Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:38]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[N:37]=[CH:36][CH:35]=1)CCC>>[C:43]([C:42]1[CH:41]=[CH:40][C:39]([N:38]2[C:34]([C:2]3[C:3]([CH3:28])=[C:4]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[N:10]=4)[CH:7]=3)=[CH:35][CH:36]=[N:37]2)=[CH:46][CH:45]=1)#[N:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2cc(NC(=O)C(F)(F)F)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2cc(NC(=O)C(F)(F)F)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from N-[6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-2,2,2-trifluoro-acetamide (Int. 5, 35 mg, 0.075 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 52 mg, 0.113 mmol) using a similar method to that used in Example 1 (Step 4), (6 mg).
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][NH:17][C:18]([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:21]2[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[Cl:49])=[O:19])[CH:10]=1)(C)(C)C.ClC(Cl)C.FC(F)(F)C(O)=O>>[Cl:49][C:43]1[CH:44]=[C:45]([Cl:48])[CH:46]=[CH:47][C:42]=1[CH:21]1[CH:20]([C:18]([NH:17][O:16][CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:50])=[O:5])=[O:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)COc1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(OCC(=O)O)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol). The crude purified product thus obtained was recrystallized from ethyl acetate to obtain 184 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[CH:23][C:22]=2[CH:33]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:23][C:22]=2[CH:33]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: Brc1ccc2oc(CC3CCCCN3)cc2c1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(Br)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (490 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (488 mg) and (RS)-2-(5-bromo-benzofuran-2-ylmethyl)-piperidine, D70 (530 mg) by a procedure similar to that described for Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(Methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (38.4 g) was dissolved in methanol and 4 g of 10% (wt/wt) palladium on carbon catalyst was added with water (1000 mL) under a nitrogen atmosphere. The mixture was then degassed before stirring under 1 atmosphere of hydrogen gas at room temperature for approximately 8 hours. At this time, the reaction mixture was filtered through celite and washed with copious volumes of methanol. The filtrate was concentrated in vacuo, To the residue was added acetonitrile before evaporation of the solvent. To give 4-[4-amino-3-(methoxycarbonylmethyl-aminocarbonyl)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a dark green oil: 34.05 g (95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:16][CH3:17].C(Cl)Cl.ClC(Cl)(O[C:25](=[O:31])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:40]([NH:43][NH2:44])(=O)[CH3:41]>>[CH3:41][C:40]1[N:13]([C:12]2[CH:14]=[CH:15][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:16][CH3:17])[CH:4]=3)=[CH:10][CH:11]=2)[C:25](=[O:31])[NH:44][N:43]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(N)cc2)ccc1C
Reactant: CC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccc(-n3c(C)n[nH]c3=O)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 4-{[4-methyl-3-(methyloxy)phenyl]oxy}aniline (Intermediate 11, 336 mg, 1.467 mmol) in DCM (50 mL) Triethylamine (296 mg, 2.93 mmol) was added followed by triphosgene (174 mg, 0.587 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Triethylamine (296 mg, 2.93 mmol) and acetohydrazide (130 mg, 1.76 mmol) were then added and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuum and the residue was dissolved in a 2M aqueous solution of NaOH (15 mL) and the mixture was heated to reflux for 12 h. The reaction mixture was neutralized with aqueous 6M HCl to pH=7 and extracted with DCM (3×50 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel using dichloromethane/methanol as eluents from 100/1 to 50/1 to yield 150 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:12][N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[C@H:10]([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:36])([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][NH:32][C:31]2=[O:35])=[CH:26][CH:25]=1)[CH:20]([F:22])[F:21].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([OH:9])([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([N:32]2[CH:33]=[CH:34][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]([F:36])([F:18])[CH:20]([F:22])[F:21])=[CH:29][CH:28]=3)[C:31]2=[O:35])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
(2R,3S)-2-(4-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.5 g), 2.66 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 6.3 g of cesium carbonate were added to 25 ml of N,N-dimethylformamide. The mixture was stirred at 80° C. for five hours. After cooling, the reaction solution was diluted with 100 ml of ethyl acetate, and washed with water (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/3) to give 1.21 g of 1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][N:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH3:29])[CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: CN(C)CCCCCCN
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Solvent: Cc1ccccc1
Product: CN(C)CCCCCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 60.9 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 6-dimethylamino-hexylamine (0.46 g) in toluene (25 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a fluffy yellow powder (0.41 g); mp 88-90° C.
