Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[N:17]=2)=[O:15])[CH2:10][C:9]1([CH3:26])[CH3:25])=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:25][C:9]1([CH3:26])[NH:8][CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[N:17]=2)=[O:15])[CH2:10]1
Reactant: CC(C)c1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc(C(=O)N2CCNC(C)(C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 55.0 mg (0.152 mmol) 4-(6-isopropyl-pyridine-2-carbonyl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was added 100 μl (1.30 mmol) TFA. The resulting mixture was stirred at RT for 12 h. The solvent was evaporated.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[S-]C#N.[K+].C(=O)([O-])O.[Na+].[NH2:20][C:21]1[CH:48]=[CH:47][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:46])[N:34]([CH3:45])[CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:27]=2)=[C:23]([F:49])[CH:22]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:65]1([CH2:71][C:72]([N:74]=[C:75]=[S:76])=[O:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C(#N)C.C(O)C.CCCCCC.C(OCC)C.C(OCC)(=O)C>[F:49][C:23]1[CH:22]=[C:21]([NH:20][C:75]([NH:74][C:72](=[O:73])[CH2:71][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[S:76])[CH:48]=[CH:47][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:46])[N:34]([CH3:45])[CH2:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[CH:27]=1
Reactant: CN1CCN(CCCN(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: N#C[S-]
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCN(CCCN(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
2-Phenylacetyl chloride (0.032 ml) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (46.6 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring for 30 min. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added acetonitrile (2 ml) to prepare a solution. 3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea (50.0 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then D-10-camphorsulfonic acid (24.9 mg) was added thereto, followed by stirring for 5 min. To the reaction mixture was added the solution of 2-phenylacetyl isothiocyanate in acetonitrile (2 ml) synthesized above, followed by stirring under a nitrogen atmosphere at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:5 to 1:8). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1.5 ml)-hexane (1.5 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (35.0 mg, 49.1%) as a white solid.
Reaction SMILES: [NH2:1][NH2:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]=[C:14]=[S:15]>C(OCC)C>[NH2:1][NH:2][C:14]([NH:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)=[S:15]
Reactant: NN
Reactant: S=C=Nc1ccc2ccccc2c1
Solvent: CCOCC
Product: NNC(=S)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrazine (1.1 g, 0.035 mole) was dissolved in 150 ml of diethyl ether in a round-bottomed flask. 2-Naphthyl isothiocyanate (4.6 g, 0.25 mole) was added dropwise to the mixture keeping the pot temperature below 30° during the addition. The reaction mixture was stirred overnight at room temperature. The reactants were then cooled and the title product filtered off. The product was air-dried, yield 4.5 g, m.p. 174°-6°.
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[C:17](=[O:27])[O:18][C:19](=[O:26])[C:20]=2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C>C(O)C>[CH:21]1([C:20]2[C:19](=[O:26])[O:18][C:17](=[O:27])[C:16]=2[C@H:13]2[CH2:14][CH2:15][C@@H:10]([OH:9])[CH2:11][CH2:12]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C2=C(C3CCCC3)C(=O)OC2=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1OC(=O)C([C@H]2CC[C@@H](O)CC2)=C1C1CCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A catalytic amount of concentrated hydrochloric acid was added to a solution of 3-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-4-cyclopentylfuran-2,5-dione (65 mg, 0.17 mmol) in ethanol (3.0 ml) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was allowed to cool and was then concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=80:20) to give the title compound as a colorless solid (40 mg, yield 88%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7](Cl)=[CH:8][CH:9]=2)[N:4]=1.P(OCC)(OCC)OCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: BrCc1ccc2ccccc2n1
Yield: 13.8 %

