Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](=O)[CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:19].O>CN(C)C=O>[CH3:19][CH:18]([N:20]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:31])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)[CH3:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2.0 g (60%, 51 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, and 11.3 g (51 mmol) of ethyl diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 5.5 g (25 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanone. The obtained mixture was stirred at 60° C. for 48 hours, followed by the addition of water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (4% ethyl acetate/n-hexane) to give 4.0 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:65])[NH:40][CH:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]#[CH:64])=[CH:59][CH:58]=2)=[CH:55][N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:64]#[C:63][C:60]4[CH:61]=[CH:62][C:57]([C:54]5[NH:53][C:52]([CH:48]6[CH2:49][CH2:50][CH2:51][N:47]6[C:45](=[O:46])[CH:41]([NH:40][C:39]([O:38][CH3:37])=[O:65])[CH:42]([CH3:44])[CH3:43])=[N:56][CH:55]=5)=[CH:58][CH:59]=4)=[CH:32][CH:31]=3)[N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.06 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (503 mg, 1.27 mmol) and Pd(PPh3)4 (122 mg, 0.106 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (1.47 mL, 10.6 mmol) and copper(I) iodide (20.0 mg, 0.106 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (542 mg). LCMS-ESI+: calc'd for C47H59N9O8: 878.0 (M+). Found: 878.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:37])[C:11]#[C:12][C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:37])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:33])([F:35])[F:34])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccccc1C(=O)CCc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
1-(2-Ethoxyphenyl)-3-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-yn-1-one (130 mg) was dissolved in methanol and hydrogenated at 40° C. and an H2 pressure of 10 bar and in the presence of Pd/C (10%). This gave, after filtration and removal of the solvent under reduced pressure, 1-(2-ethoxyphenyl)-3-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]propan-1-one (40 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.1 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), phenylboronic acid (51.7 mg, 0.423 mmol) and K3PO4 (149.7 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-biphenyl-2-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (18 mg). 1H NMR (Freebase, CDCl3) δ (ppm): 7.58 (d, 1H), 7.44 (m, 2H), 7.30 (d, 1H), 7.18 (m, 4H), 6.98 (m, 3H), 6.82 (d, 1H), 3.70 (d, 1H), 3.60 (d, 1H), 3.64 (m, 1H), 2.50 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:11]([O:12][CH3:13])[CH2:10][C:9]2[C:8](=[NH:14])[NH:7][C:6](=N)[C:5]=2[CH2:4]1.Cl.[C:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N=C1C2CCCCC=2C(=N)N1>>[NH:14]=[C:8]1[C:9]2[CH2:10][CH:11]([O:12][CH3:13])[CH:3]([O:2][CH3:1])[CH2:4][C:5]=2[C:6](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:31][C:30]2=[NH:32])[NH:7]1
Reactant: COC1CC2=C(CC1OC)C(=N)NC2=N
Reactant: N=C1CSC(NCCCc2ccccc2)=N1
Agent: Cl
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COC1CC2=C(CC1OC)C(=C1SC(NCCCc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 5,6-dimethoxy-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-phenylpropylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazoline hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-5,6-dimethoxy-4,5,6,7-tetrahydro-3-[2-(3-phenylpropylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]2([CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]2([CH2:26][N:27]([C:2]3[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=3)[CH2:28][CH2:29][CH2:30]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Reactant: c1ccc(CN2CCCC3(CCCNC3)C2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Temperature: 90 °C
Yield: 30.1 %

Procedure:
A suspension of 4-iodo-2-methyl-6-nitroaniline (1.39 g, 5 mmol), 2-benzyl-2,8-diaza-spiro[5.5]undecane (1.22 g, 5 mmol), CuI (190.5 mg, 1.0 mmol), ethylene glycol (931 mg, 15 mmol) and K3PO4 (3.2 g, 15 mmol) in isopropanol (40 mL) was sealed and heated at 90° C. for 19 h. After cooled down to room temperature, the reaction mixture was concentrated. The residue was purified by chromatography (99:1 CH2Cl2/MeOH) to afford the title compound (593 mg, 30%). 1H NMR (CDCl3) δ 1.24 (m, 2H), 1.48-1.68 (6H), 2.01-2.24 (m, 2H), 2.24 (s, 3H), 2.57 (m, 2H), 2.73 (d, J=12 Hz, 1H), 2.82 (m, 1H), 3.03 (m, 1H), 3.14 (d, J=12 Hz, 1H), 3.47 (d, J=9 Hz, 2H), 5.30 (br s, 2H NH), 7.11 (s, 1H), 7.19-7.33 (5H), 7.44 (s, 1H). ESI-MS m/z 395 (MH+).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][CH2:7][SH:8].[F:9][C:10]([F:24])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>C(O)C>[F:24][C:10]([F:9])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17]([S:8][CH2:7][CH2:6][CH2:5][NH2:4])[N:16]=1
Reactant: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Reactant: NCCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C

