Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C(OCC)C>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[CH3:9])[NH:6][C:11]([Si:12]([CH3:13])([CH3:15])[CH3:14])=[CH:10]2.[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[CH3:9])[NH:6][CH:11]=[CH:10]2
Reactant: Cc1cc(N)c(C#C[Si](C)(C)C)cc1F
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc2[nH]c([Si](C)(C)C)cc2cc1F
Product: Cc1cc2[nH]ccc2cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 10 %

Procedure:
A mixture of 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (plus ca. 10% of the undesired isomer) (10.3 g, 46.6 mmol) and copper(I) iodide (17.75 g, 93.2 mmol) in DMF (200 mL) was stirred at 100° C. for 4 hours. The mixture was then treated with ethyl ether (300 mL) and filtered. The filtrate was washed with water (200 mL) and extracted with ether. The organics were combined and washed with water, brine, and dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 5-35% ethyl acetate in hexane to give 1.9 g 5-fluoro-6-methyl-2-(trimethylsilyl)-1H-indole containing ˜10% of the undesired isomer, 5-fluoro-4-methyl-2-(trimethylsilyl)-1H-indole plus desilylated product, 5-fluoro-6-methyl-1H-indole (2.8 g) with ˜10% of the undesired isomer, 5-fluoro-4-methyl-1H-indole. Silylated material, 5-fluoro-6-methyl-2-(trimethylsilyl)-1H-indole containing ˜10% of the undesired isomer, was re-dissolved in methanol (20 mL) and stirred with potassium carbonate overnight, filtered and concentrated. All desilylated material was combined (3.7 g) and recrystallized from CH2Cl2 and hexane to provide 5-fluoro-6-methyl-1H-indole (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](C(O)=O)=[C:12]([C:17]#[N:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([C:17]#[N:18])[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c(C#N)c2C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-n2cc(C#N)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 170.1 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-cyano-pyrazole -5-carboxylic acid (0.41 g, 1.32 mmol) in 20 mL of methylene chloride was added oxalyl chloride (0.17 mL, 1.98 mmol) and 2 drops of dimethylformamide. The reaction was stirred at ambient temperature for 6 h and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and then there was added 4-dimethylaminopyridine (0.48 g, 3.96 mmol). The reaction was stirred for 10 min and then there was added (2'-methylsulfonyl-3-fluoro-[1,1']-biphen-4-yl)amine hydrochloride (0.47 g, 1.45 mmol). The resulting mixture was allowed to stir at ambient temperature for 16 h. The reaction was diluted with ethyl acetate and the organics were washed with 10% aq HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 0.6 g (81%) of the title compound as a tan solid. LRMS (ES+): 581.3 (M+Na)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([O:35][C:36](=[O:41])[CH2:37][C:38]([O-])=[O:39])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:38](=[O:39])[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:41])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)NCCCOc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.2 %