Procedure:
A magnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.0 g, 3.91 mmol) and triethyl phosphite (0.74 g, 4.45 mmol) in dry toluene (10.0 ml) was heated under reflux for 24 h. The cooled solution was adsorbed onto a quantity of silica (ca. 5.0 g) and column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:4) provided unreacted 2-bromomethylquinoline (0.12 g, 0.469 mmol--12%) as brown crystals. Further elution (ethyl acetate) secured the title compound (0.88 g, 72%) as a yellow / brown oil. Distilled at 240° C. at 0.05 mmHg using a Kugelrohr short-path distillation apparatus as a bright yellow oil which crystallised on standing (m.p. 33°-37° C.); (Found: C, 53.17; H, 5.40; N; 4.31; Cl, 11.22. C14H17ClNO3P requires C, 53.6; H, 5.46; N, 4.46; Cl, 11.3%); νmax (thin film)/cm-1 3060.5, 2981.5, 1612.5, 1598.5, 1559.5. δH (270 MHz) 1.27 (6H, t, 2×CH2CH3, 3J=6.9 Hz); 3.60 (2H, d, CH2P, 2J=22.4 Hz); 4.11 (4H, m, 2×CH2CH3); 7.47 (1H, dd, 3-H, Jo =7.0, 4J3H,P =0.8 Hz); 7.51 (1H, dd, 6-H, Jo =8.4, Jm =1.5 Hz); 7.72 (1H, d, 5-H, Jo =8.9 Hz); 8.05 (1H, d, 8-H, Jm =1.7 Hz); 8.06 (1H, d, 4-H, Jo =8.3 Hz). δC (67.8 MHz) 16.15 (CH2CH3, d, 3JC,P =6.1 Hz); 37.0 (CH2P, d, 1JC,P =134.3 Hz); 62.3 (CH2CH3, d, 2JC,P =6.1 Hz); 122.3 (3-C, d, 3JC,P =2.5 Hz), 125.1 (4a-C), 135.3 (7-C), 136.2 (4-C); 147.9 (8a-C), 154.3 (2-C, d, 2JC,P =8.6 Hz). Remaining signals fall in the narrow range 127.1-128.6 ppm; m/z 315.3, 313.2 (7.52, 22.18, M+), 277.3 (2.21), 242.1, 240.1 (1.79, 5.13), 193.1 (6.84), 179.1, 177.1 (33.1, 100), 142.2 (3.65), 109.1 (4.57).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][C@@H:14]([CH2:19][N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:21][C@H:22]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12]3)O1.Cl[C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]([NH2:56])=[O:55])[CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][C:35]([Si:32]([CH3:34])([CH3:33])[O:31][C@H:22]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][N:20]([CH2:19][C@H:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([C:54]([NH2:56])=[O:55])[CH:49]=3)[CH:10]=2)[O:15]1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:36])[CH3:37]
Reactant: CC1(C)OB(c2ccc3c(c2)CC[C@H](CN(Cc2ccccc2)C[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)O3)OC1(C)C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(N)=O)c3)ccc2O1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Argon was bubbled through a mixture of (2S)-N-{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N-(phenylmethyl)-3-(phenyloxy)-1-propanamine (Example 88, 100 mg, 0.16 mmol) and 4-chloro-2-pyridinecarboxamide in toluene (1 mL), ethanol (1 mL), and 2M aqueous sodium carbonate (1 mL) for 10 minutes. Triphenylphosphine (4 mg, 0.016 mmol, 0.1 eq.) and palladium (II) acetate (1.0 mg, 0.004 mmol, 0.025 eq.) were added, and the mixture was stirred vigorously under argon at 85° C. overnight. The reaction was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was concentrated in vacuo to remove excess solvents, and the resulting oil was purified by flash chromatography on silica gel eluted on a gradient from 75:25 to 25:75 hexanes/ethyl acetate. The title compound was obtained as a pale yellow oil (45 mg, 44%): 1H NMR (300 MHz, acetone-d6) δ8.57 (d, 1 H), 8.31 (d, 1 H), 7.96 (broad s, 1 H), 7.76 (dd, 1 H), 7.56-7.53 (m, 2 H), 7.45-7.41 (m, 2 H), 7.34-7.21 (m, 5 H), 6.91-6.86 (m, 4H), 6.80 (broad s, 1 H), 4.35-4.30 (m, 1 H), 4.26-4.18 (m, 2 H), 3.93-3.77 (m, 3 H), 2.98-2.87 (m, 4 H), 2.15-2.08 (m, 1 H), 1.73-1.59 (m, 1 H), 1,30-1.25 (m, 1 H), 0.88 (s, 9 H), 0.12 (s, 3 H), 0.08 (s, 3 H); MS m/z 638.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH:21](Cl)Cl)=[N:9]2)=[CH:4][CH:3]=1.[OH2:25]>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[Cl:20][C:18]1[CH:19]=[C:14]2[C:15]([CH:21]([OH:25])[N:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[C:13]2=[O:24])=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cc(Cl)ccc1C(Cl)Cl
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 110 °C

