Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1.[Cl:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([Cl:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[Cl:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])=[CH:21][CH:20]=[C:19]([Cl:30])[C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][NH:5][C:6]2=[N:7][CH:8]=1)=[O:17]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Reactant: COc1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 17.2 %

Procedure:
3-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (50 mg, 0.305 mmol) in N,N-dimethylformamide (3.0 mL) was sequentially treated with 2,6-dichloro-3-(propylsulfonamido)benzoic acid (356 mg, 1.14 mmol), EDCI (117 mg, 0.609 mmol), and HOBt (82.3 mg, 0.609 mmol) and heated to 60° C. After 72 hours, the reaction mixture was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was applied directly to a silica gel column and eluted with a gradient (30% to 100%) of ethyl acetate-hexanes to provide 2,6-dichloro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (67.8 mg, 0.0524 mmol, 35.4% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.63-12.59 (s, 1H), 11.04-11.00 (s, 1H), 9.83-9.79 (s, 1H), 8.59-8.570 (d, 1H), 8.47-8.45 (d, 1H), 7.60-7.57 (m, 2H), 4.03-4.01 (s, 3H), 3.21-3.13 (m, 2H), 1.83-1.73 (m, 2H), 1.02-0.97 (t, 3H); MS (APCI-neg) m/z=456.1 (M−H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.[CH3:34]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:14]1[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=2)=[N:10][CH:11]=[C:12]([CH2:15][NH:16][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)=[CH:26][CH:27]=2)[CH:13]=1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2ccc(-c3cnccn3)cc2)cnc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 48-1 (40 mg, 0.15 mmol), 4-(pyrazin-2-yl)benzoic acid 58-1 (30 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol) in DMF (0.9 mL) was added DIEA (0.08 mL, 0.45 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-((3-methyl-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 58 as a white powder. MS m/z 450.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.35 (d, 1H, J=1.6 Hz), 9.30 (t, 1H, J=6.0 Hz), 8.86 (d, 1H, J=4.8 Hz), 8.76 (m, 1H), 8.67 (d, 1H, J=2.4 Hz), 8.57 (m, 1H), 8.30-8.27 (m, 2H), 8.08-8.06 (m, 3H), 7.94 (dd, 1H, J1=5.0 Hz, J2=1.2 Hz), 7.77 (m, 1H), 4.85 (d, 2H, J=6.0 Hz), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5].C(N([CH2:34][CH3:35])CC)C.Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:37]([O:39][C:35]1[CH:34]=[CH:42][CH:41]=[CH:40][CH:45]=1)=[O:38])[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1cnc2c(N(C(=O)Oc3ccccc3)C(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1C(=O)Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.5 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (300 mg) in dichloromethane (5 ml) were dropwise added triethylamine (294 mg) and phenyl chloroformate (375 mg) under ice-cooling, and the mixture was stirred for 2.5 hours at ambient temperature. To the mixture was further added phenyl chloroformate (250 mg), and the mixture was stirred for 1.5 hours at ambient temperature. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, and phenyl chloroformate (375 mg) and diisopropylethylamine (0.506 ml) were added thereto. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel (ethyl acetate-n-hexane) to give 8-[N-(2,6-dichlorobenzoyl)-N-phenoxycarbonylamino]-4-[2-(phenoxycarbonyl)imidazol-1-yl]-3-(phenoxycarbonyloxymethyl)quinoline (250 mg).
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][C@@H:10]([C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(Br)C.II.[C:37](=[O:39])=[O:38].[Cl-:40].[NH4+]>C1COCC1>[ClH:40].[CH2:25]([O:24][C:18]1[CH:19]=[CH:20][C:21]([C:37]([OH:39])=[O:38])=[CH:22][C:17]=1[C@@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH2:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=O
Reactant: [Cl-]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: II
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C(=O)O)ccc1OCc1ccccc1)C(C)C
Product: Cl

