Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:15]2
Reactant: C#CCCC(=O)O
Reactant: Nc1c(F)cc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cc2cc(Br)cc(F)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (2 g), 4-pentynoic acid (0.62 g) and copper(I) iodide (0.60 g) in DMF (4 mL) stirred under nitrogen at room temperature was added bis(triphenylphosphine)palladium(II) chloride (0.222 g), then triethylamine (2.2 mL) was added in a portion. The reaction mixture was stirred at 80° C. in microwave reactor for 2 hrs. The solid in the mixture was filtered, the filtrate was diluted with EtOAc (30 mL), washed with brine (80 mL) and water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoic acid (D160) (700 mg) as a yellow solid. MS (ES): C11H9BrFNO2 requires 285; found 286.0 (M+H+). δH (CDCl3, 400 MHz): 2.75 (2H, t), 3.07 (2H, t), 5.45 (1H, s), 7.05 (1H, d), 7.41 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].C(N(CC)CC)C.[N:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([Cl:60])=[O:59])[C:51]=3[N:50]=2)=[CH:45][CH:44]=1>ClCCl>[Cl-:60].[Cl-:60].[Cl-:60].[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[NH:1][C:58]([C:57]1[C:51]2[N:50]=[C:49]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[NH:53][C:52]=2[CH:54]=[CH:55][CH:56]=1)=[O:59])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]
Reactant: O=C(Cl)c1cccc2[nH]c(-c3ccncc3)nc12
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(-c3ccncc3)nc12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 mL) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride (120 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[CH:12][CH:11]=3)=[N:27][CH:28]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnnc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnnc2)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(pyridazin-4-yl)phenyl)acetic acid 37-4 (43 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (117 mg, 0.3 mmol) in DMF (1 mL) was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The crude product was purified by reverse phase HPLC to give N-(5-phenylpyridin-2-yl)-2-2(4-pyridazin-4-yl)phenyl)acetamide 37 as white solid. MS m/z 367.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.45-9.44 (m, 1H), 9.22 (dd, 1H, J1=1.2 Hz, J2=11.2 Hz), 8.44 (d, 1H, J=2.4 Hz), 8.29 (d, 1H, J=8.8 Hz), 7.92 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 7.70-7.66 (m, 3H), 7.56-7.51 (m, 4H), 7.46-7.43 (m, 2H), 7.39-7.35 (m, 1H), 3.85 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([N:19]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:20]2[CH:21]=[CH:22][C:23]3[N:24]([CH2:33][CH3:34])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:18])=[O:17])[CH:5]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[CH3:43][Si:44]([C:47]#[CH:48])([CH3:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:19]([S:16]([C:4]1[CH:5]=[C:6]([C:48]#[C:47][Si:44]([CH3:46])([CH3:45])[CH3:43])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:18])[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH2:33][CH3:34])[C:25]3[C:30]([C:31]=2[CH:32]=1)=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH3:41])([CH3:40])[CH3:42]
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3)ccc21
Reactant: C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
320 mg tert-butyl [(3-chloro-5-trifluoromethylsulphonyloxy-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 4 ml dimethylformamide. 20 mg copper-1-iodide, 40 mg bis-triphenylphosphine-palladium-dichloride and 210 μl trimethylsilylacetylene are added under argon. Then the mixture is heated to 60° C. for 6 hours and then stirred overnight at ambient temperature. The mixture is then divided between saturated potassium carbonate solution and ethyl acetate. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[CH3:9][C:10]1([CH3:33])[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=2[O:11]1.O.[OH-].[Na+]>CS(C)=O.O1CCOCC1.O>[CH3:9][C:10]1([CH3:33])[CH:15]2[O:7][CH:14]2[C:13]2[CH:16]=[C:17]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=2[O:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)C=Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C2OC21
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (3.65 g, 20.5 mmol) is added to a stirred solution of Intermediate 1a (6.80 g, 19.1 mmol) in dimethylsulphoxide (70 mL) and water (0.89 g, 0.50 mmol) at 15° C. The mixture is stirred for 2 hours and then treated with a solution of sodium hydroxide (4.0 g, 100 mmol) in dioxan-water and stirred at 20° C. for 30 minutes. The mixture is concentrated to 25% volume by evaporation under reduced pressure, treated with saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, 10% acetone in hexane) to give the title compound as a yellow oil, having the following physical characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=O)([O-:3])=[O:2].O.[NH2:21][NH2:22]>C(O)C>[O:15]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]2[NH:22][N:21]=[C:6]([C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[N+:1]([O-:3])=[O:2])[C:8]1=2
Reactant: O=C1CCCC(=O)C1C(=O)c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCCc2[nH]nc(-c3ccccc3[N+](=O)[O-])c21
Yield: 44.9 %

Procedure:
3.2 g (12.2 mmol) of 2-nitrobenzoylcyclohexane-1,3-dione and 0.52 g (12.2 mmol) of hydrazine hydrate (80%) are refluxed for 4 hours in 120 ml of ethanol. The ethanol is subsequently distilled off under reduced pressure, and 80 ml of methanol are added. The solid which precipitates is filtered off with suction and dried in vacuo. 1.41 g (45% of theory) of 4,5,6,7-tetrahydro-4-oxo-3-(2-nitro-phenyl)-1H-indazole of the formula ##STR6## and of melting point 236° C. (decomp.) are obtained.