Reaction SMILES: C([C:3]1([O:12]C(=O)C)[CH2:8][C:7]2([CH3:10])[O:9][C:4]1([CH3:11])[CH:5]=[CH:6]2)#N.C[O-].[Na+].C=O>CO>[CH3:11][C:4]12[O:9][C:7]([CH3:10])([CH:6]=[CH:5]1)[CH2:8][C:3]2=[O:12]
Reactant: CC(=O)OC1(C#N)CC2(C)C=CC1(C)O2
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC12C=CC(C)(O1)C(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 12 g of 2-cyano-2-acetoxy-1,4-dimethyl-7-oxabicyclo[2.2.1]hept-5-ene in 100 ml of methanol was added 0.028 mole of sodium methoxide. The mixture was stirred at room temperature for 3 hours, then 30 ml of formalin was added and the mixture was stirred an additional hour at room temperature. The reaction mixture was washed with 100 ml of water, then with 100 ml of saturated sodium chloride solution and extracted thrice with 100 ml of methylene chloride, dried (Na2SO4), concentrated and flash chromatographed using 1:1 hexane:methylene chloride as eluent to give 6 g of the desired product as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:3][OH:4].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C=O)C>[Si:31]([O:4][CH2:3][CH:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1)[OH:1])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: O=C(Nc1cccc(C(O)CO)c1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
Benzyl 3-(1,2-dihydroxyethyl)phenylcarbamate (8 g) was dissolved in dry DMF (50 mL) and cooled to 0° C. Imidazole (2.8 g) and TBSCl (5 g) were added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water (100 mL) and extracted with EtOAc (2×100 mL). The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (6 g, 60%).
Reaction SMILES: [BrH:1].[C:2]([NH:5][C:6]([CH2:8][CH2:9][N:10]1[CH2:14][CH2:13]OC1=O)=[NH:7])(=[O:4])[NH2:3]>Br.C(O)(=O)C>[BrH:1].[BrH:1].[C:2]([NH:5][C:6]([CH2:8][CH2:9][NH:10][CH2:14][CH2:13][Br:1])=[NH:7])(=[O:4])[NH2:3]
Reactant: N=C(CCN1CCOC1=O)NC(N)=O
Agent: Br
Solvent: CC(=O)O
Product: N=C(CCNCCBr)NC(N)=O
Temperature: 120 °C
Yield: 242.8 %

Procedure:
A mixture of 44 (20 g, 0.07 mol) in 200 mL of 30-32% HBr in acetic acid was vigorously stirred along with gradual heating (temperature up to 120° C.) over a period of 1 h. The mixture was cooled and filtered. The colorless crystals were washed with acetic acid (200 mL), ether (200 mL) and dried in vacuo overnight to give 22.6 g (80%) of 45: mp 170°-172° C. (dec) (note: Incomplete reaction will occur if the stirring is not efficient); 1H NMR (DMSO-d6) δ 3.05 [t, 2, --CH2 --C(N=)], 3.5 (b, 4, --CH2 --NH--CH2), 3.78, (t, 2, BrCH2 --).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:33][CH:34]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(Cc1cccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1)S(C)(=O)=O

Procedure:
N-Methyl-N-(3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (49.0 mg, 0.238 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.050 g, 45%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.01-7.95 (m, 2H), 7.58 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H), 6.97-6.91 (m, 3H), 6.68 (s, 1H), 4.42 (s, 2H), 4.11 (t, J=6.0 Hz, 2H), 2.90 (t, J=5.9 Hz, 2H), 2.87 (s, 3H), 2.83 (s, 3H), 2.67-2.57 (m, 4H), 1.87-1.77 (m, 4H). MS=521 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[O:21][CH3:22])[CH2:5][CH2:4]1>ClCCl.CO>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(OC)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1 g (3.22 mmol) of 4-methoxy-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]piperidine. Yield: 0.85 g (94% of theory); C15H24N2O3 (M=280.36); calc.: molecular ion peak (M+H)+: 281; found: molecular ion peak (M+H)+: 281; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Reactant: c1cnc(-c2ncc[nH]2)cn1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cnccn3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate O instead of Intermediate C and with 2-(1H-imidazol-2-yl)pyrazine instead of 2-phenyl-1H-imidazole. LCMS: 377.2 m/z (M+H)+; ret. Time: 4.07 min (Analytical Method C).