Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[C:10]([CH:20]([CH3:22])[CH3:21])=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:23][C:24]1[C:38]([CH3:39])=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=1[CH3:40].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][O:28][C:27]1[CH:26]=[C:25]([CH3:40])[C:24]([O:23][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:9]=[C:10]3[CH:20]([CH3:22])[CH3:21])=[C:38]([CH3:39])[CH:37]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1O
Reactant: CC(C)c1cn([Si](C)(C)C(C)(C)C)c2ccc(B(O)O)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1Oc1ccc2c(c1)c(C(C)C)cn2[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
0.50 g (1.58 mmol) of 1-[tert-butyl(dimethyl)silyl]-3-isopropyl-1H-indol-5-yl-boronic acid (Example XII), 0.437 g (173 mmol) of tert-butyl-(4-hydroxy-3,5-dimethylphenoxy)acetate (Example IX), 0.286 g (1.58 mmol) of copper(II) acetate and 0.50 g of molecular sieve (4 Å, powdered) are suspended in 10 ml of dried dichloromethane. 0.64 ml (7.88 mmol) of pyridine and 1.10 ml (7.88 mmol) of triethylamine are added dropwise at room temperature. The batch is stirred overnight at room temperature. The batch is subsequently filtered through silica gel and washed with dichloromethane. The filtrate is concentrated and the residue is filtered through silica gel (dichloromethane). 0.525 g (62%) of tert-butyl-[4-({1-[tert-butyl-(dimethyl)silyl]-3-isopropyl-1H-indol-5-yl}oxy)-3,5-dimethylphenoxy]acetate is obtained.
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[C:13]2[C:18](=[N:19][C:20]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:17]=[C:16]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:15]=[C:14]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCOCC1>[CH2:2]([S:9][C:11]1[N:12]=[C:13]2[C:18](=[N:19][C:20]=1[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:17]=[C:16]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:15]=[C:14]2[N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Clc1nc2c(N3CCOCC3)nc(N3CCNCC3)nc2nc1N1CCOCC1
Agent: [Na]
Solvent: C1COCCO1
Product: c1ccc(CSc2nc3c(N4CCOCC4)nc(N4CCNCC4)nc3nc2N2CCOCC2)cc1

Procedure:
A solution of 0.35 g of sodium and 2 ml (about 0.017 mol) of benzylmercaptan in 100 ml of dioxane was added to a solution of 6.3 g (0.015 mol) of 6-chloro-4,7-dimorpholino-2-piperazino-pteridine in 200 ml of dioxane, and the resulting mixture was refluxed for about 2 hours. The solvent was substantially distilled off in vacuo and the residue was taken up in about 200 ml of water. After it had solidified, the reaction product was suction-filtered off, washed with water and dried in vacuo at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35].N1C=CC=CC=1>C(Cl)Cl>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34]([O:1][C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[C:18]3[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=3)=[C:9](\[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)/[CH2:10][CH3:11])=[CH:4][CH:3]=2)=[O:35])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of compound 12 (0.5 g, 1.17 mmol, ˜9:1 Z/E ratio by 1HNMR) in CH2Cl2 (10 mL) was added p-nitrophenyl chloroformate (0.35 g, 1.76 mmol) and pyridine (0.29 mL, 0.28 g, 3.58 mmol). The reaction mixture was stirred at ambient temperature for 18 h and then concentrated. The residue was purified by chromatography (silica gel, hexanes/EtOAc, 8:1) to provide 38 (0.63 g, 91%, ˜9:1 Z/E mixture) as a cream-colored solid foam. 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, J=7.4 Hz, 3H), 1.42 (s, 9H), 2.39 (q, J=7.4 Hz, 2H), 6.50 (d, J=16 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 7.1-7.8 (m, 14H), 8.3-8.4 (m, 2H).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.C1(C=CC(O)=CC=1)O>CC1C=CC=CC=1C>[N+:15]([CH:14]1[CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]2[CH2:9][CH2:8][CH:7]1[CH:12]=[CH:11]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: C1=CCCC=C1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1

