Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=3)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:37]([F:40])([F:39])[F:38])[C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=4)[CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8]3)=[N:4][CH:3]=2)=[CH:31][C:32]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CS(=O)(=O)NCc1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)NCc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 105 °C
Yield: 6 %

Procedure:
N-[3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl) -benzyl]-methanesulfonamide (77 mg, 0.177 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (76 mg, 0.265 mmol, 1.5 eq), K2CO3 (73 mg, 0.531 mmol, 3 eq), H2O (2 mL) and dichlorobis(triphenylphosphine)palladium(II)(12 mg, 0.0177 mmol, 0.1 eq) were added. The reaction mixture was heated in a pressure tube at 105° C. overnight. Solvents were removed and the residue obtained was suspended in water and extracted twice with EtOAc. The organic layers were dried, filtered end evaporated. The residue was triturated with CH3CN and filtered. The solid was purified in an Isolute Si II cartridge (DCM/MeOH, 0%-5%). The product obtained was precipitated in CH3CN and filtered to give the desired product (5 mg, 6%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.70 min, [M+H]+ m/z 469.1; 1H NMR (300 MHz, DMSO) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.80 (s, 1H), 7.73 (t, J=6.3 Hz, 1H), 7.62 (d, J=4.7 Hz, 2H), 6.74 (s, 2H), 4.29 (d, J=6.3 Hz, 2H), 2.93 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][C:16]([CH3:51])([CH3:50])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:20][CH:19]=1>O.C(OCC)(=O)C>[CH3:13][O:14][CH2:15][C:16]([CH3:50])([CH3:51])[O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:22][CH:23]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.26 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 41%).
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCC>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:19]([N+:23]1([CH3:2])[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: CCCCN1CCCC1
Solvent: CCCCCC
Product: CCCC[N+]1(C)CCCC1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 96 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (3.67 g; 11.6 mmol) is slowly added dropwise to dry and cooled (0° C.) N-butyl-pyrrolidine (1.38 g; 11.2 mmol) (exothermic) in a 25 ml glass flask. A pale-yellow solid forms. The reaction mixture is warmed to room temperature, diluted with 10 ml of n-hexane and stirred for 16.5 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. N-Butyl-N-methylpyrrolidinium bis(pentafluoroethyl)phosphinate, [BMPL][(C2F5)2P(O)O], (4.71 g; 10.7 mmol) is isolated as pale-yellow solid in a yield of 96% and a purity of 99%.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(NC2CCCc3c(OC)cccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3c(OC)cccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.18, 6.97, 6.79, 5.37, 4.53, 2.87–2.76, 2.70–2.64, 2.54, 2.01–1.86, 1.35–1.24; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1186.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:24])[CH2:27][CH2:26]1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Yield: 54 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation E) and cyclopropylamine to yield the title compound as a white solid (23 mg, 54% yield). MS (apci) m/z=366.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=O)[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].[F:20][C:21]([F:29])([F:28])[C:22]1[CH:26]=[C:25]([NH2:27])[NH:24][N:23]=1>FC(F)(F)C(O)=O>[CH3:12][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:4](=[O:9])[CH2:3][C:2]([CH3:1])([CH3:10])[CH2:7][C:6]=2[NH:27][C:25]2=[N:24][NH:23][C:22]([C:21]([F:29])([F:28])[F:20])=[C:26]12
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)C2=C(C1)Nc1n[nH]c(C(F)(F)F)c1C2(C)c1ccccc1
Temperature: 190 °C
Yield: 0.5 %

Procedure:
In a 25 mL rb flask, 5,5-dimethylcyclohexane-1,3-dione (1402.0 mg, 10.0 mmol, 1.0 equivalent) was dissolved in trifluoroacetic acid (10.0 mL, 0.47 molar), followed by addition of acetophenone (11.44 mL, 100.0 mmol, 10.0 equivalent) in one portion. The reaction was refluxed for 3 hours at 190° C., followed by addition of 3-(trifluoromethyl)-1H-pyrazol-5-amine (1511.0 mg, 10.0 mmol, 1.5 equivalent) and continued reflux for additional 2.5 hours at 190° C. The reaction mixture was cooled and evaporated to remove TFA. The crude reaction mixture was purified by HPLC to afford the desired product as a white solid (17.0 mg). 1H NMR (300 MHz, DMSO) δ 7.24 (d, J=7.6 Hz, 2H), 7.14 (t, J=7.6 Hz, 2H), 6.99 (t, J=7.1 Hz, 1H), 2.43 (d, J=4.7 Hz, 2H), 2.01 (d, J=15.8 Hz, 1H), 1.92 (s, 3H), 1.86 (d, J=15.8 Hz, 1H), 0.99 (s, 3H), 0.92 (s, 3H). LRMS (ESI+) (M+H): 376.24, retention time 0.67 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]1([C@H:16]([NH:28][C:29]([O:31][C@@H:32]2[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[O:30])[C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=2)[O:20][CH2:21][C:22](O)=[O:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>>[N:34]12[CH2:35][CH2:36][CH:37]([CH2:38][CH2:39]1)[C@@H:32]([O:31][C:29](=[O:30])[NH:28][C@H:16]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]([O:20][CH2:21][C:22]([NH:1][C:2]3[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=3)=[O:23])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:33]2
Reactant: O=C(O)COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: Nc1cccc(CO)c1
Agent: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Product: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1cccc(CO)c1