Reaction SMILES: NC1SC=CN=1.C(OCC)(=O)CC(C)=O.FC1C=C([C:24]2[C:29](=[O:30])[N:28]3[CH:31]=[CH:32][S:33][C:27]3=[N:26][C:25]=2[CH3:34])C=C(F)C=1>C(O)(=O)C>[CH3:34][C:25]1[N:26]=[C:27]2[S:33][CH:32]=[CH:31][N:28]2[C:29](=[O:30])[CH:24]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: Nc1nccs1
Solvent: CC(=O)O
Solvent: CCOC(=O)CC(C)=O
Product: Cc1cc(=O)n2ccsc2n1

Procedure:
A solution of 2-aminothiazole (50 g, 499.301 mmol), ethyl acetoacetate (96 ml, 748.885 mmol) and acetic acid (400 ml) was reacted together according to the procedure described in Intermediate 3, Step 1 to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 40 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][CH:29]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:28][CH:29]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]([OH:35])[C:31]([F:32])([F:33])[F:34])=[O:21])[C:15]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:28][CH:29]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:21])[C:15]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 19, 2.00 g, 4.84 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.11 g, 5.06 mmol), WSCI hydrochloride (1.11 g, 5.79 mmol) and HOBT (1.31 g, 9.69 mmol) in DMF (20 mL) to give 2.66 g (94%) of the target compound as pale-yellow crystals.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([OH:16])[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1.Br[CH:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:2][C:3]1[CH:4]=[C:5]([O:16][CH:22]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21]2)[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Reactant: Cc1csc(Nc2ncc(Br)cc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ol-hydrochloride (1.0 g, 3.10 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (WO 2003/062224) (1.01 g, 4.03 mmol), K2CO3 (1.29 g, 9.30 mmol), and DMF (20 mL) were reacted at 50° C. over the weekend. The reaction was cooled to room temperature, poured into water (250 mL) and extracted with EtOAc:ether (1:1). The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (40% EtOAc in hexanes) to afford tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (584 mg, 41.4% yield) as a tan solid. 1H NMR (CDCl3) δ 8.42 (bs, 1H), 8.02 (s, 1 h), 7.10 (d, 1H), 6.42 (s, 1H), 4.95 (m, 1H), 3.75-3.44 (m, 4H), 2.35 (d, 3H), 2.21 (m, 2H), 1.50 (s, 9H); Mass spectrum (apci) m/z=456.9 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](B(CC)CC)[CH3:27].S(=O)(=O)(O)O>CN(C=O)C.C(Cl)Cl.O>[CH2:26]([C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1)[CH3:27]
Reactant: CCOC(=O)C1(C)CC(c2cc(F)cc(Br)c2)=NO1
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(C)CC(c2cc(F)cc(CC)c2)=NO1
Temperature: 150 °C
Yield: 82.8 %

Procedure:
Ethyl 3-(3-bromo-5-fluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate (1000 mg, 3.03 mmol), potassium carbonate (1.67 g, 12.12 mmol) and tetrakis(triphenylphosphane)palladium (350 mg, 0.30 mmol) were suspended in DMF (10 ml). Triethylborane (1M in hexane, 4.24 ml, 4.24 mmol) was then added, and the reaction mixture was heated in a microwave oven at 150° C. for 30 min. After cooling, water (20 ml), sulfuric acid (1 M, 5 ml) and CH2Cl2 (20 ml) were added, and the mixture was shaken. The organic phase was then dried over Na2SO4, and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel using the mobile phase heptane/EtOAc gave 701 mg (83%) of ethyl 3-(3-ethyl-5-fluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1cccc([C@@H](N)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (12.3 g, 40 mmol) and Et3N (11 g, 109 mmol) in MeCN (200 ml) was added HATU (16.6 g, 43.8 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((S)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 25-d, (10.55 g, 36.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 25-e, (33 g) as red oil. The crude product was used for the next step directly.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:6])=[O:5])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+].C(Cl)Cl>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:5])=[O:6]
