c2N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.3 %

Procedure:
300 mg (0.564 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid, 105 mg (0.564 mmol) of 1-(2-diethylaminoethyl)piperazine, and 279 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 3.5 mL dimethyl formamide and stirred at room temperature for 48 hours. The reaction was extracted into ethyl acetate and washed with water. The water layer was back extracted three times with ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions containing the purified intermediate were evaporated to afford 230 mg (0.329 mmol, 58% yield) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as a white solid. 1H NMR (500 MHz, CD3CN) δ 8.59 (d, 1H), 8.09 (s, 1H), 8.09 (d, 2H), 8.01 (s, 1H), 7.61 (dd, 1H), 7.43 (m, 4H), 7.23 (d, 1H), 7.18 (d, 1H), 7.11 (t, 1H), 4.67 (s, 2H), 3.88 (s, 3H), 3.60 (s, br., 4H), 2.52 (m, 12H), 0.99 (t, 6H); MS: m/z 699.3 (M+H+).