Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1(B(O)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:25]([NH:27][OH:28])=[O:26])=[CH:18][CH:17]=1.CN(C=O)C.O>Cl.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>[OH:28][NH:27][C:25](=[O:26])[C:24]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:23][CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: CC(CCc1ccc(Br)nc1)(C(=O)NO)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCc1ccc(-c2ccccc2)nc1)(C(=O)NO)S(C)(=O)=O
Yield: 36.2 %

Procedure:
A solution of tetrakis(triphenylphosphine)palladium (0) (59 mg, 0.023 mmol, 0.1 equiv), sodium bicarbonate (45 mg, 0.73 mmol, 3.2 equiv), phenylboronic acid (42 mg, 0.35 mmol, 1.5 equiv), and 4-(6-bromopyridin-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (81 mg, 0.23 mmol, 1.0 equiv) in 1:1 DMF-water (2 mL) was heated at 130° C. for 1 h. The reaction was diluted with 0.5 M hydrochloric acid (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers (from the acidic extraction) were discarded. The aqueous phase was basified (to pH=8) with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×15 mL). The combined organic layers (from the second basic extraction) were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (1:0-9:1 dichloromethane/methanol) to provide the title compound (29 mg, 36%). LCMS m/z 349.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.69 (s, 3H), 2.13 (m, 1H), 2.55-2.65 (m, 2H), 2.83 (m, 1H), 3.06 (s, 3H), 7.40-7.50 (m, 3H), 7.78-7.83 (m, 2H), 7.89-7.92 (m, 2H), 8.50 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH:14]=[C:10]2[C:9](=[O:22])[NH:8][CH2:7]1)[CH3:2].[I:24]I>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[N:11]2[C:12]([I:24])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH:14]=[C:10]2[C:9](=[O:22])[NH:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reactant: II
Solvent: ClCCl
Product: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)c(I)n21
Temperature: 25 °C
Yield: 59.2 %

Procedure:
Ethyl[7-(3-chlorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (280 mg, 0.84 mmol) was dissolved in DCM, cooled in an ice bath and CF3COOAg (186 mg, 0.84 mmol) and Iodine (214 mg, 0.84 mmol) were added. The reaction was then warmed up at room temperature and after 1 hour was complete. It was filtered through paper, evaporated and the crude purified by silica chromatography (eluent: Hexane/AcOEt 3/2) to give 228 mg of desired product (59% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([CH:33]3[CH2:35][CH2:34]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[N:17]=[C:16]([CH:33]3[CH2:34][CH2:35]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(C2CC2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to Example 39) 250 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with ethanesulfonylchloride to give 212 mg 5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.18 min, [M−1]−=589.93.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[O:7][C@@H:6]([O:11][C:12]2[C:21]([CH3:22])=[C:20]3[C:15]([CH:16]=[C:17]([NH:24]C(=O)OCC4C=CC=CC=4)[C:18](=[O:23])[O:19]3)=[CH:14][C:13]=2[O:35][CH2:36][CH2:37][CH3:38])[C@@H:5]2[O:39]C(=O)[O:41][C@H:4]12.CCN=C=NCCCN(C)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[C:63]([OH:65])=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:39][C@@H:5]1[C@H:4]([OH:41])[C@@H:3]([O:2][CH3:1])[C:8]([CH3:9])([CH3:10])[O:7][C@H:6]1[O:11][C:12]1[C:21]([CH3:22])=[C:20]2[C:15]([CH:16]=[C:17]([NH:24][C:63]([C:55]3[NH:54][C:62]4[C:57]([CH:56]=3)=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:65])[C:18](=[O:23])[O:19]2)=[CH:14][C:13]=1[O:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCCOc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOc1cc2cc(NC(=O)c3cc4ccccc4[nH]3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@@H](O)[C@H]1O
Reaction time: 12 h
Yield: 6.4 %

