Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)#[CH:2].C#CCCCCCC.[C:22]([O:26][C:27](=[O:46])[NH:28][C:29]1([C:37]#[C:38][C:39]2[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=2)[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[CH:7]=[C:3]([C:1]#[C:2][C:42]3[CH:43]=[CH:44][C:39]([C:38]#[C:37][C:29]4([NH:28][C:27](=[O:46])[O:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31][CH2:30]4)=[CH:40][CH:41]=3)[O:4][C:5]=2[CH:11]=1
Reactant: C#Cc1cc2ccc(OC)cc2o1
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(I)cc2)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2cc(C#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)oc2c1
Yield: 90 %

Procedure:
When the product of Step D was substituted for 1-octyne and tert-butyl-5-((4-iodophenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 90% yield, as a light yellow paste. 1H-NMR (CDCl3) 1.44 (s, 3H); 1.47 (s, 9H); 1.49 (s, 3H); 3.85 (s, 3H); 4.02 (d, 2H, J=11.34 Hz); 4.09 (d, 2H, J=11.38 Hz); 5.20 (s, 1H); 6.88 (dd, 1H, J=2.24, 8.6 Hz); 6.93 (s, 1H); 6.96 (d, 1H, J=1.97 Hz); 7.38-7.41 (m, 3H); 7.46 (d, 2H, J=8.44 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(#N)C.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:43]2[CH2:44][CH2:45][N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH2:42]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-aminobenzoic acid (5 g, 36.5 mmol) in acetonitrile (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (7.67 g, 40.2 mmol), hydroxybenzotriazole hydrate (0.49 g, 3.65 mmol), 1-phenylpiperazine (11.2 ml, 3.65 mmol) followed by triethylamine (12.8 ml, 91.3 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with the addition of water and the resulting aqueous mixture extracted using dichloromethane (3×100 ml). The organics were combined, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO2) eluting with ethylacetate/dichloromethane (1:1) to afford the title compound as an off white solid. HPLC retention time 7.1 min. Mass spectrum (ES+) m/z 282 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][C:5]=2[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:3]=1.[CH3:22][C:23]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:24].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:6]2[C:7]([NH:30][C:23]([CH3:24])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:3]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=C(OCc1ccccc1)n1cc(Cl)c2c[n+]([O-])ccc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
A solution of benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (2.6 g, 8.53 mmol) in chloroform was treated dropwise with 2,4,4-trimethylpentan-2-amine (6.026 mL, 37.54 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of p-toluenesulphonyl chloride (3.578 g, 18.77 mmol). The reaction mixture was then stirred at room temperature for about 1 hour, diluted with dichloromethane and washed with saturated aq. sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to get viscous oil. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1%) to yield benzyl 3-chloro-4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (610.8 mg, 43%) as a pale yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:46])[C@H:7]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:8][CH2:9][CH:10]1[C:22]2[C:17](=[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]3=[C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]3=2)[C:16]2[C:11]1=[C:12]1[CH:38]=[CH:37][CH:36]=[CH:35][C:13]1=[C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]1=2)(C)(C)C>FC(F)(F)C(O)=O.O.C(OCC)C>[CH:23]1[C:21]2[C:20](=[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]3=[C:17]3[C:22]=2[CH:10]([CH2:9][NH:8][C@H:7]([C:6]([OH:46])=[O:5])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:11]2[C:16]3=[C:15]3[CH:31]=[CH:32][CH:33]=[CH:34][C:14]3=[C:13]3[CH:35]=[CH:36][CH:37]=[CH:38][C:12]3=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](Cc1ccccc1)NCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21

Procedure:
A solution of Nα-17-tetrabenzo(a,c,g,i)fluorenylmethyl-L-phenylalanine tert-butyl ester (421.1 mg, 0.702 mmol) in trifluoroacetic acid (3.6 ml) and water (0.2 ml) was sonicated for 3.5 h at room temperature. The solvent was removed in vacuo to give a brown residue. Trituration in diethylether gave the compound (53) as a yellow solid which was chilled overnight, filtered, washed with ether, and finally dried (352.7 mg, 92%);
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br.N#N>C1COCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[C:15]([Cl:21])=[N:16][CH:17]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: C[Mg]Br
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 100 mL, round-bottomed flask was added 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide from Step 1 (250 mg, 642 μmol) and THF (10 mL). To this solution, methylmagnesium bromide (3.0 N, 4 mL, 12 mmol) was added in under N2 protection. The suspension was stirred at 25° C. for 3 h. The mixture was quenched by aqueous saturated NH4Cl. The aqueous part was extracted by 10% methanol-DCM (3×), and the combined organic was dried over MgSO4, and concentrated in vacuo to provide the title product as a yellow oil (250 mg), which was taken on to the next step without further purification. MS (ESI positive ion) m/z: 407 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][OH:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.7 %