Procedure:
To the compound (R)—N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-Phenylpropyl amine compound of formula (F) 25.8 Mg turnings, 400 ml THF, 0.87 g ethyl bromide and 3 crystal of iodine were added and reaction heated to 50° C. to 55° C. and further raised to 65° C. to 70° C. The reaction mass cooled to −60° C. to 70° C. and slowly added 200 g dry ice and stirred for 1 hour. Further the reaction temperature raised to −5° C. to 0° C. followed by slowly addition of 700 ml of 10% ammonium chloride solution. The reaction temperature raised to 25° C. to 35° C., maintained for 30 minutes and finally filtered and washed with 2×25 ml R.O. Water. Layers were separated and further aqueous layer was charged and cooled to 0° C. to 5° C. and adjusted pH at 1 to 2 using conc. Hydrochloric acid solution followed by addition 500 ml MDC. The reaction temperature was raised to 25° C. to 35° C. followed by separation of layers and MDC was distilled under vacuum below at 50° C. The reaction mass was cooled to 25° C. to 35° C. followed by addition of 50 ml of methanol+300 ml of diisopropylether and cooled to 0° C. to 5° C. and finally washed with 2×25 ml diisopropylether to afford the title compound (R)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride of formula (G).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12](C)[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10](C(O)=O)[C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1>O1CCCC1.ClC(Cl)(Cl)C(O)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[NH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(F)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)[nH]c1C(=O)c1ccc(F)cc1

Procedure:
5-(p-fluorobenzoyl)-3-hydroxycarbonyl-1,4-dimethylpyrrole-2-acetic acid (1 mmole) is dissolved in 5 ml tetrahydrofuran containing 2 ml of trichloroacetic acid. The reaction mixture is heated to reflux for 5 hours before it is evaporated in vacuo to remove most of the solvent. The resulting oil is triturated with about 10 ml of water, filtered and dried in vacuo to afford 5-(p-fluorobenzoyl)-4-methylpyrrole-2-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].O=[CH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CO.C(OCC)C>[CH2:14]([N:13]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecanamine (2.0 g, 4.2 mmol) in methanol (50 ml) was treated with sodium cyanoborohydride (0.55 g, 8.4 mmol) and ethyl 4-oxobutyrate (1.04 g, 8.4 mmol). The resulting mixture was stirred at 22° C. for 16 h, diluted with diethyl ether (350 ml), washed with water (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/AcOEt 9:1 to 6:1) to afford the title compound (1.8 g, 73%) as a liquid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]([F:24])([F:23])[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19])=[O:13].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:1].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]([F:24])([F:23])[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19])=[O:13]
Reactant: c1ccncc1
Reactant: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F
Product: O=C(CCCCCCCCCCc1ccccn1)OCC(F)(F)C(F)C(F)(F)F
Product: [Br-]

Procedure:
The process of claim 2 comprising (a) reacting at reflux about 1 mole of 2,2,3,4,4,4-hexafluorobutanol and about 1 mole of 11-bromoundecanoic acid to obtain 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate and then (b) reacting about 1 mole of 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate with about 1 mole pyridine to obtain 2,2,3,4,4,4-hexafluorobutyl 11-pyridylundecylate bromide.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([C:25]([O:27][CH2:28][CH3:29])=[CH2:26])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(OCC)c1cc(C(=O)OC)cc(Cl)n1

Procedure:
Add methyl 2,6-dichloroisonicotinate (2.06 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0) (578 mg, 0.5 mmol), triphenyhlphosphine (263 mg, 1 mmol) and toluene (25 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(1-ethoxyvinyl)tin (4.05 mL, 12.0 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride respectively. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[I:14][CH3:15]>C(#N)CCC>[I-:14].[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:8]2[CH:9]=[N+:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: CI
Reactant: Nc1nc(-c2cccnc2)c(Cl)s1
Solvent: CCCC#N
Product: C[n+]1cccc(-c2nc(N)sc2Cl)c1
Product: [I-]

