Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.C[Si](Cl)(C)C.C(N(CC)CC)C.Cl[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.C(#N)C.CO>[C:25]1([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:1]2[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:2]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
3-(4-Imidazolyl)propionic acid (1.0 g, 7.1 mmol) was suspended in a mixture of dichloromethane (5 ml) and acetonitrile (25 ml). Trimethylsilyl chloride (781 mg, 7.2 nmmol) was added and the mixture refluxed for 4 hours. Triethylamine (1 ml) was added, and refluxing continued for 15 minutes. Cooled, triethylamine (1 ml) added followed by chlorotriphenylmethane (1.99 g, 7.1 mmol) in dichloromethane (10 ml), and the mixture stirred at ambient temperature for 2 hours. MeOH (20 ml) was added, the mixture stirred for 30 minutes, then evaporated to dryness. Water (50 ml) was added to the residue, and the pH adjusted to 8-8.5 with triethylamine. The precipitate was filtered off, washed with diethyl ether, and dried to give the desired product (2.25 g). MS (ESP): 383 (MH+) for C25H22N2O2;
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10]Br)=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:14]([N:16]([CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]2[C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15].[CH:41]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42]1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][NH:46][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:14]([N:16]([CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]2[C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15]
Reactant: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCBr)c2Cl)nc2ccccn12
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCNC3CCCC3)c2Cl)nc2ccccn12
Temperature: 90 °C

Procedure:
To 0.1 ml of a 0.2 M solution of (2-chloro-3-bromoethoxy-4-methoxyphenyl)-N-({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)-N-(3-methylbutyl)carboxamide in N-methylpyrrolidinone is added 0.1 ml of a 1 M solution of cyclopentylamine. The mixture is heated at 90 ° C. for 15 h in a sealed vial. After cooling to room temperature, the reaction mixture is diluted with 0.5 ml of ethyl acetate and washed with 0.5 ml of 1 N aqueous sodium hydroxide. The organic layer is separated and purified by preparative TLC eluting with 9/1/0.5 ethyl acetate/methanol/triethylamine to obtain 11 mg of the title compound. Mass Spec m/z (M++1) 633.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)[CH3:14]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)c2cccnc12)OCC

Procedure:
180 g of 5-chloro-8-hydroxyquinoline, 237 g of 2-bromoacetaldehyde diethyl acetal and 200 g of potassium carbonate are stirred for 4 h at 120° C. in 800 ml of dimethylformamide. After cooling, the mixture is poured into 2.5 liters of water, and the product is filtered off under suction and dried in vacuo, melting point 51°-53° C.
Reaction SMILES: [C:1]([O:11]CC)(=O)[CH2:2][C:3]([C:5]([O:7]CC)=[O:6])=O.[OH-].[Na+].S(O)(O)(=O)=O.[CH3:21][S:22][C:23](=[NH:25])[NH2:24].Cl>O>[CH3:21][S:22][C:23]1[NH:25][C:1](=[O:11])[CH:2]=[C:3]([C:5]([OH:7])=[O:6])[N:24]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C(=O)O)cc(=O)[nH]1
Reaction time: 15 h

Procedure:
Neat diethyl oxalacetate (23.5 g, 125 mmol) was added to a solution of sodium hydroxide (15 g, 0.375 mol, 3 eq) in water (150 mL), giving a yellow solution. Solid S-methylisothiourea sulfate (17.4 g, 62.5 mmol, 0.5 eq) was added to the stirred solution. The mixture was stirred 15 hours. Concentrated HCl (40 mL, 0.48 mol) was added bringing the pH to 1, the resultant pale orange-pink suspension was stirred vigorously for 2 hours then filtered. The filter cake was washed with water (100 mL), and dried under high vacuum to afford 2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid as an off-white solid. 1H NMR (500 MHz, DMSO-d6) □ 13.22 (br s, 1H), 6.60 (s, 1H), 3.37 (br s, 1H), 2.53 (s, 3H); ESI-MS m/z 186.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:20]1[C:19](=[O:24])[CH2:23][CH2:22][CH:21]=1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)C2=CCCC2=O)c(Cl)n1
Yield: 90 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.53 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1.S(=O)(=O)(O)O.[CH2:37](O)[CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:37][CH3:38])=[O:12])[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1
Reactant: Nc1nc(CCCC(=O)O)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1

