Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[O:6][CH2:7][C:8](=[O:14])[C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.C1(N)CC1.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][N:40]=2)[C:35]([CH:42]=O)=[CH:34]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:33]1[C:41]2=[N:40][CH:39]=[CH:38][CH:37]=[C:36]2[C:35]([CH:42]=[C:7]2[O:6][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2=[O:14])=[CH:34]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(NC2CC2)OCC1=O
Agent: NC1CC1
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: COC(=O)CC(=O)OC
Product: COC(=O)C1=C(NC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 1.5 %

Procedure:
To a solution of methyl 2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylamine, and 7-azaindole-3-carboxaldehyde (0.37 g, 2.5 mmol) in ethanol (6.0 mL), L-proline (0.029 g, 0.25 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.012 g, y. 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[C:3]([Br:28])=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc2c(c1Br)C1CCC2CN(C(=O)C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (20 mg, 0.0204 mmol) was placed in CH2Cl2 (3 mL) and acetic acid (0.1 mL). NBS was added. The reaction was stirred for 30 min. and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-8% MeOH/CH2Cl2 as the eluting solvent to obtain 1-(4-amino-3-bromo-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone as a yellow film (14.82 mg, 58%). LCMS (m/e) 363 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.18 (d, 1H, J=10.6 Hz), 6.57 (d, 1H, J=8.34 Hz), 4.25-4.10 (m, 1H), 4.03 (bs, 2H), 3.90-3.78 (m, 1H), 3.50-3.40 (m, 1H), 3.40-3.26 (m, 1H), 3.12-3.00 (m, 2H), 2.30-1.90 (m, 2H), 1.80-1.65 (m, 2H).
Reaction SMILES: C[O-].[Na+].[O-]CC.[Na+].CC(C)[O-].[Na+].CC(C)([O-])C.[Na+].[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([NH2:28])[C:22]([N+:29]([O-:31])=[O:30])=[CH:21][C:20]=1[N+:32]([O-:34])=[O:33].CC([N:38](C)C)=O>CN(C=O)C.CS(C)=O>[CH:19]1[C:20]([N+:32]([O-:34])=[O:33])=[C:21]([NH2:38])[C:22]([N+:29]([O-:31])=[O:30])=[C:23]([NH2:28])[C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: CC(=O)N(C)C
Reactant: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: CC(C)[O-]
Agent: CC[O-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c(N)c1[N+](=O)[O-]

Procedure:
Similarly, when Example 4(a) is repeated except that DMSO is replaced by a volumetrically equivalent amount of DMF or DMAC and sodium methoxide is replaced by a stoichiometrically equivalent amount of sodium ethoxide, sodium n-propoxide, sodium isopropoxide, or sodium tert-butoxide respectively, a mixture of picramide and DATB is produced. The DATB is purified by crystallization from DMF and DMSO.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.ClC(C(Cl)=O)=O.[NH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[C:32]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])=[CH:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([NH:29][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:31]=[C:32]2[CH2:40][C:41]([OH:43])([CH3:42])[CH3:44]
Reactant: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(CC(C)(C)O)c2cc(F)ccc21
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (250 mg, 1.07 mmol) in DCM (10 mL) is cooled to 0° C., treated with DMF (20 μL) and ClCOCOCl (280 μL, 3.21 mmol), and stirred for 20 min. Toluene (10 mL) is added and the mixture is concentrated in vacuo. The residue is dissolved in pyridine (10 mL) and treated with DMAP (5 mg) and 1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol (0.72 mmol). The mixture is stirred at rt for 12 h. The mixture is diluted with saturated aqueous Na2CO3, extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20%-60% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (218 mg, 70%). MS: 437 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.14 (s, 6H), 2.77 (s, 2H), 3.29 (s, 3H), 7.03 (m, 1H), 7.37 (s, 1H), 7.35-7.55 (m, 3H), 7.65 (m, 1H), 8.19 (m, 1H), 8.34 (m, 1H), 9.22 (s, 1H).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:5]2[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(S(C)(=O)=O)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc(OC)c1OC
Reaction time: 24 h
Yield: 49.3 %