Procedure:
A suspension of 10 g of 5-chloro-4-(pyridin-3-yl)-thiazol-2-amine (obtained in Example 1b) in 50 ml of butyronitrile was heated at reflux for 2 h with 10 ml of iodomethane. After cooling down of the mixture, the resulting solid was filtered off and recrystallized from methanol to give 13,3 g of 3-(2-amino-5-chlorothiazol-4-yl)-1-methylpyridinium iodide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28](=[O:30])[CH3:29]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:27][C:28](=[O:30])[CH3:29])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (prepared according to Example 16, Steps A-D; 10.07 g, 31.0 mmol) in DMF (150 mL) at ambient temperature was added cesium carbonate (30.3 g, 92.9 mmol), followed by chloroacetone (5.2 mL, 65.1 mmol). The resulting mixture was vigorously stirred at ambient temperature for 1 hr, then diluted with water (1000 mL). After stirring for 1 hr, the precipitate that formed was collected by filtration, washed with water, and air-dried. This material was dissolved in boiling ethanol (150 mL), and then of water (80 mL) was added. The resulting mixture was cooled at 2° C. for 16 hr. The crystals that formed were collected by filtration, washed with 50/50 water/ethanol, and dried under vacuum to afford the title compound as a light orange powder (8.13 g, 69%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[O:28][CH2:29][CH:30]=[CH2:31])[CH2:17][C:16]2[C:18]3[C:12]([CH:13]=[CH:14][CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:29]([O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:6]1([C:4]([OH:5])=[O:3])[CH2:17][C:16]2[C:18]3[C:12]([CH:13]=[CH:14][CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)=[O:32])[CH:30]=[CH2:31]
Reactant: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2cccc3cccc(c23)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
The mixture of 2-(2-allyloxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid ethyl ester (23) (107 mg, 0.26 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out from the water. The precipitate is filtered to give a pure product (24) as white solid (98 mg, 94%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:12]=[CH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7].[C:13]1([Si:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:26]1([Si:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:12]=[CH:11][C:9](=[O:10])[NH:8][C:6]2=[O:7])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1ccn(CCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn(CCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
1-(3′-hydroxypropyl)uracil (0.193 g, 1.134 mmol) was dissolved in dry pyridine (4 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.432 g, 1.46 mmol) in dry pyridine (3 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 4 h30. As TLC monitoring evidenced the presence of unreacted starting material, more triphenyl slyl chloride (0.204 g, 0.69 mmol) in dry pyridine (1 mL) was added. After a further 15 min at 0° C., the reaction had reached completion and was quenched with CH3OH (50 μL). Removal of the solvent in vacuo afforded a crude yellow oil which was purified by silica gel chromatography, using a Jones Chromatography Isolute SI column eluted with a gradient of 0→5% CH3OH in CHCl3. The title compound was obtained as a white solid (0.392 g, 81%) from the fractions with Rf=0.52 (10% CH3OH/CHCl3). Some compound starting material was also recovered (34 mg, 18%).
Reaction SMILES: [Cl:1][CH2:2][C:3](OC)(OC)[O:4][CH3:5].[NH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13]C=1O>C(O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:5]2[O:4][C:3]([CH2:2][Cl:1])=[N:10][C:11]=2[CH:16]=1
Reactant: COC(CCl)(OC)OC
Reactant: Nc1cc(Br)ccc1O
Solvent: CCO
Product: ClCc1nc2cc(Br)ccc2o1
Reaction time: 48 h