Procedure:
396 mg (0.86 mmol) of 4-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)butyric acid (from example 130) in 20 ml of ethanol are, after addition of 0.10 ml of sulfuric acid, heated under RF for 20 hours. The mixture is concentrated under reduced pressure, dichloromethane and a little methanol are added and the mixture is extracted with sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2=[O:12].[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)O[C:14]2=[O:15].CN(C1C=CC=CN=1)C.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[C:8](=[N:18][C:19]3[C:13]([C:14]1=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]2=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2cccc(F)c2-n2c1nc1ccccc1c2=O
Yield: 14 %

Procedure:
A solution of 7-fluoroisatin (300 mg, 1.8 mmol), isatoic anhydride (1.2 g, 7.3 mmol), and dimethylaminopyridine (222 mg, 2 mmol) in 5 mL of pyridine were heated at reflux temperature for 64 h. 50 mL of 0.2N HCl and 100 mL of chloroform were added and the chloroform layer was separated. The water layer was extracted with chloroform and the combined organic extracts were concentrated. Chromatography on silica gel eluting with chloroform gave the title compound in 14% yield: mp 264°-267° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H) 8.02 (d, 1H) 7.82-7.92 (m, 1H) 7.79 (d, 1H) 7.64-7.74 (m, 1H) 7.52-7.64 (m, 1H) 7.40-7.49 (m, 1H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([NH:12][CH:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)(=O)C>>[NH2:12][C@@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 8 h

Procedure:
A reaction solution (100 ml) containing 100 mM potassium phosphate buffer (pH 6.5), 1 U of N-acylamino acid racemase, 1 U of D-aminoacylase, and 15% N-acetyl-DL-tryptophan was incubated at 30° C. overnight. As the reaction progressed, D-tryptophan produced was saturated in the aqueous phase and precipitated upon oversaturation in the aqueous phase, during which process the reaction was continued. The D-tryptophan precipitated in the aqueous phase was separated by filtration, washed with water, and dried (70% recovery). The optical purity of D-tryptophan thus produced was determined as follows. CHIRALPAK WH (DAICEL CHEMICAL INDUSTRIES, LTD.) was used to measure the purity at room temperature using 0.25 mM cupric sulfate as eluent (flow rate, 1 ml/min; detection wavelength, 254 nm). As a result, D-tryptophan with the optical purity of nearly 100% ee was obtained by the method of the present invention.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([O-:35])=[O:34].O>O1CCCC1>[CH3:24][C@@H:5]1[CH2:6][C@@H:7]2[C@:21]([CH3:22])([CH2:20][CH:19]=[C:18]3[C@H:8]2[CH2:9][CH2:10][C:11]2[C@:16]3([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=2)[C@H:4]1[C:3](=[O:25])[CH2:2][O:1][S:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)(=[O:43])=[O:44]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After dissolving 10.0 g (29.4 mmoles) of 21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of tetrahydrofuran, 7.14 ml (51.4 mmoles) of triethylamine, then at 0° C. 11.4 g (51.4 mmoles) of 4-nitrobenzenesulfonyl chloride are added to the above solution. Subsequently, the reaction mixture is stirred at room temperature for 2 hours, then dropwise added to 450 ml of water while stirring. The precipitate is filtered off, dried and recrystallized from ether to obtain the title compound in a yield of 13.5 g (87.66%), m.p.:151°-160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][CH2:11][O:10]1)=[O:8].[BH4-].[Na+]>CO>[CH3:20][C:16]1[CH:15]=[C:14]([C:9]2([CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[OH:8])[CH2:13][CH2:12][CH2:11][O:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C2(C(=O)c3ccccn3)CCCO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C2(C(O)c3ccccn3)CCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of Example 91D (478 mg, 1.79 mmol) in methanol (10 mL) was added NaBH4 (135 mg, 3.55 mmol) portion wise, and the mixture was stirred overnight at room temperature. After evaporating most of the solvent, the residue was diluted with 10 mL of water, and extracted with ethyl acetate (15 mL×3). The combined organic phases was dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=3:1) to give the title compound (182.7 mg, 38%). LC-MS: m/z (M+H): 270. 1H NMR (400 MHz, CDCl3): δ ppm 8.27 (d, J=4.4 Hz, 1H), 6.93-7.59 (m, 7H), 4.83 (d, J=6.0 Hz, 1H), 4.63 (d, J=6.0 Hz, 1H), 3.87-4.07 (m, 2H), 2.60-2.65 (m, 1H), 2.28-2.31 (m, 1H), 2.21 (s, 3H), 1.79-1.92 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (from Intermediate B11 step 1) (350 mg; 1.06 mmol; 1 eq.) and 10% Pd/C (˜50% H2O) (67 mg) in MeOH (2 mL) and THF (2 mL) was stirred at room temperature for 3 hours under a H2 atmosphere (10 bars). The catalyst was filtered off and the solution concentrated in vacuo. Purification by column chromatography (heptane/EA) afforded the title compound (330 mg, 94%) as a colourless oil. HPLC (max plot) 97.4%; Rt 5.20 min.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].[Na].[CH2:9]([CH:13]([C:19]([CH3:21])=O)[C:14](OCC)=[O:15])[CH:10]([CH3:12])[CH3:11]>CO>[CH2:9]([C:13]1[C:14](=[O:15])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][C:19]=1[CH3:21])[CH:10]([CH3:12])[CH3:11]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(CC(C)C)C(C)=O
Agent: [Na]
Solvent: CO
Product: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1CC(C)C
Yield: 63.4 %