Procedure:
Sodium hydride (50% w/w dispersion in oil; 0.57 g.) was added to ethanol (10 ml.) portionwise. To the resulting solution was added 3-aminopropanethiol hydrochloride (0.75 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino-6-chloropyrazine (0.5 g.) was added in one portion and the mixture heated under reflux on the steam bath overnight. The mixture was cooled, evaporated, water (10 ml.) added and the mixture extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated to yield an oil, which was chromatographed eluting with methanol/methylene chloride/ammonia 10:40:1 v/v/v to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine as a pale yellow solid (0.39 g.) which was used without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:40])[C:27]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=2)([OH:32])[C:28]([F:31])([F:30])[F:29])=[C:22]([Cl:41])[CH:21]=1>C(Cl)Cl>[Cl:41][C:22]1[CH:21]=[C:20]([NH:19][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:25]=[CH:24][C:23]=1[CH:26]([CH3:40])[C:27]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=1)([OH:32])[C:28]([F:31])([F:30])[F:29]
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1ccc(NC(=O)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-diisopropylethylamine (0.117 ml) and benzoyl chloride (0.024 ml) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (25 mg) in DCM (3 ml). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. Purification by preparative HPLC (Phenomenex Gemini Axia-C18 column, solvent gradient 30-95% CH3CN in 0.1% HCOOH[aq]) gave the title compound (35 mg) as a white foam. MS (m/e)=469.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.C[Si]([N:29]=[C:30]=[O:31])(C)C.Cl.[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:30]([NH2:29])=[O:31])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nccn2c(C3CCN(C(N)=O)CC3)nc(Br)c12
Reaction time: 0.25 h
Yield: 70 %

Procedure:
1-Bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.169 mmol, 50 mg) was dissolved in dichloromethane (1 ml) and triethylamine (0.545 mmol, 76 μl) and trimethylsilyl isocyanate (0.186 mmol, 25.3 μl) were added at 0° C. After stirring at room temperature for one hour water and 2N hydrochloric acid was added and stirred for 15 minutes. The reaction mixture was basified with 2 N aqueous sodium hydroxide until pH=10 and extracted three times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrate in vacuo to afford 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxamide (40 mg).
Reaction SMILES: O[C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:24][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[O:16])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1cccc(C(=O)CC)c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc2c(=O)c(C)c(-c3ccc(C#N)cc3)oc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A solution of 5.2 g of ethyl 2-hydroxy-3-propionylbenzoate in 30 ml of anhydrous pyridine was added dropwise over 20 minutes at room temperature into a stirred mixture of 4 g of 4-cyanobenzoyl chloride in 30 ml of anhydrous pyridine. The solution was stirred for 1 hour at the same temperature, then 2.6 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added and the solution was heated at 100° C. for 2 hours. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was quenched with 100 ml of water containing 40 ml of 6N aqueous hydrochloric acid solution. The mixture was extracted twice with 100 ml aliquots of dichloromethane, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with n-hexane-ethyl acetate gradient (95:5 to 60:40), obtaining 3 g of the title compound after crystallization from ethanol, m.p. 181°-183° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c(Br)cccc12
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cccc2c(Br)cccc12
Yield: 63.3 %

Procedure:
A suspension of 1-bromo-5-hydroxy-naphthalene (1.56 g, 7.0 mmol, prepared according to patent WO0146181), K2CO3 (1.45 g, 10.5 mmol), tetrabutylammonium chloride (15 mg, 0.05 mmol) and dimethyl sulfate (1.32 ml, 10.5 mmol) in MeCN was refluxed for 1 hour. After the addition of water, the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed under reduced to provide 1-bromo-5-methoxy-naphthalene (1.05 g, 64%) as a white solid, MS: m/e=236 (M+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7](Cl)(=[O:9])=[O:8])[N:3]=1.C(O)(=O)C.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:17]=1[NH2:18]>>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:18][C:17]2[C:16]([F:15])=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])(=[O:9])=[O:8])[N:3]=1
Reactant: Nc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Product: Nc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1