Procedure:
A solution of 2-(N-methyl-N-t-butoxycarbonylamino)ethanol (116 mg, 0.7 mmol) in methylene chloride (1 ml) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (5 ml). Diethyl azodicarboxylate (261 mg, 1.5 mmol) was then added dropwise and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured onto a column of silica and eluted with a gradient of methylene chloride/acetonitrile/methanol (70/30/0 to 70/20/10). The partially purified product was further purified by column chromatography eluting with a gradient of methylene chloride/ether/methanol (60/40/0 to 60/10/30). The pure oil was crystallised from ether, collected by filtration and washed with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-t-butoxycarbonylamino)ethoxy)quinazoline (450 mg, 63%). m.p. 194-196° C. 1H NMR Spectrum: (CDCl3) 1.46(s, 9H); 3.05(br s, 3H); 3.72(br s, 2H); 4.02(s, 3H); 4.27(br s, 2H); 7.0(s, 1H); 7.2-7.3(m, 3H); 8.54(t, 1H); 8.69(s, 1H) MS-ESI: 499 [MNa]+
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([NH2:18])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([O:30]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(C1NC=CN=1)(C1NC=CN=1)=O.CS(O)(=O)=O.C(=O)([O-])O.[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[C:26](=[O:30])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([NH2:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 40 °C

Procedure:
(2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (291 mg, 1.17 mmol) was mixed with triethylamine (193 □l, 1.37 mmol) and toluene (2.4 ml) at 20° C. di-t-butyldicarbonate (310 mg, 1.42 mmol) as a solution in toluene (2.0 ml) was added to the reaction mixture, and the mixture was stirred at 40° C. until the reaction was complete. The solution was diluted with toluene (3.9 mL) and carbonyl diimidazole (462 mg, 2.85 mmol) was added and agitation was continued until the reaction was deemed to be complete. Methanesulfonic acid (663 □l, 10.2 mmol) was added and agitation was continued until the reaction was deemed to be complete. After lowering the temperature to 20° C., aqueous potassium hydrogen carbonate (10.2 ml, 1N, 10.2 mmol) was added and the mixture was stirred at 20° C. until the reaction was complete. The aqueous layer was separated and the toluene layer washed with water (3 mL), citric acid (1N, 3 mL) and water (3 mL). The four aqueous washes were twice back-extracted with dichloromethane (2×3 mL). The three organic extracts were combined to give (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a solution in toluene and dichloromethane (176 mg, 0.64 mmol, 55%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:33]1([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)=[O:32])[CH:4]=1)[N:36]1[CH2:37][CH2:38][N:33]([C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:35]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: COC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 5.3 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of methyl piperazine-1-carboxylate as secondary amine and 1 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH:6]=1.[CH2:12](I)[CH3:13]>CN(C)C=O>[CH2:12]([N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][C:7]1=[O:11])[CH3:13]
Reactant: COC1=CC(=O)NCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(=O)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Sodium hydride (in the form of a 60% dispersion in oil) (447 mg) is suspended in N,N-dimethylformamide (10 ml), and thereto is added dropwise a solution of 4-methoxy-5,6-dihydro-2(1H)-pyridone (1.29 g) in N,N-dimethylformamide (30 ml). The mixture is stirred under ice-cooling for 30 minutes, and thereto is added dropwise ethyl iodide (0.97 ml). The mixture is stirred under ice-cooling for 30 minutes and further at room temperature for 2.5 hours. The reaction mixture is poured onto water and extracted with chloroform. The extract is washed with a saturated sodium chloride solution and dried. After evaporating the solvent, the residue is dissolved in ethanol (120 ml) and thereto is added 10% hydrochloric acid (60 ml), and the mixture is allowed to stand at 25° C. for 5 hours. After distilling off the solvent under reduced pressure, the residue is dissolved in chloroform, washed with 5% aqueous sodium hydrogen carbonate solution and water, and then dried. The solvent is distilled off to give 1-ethyl-2,4-dioxopiperidine (1.12 g, 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:8]1.N1C=CC=CC=1[C@H]1CC[C@H](N)C1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](c2ccccn2)C1
Agent: N[C@H]1CC[C@H](c2ccccn2)C1
Product: N[C@H]1CC[C@@H](c2ccccn2)C1
Yield: 99 %