Procedure:
1.79 mL (13.3 mmol) 2-chloro-1,1,1-trimethoxy-ethane are added dropwise at RT to a solution of 2.5 g (13.29 mmol) 2-amino-4-bromophenol in 20 mL ethanol and stirred for 48 h. Then 0.4 mL 2-chloro-1,1,1-trimethoxy-ethane are added and stirred for 20 h. The reaction mixture is evaporated down. The purification is carried out by column chromatography on silica gel (DCM/ethanol 80:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:13]=[C:12]([CH3:34])[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:35])=[N:3]1.I[CH2:37][C:38]([NH2:40])=[O:39].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:38](=[O:39])[CH2:37][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][C:17]([O:16][C:14]2[CH:15]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:35])[CH:5]=3)=[O:8])[CH:11]=[C:12]([CH3:34])[CH:13]=2)=[CH:18]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 74.6 %

Procedure:
In the same manner as in Reference Example 5 and using 1,3-dimethyl-N-{3-methyl-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (3.88 g, 7.89 mmol), iodoacetamide (1.90 g, 10.27 mmol), N,N-diisopropylethylamine (1.80 mL, 10.3 mmol) and N,N-dimethylformamide (20 mL) as starting materials, the title compound (3.23 g, 75%) was obtained as a pale-yellow oil.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]1([C:19]([C:21]#[CH:22])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([C:21]1[CH:22]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
6.23 g (0.039 mole) of diazooxindole and 6.6 g (0.051 mole or 1.3 equiv) of the phenylethynyl ketone prepared as in part A above (dried on a porous plate before being weighed out) are suspended in benzene (275 ml) and the mixture is refluxed under N2 for 19 hours. The reaction mixture is cooled and the precipitates that form are filtered off, washed well with anhydrous ether (150 ml) and dried in a vacuum oven at ~70° for 1-1/2 hours. Yield: 10.3 g, m.p. 308°-311°. Additional product of 400 mg is obtained on refluxing the filtrate for another 24 hours. Total crude yield: 94.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=O.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:12]([C:11]2[CH:16]=[CH:17][N:18]=[CH:19][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CSC(N)N
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Temperature: 140 °C
Yield: 43 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (100 mg, 0.27 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (86 mg, 0.39 mmol, 1.45 eq) in pyridine (2 mL) in a sealed tube was heated at 140° C. for 4 hrs. After cooling the mixture was poured into water, extracted with EtOAc, and the combined organic fractions were dried over anhydrous MgSO4. After filtration and solvent evaporation the resulting residue was subjected to silica gel column chromatography (EtOAC:Hex=1:1) to give the desired product (46 mg). [4.99 min; 397(M+1)]
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH3:38][CH:39]([NH2:41])[CH3:40]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:30]([NH:41][CH:39]([CH3:40])[CH3:38])=[O:36])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CC(C)N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)NC(C)C)ncc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (0.10 g, 0.40 mmol) in tetrahydrofuran (2 mL) was added pyridine (0.1 mL). The mixture was cooled to 0° C. and triphosgene (59.4 mg, 0.20 mmol) in tetrahydrofuran (2 mL) was added dropwise. After the reaction mixture was stirred for 1 h, propan-2-amine (0.10 g, 1.7 mmol) was added and the mixture was stirred for 2 h. The reaction was quenched with methanol (2.0 mL), and the mixture was purified by preparative TLC (Hexanes/ethyl acetate=1:1) to give the desired product (20.6 mg, 15%). LCMS (ESI): RT (min)=1.163, M+H+=338.1, method=A; 1H NMR (DMSO-d6, 400 MHz): δ 9.05 (s, 1H), 8.94 (s, 1H), 8.09 (s, 1H), 7.95 (t, J=0.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.64 (dd, J=1.6, 8.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.15-7.11 (m, 1H), 6.89 (d, J=6.8 Hz, 1H), 3.83-3.78 (m, 1H), 2.22 (s, 3H), 1.13 (d, J=6.6 Hz, 6H).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][CH2:15]2.[Br:24]C1C=CC2C(=CC=CC=2)C=1Br.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:24][CH:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([Br:11])[CH:13]=2)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16]1
Reactant: Brc1ccc2ccccc2c1Br
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccc2ccccc2c1
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene naphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol ) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.