Procedure:
Nitroguanidine (53.1 g) was added to a solution of sodium (17.6 g) in methanol (500 ml). The mixture was heated under reflux for 45 minutes. Ethyl α-isobutylacetoacetate (95.0 g) was then added dropwise to the refluxing mixture over 30 minutes. Refluxing was continued for a further 61/2 hours. Most of the methanol was removed and the residue was dissolved in water. Unreacted β-keto-ester was removed by extraction with chloroform and the solution was acidified with concentrated hydrochloric acid. The separated solid was washed with water and dried, giving 5-isobutyl-6-methyl-2-nitraminopyrimid-4(3H)-one (formula IV, R1 = CH3, R = isobutyl) (73.2 g). A sample recrystallised from ethanol had a melting point of 179°-181° (decomp.).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C>[Pd].[H][H]>[NH:8]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCOCCOCCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: C1COCCOCCOCCN1
Yield: 60 %

Procedure:
A quantity of the 1-benzyl-1-aza-4,7,10-trioxacyclododecane compound (3) prepared in Example 3 (45.1 g, 0.17 mol), ethanol (7 g), and 10% palladium on carbon (0.5 g) were shaken in hydrogen atmosphere at more than 50 psi (1 psi=6.9×103 Pa=0.07 kg cm-2). Hydrogen gas was recharged several times into the reaction chamber to keep the pressure elevated. Shaking was continued until the pressure lowering stopped (4 days). After the palladium carbon was filtered, the solvent was evaporated. The pure compound (4) was sublimed from the residue with gentle heating using a water bath (75°-77° C.; crude material melted at this temperature). The sublimate was white needles and was hygroscopic. Yield 60%; 1HNMR (D2O): δ 2.53-2.70 (t, 4H, N--CH2), 3.5-3.75 (m, 12H, O--CH2), no signal at 7.1 (Ar--H of benzyl group, possible contaminant).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc2c1OCCO2
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OCCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,3-dihydro-benzo[1,4]dioxin-5-yl)-hydrazine according to the method described for example 43. MS: M=451.2 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16])[CH3:2].[N:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[CH:24]=[CH:23]2)=[C:18]=[S:19]>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12][C:18]([NH:17][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[CH:24]=[CH:23]3)=[S:19])=[O:10])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16])[CH3:2]
Reactant: Cn1ccc2cc(N=C=S)ccc21
Reactant: CCc1nc(C(=O)NN)c(OC)cc1OC
Solvent: CCO
Product: CCc1nc(C(=O)NNC(=S)Nc2ccc3c(ccn3C)c2)c(OC)cc1OC
Yield: 73.3 %

