Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]([CH:19]=[C:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][C:3]1=[O:31].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].C(Cl)Cl>O>[CH3:1][N:2]1[C:11]2[CH:10]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:7]3[C:26](=[O:28])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:5]([C:6]=23)[CH2:4][C:3]1=[O:31]
Reactant: CCOC(=O)C(=CN1CC(=O)N(C)c2cc(CN3CCOCC3)ccc21)C(=O)OCC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)N(C)C(=O)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Diethyl 2-{[4-methyl-6-(morpholin-4-ylmethyl)-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methylene}malonate (915 g, 2.20 mol) is added to Eaton's reagent (4.05 kg, 7.7 wt % phosphorus pentoxide dimer in methanesulfonic acid). The resulting dark red mixture is heated to 90° C. After 2 h, the reaction is cooled to less than 30° C. and poured into 9 kg of ice. A solution of 50% NaOH (3.9 kg) in water (3.8 liter) is added while maintaining less than 35° C. until the pH is 10. Methylene chloride (4 liter) is added and the phases separated. The aqueous is washed with methylene chloride (3×4 liter) and the combined organics are concentrated in vacuo to 4.5 liter total volume. Acetonitrile (4.5 liter) is added and the mixture concentrated to 4.5 liter total volume. Acetonitrile (1.8 liter) is added and the mixture concentrated to 4.5 liter total volume. The resultant slurry is cooled to 0° C. and the precipitate collected by filtration, washed with 2×1 liter of 0° C. acetonitrile and dried in a vacuum oven at 50° C. overnight to give a white solid (756 g). Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ1.27, 2.38, 3.36, 3.59, 4.21, 5.08, 7.33, 7.73, 8.48; 13C NMR (DMSO-d6) δ172.2. 164.2, 161.6, 146.8, 135.4, 131.0, 127.3, 126.4, 119.2, 117.3, 111.3, 66.2, 61.9. 59.9, 53.1, 28.6, 14.3.
Reaction SMILES: [CH2:1]([C:4]1([CH2:13][CH2:14][CH3:15])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].C(N(CC)CC)C.[CH2:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]1[O:26][CH2:25]1>CN(C)C=O.O>[CH2:28]([O:27][CH2:23][CH:24]([OH:26])[CH2:25][N:8]1[C:9](=[O:10])[C:4]([CH2:1][CH2:2][CH3:3])([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[NH:6][C:7]1=[O:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOCC1CO1
Reactant: CCCC1(CCC)C(=O)NC(=O)NC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CCC)(CCC)C1=O
Temperature: 60 °C
Yield: 47.6 %

Procedure:
A solution of 5,5 dipropyl-(1H,3H,5H)-pyrimidine-2,4,6-trione (30.8 g, 0.15 mole) in dimethylformamide (30 ml) containing triethylamine (2.02 g, 0.2 mole) was mixed with butyl glycidyl ether (13 g, 0.1 mole). The mixture was heated at 60° C. for 6 hours. The solution was then diluted with water (150 ml) and extracted with toluene (2×50 ml). The organic layer was separated, washed with water (2×100 ml) dried and extracted with 5% aqueous sodium carbonate (6×100 ml). The toluene phase was then extracted with 1M aqueous sodium hydroxide (2×100 ml), the aqueous layers separated, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated oily product was extracted with toluene (100 ml), and the organic layer was separated, washed with water, dried and evaporated to yield the title compound (16.3 g; 51.6%); purity by HPLC 96.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:9]([CH2:10][C@@H:11](C(O)=O)[NH2:12])=[CH:8][NH:7]2.O.C(OCC)(=O)C.Cl>C1(CC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cccc2[nH]cc(C[C@H](N)C(=O)O)c12
Agent: Cl
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc2[nH]cc(CCN)c12
Reaction time: 0.01 h

