Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][OH:27].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][OH:27]
Reactant: OCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A stirred solution of 15.0 grams (0.056 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) and 15.0 grams (0.109 mole) of potassium carbonate in 200 mL of DMF was cooled to 0-4° C. and 8.4 grams (0.067 mole) of 2-bromoethan-1-ol was slowly added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred during an 18 hour period. After this time water was added to the reaction mixture, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 17.1 grams of residual oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH2:18]([CH:20]([C:23]1[C:24]2[N:25]([C:30](I)=[C:31]([CH3:33])[N:32]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:21][CH3:22])[CH3:19].Cl>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:12])=[C:10]([C:30]3[N:25]4[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH:20]([CH2:18][CH3:19])[CH2:21][CH3:22])[C:24]4=[N:32][C:31]=3[CH3:33])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2occ(C)c12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3oc4cccc(OC)c4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.7 %

Procedure:
4-Methoxy-3-methyl-benzofuran (240 mg, 1.50 mmol) added to THF (6 ml) and cooled to −72° C. n-Butyl lithium (1.0 ml, 1.60 mmol) added and stirred for 5 minutes, warmed to ambient temperature for 10 minutes and cooled again to −72° C. Zinc chloride (0.5 N in THF, 3.2 ml, 1.6 mmol) added, stirred for 5 minutes then warmed to ambient temperature and stirred for 10 minutes. 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (240 mg, 0.69 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 64 mg, 0.08 mmol) are added. The mixture is heated to 60° C. for 4 hrs, cooled to ambient temperature, added to HCl (1N) and extracted twice with EtOAc. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 30% ethyl acetate in hexane) to give the title compound (54 mg, 21% yield). ES-MS (m/z): calc'd for C23H27N3O2: 377.5. found 378.1 (M+H)+1H NMR (400 mHz, CDCl3): δ 7.27 (t, 1H), 7.18 (d, 1H), 6.74 (s, 1H), 6.70 (d, 1H), 3.99 (s, 3H), 3.39 (bs, 1H), 2.55 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H), 1.87 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].O[C:13]1[C:21]2[N:20]=N[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[NH2:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:21]=1[NH:20][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
4-Cyanobenzoic acid (294 mg, 2 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (768 mg, 4 mmol), hydroxybenzotriazole (324 mg, 2.4 mmol), triethylamine (808 mg, 8 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give N-(2-aminophenyl)-4-cyanobenzamide (364 mg, 77%) as a grey solid. LC-MS (m/z) 238 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][N:36]([S:39]([C:42]4[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:15][CH2:14]1.O>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:1]([CH2:3][C:4]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][N:36]([S:39]([C:42]4[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=4)(=[O:41])=[O:40])[C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:17][CH2:18]1)=[O:6])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCNCC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)CC#N)CC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.4 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF), oxalyl chloride (0.082 mL, 0.94 mmol) was added. The mixture was stirred at room temperature for 50 min. To the above solution cooled in an ice bath, a solution of 4-(4-(piperidin-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (58 mg, 0.11 mmol) and TEA (0.450 mL, 3.22 mmol) in DMF (2 mL) was added. The mixture was stirred for 2 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 4-(4-(1-(2-cyanoacetyl)piperidin-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)=[O:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.CCOC(C)=O.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>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(Br)s2)cc1F
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a suspension of 5-bromo-thiophene-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (100 mg, 0.235 mmol), Pd(PPh3)4 (4.1 mg, 0.0035 mmol), and 4-trifluoromethyl phenyl boronic acid (53.5 mg, 0.282 mmol) in toluene (1 mL) was added 2N—Na2CO3 (0.5 mL)/EtOH (0.5 mL). The mixture was stirred 3 hours at 110° C. and was diluted with EtOAc. The mixture was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (90 mg, 78%).
Reaction SMILES: [NH2:1][C@H:2]([CH3:21])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C[Si](C)(C)NC(=O)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C@H:34]1[O:36][CH2:35]1.Cl.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:30][C:31]1[CH:32]=[C:33]([C@@H:34]([OH:36])[CH2:35][NH:1][C@H:2]([CH3:21])[CH2:3][C:4]2[C:12]3[C:7](=[C:8]([CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCN(CC)C(=O)Cc1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: Clc1cccc([C@@H]2CO2)c1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: CCN(CC)C(=O)Cc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 2-{3-[(2R)-2-aminopropyl]-1H-indol-7-yl}-N,N-diethylacetamide (1.0 g, 3.48 mmol) in dimethylsulfoxide (5 mL) is added N-trimethylsilylacetamide (0.50 g, 3.83 mmol), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added (R)-(+)-3-chlorostyrene oxide (0.89 mL, 6.96 mmol), and the mixture is stirred at 110° C. for 2 hours. After cooling, a 2 N hydrochloric acid (5 mL) is added to the mixture, and the mixture is stirred at room temperature for 0.5 hour. To the mixture are added a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform) to give the title compound (0.90 g, yield: 59%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:29])[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>>[CH3:22][C:23]1([CH3:29])[NH:24][CH2:25][CH2:26][N:27]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:28]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)CNCCN1
Product: CC1(C)CN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CCN1
Temperature: 60 °C
Yield: 67 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 57 mg, 0.202 mmol) and 2,2-dimethylpiperazine (46.1 mg, 0.404 mmol, Chem-Impex International, Wood Dale, Ill.), heating at 60° C. for 1 h. Purification by filtration provided 2-(3-(3,3-dimethylpiperazin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (67% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 6H) 2.87 (t, J=6.85 Hz, 2H) 2.92-2.99 (m, 2H) 3.44 (td, J=6.85, 2.15 Hz, 2H) 3.61 (s, 2H) 3.74 (t, J=4.69 Hz, 2H) 6.94 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.39 (t, J=7.82 Hz, 1H) 7.66 (d, J=6.85 Hz, 1H) 7.89 (d, J=6.46 Hz, 1H) 8.87 (s, 1H) 11.77 (br. s., 1H). MS (ESI, pos. ion) m/z: 377.1 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([CH:12]=[C:13](Br)Br)=[CH:10][CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CCCCCC.Cl[C:32]([O:34][CH3:35])=[O:33]>C1COCC1.C([O-])(O)=O.[Na+].[NH4+].[Cl-]>[CH3:35][O:34][C:32](=[O:33])[C:13]#[C:12][C:11]1[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][CH:10]=1
Reactant: CCCCNc1nc(C(F)(F)F)ccc1C=C(Br)Br
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCNc1nc(C(F)(F)F)ccc1C#CC(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
A solution of butyl-[3-(2,2-dibromo-vinyl)-6-trifluoromethyl-pyridin-2-yl]-amine (1.02 g, 2.54 mmol) in THF under nitrogen at −78° C. was slowly treated with 2.5 M BuLi in hexane (2.0 mL, 5.00 mmol) and then stirred for 30 min at −78° C. and 30 min at −0° C. The mixture was treated with methyl chloroformate (0.235 mL, 3.05 mmol) at −78° C. and warmed to 0° C. for 1 hr. The mixture was diluted with 1:1 mixture of saturated NaHCO3 and NH4Cl solution and the aqueous layer was extracted with ether (×3). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=10/1) to give the title compound (78 mg, 10%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:13](=[O:14])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:28][CH:27]=[CH:26][C:25]=3[F:29])[CH:6]=[N:7]2)[CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(Cc2c(F)cccc2F)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (Intermediate 34) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionamide as a light yellow solid (690 mg, 65%); ES+-HRMS m/e calcd for C30H33N5O4SiF4 [M+H+] 632.2311 found 632.2311. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.08 (s, 6H) 0.80 (s, 9H) 3.24-3.34 (m, 1H) 3.49 (dd, J=14.5, 5.7 Hz, 1H) 3.83 (t, J=5.1 Hz, 2H) 4.00-4.10 (m, 2H) 5.69 (dd, J=9.8, 5.6 Hz, 1H) 5.89 (d, J=2.7 Hz, 1H) 6.43 (d, J=2.1 Hz, 1H) 6.96 (t, J=8.0 Hz, 2H) 7.18-7.52 (m, 4H) 7.54 (d, J=2.1 Hz, 1H) 8.20 (d, J=2.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5].[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30](O)=[O:31]>CN(C=O)C.CC(O)=O>[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([N:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])=[O:31]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O)N[N+](=O)[O-]
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Yield: 53.4 %