Procedure:
45.1 g of 1,3-cyclohexadiene (EMKA), 41.9 g of ω-nitrostyrene, 60 g of o-xylene and 1 pinch of hydroquinone are treated in an autoclave at 200° C. and under a nitrogen pressure of 60 bar for 24 hours. The solvent is stripped off and the residue is distilled under a high vacuum. Boiling point 0.05 =120°-160° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:21])[C:14]([C:18]([OH:20])=O)=[N:15][CH:16]=2)[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:44]([O:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][NH2:51])[CH3:45].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[CH2:44]([O:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][NH:51][C:18]([C:14]1[C:13]([OH:21])=[C:12]2[C:17](=[CH:16][N:15]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:28])[C:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11]2)=[O:20])[CH3:45]
Reactant: O=C(O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (35 mg, 0.094 mmol) and HOBt (13 mg, 0.094 mmol) were added to 2 mL of CH2Cl2. EDC (25 mg, 0.13 mmol) was added, and the mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (16 mg, 0.094 mmol) and Hunig's base (0.033 mL, 0.19 mmol) were then added, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 13 mg of the title compound. MS: (+) m/z 486.39 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34]Br)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1.C(OCC)(=O)C>C1OC1C.CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34][S:44][C:43]2[N:39]([CH3:38])[N:40]=[N:41][N:42]=2)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reactant: Cn1nnnc1S
Agent: CC1CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CSc1nnnn1C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 563 mg (1 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-bromo-2-butenoate in a mixture of 2 ml propylene oxide and 4 ml of dimethylformamide at 0° was added 128 mg (1.1 mmol) of 1-methyl-5-mercapto-1,2,3,4-tetrazole. After 1 hour at 0°, the solution was added to a large amount of ethyl acetate and washed thoroughly with brine. The ethyl acetate layer was dried and evaporated to provide the title product: nmr (CDCl3) δ 2.20 and 2.37 (s, 3, CH3), 3.83 and 3.86 (s, 3, N--CH3), 4.43 (s, 2, --CH2S--), 5.88 (d, 2, C4 --H), 5.50 (q, 1, C3 --H), 4.57 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:15]=1[C:16](OC)=[O:17].Cl>CCCCCC.O1CCCC1.O>[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:15]=1[C:16](=[O:17])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: COC(=O)c1cc(OC)ccc1N
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N)c(C(=O)Cc2nnnn2C)c1
Reaction time: 3 h

Procedure:
A solution of butyl lithium in hexane (2.5M, 18.5 ml) was added to a stirred solution of 1,5-dimethyl-tetrazole (4.55 g) in dry tetrahydrofuran (100 ml) at 0°. After 30 minutes methyl 2-amino-5-methoxybenzoate (2.8 g) was added and stirring was continued for 3 hours. The reaction mixture was poured into water (200 ml), acidified with hydrochloric acid (5N) to pH 1, and extracted with dichloromethane (3×100 ml). The extract was dried over anhydrous magnesium sulphate and evaporated. The residue was recrystallised from industrial methylated spirit to give the novel compound 1-(2-amino-5-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 170°-172°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25]>>[F:25][C:24]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 1-bromomethyl-2,4-bis-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][B:4]([OH:6])[OH:5].O.O.O.O.O.O.O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CCOCC.CCCCCC>[CH3:16][C:15]1([CH3:17])[C:18]([CH3:20])([CH3:19])[O:6][B:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[O:5]1
Reactant: CC(C)CB(O)O
Reactant: CC(C)(O)C(C)(C)O
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)CB1OC(C)(C)C(C)(C)O1
Reaction time: 24 h
Yield: 48.4 %

Procedure:
A solution of 50.13 g (0.494 mol) of 2-methylpropylboronic acid in 300 mL of ether, prepared by a procedure substantially similar to the foregoing, was contacted with 112.63 g (0.494 mol) of pinacol hexahydrate and stirred for 24 hours. At the end of this period, the resulting reaction mixture was diluted with 500 mL of hexane. A top layer formed which was separated from the rest of the mixture and contacted with 18 mL of water. After stirring for 15 minutes, 9.52 g of a solid separated, which was removed by filtration. The remaining hexane layer was dried over Na2SO4 and residual solvent was removed by evaporation. The remaining material was then distilled using a 6" spinning band distillation column, to obtain 43.98 g (0.239 mol, 48.4%) of an oil, bp: 65°-72°/13 mm, 1H NMR (90 MHz, CDCl3): δ0.65 (d, J=6.6 Hz, 2), 0.93 (d, J=6.6 Hz, 6), 1.25 (s, 12), 1.86 (hep, J=6.6 Hz, 1); Anal. Calcd. for C10H21O2B: C, 65.25; H, 11.50; B, 5.87; Found: C, 65.07, H, 11.52; B, 6.01.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][C:27]=3[O:38][CH3:39])=[N:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:35]1[CH2:34][CH2:33][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22]3[N:21]=[CH:20][C:19]4=[CH:18][CH:17]=[C:16]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][CH3:8])[N:24]4[N:23]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:37][CH2:36]1
Reactant: O=Cc1ncc[nH]1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C2CCN(Cc3ncc[nH]3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 8.8 %

Procedure:
Imidazole-2-carboxaldehyde (0.011 g, 0.112 mmol) and [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (53 mg, 0.12 mmol) were treated with sodium triacetoxyborohydride (0.033 g, 0.157 mmol) and acetic acid (0.064 mL, 0.112 mmol) in tetrahydrofuran (0.900 mL) at room temperature overnight. The reaction mixture was then concentrated and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. It was dried on NaSO4, filtered and concentrated. The product was isolated by reverse phase hplc (Gilson) to afford {4-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-2-methoxy-phenyl}-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow foam (5 mg, 9%). 1H-NMR (CDCl3) δ 9.63 (s, 1H), 8.69 (s, 1H), 8.29 (d, J=8.7 Hz, 1H), 8.00 (d, J=6.2 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.02 (s, 2H), 6.83 (d, J=4.7 Hz, 1H), 6.73 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.71 (s, 2H), 2.97 (d, J=11.4 Hz, 2H), 2.49 (m, 1H), 2.25 (m, 2H), 1.85 (m, 5H); LC/MS (ESI+): 510.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Temperature: 0 °C
Yield: 51.5 %

