Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:36]
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH2:33][C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.[CH3:43][C:44](OC(C)=O)=[O:45]>C1COCC1>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([CH2:33][N:16]([CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]([C:44](=[O:45])[CH3:43])=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:13]3[CH:12]=[CH:11][C:10]4[O:6][CH2:7][O:8][C:9]=4[CH:14]=3)=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCn1cnc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCn1c(C(C)=O)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.2 equivalents in 175 μl hexane) is added to a solution of 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-4-phenyl-1H-imidazol-5-yl)methyl]methanamine (118 mg), obtained as a minor product in Example 2, step 4, in 10 mL anhydrous THF under N2 at −78° C. The resulting mixture is stirred at −78° C. for 1 hour. Ac2O (118.4 mg, 1.2 equivalents) is added. The reaction mixture is stirred at −78° C. for 2 more hours, warmed to room temperature, and stirred overnight. The reaction is quenched with 5 mL of H2O and diluted with 20 mL ethyl acetate. The organic phase is collected, washed with brine, dried and concentrated. Purification via silica gel chromatography provides the title compound (Compound 8).
Reaction SMILES: C([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])(=O)C.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:8]1[NH:4][C:5](=[O:18])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:7]1=[O:9]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NC(=Cc2ccccc2F)C(=O)N1c1cc(F)ccc1F
Yield: 50.9 %

Procedure:
N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4dione (2.29 g, 8.65 mmol), 2-fluorobenzaldehyde (1.13 g, 9.1 mmol) and triethylamine (1.75 g, 17.3 mmol) were heated under reflux in DMF (15 mL) for 3 hours. The solution was cooled, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered, concentrated, and purified by column chromatography to give 1.4 grams of 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione, m.p. 180°-183° C.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.CC(C)([O-:16])C.[K+].S1CCN=C1>C(O)(C)(C)C>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:16])[N:3]=1)[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Agent: C1=NCCS1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
The process of Example 5 was repeated using 5.0 g (0.24 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline, 25 ml of t-butylalcohol and 2.69 g (0.024 mol) of potassium t-butoxide. The HPLC assay set forth in Example 3 indicated that 90% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CCCCCCCCCCC.Cl.[CH3:31][O:32][NH:33][CH3:34]>S(Cl)(Cl)=O.C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:33]([CH3:34])[O:32][CH3:31])=[O:12])=[CH:13][CH:14]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(OCc2ccccc2F)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCCCCCCC
Product: CON(C)C(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
4-(2-fluorobenzyloxy)benzoic acid (P2, 5.5 g, 22.3 mmol) was suspended in thionyl chloride (16.5 mL) and heated to 65° C. and held for 3 hours during which time the reactor was kept under a slow sweep of nitrogen. The mixture was then concentrated to a thick oil under hi vac to remove all traces of residual thionyl chloride. The residue was then diluted in CH2Cl2 (20 mL) and cooled to 0° C. In a separate flask, a solution of diaza(1,3)bicycle[5.4.0]undecane (DBU, 8.0 mL, 8.15 g, 53.52 mmol) and N-methoxy-N-methyl amine hydrochloride (2.61 g, 26.76 mmol) in CH2Cl2 (20 mL) was made and slowly added to the solution at 0° C. After warming to 20-25° C., the mixture was washed with 1 M HCl and then with a saturated NaHCO3 solution. After drying over Na2SO4, the solution was concentrated to a thick residue. The mixture was then purified by flash column chromatography eluting with 0→100% EtOAc/hexanes (gradient). Concentration of the fractions containing the title compound gave an oil that crystallized upon standing (6.0 g, 93% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:11]1[CH:10]=[CH:9][C:7]2[O:8][CH:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: CC1Cc2ccccc2O1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 215 ml of bromine in 450 ml of methylene chloride is added dropwise over 21/2 hours to an ice-cooled mixture of 562.3 g of 2,3-dihydro-2-methylbenzo[b]furan, 1600 ml of methylene chloride, 1600 ml of water and 352.5 g of sodium bicarbonate. After the mixture has been stirred for another 11/2 hours at the same temperature, the aqueous phase is separated and extracted with two 300 ml portions of methylene chloride. The combined organic phases are washed with 2×250 ml of water, dried over sodium sulfate and concentrated. After removal of all constituents having a boiling point below 99° C. under a pressure of 8 mbar, there are obtained 750.7 g of 5-bromo-2,3-dihydro-2-methylbenzo[b]furan as residue.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[C:15](=[O:18])[CH2:16][CH2:17][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O=C1CCOCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Product: Cn1ncc([N+](=O)[O-])c1N1CCOCCC1=O
Yield: 13 %