Procedure:
A flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid hydrazide (34 mg; 0.15 mmol), 5-isothiocyanato-1-methyl-1H-indole (28 mg; 0.15 mmol) and ethanol (2 mL) and the mixture was heated at reflux for three hours. The reaction was then cooled, and the precipitate was filtered and dried to give N-[6-Ethyl-3,5-dimethoxy-pyridine-2-carboxamidyl]-N′-(1-Methyl-1H-indol-5-yl)-thiourea (44 mg; 0.11 mmol).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].C([O:14][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=O)C>CO.O>[CH3:9][O:10][NH:11][C:15]([C:17]1[C:18](=[O:45])[C:19]2[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[N:21][C:20]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CONC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (0.5 mL) was added to a mixture of O-methylhydroxylamine hydrochloride (220 mg) and 2-(3-imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 3 Step A, 3.0 mg, 0.006 mmol) in 0.5 mL of methanol. The reaction mixture was kept in a sealed tube at 110° C. for 2 days with stirring. After cooling to room temperature the solution was diluted with water and extracted with dichloromethane. The crude product, after concentration, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Imidazol-1-yl-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methoxy-amide was obtained as a white solid (1.9 mg, 65%). 1H NMR (400 MHz, CDCl3) δ (ppm): 11.98 (br, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.03 (br, 2), 6.74 (s, 1H), 5.80 (br, 1H), 3.89 (s, 3H), 3.00 (m, 8H), 2.17 (m, 2H), 1.92 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H25N7O3: 460.20 (M+H). Found. 460.2.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([NH:13][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1ccccc1

Procedure:
E & Z 3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one is reacted with 0.022 gms. of aniline by refluxing in tetrahydrofuran (1.2 mL) for 12 hours to yield a quantitative amount (39 mg) of the named compound as a solid following concentration in vacuo, dilution with isopropanol and filtration.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[C:19]1([CH2:25][CH2:26][CH2:27]O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Reactant: OCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OCCCc1ccccc1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (590 mg; 2.31 mmol), 3-phenylpropanol (520 mg; 3.71 mmol), dicyclohexylcarbodiimide (815 mg; 3.95 mmol), camphorsulphonic acid (180 mg; 0.77 mmol) and 4-dimethyl aminopyridine (95 mg; 0.77 mmol) in methylene chloride (15 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo. The crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (20% ethyl acetate in hexane) to obtain 800 mg (93%) of the product as an oil, 1H NMR (CDCl3, 300 MHz): δ 0.85 (t, 3H); 1.23,1.26 (s, 3H each); 1.63–1.94 (m, 9H); 2.32 (m, 1H); 2.69 (m, 2H); 3.21 (m, 1H); 3.35 (m, 1H); 4.17 (m, 2H); 5.24 (m, 1H); 7.14 (m, 3H); 7.7.23 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH2:13][CH3:14])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O)=O.C([O-])(=O)C.[NH4+:19].N>C(O)(=O)C>[CH2:13]([C:4]1[NH:3][CH:1]=[N:19][C:5]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: CCC(NC=O)C(=O)c1cccnc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Product: CCc1[nH]cnc1-c1cccnc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
A mixture of 2-formylamino-1-(3-pyridyl)-1-butanone (640 mg) and ammonium acetate (5.13 g) in acetic acid (5 ml) was stirred at 100° C. for 1.5 hours. After cooling, 28% aqueous ammonia was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-diethyl ether to obtain 5-ethyl-4-(3-pyridyl)imidazole (520 mg) as colorless powder.