Procedure:
A suspension of 4-methyltryptophan (1.14 g, 5.2 mmol, Sigma) in diphenylmethane (45 mL) was heated at reflux until complete solution was obtained. The solution was then mixed with 45 mL water and 45 mL ethyl acetate, and the pH brought to 1 or lower with concentrated HCl. The mixture was vortexed vigorously for 30 seconds, and centrifuged to provide three layers. The middle (aqueous) layer was washed with ethyl acetate, and adjusted to pH 10 or higher with 10 N NaOH. The resulting white precipitate was extracted into ethyl acetate, and the extract evaporated to dryness under vacuum, to yield crude 4-methyltryptamine base. The crude base was dissolved and acidified in 50 mL EtOH containing 6 mmol 6 N HCl, and the resulting 4-methyltryptamine hydrochloride was crystallized from solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([NH2:24])=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: N
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(N)=O)[nH]n1
Yield: 32 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of morpholine, to the title compound (12 mg, 32%) which was obtained as an off white solid. MS: m/e=313.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[O:23])=[CH:20][CH:19]=1)#[N:17].Cl>C(O)(C)C.C(OCC)C>[ClH:1].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:23])=[CH:32][CH:33]=1)#[N:17]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: N#Cc1ccc(C(=O)Nc2cccc(N)c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccc(C#N)cc4)c3)c2cc1OC
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (225 mg) was added to 3-(4-cyanobenzamido)aniline (261 mg) in isopropanol (8 ml). A 1M solution of hydrogen chloride in diethyl ether (1.0 ml) was added and the reaction mixture stirred and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane and diethyl ether. The title compound was obtained as a solid (399 mg); NMR: 3.99 (s, 3H), 4.01 (s, 3H), 7.37 (s, 1H), 7.45 (m, 2H), 7.65 (m, 1H), 8.02 (m, 2H), 8.12 (m, 2H), 8.20 (m, 1H), 8.31 (s, 2H), 8.80 (s, 1H), 10.71 (s, 1H), 11.44 (s, 1H); m/s: M+H+ 426.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([CH3:21])[C:18](=[O:20])[CH3:19]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:17]([CH3:21])[C:18](=[O:20])[CH3:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
The process as indicated in Example 1 was repeated a number of times, utilizing molar quantities each of 4-benzyloxyphenol and 3-chloro-2-butanone, and varying quantities of base, catalyst and solvent, as well as differing times and temperatures.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH:3]=[C:2]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[C:7]=1[O:8][CH3:9]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C(=O)C=Cc2cc(OC)c(OC)c(-c3cccs3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
3-(3-Bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (0.105 g, 0.2 mmol) from Ex-1A was dissolved in ethylene glycol dimethyl ether (20 mL). Tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min. 2-Thiopheneboronic acid (0.128 g) and sodium carbonate solution (2 M, 0.5 mL) were added. The mixture was stirred at reflux under nitrogen overnight. Upon cooling to room temperature it was poured into water (100 mL) and extracted with dichloromethane (100 mL). The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 4:1, 2:1) gave 0.079 g (90%) of the desired 3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one product as a slightly yellow residue. 1H-NMR (300 MHz, CDCl3): 7.79 (d, 1H), 7.56 (m, 2H), 7.42 (d, 1H), 7.39 (d, 1H), 7.29 (s, 2H), 7.10-7.16 (m, 2H), 3.89-4.00 (m, 15H). Anal. Calculated for C24H24O6S C: 65.44, H: 5.49, S: 7.28; found C: 65.69, H: 5.59, S: 6.99.
Reaction SMILES: [C:1]([Li])(C)(C)C.[F:6][C:7]([F:24])([F:23])[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1.IC.O>CCCCC.O1CCCC1>[CH3:1][C:11]1[CH:10]=[C:9]([O:8][C:7]([F:23])([F:24])[F:6])[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: Cc1cc(OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 4 h

Procedure:
tert-Butyl 2-methyl-4-trifluoromethoxyphenyl carbamate may be prepared in the following manner: 106 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise over 1 hour to a solution, kept at −70° C. under an argon atmosphere, of 20 g of tert-butyl 4-trifluoromethoxyphenylcarbamate in 250 ml of anhydrous tetrahydrofuran. The mixture is stirred for 4 hours at −20° C., cooled to around −70° C., supplemented with 10.3 g of iodomethane and then stirred for 16 hours at a temperature close to 20° C. After hydrolysis with 100 ml of distilled water, the mixture is extracted with three times 60 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in petroleum ether, separated by filtration, washed with the same solvent and dried under reduced pressure (2 kPa). 15.1 g of tert-butyl 2-methyl-4-trifluoromethoxyphenylcarbamate are thus obtained in the form of a light orange-coloured solid melting at 98° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:36])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20]>>[CH3:8][N:9]([CH3:36])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: CN(C)c1ccccc1Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccccc1Nc1cc(-c2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((2-(dimethylamino)phenyl)amino)-4-phenylbenzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-85% acetonitrile/0.1% trifluoroacetic acid aqueous solution], subsequently ethyl acetate and water were added to it, and it was adjusted to pH6.5 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and solid matter was filtrated to give 2-((2-(dimethylamino)phenyl)amino)-4-phenylbenzoic acid 17 mg of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+]>CN(C=O)C.O>[CH3:22][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Reaction time: 18 h