Procedure:
The title compound was prepared as described in Example 1 Step 11 with 3-aminobenzyl alcohol and 2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)acetic acid replacing 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride and 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoic acid respectively. Crude material used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O>>[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[S:18][C:15]([NH:14][C:13]2[C:8]([O:7][C:6]3[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:16][N:17]=1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reactant: O=C(Cl)CCCBr
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCCBr)s1

Procedure:
Example 102a was synthetized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with 4-bromobutanoyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[ClH:15].N1C=CC([C:21]([NH2:23])=[NH:22])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:15].[NH2:23][C:21]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[NH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (8.93 g, 44.6 mmol) and pyrazole carbox-amidine hydrochloride (6.536 g, 44.6 mmol) was added Hunig's base (7.77 ml, 44.6 mmol) and DMF (25 ml). The reaction was heated at 60° C. for 15 hours. The reaction was then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separated out as a white solid, which was filtered, washed and dried (10.9 g, 88%). M.p.=169-172° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.09 (d, J=8.8 HZ, 1H), 6.9-7.9 (br. s, 3H), 3.83 (d, J=13.6 Hz, 2H), 3.63 (m, 1H), 2.88 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for C11H22N4O2.1.06HCl.0.2H2O: C, 46.39; H, 8.31; N, 19.68. Found C, 46.43; H, 8.31; N, 20.68.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:16])[CH2:14][CH3:15].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>CO.O1CCCC1.C(O)=O>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH2:13][CH2:14][CH3:15])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:22]
Reactant: CCCN
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Solvent: C1CCOC1
Solvent: O=CO
Product: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of 3.6 g of D-glucose, 1.3 g of n-propylamine and 15 ml of methanol is heated at 60° C. for 30 minutes. The reaction mixture is condensed to dryness under reduced pressure and the residue is washed with ether, whereby 4.4 g of 1-n-propylamino-1-deoxy-D-glucose are obtained as a crude product. 4.4 g of said crude product are dissolved in 50 ml of methanol and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise thereto at 0° to 5° C. The solution is stirred at room temperature for one hour and the reaction solution is condensed under reduced pressure. The residue thus obtained is dissolved in 20 ml of formic acid and allowed to stand at room temperature for 20 minutes. 200 ml of ether-n-hexane mixture(1:1) is added to the solution and the resultant oily product is washed with ether repeatedly. 5.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-glucopyranosylurea are thereby obtained as brownish caramel, which can be, if desired, further purified by silica gel chromatography (Solvent: chloroform-ethyl acetate-methanol(1:2:1)) and obtained as colorless caramel.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2([C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]2)[C:16]1=[O:30].C(N(CC)CC)C>COCCOC.C1(C)C=CC=CC=1>[C:1]([N:24]1[C:17]2([C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][C:13]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:11]([Cl:10])[CH:12]=3)[C:16]2=[O:30])[C:27](=[O:28])[NH:26][C:25]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)c1ccccc1
Reaction time: 3 h
Yield: 15.8 %

Procedure:
A solution of benzoyl chloride (0.63 g.) in 1,2-dimethoxyethane (10 ml.) was added dropwise to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) and triethylamine (0.51 g.) in 1,2-dimethoxyethane (50 ml.) cooled at 0°-5° C. When the addition was completed, the solution was stirred at 20°-25° C. for three hours. Silica gel (5 g., Merck type 7734) was added to the solution and the mixture was evaporated The residue obtained was added to the top of a column of silica gel (75 g., Merck type 7734) made up in toluene. The column was eluted with increasing concentration of ethyl acetate in toluene up to 25% v/v and the fractions containing the major product [Relative flow value: 0.4, on Merck SiO2TLC plates No. 5715; eluant: EtOAc/Toluene, 1:1 v/v] were collected, combined and evaporated. The solid thereby obtained was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzoyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.34 g.), m.p. 251°-253° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([F:9])[CH:5]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1cc(F)c(O)c(F)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(F)c(O)c(F)c1
Yield: 27.6 %