Procedure:
The title compound (498 mg, 99%) was prepared from cis-N-[3-(2-pyridyl)cyclopentyl]phthalimide (905 mg, 3.10 mmol) in a manner similar to that described for the preparation of trans-3-(2-pyridyl)cyclopentylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:28])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:26])[CH3:25])[C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:28])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:26])[CH3:25])/[C:19](=[N:30]/[OH:31])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2/C1=N\O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-acetoxy-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (the compound of Preparation Example 65) (200 mg) in pyridine (2 mL) was added hydroxylamine.hydrochloride (61 mg). After stirring at room temperature for 2.5 hours, two products were observed by TLC. After the solution was diluted with ethyl acetate, the solution was washed with water and saturated sodium chloride water. The crude products obtained after drying with anhydrous sodium sulfate, removing the solvent by evaporation were purified by silica gel column chromatography (ethyl acetate/hexane), the fraction that was eluted by a solvent with a higher polarity (the fractions that demonstrated low Rf values) were collected, and (7Z)-6-acetoxy-7-hydroxyimino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)ethyl]-methyl-amide was obtained. Thereafter, to methanol (1 mL) was added excess potassium carbonate. The solution was stirred at room temperature for 1 hour. Water was added, the solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by LC-MS, and the title compound (0.9 mg) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][N:10]([NH:15]C(=O)C)[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[NH2:15][N:10]1[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:13][NH:12][C:11]1=[O:14]
Reactant: CC(=O)NN1CC(c2ccc(F)cc2)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NN1CC(c2ccc(F)cc2)=NNC1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a slurry of N-[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-acetamide (0.48 g, 1.9 mmol) in MeOH (5 mL) is added 37% aqueous HCl. The mixture is heated to reflux for 3 h, and then cooled to rt. The mixture is basified with 1 M aqueous NaOH to pH ˜12. The resulting precipitate is collected by filtration and dried to afford 4-amino-6-(4-fluoro-phenyl)-4,5-dihydro-2H-1,2,4-triazin-3-one (0.35 g, 88%). MS: 209 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.67-7.75 (m, 2H), 7.18-7.29 (m, 2H), 4.75 (s, 2H), 4.45 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Brc1ccccn1
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(c2ccccn2)CCN1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
(S)-(+)-2-Methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120° C. for 14 hours. The reaction mixture was allowed to cool to 23° C. and partitioned between ethyl acetate and water. The layers were separated, and the water layer extracted twice with ethyl acetate. The aqueous phase was brought to pH ˜11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with ethyl acetate (2×) and dichloromethane (2×). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.6 g (67% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[C:42]([OH:55])[CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:41]=[C:42]([OH:55])[CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NS(=O)(=O)c4ccc(F)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 60.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.11 mmol) was treated with 4-fluoro-N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (69 mg, 0.18 mmol), cesium carbonate (2M, 180 μl, 0.36 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) according to the method described in Example 3 to give 42 mg (56% yield) of the title compound. Purity 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:38])=[O:35]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 90%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[S:57](Cl)(=[O:59])=[O:58].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][S:57]([C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)(=[O:59])=[O:58])=[O:43]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNS(=O)(=O)c2ccc3ccccc3c2)s1
Reaction time: 8 h
Yield: 22.1 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (1.85 g) was dissolved in dimethylformamide (20 ml). 2-Naphthalenesulfonyl chloride (0.62 g) and triethylamine (1.75 ml) were added under ice-cooling, and the mixture was allowed to stand overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.32 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)naphthalene-2-sulfonamide.