Procedure:
Palladium on carbon (10%, 85 mg) was added to 25b (425 mg, 0.729 mmol) in anhydrous THF (4.90 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (325 mg, 99%). EDCI (116 mg, 0.6026 mmol) and 1H-indole-2-carboxylic acid (77.7 mg, 0.4821 mmol) were added to the amine (108 mg, 0.2410 mmol) in 30% pyridine/CH2Cl2 (6.70 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 3:1 Hexane:Ether→40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (91.0 mg, 64%). Triethylamine (150 μL) was added to the carbonate (91.0 mg, 0.1536 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 48 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26j as a colorless amorphous solid (17.5 mg, 20%, 13% over 3 steps): 1H NMR (CD2Cl2, 400 MHz) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.40-7.36 (m, 1H), 7.24-7.20 (m, 1H), 6.98 (s, 1H), 6.01 (s, 1H), 5.15 (d, J=6.5 Hz, 1H), 4.32-4.25 (m, 1H), 4.11-4.04, (m, 1H), 3.62-3.59 (m, 2H), 3.53 (s, 3H), 3.18-3.12 (m, 1H), 2.64 (s, 1H), 2.49 (s, 3H), 2.18 (s, 1H), 1.95-1.91 (m, 2H), 1.36 (d, J=9.6 Hz, 3H), 1.29 (d, J=9.8 Hz, 3H), 1.12 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.1, 159.0, 148.8, 146.9, 143.4, 136.9, 129.8, 127.6, 125.5, 123.5, 123.0, 122.6, 122.3, 121.2, 116.0, 112.0, 107.3, 104.3, 102.2, 82.8, 71.0, 70.1, 69.1, 60.2, 59.7, 25.7, 23.1, 23.4, 10.5, 10.2; IR (film) νmax 3630, 3304, 2926, 2854, 2359, 2332, 1713, 1705, 1539, 1387, 1240, 1103, 947, 930, 822, 739 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C30H34N2O9, 567.2342. found, 567.2367.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32].CCOCC>O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[CH:31]=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mol) 2,5-bis-tert.-butyloxycarbonylamino-bromobenzene from step A are dissolved in 100 ml of water-free tetrahydrofuran under argon. Gradually 17 ml of a 1.6 molar methyl lithium ether solution (0.03 mol) are added. The reaction mixture is cooled to −20° C. Subsequently 7 ml of 1.5 molar t-butyl lithium solution (0.01 mol) are added gradually. After ending the addition the solution is stirred for 30 minutes at −20° C. Subsequently 1.2 g of dimethylformamide (0.02 mol) are added and the reaction mixture is stirred for an hour at −20° C. After slow heating to room temperature the reaction mixture is hydrolyzed with water and then poured into ether, the aqueous phase is extracted with ether and then the organic phase is dried with magnesium sulfate. The solvent is distilled off in a rotary evaporator and the residue is purified on silica gel with petroleum ether/ethyl acetate (9:1).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccncc5)CC4)c(Cl)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 42.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (19 mg, 0.052 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.16 mmol, 0.16 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.058 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 42%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.52-2.55 (m, 2H, piperazine NCH2), 2.63-2.66 (m, 2H, piperazine NCH2), 3.58 (q, J=6.7 Hz, CHCH3), 3.68 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.06 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.11 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.54 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 13.30 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.C([NH:4][C@H:5]([C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:6][C:7](=[O:9])[OH:8])=O.[CH3:24]O>>[CH3:24][O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10](=[O:11])[NH:12][CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21](=[O:23])[NH:4]1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution containing 11.6 g of hydrogen chloride dissolved in 400 ml of methanol was fed 61.6 g of N-formyl-α-L-aspartyl-L-phenylalanine and the resulting mixture was reacted at 40°-45° C. for 6 hours. Then, the resulting solution was distilled under reduced pressure to remove methanol. The residue was dissolved in 100 ml of dioxane and 200 ml of water. A 20% aqueous sodium carbonate solution was added dropwise to the resulting solution so as to adjust its pH at 7.8 and thereafter further reaction was conducted at 40°-45° C. for 20 hours. Then, the reaction mixture was cooled to room temperature and the crystal thereby deposited was filtered, washed with dioxane and then with water, and dried to obtain 40.6 g of 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH3:42][N:43]([CH3:48])[C:44](=[O:47])[CH2:45]Cl>>[CH3:42][N:43]([CH3:48])[C:44](=[O:47])[CH2:45][N:20]1[CH2:19][CH2:18][N:17]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:6]4[C:2]([CH3:1])=[N:3][N:4]([C:23]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:5]=4)[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH2:22][CH2:21]1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: CN(C)C(=O)CCl
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(=O)N(C)C)CC3)c2c1
Yield: 90.6 %

Procedure:
80 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187 and 27 mg N,N-dimethyl-2-chloroacetamide were reacted in the same manner as in Example 190, to give 84 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:45])[C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[S:28]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)(=[O:30])=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:45])[C:10]([CH3:44])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[S:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of tert-butyl 4-({6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)piperazine-1-carboxylate (Example 47c, 0.141 g) dissolved in DCM (10 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction was purified by SCX, flushing with methanol (impurities), and eluting the product with 0.7 N methanolic ammonia. Purification by preparative HPLC (Xbridge column using a 95-5% gradient of aqueous ammonia in acetonitrile as eluent) followed by concentration under reduced pressure gave a white solid. This was combined with material from another reaction (scale: 0.097 g of starting material) to give the title compound (0.034 g) as a white solid.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6](B(O)O)=[CH:5][CH:4]=[C:3]3[CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[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.C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]2[C:7]3[C:12]4[C:3]([CH2:2][CH2:1][C:11]=4[CH:10]=[CH:9][CH:8]=3)=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc2c3c(cccc13)CC2
Reactant: Brc1ccc(I)cc1
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: Cc1ccccc1
Product: Brc1ccc(-c2ccc3c4c(cccc24)CC3)cc1
Yield: 82.5 %