Procedure:
A solution of silver nitrate (12.1 g.) in water (50 cc.) is added to a solution of 7-chloro-2-(5-chloro-2-dichloromethyl-benzoylamino)-1,8-naphthyridine (9.5 g.) in dimethylformamide (300 cc.) heated to a temperature of about 110° C. The reaction mixture is further heated to a temperature of about 110° C for 20 minutes and the suspension obtained is filtered hot. The filtrate obtained is poured into water (500 cc.) and the product which precipitates is filtered off. Recrystallisation from dimethylformamide gives 6-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (5 g.) melting at 306° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=O.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:20][N:19]=1
Reactant: NN
Reactant: Cc1ccsc1C(=O)c1ccccc1C(=O)O
Solvent: CCO
Solvent: O
Product: Cc1ccsc1-c1n[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-methylthiophene-2-carbonyl)benzoic acid (0.446 g, 1.81 mmol) and hydrazine hydrate (0.41 mL, 7.3 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.23 (m, 1H), 8.01-7.80 (m, 2H), 7.68 (d, J=5.1, 1H), 7.62-7.42 (m, 1H), 7.10 (d, J=5.1, 1H), 2.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CN(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(Br)cc(C(=O)O)c1
Reaction time: 3 h

Procedure:
Methyl 3-bromo-5-[(dimethylamino)methyl]benzoate (0.30 g, 1.1 mmol, from Step A) was dissolved in tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.555 g, 13.2 mmol) in water (6 mL) was added. After stirring for 3 hours, the mixture was rotovapped to remove THF and reduce the volume of water. The mixture was diluted with an equivalent volume of acetonitrile and filtered. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation to afford a white solid. Yield: 0.26 g (91%); LC-MS: 258.0, 260.0 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 7.86 (dd, 1H), 7.76 (dd, 1H), 7.43 (dd, 1H), 3.38 (s, 2H), 2.14 (s, 6H).
Reaction SMILES: C(O)C.[CH:4]1([N:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:12]([CH3:29])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([N:10]2[C:14]3[C:15](=[O:16])[NH:17][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][C:13]=3[C:12]([CH3:29])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccccc1C(=O)Nc1c(C)nn(C2CCCCC2)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 10 h
Yield: 72.3 %

Procedure:
To a 2 ml ethanol solution of 100 mg (0.28 mmol) of the compound obtained in Example 9, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at 90° C. for 10 hours. Then, the reaction mixture was brought to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 68.5 mg (72%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14]OS(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: COc1c(O)c(Br)cc(C=O)c1Cl
Solvent: C1CCOC1
Product: COc1c(Br)cc(C=O)c(Cl)c1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To the mixture of aldehyde 156 (15.0 g, 56.5 mmol) in THF (300 mL) were added dimethylsulfate (7.0 mL, 73.5 mmol) and LiOH monohydrate (3.1 g, 73.5 mmol). The mixture was stirred for 3 hours at 65° C. The mixture was cooled to r.t. and filtered to remove insoluble materials through celite. The filtrate was extracted with EtOAc/aq. 50% NaCl solution (200 mL/500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 157 (11.1 g, 70%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[NH:44])[NH:42]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[N:44]=[C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt3 (3.6 g, 36 mmol) in toluene (150 mL) was added isobutylchloroformate (4.1 g, 30 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.4˜7.3 (5H, m), 4.7 (2H, s), 4.69 (2H, s), 4.2˜4.04 (2H, m), 3.02˜2.84 (3H, m), 2.04˜1.94 (2H, m), 1.84˜1.7 (2H, m), 1.46 (9H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([CH2:17]O)[O:16][CH2:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(Cl)(=O)=O>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][C:11]1([CH2:17][F:19])[O:16][CH2:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(OCC1(CO)OCCCO1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCC1(CF)OCCCO1)c1ccccc1
Reaction time: 20 h
Yield: 46.4 %