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:41])[C:31]1=[O:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:41])[C:31]1=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(CCCCI)c(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCCC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N-(diphenylmethylene)glycine t-butyl ester (1.30 g, 4.40 mmol) in 10 mL of DMF is treated with sodium hydride (60% in mineral oil, 0.250 g, 6.25 mmol) at 25° to give a red orange solution. After 1 h, the temperature is raised to 60° C. and a solution of the title B compound, 3-(4-iodobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (1.58 g, 4.41 mmol) in 10 mL of DMF is added dropwise over 10 min. After stirring for 5 h at 60° C. and 58 h at 25° C. the solvent is evaporated under reduced pressure, and the residue is partioned between 75 mL of ethyl acetate and 25 mL of water. The organic solution is washed with three 25 mL portions of brine, dried over anhydrous MgSO4, and concentrated to give 2.15 g of 2-(benzhydrylideneamino)-6-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)hexanoic acid t-butyl ester as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:14]3)=[CH:10]2)=[CH:5][CH:4]=1>Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[N:14]3)=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(-n3nc(OCCN4CCOCC4)cc3C)cc2c1
Agent: Cl
Product: Cc1cc(OCCN2CCOCC2)nn1-c1ccc2ccc(O)cc2c1
Yield: 95 %

Procedure:
A solution of 4-{2-[1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate (1.3 g, 3.24 mmol) in HCl conc. (20 ml) was heated at 90° C. during 6 hrs, it was cooled down and evaporated to dryness in a rotavapor. The remaining crude oil was stirred with ethyl ether and the resulting solid precipitate was filtered; washed with more ethyl ether, and dried yielding 1.2 g (95%) of 4-{2-[1-(7-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate in the form of a white solid with a m.p.=103-107° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[C:11]([CH3:23])[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:27][C:13]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]([CH3:23])=[C:10]2[C:9]=1[C:8](=[O:24])[N:7]([CH3:25])[C:6](=[O:26])[N:5]2[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (103 mg, 0.29 mmol) and hexachloroethane (400 mg, 1.7 mmol) are dissolved in anhydrous THF, and then 1.0M LiHMDS in THF (1.4 mL, 1.4 mmol) is added dropwise. The reaction mixture is stirred at room temperature for an hour, and then quenched with saturated ammonium chloride aqueous solution. The mixture is purified by silica-gel column chromatography to give pure product as off-white solids (yield: 64%). MS (ESI) m/z 390.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[O:19]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:21]1[CH2:22][CH2:23][O:19][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CCOC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCOC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with tetrahydro-furan-3-ylamine following general procedure B to afford 8-methoxy-4-(tetrahydro-furan-3-ylamino)-quinoline-3-carboxylic acid ethyl ester (275 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (190 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(tetrahydro-furan-3-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (10 mg). LCMS: m/z 342 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(O)c3ccc(Cl)cc3Cl)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (76 mg, 0.427 mmol) in dry THF (4 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (0.52 mL). After 30 minutes 2,4-dichloro-benzaldehyde (60 μL) was added slowly into the reaction mixture and then stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-7-carbonitrile as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.[C:24](O)(=[O:26])C>O>[NH2:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][C:9]([CH:24]=[O:26])=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)c1cc(C=O)cc(C(C)C)c1N
Temperature: 120 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 2,6-diisopropylaniline (10.0 g, 56.4 mmol) in acetic acid (160 ml) were added water (40 ml) and hexamethylenetetramine (15.8 g, 0.113 mol) and stirred at 120° C. for 3 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 200 g, developing solvent; hexane:ethyl acetate=10:1) to provide 10.6 g (yield 92%) of 4-amino-3,5-diisopropylbenzaldehyde as yellow solid.