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 7) (2.0 g, 6.5 mmol) in tetrahydrofuran (50 mL) was added 3,4,5-trimethoxyaniline (1.8 g, 9.7 mmol) and 4-toluenesulfonic acid monohydrate (60 mg). After stirring for 24 hours, silica gel (10 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (50:50) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give tert-butyl 1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethylcarbamate (1.3 g) as a white solid. 1H NMR (CDCl3): δ8.30 (s, 1H), 7.49 (br, 1H), 6.95 (s, 2H), 5.40-5.30 (m, 1H), 5.00-4.83 (m, 1H), 3.89 (s, 6H), 3.84 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.43 (s, 9H). MS m/z 406 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
To a solution of 4-benzyloxy-2-chlorobenzoic acid (788 mg) in tetrahydrofuran (7.9 ml) was dropwise added a boran-dimethyl sulfide complex (10.0 M, 0.6 ml) at room temperature under a nitrogen atmosphere, and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid (1.5 ml) was dropwise added carefully, which was followed by stirring for 30 min. Water was added to the reaction mixture and the resulting product was extracted three times with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (778 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[O:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)F)oc2c1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)oc2c1

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzoxazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzoxazole.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[C:12](Br)=[N:13][C:14]([F:17])=[CH:15][CH:16]=1)C(=O)C(F)(F)F)[CH:2]=[CH2:3].[Cl-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.[Cl-].[Cl-].[Cl-].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][C:14]1[N:13]=[C:12]2[C:2]([CH3:3])=[CH:1][NH:4][C:11]2=[CH:16][CH:15]=1
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccc(F)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[NH3+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(F)nc12
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of N-allyl-N-(2-bromo-6-fluoro-pyridin-3-yl)-2,2,2-trifluoro-acetamide (3.41 g, 10.43 mmol), palladium acetate (94 mg, 0.42 mmol), tetra(n-butylammonium) chloride (3.19 g, 11.47 mmol) and triethylamine (2.37 g, 23.4 mmol) in anhydrous DMF (20 mL) is stirred at 10° C. under N2 for an hour. DMF is evaporated off and the residue is mixed with water (12 mL) and stirred at rt for an hour. EtOAc (15 mL) is added and stirred at rt overnight. The organic layer is separated and the aqueous layer is extracted with EtOAc (35 mL). The combined organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10-60% EtOAc in heptane to afford 5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine (1.5 g) as a solid. MS: 151 (M+H); 1H NMR (300 MHz, CDCl3) δ 2.38(s, 3H), 6.77(d, H), 7.28(s, H), 7.74(dd, H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 5 h
Yield: 28.9 %

Procedure:
(3S)-3-(dimethylamino)pyrrolidine (161 μl, 1.27 mmol) and triethylamine (177 μl, 1.27 mmol) were added to a dimethyl sulfoxide (9 ml) solution of tert-butyl N-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-β-alaninate (I-278) (335 mg, 0.847 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (120 mg, 29%) as a brown oily substance.
Reaction SMILES: [C:1]1(=O)O[C:4](=[O:5])[CH:3]=[CH:2]1.CC(C)=O.CCC[CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:4]([O:5][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2][CH3:1]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCOCCCC

Procedure:
Amines can be reacted with maleic anhydride to give the corresponding half-amide derivative. Generally, a polymer containing maleic anhydride is reacted in solution or suspension with an amine in an inert or non-reactive solvent, such as acetone, heptane, benzene or dibutylether, to provide the desired half-amide derivative. This material then must be isolated and repackaged into a useful product.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:22][O:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28](Cl)=[O:29].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:29]
Reactant: COC(C(=O)Cl)=C(OC)c1ccccc1OC
Reactant: CCCCCCCCCCCCCCCCCCCCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)C(OC)=C(OC)c1ccccc1OC
Reaction time: 8 h
Yield: 83.3 %

Procedure:
2.9 g of 1-eicosanol dissolved in 50 ml of anhydrous pyridine are placed in a 100 ml flask equipped with a stirrer, a thermometer and a dehydrating valve. To this solution there are added 2.5 g of trimethoxycinnamoyl chloride and 0.01 ml of POCl3. The reaction mixture is left alone at room temperature overnight and is then poured into 200 ml of water. After filtration, the precipitate formed is crystallized from 30 ml of methanol. After drying, 4.2 g of eicosyl trimethoxycinnamate having the following characteristics are obtained:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:15])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([CH3:15])([CH3:12])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(Br)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(Br)ccc2O1