Procedure:
To a toluene (100 ml) solution of (2-(hydroxymethyl)-1,3-dioxan-2-yl)methyl benzoate (4.76 g, 18.8 mmol), 1,8-diazabicyclo[5.4.0]unedec-7-ene (8.43 ml, 56.4 mmol) was added, cooled on ice and nonafluoro-1-butanesulfonyl chloride (5.06 ml, 28.2 mmol) was added. The mixture was stirred under ice-cool for 15 minutes, and at 40° C. for 20 hours, and further stirred at room temperature for 8 days. The reaction mixture was extracted by adding water and ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtrated through silica gel, and then, the filtrate was concentrated. The residue was subjected twice to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.22 g, yield: 46.4%).
Reaction SMILES: CO[C:3](=[C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]1=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[CH:33][CH:32]=1>CN1C(=O)N(C)CCC1.C(OCC)(=O)C>[CH3:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:3](=[C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[O:29])[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:12]4)=[CH:6][CH:5]=3)=[CH:32][CH:33]=2)[N:38]=[CH:39]1
Reactant: Cn1cnc(-c2ccc(N)cc2)c1
Reactant: C=CCOC(=O)NC1(c2ccc(C(OC)=C3C(=O)Oc4ccccc43)cc2)CC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NC1(c2ccc(C(Nc3ccc(-c4cn(C)cn4)cc3)=C3C(=O)Oc4ccccc43)cc2)CC1

Procedure:
1.05 g of allyl (1-{4-[methoxy-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)-carbamate and 0.47 g of 4-(4-aminophenyl)-1-methylimidazole in 3 mL of DMPU were reacted in the microwave reactor at 180° C. After cooling, the mixture was diluted to 150 mL with ethyl acetate, extracted 2× with water, and the organic phase was dried over MgSO4 and evaporated down to the residue with silica gel. The substance was chromatographed with dichloromethane/methanol (97:3) on silica gel 70 at a flow rate of 30 mL/min Residue: 0.6 g of yellow oil.
Reaction SMILES: [OH-].[Na+].[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:4]=[N-:5].[SH:22][CH2:23][CH2:24][OH:25]>CO>[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][S:22][CH2:23][CH2:24][OH:25])=[N+:4]=[N-:5]
Reactant: OCCS
Reactant: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCCOCCSCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
Aqueous NaOH (3.33 g in 20 ml H2O, 1.5 equiv.) was added dropwise to a solution of tosylate 3 (15.8 g, 55.5 mmol) and β-mercaptoethanol (5.8 ml, 1.5 equiv.) in MeOH (200 ml). The resulting mixture was stirred at RT for 72 h then methanol was evaporated under reduced pressure. The resulting suspension was diluted with water (50 ml) and extracted with CH2Cl2 (6×50 ml). The combined organic layers were dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 8:2 then 6:7) afforded sulfide 4 as a colorless liquid (8.41 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:23]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:22]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:23][C:3]1[C:2]([Br:1])=[CH:22][C:6]2[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(Br)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Yield: 83.3 %

Procedure:
A mixture of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (52 g, 127 mmol), iron filings (21.3 g, 382.2 mmol) and NH4Cl (41 g, 764.4 mmol) in MeOH/THF/H2O (2/2/1, 500 mL) was stirred at reflux for 3 hour. After filtered and concentrated, the resulting residue was purified using column chromatography (petroleum ether/EtOAc/dichloromethane=20:1:20) to provide ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (40 g, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.94˜7.98 (m, 2H), 7.08 (t, J=8.0 Hz, 2H), 6.83 (s, 1H), 4.32˜4.36 (m, 2H), 4.18 (s, 2H), 1.35 (t, J=8.0 Hz, 3H). MS (M+H)+: 378/380.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+].[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=1>O1CCOCC1>[F:41][C:42]1[CH:43]=[C:44]([N:13]2[CH2:12][CH2:11][N:10]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)[CH:9]([CH3:8])[CH2:14]2)[CH:45]=[CH:46][CH:47]=1
Reactant: Fc1cccc(I)c1
Reactant: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC1CN(c2cccc(F)c2)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (0.037 g, 0.074 mmol), ruphos palladium(ii) phenethylamine chloride (6.06 mg, 7.42 μmol), and sodium tert-butoxide (0.029 g, 0.297 mmol). Dioxane (0.742 ml) and 1-fluoro-3-iodobenzene (0.013 ml, 0.111 mmol) were added and the reaction was flushed with argon and stirred at 100° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 1-(4-(3-fluorophenyl)-2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.64-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.97 (d, J=10.1 Hz, 1H), 7.68 (d, J=5.8 Hz, 1H), 7.24 (q, J=8.2 Hz, 1H), 7.05 (br. s., 1H), 6.87-6.76 (m, 2H), 6.56 (dt, J=1.9, 8.2 Hz, 1H), 4.02 (d, J=3.1 Hz, 1H), 3.61-3.44 (m, 3H), 3.29-3.22 (m, 1H), 1.08 (d, J=6.3 Hz, 5H). m/z (ESI) 479.2 (M+H)+.