Procedure:
Five point nine gram of the 5-acenaphthene boronic acid obtained and 10.2 gram of 4-bromo iodobenzene were dissolved into 100 milliliter of toluene. Further adding tetrakistriphenylphosphinepalladium in an amount of 1.7 g and 2M-sodium carbonate aqueous solution in an amount of 45 milliliter, an atmospheric air was replaced with argon gas. The resultant solution was refluxed under heating for 6 hours, cooled by leaving it standing and the organic layer was extracted with the use of toluene. Washing with the use of a saturated sodium chloride solution, the organic layer was dried with anhydrous sodium sulfate, and the organic solvent was distillated by means of an evaporator. After refining the residues by means of silicagel column chromatography (spreading solvent: hexane), 9.2 g of the aimed intermediate product 5-(4-bromophenyl) acenaphthene as a pale yellow solid was obtained (yield: 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].Cl>CN(C=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)morpholine (1.7 g, 12.96 mmol) in DMF (2 mL) was added NaH (0.52 g, 60% dispersion in oil, 12.96 mmol). The reaction mixture was stirred at r.t. for 10 minutes, then cooled to 0° C. A solution of 2-fluoronitrobenzene (1.5 g, 10.63 mmol) in DMF (2 mL) was added over 5 min. The reaction mixture was allowed to warm to r.t., then was stirred for 2 h before the addition of 2M aqueous HCl (50 mL). The aqueous fraction was separated, neutralised with aqueous sat. NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.4 g, 90%) as a yellow oil that was used without further purification. LCMS (ES+) 253.0 (M+H)+, RT 2.06 minutes (Method 5).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12](=[O:13])[CH2:11][CH2:10][C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[C:7]3=[O:18])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Yield: 72.5 %

Procedure:
To a solution of 69.4 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 109 mg (3 equivalents) of N-phenylpiperazine, and the mixture heated under reflux for 17 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 63.5 mg of the desired compound (yield 72.5%). The fumarate was obtained by converting the product to fumarate in a conventional manner, followed by recrystallization from acetoneether.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[S:13]1([CH2:19][CH:18]=[CH:17][CH2:16]1)(=[O:15])=[O:14].[OH-].[K+]>O.C([O-])(O)=O.[Na+]>[Br:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH:17]1[CH2:18][CH2:19][S:13](=[O:15])(=[O:14])[CH2:16]1)[CH2:8]2
Reactant: O=S1(=O)CC=CC1
Reactant: Brc1cccc2c1CCNC2
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=S1(=O)CCC(N2CCc3c(Br)cccc3C2)C1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution containing 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.5 g, 6 mmol) and butadiene sulfone (1.2 g, 10.2 mmol) in water (20 mL) is added 1N KOH (10 mL). The reaction mixture is stirred at 70° C. for 24 hours. After cooling to ambient temperature, the reaction mixture is diluted with saturated NaHCO3 solution and extracted with dichloromethane three times. The organic phase is washed with brine and dried over Na2SO4 before drying by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 5-bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinoline as a wax-like solid. MS m/z 330.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)[CH:22]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1>>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:29]2[N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:32]=[CH:31][N:30]=2)=[CH:38][CH:39]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)CC1CCNCC1

Procedure:
Intermediate 34 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 496. 1H NMR (Varian 0.300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 2H), 8.1 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ 4.5 (s, 2H), 3.3-3.2 (m, 6H), δ 3.0 (s, 3H), 2.9 (t, 2H), δ 2.7 (t, 2H), δ 1.6 (m, 1H), δ 1.2 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) was dissolved in tetrahydrofuran (2 mL). Dimethylsulfamoyl chloride (18 mg, 0.122 mmol) was added to the reaction mixture followed by triethylamine (34 uL, 0.244 mmol). The suspension was stirred at rt overnight. The reaction was concentrated under vacuum. The compound was triturated with 1:1 ether-hexanes to yield desired product (22 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.92 (1s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.20 (m, 3H), 7.35-7.25 (m, 4 H), 7.12 (d, 1 H), 5.64 (s, 2 H), 3.90-3.20 (m, 5H), 2.70-2.05 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].BrCCC>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH2:37][CH2:36][CH3:38])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Solvent: CCCBr
Solvent: ClCCCl
Product: CCCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Yield: 31.4 %

Procedure:
The same procedure as E54 from 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (146.6 mg, 0.325 mmol), Hunig's base (0.171 mL, 0.976 mmol) and 1-bromopropane (80 mg, 0.651 mmol) in DCE (5 mL), except that the time was prolonged to 3 days, to afford the title compound (50 mg, 0.102 mmol, 31.2% yield). LCMS: rt=3.41 min, [M+H+]=493