Procedure:
5 g of 5-bromosalicylic acid were heated under reflux with 6.7 g of acetone in a mixture of 25 ml of trifluoroacetic acid with 5 ml of trifluoroacetic anhydride for 5 h. For workup, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with sodium hydrogencarbonate solution and extracted repeatedly with diethyl ether. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; 9/1 n-heptane/ethyl acetate). 244.1 was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:40]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:40])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
A mixture of 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid (1.10 g), 1-hydroxybenzotriazole ammonia complex (0.53 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide as pale-yellow crystals (1.10 g, yield 99%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 139-140° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12](=[O:14])[C:11]3([CH2:19][CH2:18][N:17]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([N:35]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]2=[O:43])=[CH:30][C:29]=1[CH3:44].F[B-](F)(F)F.[H+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CN(C1CCCCC1)C1CCCCC1>CN1CCCC1=O.[Pd]>[CH3:34][C:33]1[CH:32]=[C:31]([N:35]2[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:36]2=[O:43])[CH:30]=[C:29]([CH3:44])[C:28]=1/[CH:24]=[CH:23]/[S:20]([N:17]1[CH2:16][CH2:15][C:11]2([N:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=3)[NH:13][C:12]2=[O:14])[CH2:19][CH2:18]1)(=[O:22])=[O:21]
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1Br
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)phenyl)-8-(vinylsulfonyl)-1,3,8-triazaspiro[4.5]deca-1-en-4-one (150 mg, 0.387 mmol) synthesized according to the method described in Schemes 2, 3, and 12 of WO2010/126030(A1), 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (169 mg, 0.542 mmol), bis(dibenzylidineacetone) palladium (45 mg, 0.077 mmol), tri-tert-butylphosphine tetrafluoroboric acid (22 mg, 0.077 mmol), and methyldicyclohexylamine (0.123 mL, 0.581 mmol) in N-methyl-2-pyrrolidone (0.97 mL) was stirred at 100° C. for one hour under nitrogen atmosphere. The reaction mixture was cooled, quenched with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford (E)-1-(3,5-dimethyl-4-(2-((4-oxo-2-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)vinyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (197 mg, 82%).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[CH3:8])C.C(O)C.[OH-].[K+]>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC(=O)CCC(C)(C)c1ccc(OC)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)(C)CCC(=O)O)cc1C
Temperature: 60 °C
Yield: 96.8 %

Procedure:
To a solution of 4-(4-methoxy-3-methylphenyl)-4-methyl-pentanoic acid ethyl ester (Compound 4, 6.8 g, 25.8 mmol) and 20 mL of absolute ethyl alcohol was added aqueous 5M KOH (6 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered. The solvent was removed to give 5.9 g (97%) of the title compound as a dark oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:33])[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:32][O:31][C:27]1[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=[C:25]([CH3:33])[C:26]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CCOC(=O)CCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under cooling with ice, aluminum chloride (4.08 parts) was added in small portions to a mixed solution of ethyl 9-chloroformylnonanoate (3.52 parts) and 3,4,5-trimethoxytoluene(formulaVII wherein R=H3CO, X=H, Y=H3CO) (2.21 parts) in nitrobenzene (20 volume parts). The mixture was stirred at 0° C. for 16 hours and, then, at room temperature for 1.5 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. By a procedure similar to that described in Example 1 (2), the extract was hydrolyzed and subjected to column chromatography on silicic acid. The fraction eluted by benzenediethyl ether (9:1) yielded 9-(2',3',4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OCH3, n=8, in the free form) (1.82 part). From the fraction eluted by benzene-diethyl ether (5.7:1), there was obtained 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, R=H3CO, X=H, Y=OH, n=8, in the free form) (0.67 part) as colorless needles melting at 75°-76.5° C.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH2:2]1.[Br:13]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:13][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2c3c(c1)CCN3CCC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cc2c3c(c1)CCN3CCC2
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A solution of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (4.0 g, 25.2 mmol) in N,N-dimethylformamide (160 ml) cooled to −30° C. was treated with a solution of N-bromosuccinimide (4.5 g, 25.3 mmol) in N,N-dimethylformamide (30 ml) dropwise over 5 minutes. The mixture was stirred for a further 15 minutes then treated with 10% aqueous sodium sulfite (100 ml) then diluted with water (500 ml) and ethyl acetate (300 ml). The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (100 ml), then water (3×150 ml). The organic layer was dried with anhydrous sodium sulfate and evaporated to dryness to give 8-bromo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline as a pale brown oil (5.2 g) which was used without further purification. 400 MHz 1H NMR (CDCl3) δ: 7.02 (m, 1H), 6.94 (m, 1H), 3.25 (t, 2H), 2.95 (m, 2H), 2.89 (t, 2H), 2.65 (t, 2H), 2.06 (m, 2H); LCMS: 238 and 240 [M+H].