Procedure:
To a solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (200 mg, 0.458 mmol), monoethylmalonate (91 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 mL) is added TBTU (191 mg, 0.596 mmol). The mixture is stirred at rt for 18 h. The solution is diluted with EA (50 mL) and washed twice with sat aq. NaHCO3 solution (50 mL) followed by brine (50 mL). The org. extract is dried over Na2SO4, filtered and concentrated to give crude ethyl 3-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy) propyl)amino)-3-oxopropanoate (298 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+H]+=551.38. This material is dissolved in methanol (2 mL), THF (2 mL) and 2 N aq. LiOH (1 mL). The solution is stirred at rt for 2 h before it is concentrated, diluted with DCM (20 mL) and washed with 2 N aq. HCl (10 mL). The aq. phase is extracted three times with DCM (3×20 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (105 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=523.21; 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 3.99 (s, 3H), 3.92 (t, J=6.2 Hz, 2H), 3.52 (t, J=6.9 Hz, 2H), 3.31 (s, 2H), 3.22-3.31 (m, 1H), 2.75 (q, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.04-2.15 (m, 4H), 1.85-1.95 (m, 4H), 1.73-1.82 (m, 2H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([NH2:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]([NH:13][C:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:26])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(C)(N)Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Racemic 2-amino-2-methyl-3-phenyl-propionic acid methyl ester (200 mg, 0.87 mmol) and 5-chloro-1H-indole-2-carboxylic acid (170 mg, 0.87 mmol) were coupled according to Procedure A (2:1 dichloromethane/dimethylformamide solvent) and the product purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes. Yield 286 mg, 89%; HPLC (60/40) 9.63 minutes (85%); TSPMS 371/373 (MH+, 100%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4ccccc4)c3)c2cc1OC
Yield: 47.1 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in the previous step to afford 1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (77.6 mg, 42%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.72 (s, 6H), 3.99 (s, 6H), 6.57 (s, 1H), 6.94 (d, J=6 Hz, 1H), 7.18 (d, J=6.6 Hz, 1H), 7.17-7.20 (m, 2H), 7.35-7.56 (m, 7H), 8.56 (s, 1H), 8.64 (s, 1H), 9.28 (s, 1H); LC-MS (ESI) m/z 550 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([Br:35])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To N-Boc-4-hydroxy piperidine (20 g, 100 mmol) in THF (200 ml) at 0° C. was added triphenylphosphine (28.85 g, 110 mmol) followed by carbon tetrabromide (36.48 g, 110 mmol). The solution was stirred at room temperature for 2 h then filtered and concentrated under vacuum. Flash column chromatography using dichloromethane in hexane (10-70%) yielded the product as a colourless oil (23.6 g); δH (CDCl3) 1.47 (9H, s, t-Bu), 1.93 and 2.04 (4H, m, 3,5-piperidinyl CH2), 3.31 and 3.66 (4H, m, 2,6-piperidinyl CH2), and 4.39 (1H, m, 4-piperidinyl H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[O:35])=[CH:32][CH:31]=1)=[O:28]
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.34 g of 1-[2-(4-chlorophenyl)ethyl]piperazine and 1.57 g of Hunig base (=N-ethyldiisopropylamine) are introduced into 40 ml of tetrahydrofuran. 2.36 g of 4-chloroacetylaminobenzoic acid chloride [see J. Med. Chem. 28 (1985) 910] are added thereto in small portions. After 30 minutes at 40°, the solution is concentrated by evaporation. The residue is chromatographed over silica gel, and recrystallisation is carried out from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH2Cl2 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2-dimethyl-propionyl chloride (274 mL, 2.22 mol) at 0° C. under N2. The ice bath was removed and stirring was continued at room temperature for 2 hours. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4 and evaporated to afford 2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (350 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.49 (dd, J=1.6, 8.4 Hz, 1H), 2.27 (s, 1H), 1.30 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH3:23])(=O)=O.[C:24](=[O:27])([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:10][CH2:2][CH2:3][CH2:4][O:27][CH3:24])=[O:11]
Reactant: O=C(O)c1cc2c([nH]1)CCCC2
Reactant: COCCCCOS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCCCOC(=O)c1cc2c(n1CCCCOC)CCCC2
Temperature: 25 °C
Yield: 131.1 %

Procedure:
A solution of 4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (280 mg), 4-methoxybutyl methanesulfonate (775 mg) and cesium carbonate (2.77 g) in N,N-dimethylacetamide (25 ml) was stirred at 65° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (375 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2].B.[Na].CO.Cl>O1CCCC1>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[CH:4]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2]
Reactant: CCC1=C(c2cccc(Cl)c2)C(=O)N(c2cccc(C(C)C)c2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1CN(c2cccc(C(C)C)c2)C(=O)C1c1cccc(Cl)c1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
5.0 g (14.7 mmol) of 4-ethyl-3-(3-chlorophenyl)-1-(3-isopropylphenyl)-3-pyrroline-2-one synthesized in Example 4 and 0.56 g (14.7 mmol) of sodium boron hydride were dissolved in 70 ml of tetrahydrofuran, and 11 ml of methanol were slowly added to the solution over about 1 hour, while the solution was heated under reflux. Reaction was allowed to proceed at the same temperature for further 1 hour, and the reaction mixture was then poured into 1 N hydrochloric acid, followed by extraction with ethyl acetate. The resultant organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and water in this order, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the resultant residue to achieve crystallization, followed by recrystallization from etherpetroleum ether, thereby obtaining 4.5 g of the desired product in the state of colorless crystals (yield 90%). m.p. 88.5°-90.0° C.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:27]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCSC1=O
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
2.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2.44 g of (1R,3S) 2,2-dimethyl-3[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 70-21682] in 50 ml of benzene and 3 ml of pyridine were added thereto dropwise at 0° C. The mixture was stirred at 20° C. for 24 hours and was then poured into aqueous 2N hydrochloric acid solution. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with benzene. The product was crystallized from ethyl acetate to obtain 1.8 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:35][O:36][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 31 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (58 mg, 0.25 mmol), triethyl orthoformate (0.5 ml), p-anisidine (58 mg, 0.47 mmol), and acetic acid (0.06 ml) were used to give 26 mg (0.078 mmol, 31% yield) of the title compound.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH:2]=[CH2:3].SC1N=CNN=1.[CH2:16]([N:19]([CH2:23][CH:24]=[CH2:25])[C:20](Cl)=[O:21])[CH:17]=[CH2:18].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:19]([CH2:23][CH:24]=[CH2:25])[C:20]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH:2]=[CH2:3])=[N:6]1)=[O:21])[CH:17]=[CH2:18]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: C=CCSc1nc[nH]n1
Agent: Sc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCSc1ncn(C(=O)N(CC=C)CC=C)n1