Procedure:
3-Trifluoromethylbenzyl bromide (50 mmole) and sodium p-toluenesulfinate (65 mmole) were dissolved in 100 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The compound was purified by recrystallization (EtOH). Colorless plates, mp 139°-140°: IR (KBr) 2954, 1614, 1598, 1450, 1332, 1312, 1288, 1164, 1142, 1116, 1074 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.34 (s, 2H), 7.16 (s, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.42 (m, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H); MS m/e 315 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 84 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (1 g, 4.34 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.35 g, 2.17 mmol), WSC hydrochloride (1.25 g, 6.52 mmol) and HOBT (0.30 g, 2.22 mmol), to obtain 0.68 g of the title compound as a white solid (84%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:14]([O:16][CH3:17])[CH3:15])=[O:18]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@@H](N)C(C)(C)C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of [1(S)-(methoxy-methyl-carbamoyl)-2,2-dimethylpropyl]-carbamic acid-tert-butyl ester (1.686 g, 6.15 mmol) in dichloromethane (20 mL) at 0° C. was added trifluoroacetic acid (17 mL). The reaction was allowed to stand for 16 hours at <5° C. before the solvents were removed in vacuo to give a bright yellow oil. The residue was dissolved in methanol (30 mL) and was treated portionwise with Dowex 1X8-400 basic resin until pH 9. Filtration and removal of the solvents in vacuo gave the title compound as a pale yellow oil (990 mg, 92%). The material was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[SH:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C.Cl>CN(C)C=O>[C:31]([CH2:30][S:29][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:33])=[O:32]
Reactant: O=C(O)CS
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CCl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CSCC(=O)O)n1
Yield: 44.3 %

Procedure:
To 5.96 g of 6-(chloromethyl)-4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, methyl ester 0.25 g KI dissolved in 30 ml dimethylformamide, was added a solution of 1.38 g mercaptoacetic acid and 3.04 g triethylamine in 30 ml dimethylformamide. After stirring overnight the formed triethylamne/HCl was filtered off, and the dimethylformamide of the filtrate distilled off in vacuo . The residue was stirred with water/ethylacetate and the pH was adjusted to 2 with 2n HCl. The organic phase was washed with water, dried and evaporated, 6.8 g solid of title compound. Crystallization from ethanol yielded 3.01 g title compound and from the concentrated filtrate another batch of 0.37 g title compound was obtained. M.P. 135° C.
Reaction SMILES: [K].[N+:2]([C:5]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:4])=[O:3].OS(O)(=O)=O.[CH3:21]O>>[N+:2]([C:5]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:6]=1[C:7]([O:9][CH3:21])=[O:8])([O-:4])=[O:3]
Reactant: CO
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K]
Product: COC(=O)c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The potassium salt of 5-nitroorotic acid (25.0 g, 0.1 mol) was dissolved in MeOH (75 ml). Concentrated H2SO4 (21 mL) was added drop wise. The reaction was refluxed for 12 hrs. After cooling to room temperature, the white precipitate was collected by filtration, washed with water (50 mL×4), and dried under vacuum for 48 hrs. to afford compound 2 as a white power (26.0 g, 75%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.I[CH2:27][CH2:28][CH2:29][CH3:30].C([Li])(C)(C)C>>[CH2:27]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCI
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Product: CCCCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
In analogy to the procedure described in example 27 c], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with 1-iodobutane in the presence of tert-butyllithium to form 3-butyl-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as dark brown oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:29]O>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([O:12][CH3:29])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1

Procedure:
A solution of 3-cyclopentyloxy-4-benzyloxybenzoic acid (5.1 g; that is prepared as described in Reference Example 38) in methanol (150 mL) and concentrated sulfuric acid (1 mL) is heated at reflux for 6 hours, and then it is cooled and concentrated in vacuo. The resulting residue is treated with ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer is collected, dried and evaporated. The resulting oil is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and pentane (1:4 v/v) as eluent, to give methyl 3-cyclopentyloxy-4-benzyloxybenzoate (4.8 g), in the form of a white solid, m.p. 58°-59° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:4][C:3]=1[C:16]([C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1I)=[O:17].NC1C=CC(CC2C=CC(Cl)=CC=2)=CC=1C(C1N(C)N=CC=1I)=O>>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19]3[CH:20]=[N:21][N:22]([CH3:23])[C:18]=3[C:16](=[O:17])[C:3]=2[CH:4]=1
Reactant: Cn1ncc(I)c1C(=O)c1cc(Cc2ccccc2Cl)ccc1N
Agent: Cn1ncc(I)c1C(=O)c1cc(Cc2ccc(Cl)cc2)ccc1N
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4Cl)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 6 in EXAMPLE 13 using [2-amino-5-(2-chlorobenzyl)phenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone (EXAMPLE 15, step 4), instead of [2-amino-5-(4-chlorobenzyl)phenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH:31]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1ccc(C2=CCNCC2)nc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C2=CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)nc1
Yield: 47.8 %

Procedure:
(2R,3S)-2-(2,4Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-methyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.63 g, 9.3 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.63 g of the intended substance (yield 47.8%).