Procedure:
Following the procedure for Intermediate 202 starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and 1,4-oxazepan-5-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepan-5-one as an orange solid (40 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 4.18 (dd, J=13.3, 6.4 Hz, 1H), 4.12-3.99 (m, 2H), 3.96-3.82 (m, 2H), 3.77 (s, 3H), 3.64 (dd, J=15.7, 6.4 Hz, 1H), 3.08 (ddd, J=15.6, 8.5, 2.1 Hz, 1H), 2.94 (ddd, J=15.6, 7.5, 1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C[Al](C)C.[CH:15]1([N:20]2[C:32]3[C:31]4[CH:30]=[CH:29][C:28]([C:33](OC)=[O:34])=[CH:27][C:26]=4[NH:25][C:24](=[O:37])[C:23]=3[CH:22]=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.N>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:33]([C:28]1[CH:29]=[CH:30][C:31]3[C:32]4[N:20]([CH:15]5[CH2:16][CH2:17][CH2:18][CH2:19]5)[N:21]=[CH:22][C:23]=4[C:24](=[O:37])[NH:25][C:26]=3[CH:27]=1)=[O:34])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCCC3)c12
Agent: C[Al](C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCCC3)c12)N1CCc2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 148 mg of 5-chloroindoline in 1 mL of toluene was added 0.54 mL of a 1.8 M trimethylaluminum solution in toluene at 0° C., followed by stirring at room temperature for 2 hours (solution A). Under a nitrogen atmosphere, to a mixture of 100 mg of methyl 1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylate and 3 mL of toluene was added the solution A, followed by stirring at 70° C. for 8 hours. After cooling to room temperature, to the reaction mixture was added diluted hydrochloric acid, and the mixture was poured into a mixture of water and ethyl acetate. The pH was adjusted to 10 with 28% aqueous ammonia. The insoluble material was separated by filtration. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0-92/8) to obtain 65 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:13][CH2:12]2)=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)cc1
Yield: 73.4 %

Procedure:
0.65 g (0.00275 mol) of 1-(3-nitro-benzyl)-piperidin-4-ol and 1.9 ml (0.0136 mol) of triethylamine were dissolved in 27.5 ml of toluene, treated with 1.09 ml (0.00825 mol) of 4-methyl-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.715 g (73%) of 1-(3-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 90°-93°.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.Br[C:17]1[CH:33]=[CH:32][C:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][C:19]=2[C:18]=1[O:34][CH3:35]>CN(C)C=O.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>[CH3:35][O:34][C:18]1[C:19]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:22][CH2:21][C:20]=2[CH:32]=[CH:33][C:17]=1[CH3:1]
Reactant: COc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 115 °C
Yield: 82.5 %

Procedure:
Add potassium carbonate (5.65 g, 40.91 mmol), tetrakis(triphenylphosphine)palladium (1.576 g, 1.363 mmol) and trimethylboroxine (2.053 g, 2.3 mL, 16.35 mmol) to a solution of 7-bromo-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.8 g, 13.63 mmol) in dimethylformamide (40 mL) under nitrogen. Heat the mixture to 115° C. for 6 h. Add water and extract the aqueous phase twice with EtOAc. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as a solid (3.23 g, 83%). GC-MS m/z 287 (M+).
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCC[CH2:11][CH3:12].[C:15]([O-:28])(=[O:27])CCCCCCCCCCC.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.O=C=[N:49]C1CC(C)(C)CC(C)(CN=C=O)C1>>[C:1]([OH:14])(=[O:13])[CH:2]=[CH2:3].[NH2:49][C:15]([O:28][CH2:11][CH3:12])=[O:27]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a reactor, 0.73 g of dibutyltin dilaurate, 0.64 g of 4-methoxyphenol, and 222.0 g of isophorone diisocyanate were charged. The mixture was stirred and air sparge was applied while stirring. 116.0 g of hydroxyethyl acrylate was added slowly to the stirring mixture. The mixture was stirred at 60° C. for 4 hours, then 266.0 g of the reaction product of tetrahydrophthalic anhydride and a mixture of ethylene and propylene glycols, available commercially from Great Lakes Chemical Company as “PHT4-diol,”was added and the temperature was increased to 95° C. The reaction was kept at 95° C. for 4 hours before discharge. The viscous liquid become solids upon cooling to room temperature.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=[CH2:17])[C:13](=[O:14])[N-:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5].[Na+].[CH2:19]([O:26][CH2:27]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][CH2:27][N:9]1[C:7](=[O:8])[C:6]([CH2:15][CH:16]=[CH2:17])([CH:4]([CH2:3][CH2:2][CH3:1])[CH3:5])[C:13](=[O:14])[N:12]([CH2:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCOCc1ccccc1
Reactant: C=CCC1(C(C)CCC)C(=O)[N-]C(=O)NC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(C)CCC)C(=O)N(COCc2ccccc2)C(=O)N(COCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
Sodium secobarbital (25.5 g.) was dissolved in 250 ml of hot dimethylformamide. The solution was vigorously stirred and allowed to cool to room temperature to provide a fine suspension. To the suspension was added chloromethyl benzyl ether (16.5 g.) over a period of 10 minutes. The reaction mixture was stirred overnight and poured into 500 ml of ice water; the mixture was stirred for 1 hour and was extracted into methylene chloride. The methylene chloride solution was dried and the methylene chloride evaporated under reduced pressure to yield an oil. This crude oil was adsorbed on 60-200 mesh silica gel; elution with a solvent mixture containing 1 part of ethyl acetate and 20 parts of benzene (by volume) provided pure 1,3-dibenzyloxymethyl-5-allyl-5-(2-pentyl) barbituric acid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O-:2].[K+].C[O-].[Li+].[Br:7][C:8]1[C:9](Cl)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.Cl>C1(C)C(C)=CC=CC=1.C(O)(C)(C)C>[Br:7][C:8]1[C:9]([O:2][CH3:1])=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: C[O-]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1C
Product: COc1c(Br)cnc2[nH]ccc12
Temperature: 117 °C
Yield: 25.2 %