Procedure:
2,6-Difluoro-4-aminophenol (1.49 g, 5.65 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.23 g, 8.48 mmol) in dioxan (50 ml) were refluxed under nitrogen for 2.5 hours. The solvent was evaporated and the product was converted to the free base, purified by flash chromatography (silica, methanol-ammonia/chloroform), triturated with methanol, filtered, washed and dried to give the title compound (0.58 g), m.p. 274°-5° (dec).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([CH3:6])=O.C(O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.O.[NH3:29]>O1CCOCC1.O>[OH:1][N:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:6])[N:29]=[C:21]1[C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: CC(=O)C(=NO)c1cccnc1
Reactant: N
Reactant: COc1ccc(C=O)cc1OC
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2nc(C)c(-c3cccnc3)n2O)cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-hydroxyimino-1-(3-pyridyl)acetone (1.64 g) in a mixture of dioxane (30 ml), ethanol (10 ml), and water (5 ml) were added 3,4-dimethoxybenzaldehyde (1.66 g) and conc. ammonia water (0.69 ml). The solution was stirred at 60° C. for 2 hours. Additional ammonia water (0.7 ml) was added thereto, and the solution was stirred at 45° to 50° C. for 1 day. The mixture was evaporated, and the residue was dissolved in chloroform, and subjected to column chromatography on silicagel eluting with a mixture of chloroform and methanol. The fractions were collected and evaporated, and the residue was triturated with diisopropyl ether to give 1-hydroxy-2-(3,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.20 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=CC=C[CH:15]=3)[C:10]([NH2:17])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[CH3:34][N:31]1[CH2:32][CH2:33][CH:28]([C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:36]([NH:17][C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[C:16]([CH3:15])[CH:11]=4)=[O:38])[CH:20]=3)[NH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Nc1ccc(-c2ccncc2)c2ccccc12
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)ccc1-c1ccncc1

Procedure:
The title compound was prepared in a similar manner to Example 1 from 3-methyl-4-(pyridin-4-yl)aniline (prepared as for D3 from 4-bromo-3-methylaniline) (0.17 g, 0.9 mmole), 5-amino-3-(1-methylpiperdin-4-yl)-1H-indole (D2, 0.17 g, 0.75 mmole), triphosgene (0.10 g, 0.35 mmole) and triethylamine (0.07 ml). This was obtained as a buff powder (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1=[O:34].[C:37]1(C)C=CC=CC=1>>[OH:29][C:28]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:30][CH2:31][CH:32]([CH3:37])[CH3:33])[C:20](=[O:34])[C:19]=1[C:18]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=2[S:7](=[O:8])(=[O:9])[N:10]=1
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: Cc1ccccc1
Reactant: CCCCN1C(=O)C(=C(SC)SC)C(=O)c2cccnc21
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Yield: 49 %

Procedure:
The product of Example 309G (37.5 mg, 0.15 mmol) and the product of Example 340D (50 mg, 0.15 mmol) were reacted in toluene (5 mL) at 100° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a Biotage-12 m column eluting with 2:98 methanol:dichloromethane to give the title compound as a yellow solid (36 mg, 49%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.99 Hz, 6 H), 1.57 (m, 2 H), 1.66 (m, 1 H), 4.45 (d, J=7.35 Hz, 2 H), 4.64 (s, 3 H), 4.71 (s, 3 H), 7.43 (s, 1 H), 7.46 (m, 1 H), 8.54 (d, J=6.99 Hz, 1 H), 8.87 (s, 1 H), 14.45 (br.s, 1 H). MS (DCI+) m/z 510 (M+NH4)+.
Reaction SMILES: [CH:1]1C=CC=CC=1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O)([O-:9])=[O:8].[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19].CCCCCC>>[CH3:1][C:19](=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[N+:7]([O-:9])=[O:8])[C:18]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Into 500 ml of benzene, 21.0 g (139.0 mmol) of 2-nitrobenzaldehyde (manufactured by Aldrich Chemical Co., Inc.) and 50.0 g (138.0 mmol) of Wittig reagent (carbethoxyethylidene triphenylphosphorane, manufactured by Aldrich Chemical Co., Inc.) were dissolved; and the mixture was stirred at room temperature for one night. After the completion of the reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure, ethanol was added thereto, and the precipitated crystal was filtered out. The filtrate was concentrated under a reduced pressure, so as to yield an oily product, which was then refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/4), whereby 32.1 g of the aimed compound were obtained as an oily product (yield: 98.2%).
Reaction SMILES: C[O:2][C:3](OC)([CH3:32])[C:4]([C:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:9]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][O:27][N:26]=3)=[CH:21][CH:20]=2)[C:8](=[O:30])[C:7]=1[OH:31])=[O:5].C(O)(=O)C>O>[O:5]=[C:4]([C:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:9]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][O:27][N:26]=3)=[CH:21][CH:20]=2)[C:8](=[O:30])[C:7]=1[OH:31])[C:3](=[O:2])[CH3:32]
Reactant: COc1ccccc1C1C(C(=O)C(C)(OC)OC)=C(O)C(=O)N1c1ccc(-c2ccon2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C1C(C(=O)C(C)=O)=C(O)C(=O)N1c1ccc(-c2ccon2)cc1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
4-(2,2-dimethoxypropionoyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrol-2-one (0.08 g, 0.17 mmol) was added with acetic acid (0.1 mL) and water (0.9 mL). The mixture was stirred at 95° C. for 15 min. Then, water was added, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from dichloromethane and ether to give 4-(1,2-dioxopropyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrol-2-one (0.05 g, 70%) as yellow crystals.