Procedure:
A mixture of 7.1 g. 3-allylthio-1,2,4-triazole, (m.p. 27° - 30° C., prepared from 3-mercapto-1,2,4-triazole in an analogous manner to that described in Example 1), 8.0 g. diallylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 48 hours. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-allylthio-1,2,4-triazole, b.p. 120° - 122° C./0.1 mm. (95.2% 1-isomer by GLC assay).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1/[CH:24]=[CH:25]/[C:26](O)=[O:27]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26](=[O:27])/[CH:25]=[CH:24]/[C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)/C=C/c1ccco1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)/C=C/c3ccco3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and (E)-3-furan-2-yl-acrylic acid following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=380.1 [M+H]+.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N-:7][CH3:8].[F:9][C:10]1[C:11]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:12]([CH:20]=[C:21]([CH:24]=O)[C:22]=1[F:23])[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14].[O:35]1CCCC1.CO>>[F:9][C:10]1[C:11]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:12]([CH:20]=[C:21](/[CH:24]=[N:1]/[O:2][CH2:3][CH2:4][CH2:5][C:6](=[O:35])[NH:7][CH3:8])[C:22]=1[F:23])[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: C1CCOC1
Reactant: C[N-]CCCCON
Solvent: CO
Product: CNC(=O)CCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 13 h
Yield: 79 %

Procedure:
To 4-aminooxy-N-methyl-butylamide (1.79 g, 13.54 mmol) obtained in Step B were added a mixed solvent of tetrahydrofuran/methanol (3:1, 100 ml) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (5.00 g, 10.41 mmol) obtained in Step F of Example 1, and the mixture was stirred for 13 hours. The reaction mixture was concentrated under reduced pressure to an extent where a little solvent remained, and acetonitrile was added thereto to precipitate the product. This precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyimino)-methyl]-benzamide (4.93 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[N:6]=[CH:5][N:4]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-1H-imidazole (1.0 eq.) in thy THF (0.4 M solution) was added NaH (60%, 1.2 eq.) portionwise at 0° C. The mixture was stirred for 2 hr at 0° C., then SEMCl (1.2 eq.) was added and the mixture was stirred for 12 hr at RT. The reaction was quenched by the addition of sat. aq. NH4Cl solution and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E1 as an oil. 1H NMR (300 MHz, CDCl3) δ: 7.45 (1H, s), 7.00 (1H, s), 5.21 (2H, s), 3.47 (2H, t, J=8.2 Hz), 0.89 (2H, t, J=8.2 Hz), 0.00 (9H, s). MS (ES) C9H17BrN2OSi requires: 276/278, found: 277/279 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>ClCCl>[C:30]1([S:36]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([CH2:6][N:7]3[C:11]4=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[CH3:20])=[C:4]([Cl:23])[CH:3]=2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NS(=O)(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg) in dichloromethane (2 ml) was added pyridine (95.7 mg). Benzenesulfonyl chloride (117 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol was added to the residue for crystallization, and the crystals were collected by filtration, dried under reduced pressure to give the objective compound (213 mg) as colorless crystals.