Procedure:
After 2.25 g (5.0 mmols) of HCl.H-Pro-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 1.86 g (53.4%) of Z-PyroGlu-Pro-Arg(NO2)-CHA.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]2[S:27][C:26]3[C:28]4[C:19]([CH:20]=[N:21][C:22]=4[N:23]=[CH:24][CH:25]=3)=[CH:18]2)=[O:16])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:29]([N:7]1[CH2:8][CH2:9][CH2:10][N:4]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[S:27][C:24]3[N:23]4[C:19](=[CH:20][N:21]=[C:22]4[CH:28]=[CH:26][CH:25]=3)[CH:18]=2)=[O:16])[CH2:5][CH2:6]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCCCN1CCCNCC1)C1C=C2C=Nc3nccc(c32)S1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Yield: 55 %

Procedure:
In 10 ml of ethanol were suspended 606.9 mg (1.3 mM) of N-[3-(hexahydro-1,4-diazepin-1-yl)propan-1-yl]-5-thia-1,8-diazaacenaphthylene-4-carboxamide trihydrochloride and 342.1 mg (2.0 mM) of benzyl bromide, followed by addition of 0.91 ml (6.5 mM) of triethylamine, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=2/3) to provide the title compound as deep-red liquid (320.0 mg, 55.0%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1ccn(-c2nc(N)nc(S(C)=O)c2C#N)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(3-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:42]2[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(C)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
N,N-dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-acetylphenylboronic acid (67 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[PH2](=O)O.II>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 110 °C
Yield: 72.3 %

Procedure:
To a solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol (420 mg, 1.10 mmol) in acetic acid (20 mL) was added phosphinic acid (50% aqueous solution, 0.60 ml, 5.51 mmol) and iodine (700 mg, 2.76 mmol). The resulting solution was heated at 110° C. overnight and the solvent was removed. The residue was diluted with water and pH was adjusted to 8-10 with 6N NaOH solution. The mixture was then extracted by CH2Cl2, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 260 mg (yield: 72%) title compound. LCMS (method B): [MH]+=327, tR=2.52 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[C:14]=2[O:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:41].B(Br)(Br)Br>C(OC(=O)C)C.C(OCC)C>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:39][CH:40]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]3)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(S(C)(=O)=O)c(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CS(=O)(=O)c1c(F)cc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Temperature: 0 °C
Yield: 20 %

Procedure:
Dissolve the compound of Example 79 in ethylacetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3(10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the 6-(3,5-difluoro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL) and ethyl acetate (6.0 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to give 31 mg of the title compound (20%): mass spectrum (ion spray): m/z: 554.3 (M+H−HCl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:42]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (28.58 g) obtained in Example 23-4 was dissolved in anhydrous DMF (560 ml) and added with triethylamine (20.35 ml) and ethyl bromoacetate (12.14 ml) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in ethyl acetate and washed with water, followed by drying with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (21.265 g) as a colorless oily substance.