Reactant: BrCCCBr
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Compound 63 (7.8 g, 33.9 mmol) was dissolved in DMF (100 mL). 1,3-Dibromopropane (35 mL, 343.0 mmol) and then in portions NaH (2.7 g, 67.5 mmol) were added, whereupon the temperature rose to 50-60° C. The reaction mixture was stirred at this temperature for 1 h (TLC monitoring, CH2Cl2), carefully poured into ice/water mixture, and extracted with ethyl acetate. The extract was evaporated. The residue washed with hexane to remove the 1,3-dibromopropane. Compound 64 (9.7 g, 82%) was obtained as a viscous yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@@H:14]1Br)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2].[Cl-].[Zn+2].[Cl-]>[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:14]1[O:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Cc1ncccc1O
Agent: [Cl-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
6 g (73.7 mmol) of zinc oxide, 2.6 g (19 mmol) of zinc chloride and 4 g of 4 Å molecular sieve are mixed. This mixture is desiccated perfectly and 2 g (18.3 mmol) of 2-methyl-3-pyridinol and 6.6 g (18.6 mmol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide in 40 ml of toluene and 40 ml of acetonitrile are then added. The mixture is stirred at 60° C. for 18 hours and then filtered. The filtrate is concentrated under reduced pressure and the evaporation residue is purified by chromatography on silica gel using an ethyl acetate/hexane mixture (7/3 then 100% ethyl acetate; v/v) as the eluent to give the expected product in the form of a beige solid (yield=7%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg) obtained in Example 6, steps 1-6, (3-fluorophenyl)boronic acid (182 mg), dichlorobis(triphenylphosphine)palladium (35 mg) and potassium carbonate (415 mg) in DME-water (1:1, 10 ml) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5-12% ethyl acetate/hexane) to give the title compound (281 mg, 77%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(OCCCC)(=O)C>[N:26]1([C:32]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 99.2 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of butyl acetate and 3.57 g (25.9 mmol) of potassium carbonate, and the resultant mixture was stirred at 50° C. To the mixture was added dropwise 3.87 g (25.9 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 50° C. for 6 hours. After completion of the reaction, the resultant opaque mixture was subjected to filtration, and washed with butyl acetate, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.09 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: [C:1]([NH2:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[ClH:13].[Cl:14]Cl>O>[Cl:13][NH:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: NC(=O)c1ccc(C(N)=O)cc1
Reactant: Cl
Solvent: O
Product: O=C(NCl)c1ccc(C(=O)NCl)cc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
16.4 grams (0.10 mols) of terephthalamide were suspended in 500 ml. of a 17% by weight hydrochloric acid solution and heated in an enamel autoclave at 34°C. Then, by means of a dosing bulb and under intensive mixing, 22.8 grams (0.32 mols) of liquid chlorine was introduced into the autoclave. With water cooling, the reaction temperature was maintained at about 35°C. The reaction pressure amounted to 10 atm. After 5 minutes, the reaction from the autoclave, filtered and the residue washed with 200 ml. of water. The residue was then dried under vacuum at 70°C. There resulted 22.6 grams (97% of theory) of N,N'-dichloro-terephthalamide.