Procedure:
0.365 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate (Compound 3-1 of the present invention) was dissolved in 4 ml of 1,4-dioxane, to this was added a mixed solution of 1 ml of conc. hydrochloric acid and 1 ml of water while stirring, then, the mixture was heated for 5 hours and 45 minutes while stirring under reflux condition. Thereafter, the solution was allowed to cool, and ice water was poured into the reaction solution, ethyl acetate and saturated saline were added to the solution which was separated subsequently, and aqueous sodium hydrogen carbonate was added to the organic layer before separation, aqueous hydrochloric acid was added to the aqueous layer to acidify it, then, ethyl acetate was added before separation, the organic layer was washed with saturated saline, and dried over magnesium sulfate, then, concentrated to obtain 0.183 g of 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl)[C:20]1[O:25][CH2:24][CH2:23][O:22][N:21]=1.O>CN(C)C=O>[CH3:16][O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:13][C:10]1[CH:11]=[CH:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)[C:20]1[O:25][CH2:24][CH2:23][O:22][N:21]=1
Reactant: CON=C(C1=NOCCO1)c1ccccc1CCl
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C1=NOCCO1)c1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 0.97 g of 1-(para-chlorophenyl)-3-hydroxypyrazole in 20 ml of anhydrous dimethylformamide (DMF) was admixed with 0.13 g of sodium hydride and then stirred at 20-25 ° C. for approximately one hour. 1.34 g of the oxime from Example 2 were then added and the mixture was stirred at 60° C. for approximately three hours and then at 20-25° C. for approximately 14 hours. 300 ml of water were added and the mixture was then extracted with methyl tert-butyl ether (MTBE). The combined organic phases were washed with water and dried, and the solvent was then removed. The residue was chromatographed over silica gel (cyclohexane/ethyl acetate mixture [1:1]), giving 1.15 g of the title compound as a light-beige amorphous powder of m.p. 56-59° C.
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[O:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 270-271° C. (diethyl ether).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[C:19]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:34]C(OC(Cl)=O)C.Cl.C(OCC)C>ClCCCl>[ClH:34].[C:28]1([S:25]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:17]=3)[NH:21][CH:20]=2)(=[O:26])=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCN(Cc4ccccc4)CC3)cc12
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCNCC3)cc12

Procedure:
A stirred mixture of 5-[2-(4-benzylpiperazin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole (0.110 g, 0.24 mmol) and 1-chloroethylchloroformate (0.05 mL, 0.36 mmlole) in 1,2-dichloroethane (2 mL) was heated to reflux for 12 hours. The reaction mixture was cooled and concentrated in vacuo to a brown glass. The glass was taken up in methanol (4 mL) and heated to reflux for 6 h, then cooled and concentrated in vacuo to a semi solid. This solid was dissolved in diethyl ether and treated with 1 N HCl in diethyl ether (0.22 mL, 0.22 mmol) to afford a white precipitate isolated by vacuum filtration. Mp: 220° C. MS (ES+): 370 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[F:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(C)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:17]1([CH2:16][N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[F:29])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Cc1cccc(NCC2CCCC2)c1F
Product: Cc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1F

Procedure:
The title compound was prepared via {2-[3-(2-fluoro-3-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-fluoro-3-methyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[N:9][C:8](C(OCC)=O)=[CH:7]2)([O-])=O.CC(C)=O.C(O)(=O)C.[H][H]>C(O)C.[Pt]=O.[O-2].[O-2].[Mn+4]>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH2:7][CH:8]=[N:9]1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2nn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: C1=NNc2ccccc2C1
Reaction time: 24 h

Procedure:
A mixture of ethyl 6 nitrocinnolin-3-yl carboxylate (0.7 g.) and platinum oxide (100 mg.) in dry ethanol (20 ml.) acetone (20 ml.) and glacial acetic acid (0.5 ml.) was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 24 hours. The mixture was then heated to boiling point on a steam bath, and manganese dioxide (10 g.) was added to the boiling solution. (The above-mentioned reducing conditions resulted in the formation of relatively small amount of the 1,4-dihydrocinnoline derivative, and the manganese dioxide was used to convert this into the corresponding cinnoline derivative.) The suspension was heated under reflux for 30 minutes and then filtered through Celite. Kieselgel 60 (1 g.) was added to the filtrate, and the mixture was evaporated to dryness. The residue was placed on the top of a silica column (50 g. Kieselgel 60). Elution with ethyl acetate, evaporation of the appropriate fractions and recrystallisation from aqueous ethanol gave ethyl 6-isopropylaminocinnolin-3-yl carboxylate, m.p. 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2F)cn1
Yield: 60.2 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(2-thienyl)ethylamine (0.0196 g, 0.154 mmol) gives the title compound (0.03444 g, 60.2%): TOF MS ES+ 372.1 (M+H)+, HRMS calcd for C19H19N3O2FS 372.1182 (M+H)+, found 372.1168, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.