Procedure:
5-Amino-3-chlorosulfonyl-1,2,4-triazole (20 g of about 92 percent purity, 0.1 mole) was slurried in 168 g (2.8 moles) of acetic acid and 14.2 g (0.11 moles) of 2,6-difluoroaniline were added. The mixture was stirred and heated at 90° C. for 11 hours at which time analysis by HPLC a 76 percent conversion to the title compound and 9 percent conversion to its 5-acetylamino derivative. Water was added and the mixture cooled to 10° C. The solids were collected by filtration, washed with water, and dried at 60° C. to obtain 14.8 g (53 percent of theory) of the title compound as a 96 percent purity product. Analysis of the filtrate by HPLC showed that it contained another 26 percent of theory and the total yield was 79 percent of theory.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[S:17][C:16]2[C:11](=[N:12][CH:13]=[CH:14][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=3[F:36])=[O:27])=[C:21]([F:37])[CH:20]=2)[CH:10]=1)=[O:8])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:37][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][CH:4]=[O:3])=[O:8])[S:17][C:16]=12
Reactant: CCOC(CNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCC=O)sc34)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (300 mg, 0.53 mmol) in 10 ml of THF was added 2 ml of 2M HCl. The mixture was heated under nitrogen at 60° C. for 4 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 250 mg, 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[Br:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>>[Br:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:16]1[CH2:17][CH:18]2[CH:14]([CH2:13][N:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=3)[CH2:19]2)[CH2:15]1)=[O:24]
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Reactant: O=C(O)c1cccc(F)c1Br
Product: O=C(c1cccc(F)c1Br)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 2-bromo-3-fluorobenzoic acid. MS (ESI): mass calculated for C21H17BrF2N4O, 458.1; m/z found 459.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.95 (d, J=19.8, 1H), 8.01 (s, 1H), 7.59 (dt, J=13.3, 6.7, 1H), 7.52-7.40 (m, 1H), 7.40-7.28 (m, 1H), 7.18-7.05 (m, 2H), 4.01 (dt, J=12.8, 8.4, 2H), 3.95-3.85 (m, 1H), 3.80-3.48 (m, 4H), 3.27-3.04 (m, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=4)=[C:3]([CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1c(COc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: N#Cc1ccc(-c2c(COc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
Compound 83b was reacted under Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile using the procedures described in Example 1, Step E to afford compound 83c as a white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H21N7O2: 464.2 (M+H). Found 464.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].O>ClCCl>[Br:21][CH2:22][CH2:23][CH2:24][C:25]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)=[O:26]
Reactant: O=C(Cl)CCCBr
Reactant: COC(=O)/C=C/c1ccc(N)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(NC(=O)CCCBr)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
To a mixture of methyl (E)-3-(6-aminopyridin-3-yl)acrylate (700 mg) and triethylamine (477 mg) in dichloromethane (6 ml) was added dropwise 4-bromobutyryl chloride (801 mg) under nitrigen in ice water bath and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. the residue was chromatographed on silica gel eluting with chloroform and purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:1, v/v) to give methyl (E)-3-[6-(4-bromobutyramido)pyridin-3-yl]acrylate (101 mg).
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][NH:7]1)#[N:4].Cl[C:12]1[C:17]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]=2[O:15][C:14]([CH3:25])([CH3:24])[N:13]=1>CN(C)C=O>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][C:14]([CH3:24])([CH3:25])[N:13]=[C:12]([N:7]3[CH2:8][CH2:9][NH:10][C:6]3=[N:5][C:3]#[N:4])[C:17]=2[CH:18]=1)#[N:23]
Reactant: N#CN=C1NCCN1
Reactant: CC1(C)N=C(Cl)c2cc(C#N)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)N=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
To a suspension of sodium hydride (0.24 g) in dimethylformamide (10 ml) was added 2-cyanoiminoimidazolidine (1.00 g) with ice-cooling and the mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-cyano-2,2-dimethyl-2H-1,3-benzoxazine (1.09 g) was added to the mixture and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was extracted with addition of ethyl acetate and an aqueous sodium bicarbonate solution. The ethyl acetate layer was successively washed with water and aqueous saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to obtain 6-cyano-4-(2-cyanoimino-imidazoline-1-yl)-2,2-dimethyl-2H-1,3-benzoxazine (0.23 g) (Compound 19).