Procedure:
Potassium methoxide (103 mg), lithium methoxide (27 mg) and tert-butanol (40 μl) were added to a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (81 mg) in xylene (3.5 ml), and the mixture was heated under reflux at 117° C. for 16 hours. The reaction solution was brought to pH 4 by adding concentrated hydrochloric acid in small portions and separated by adding ethyl acetate and distilled water. The resulting aqueous layer was brought to pH 8 by adding a 5 N aqueous sodium hydroxide solution and separated by adding ethyl acetate. All the resulting organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developed with ethyl acetate-hexane) to give the title compound (20 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(C#N)c(O)n1
Product: Cc1nc(O)c(C#N)c(C)c1Br

Procedure:
In a method to prepare 5,6,7-tri-substituted-5-deazapteridine, for example, 3-cyano-2-hydroxy-4,6-dimethylpyridine (commercially available) may be brominated with N-bromosuccinimide, affording the corresponding 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine: The bromo compound was in turn may be treated with phosphorus oxychloride in the presence of N,N -dimethylformamide, yielding 2-chloro-5-bromo-3-cyano-4,6-dimethylpyridine. The so-prepared pyridine was cyclized with quanidine carbonate in N,N-dimethylacetamide, yielding the targeted 5,6,7-tri-substituted-5-deazapteridine, for example, 2,4-diamino-6-bromo-5,7-dimethylformamide. Example 19 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:15](=[O:17])[CH3:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[OH:27][C:26]1[C:25]([CH3:28])=[CH:24][C:21]([CH2:22][CH2:16][C:15]([C:9]2[S:10][C:11]([CH2:12][CH2:13][CH3:14])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)=[O:17])=[CH:20][C:19]=1[CH3:18]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of 1-(4-phenyl-5-propyl-thiophen-2-yl)-ethanone (450 mg, 1.84 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (331 mg, 2.21 mmol) in ethanol (4 mL) and 5 N HCl in isopropanol (2 mL) is stirred at rt for 18 h. The dark solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (5 mL) and THF (5 mL) and treated with Pd/C (100 mg, 10% Pd). The slurry is stirred under 1.8 bar of H2 for 16 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified by CC prep. TLC plates with heptane:EA 2:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (550 mg) as a colourless oil; LC-MS: tR=1.13 min; [M+1]+=379.20, 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.45-7.28 (m, 5H), 6.85 (s, 2H), 4.48 (s, 1H), 3.17-3.10 (m, 2H), 2.96-2.89 (m, 2H), 2.87-2.80 (m, 2H), 2.21 (s, 6H), 1.74-1.64 (m, 2H), 0.94 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].O1CCCC1.[CH3:11][C:12]1[CH:13]([Li])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>CCCCCC>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH3:11]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1C(C)=Cc2ccccc21
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
In a three-necked flask equipped with a mechanical stirrer were charged 44.5 g (345 mmol) of dimethyldichlorosilane, 300 ml of tetrahydrofuran and n-hexane, to which was added at -78° C. a 2-methylindenyllithium solution, followed by stirring at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, 100 ml of hexane was added and insoluble matter was removed by centrifugation. After the solvent was distilled off under reduced pressure, distillation under reduced pressure (113° C./7mmHg) afforded 14.9 g (67 mmol, yield: 58%) of dimethyl(2-methylindenyl)silyl chloride as a pale yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].Cl(OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)(=O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Temperature: 100 °C

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 1.56 parts of triphenylmethyl perchlorate and 30 parts of acetic anhydride was heated at 100°C for thirty minutes. After cooling, the reaction mixture was poured into sodium bicarbonate solution and the resulting mixture was washed with water, dried and the ether was evaporated to give an oil which was chromatographed on silica gel using a 1:1 mixture of chloroform and light petroleum (b.p. 40°-60°C) for elution. This yielded 0.14 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5°C (after crystallisation from light petroleum (b.p. 40°-60°C). This product was shown by spectral means to be the same as that prepared in Example 13.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:34](I)[CH3:35]>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([O:22][CH2:34][CH3:35])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1cc(C(=O)O)c2cccc(OCc3ccccc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred mixture of 8-benzyloxy-4-carboxy-2-methylquinoline (700 mg), potassium carbonate (659 mg) and N,N-dimethylformamide (0.3 ml) was dropwise added ethyl iodide (409 mg) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at ambient temperature. To the mixture was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, dried over magnesium sulfate. The solvent was removed, and the residue was crystallized from diisopropyl ether to give 8-benzyloxy-4-ethoxycarbonyl-2-methylquinoline (686 mg) as solid.