Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:18][CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].C([BH3-])#N.[Na+].O>O1CCCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:18]([CH2:1][CH3:2])[CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC=O
Reactant: CCN[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
150 μl (2.4 mmol) of acetaldehyde are added to 369 mg (1.5 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-ethylaminopropanoate in 5 ml of tetrahydrofuran then stirred for 30 minutes at ambient temperature. After cooling to 0° C., 189 mg (3 mmol) of sodium cyanoborohydride are added and the reaction medium is stirred at ambient temperature for 36 h. Water is added and the medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered then concentrated. The crude residue obtained is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 150 mg (38%) of methyl (S)-3-tert-butoxycarbonylamino-2-diethylaminopropanoate are obtained in the form of a colourless oil.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[C:14]1(=O)[O:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]2[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1CCCN1c1cccc2cccnc12
Temperature: 25 °C
Yield: 5.4 %

Procedure:
Potassium hydride in oil was washed with dry pentane (in a dry nitrogen atmosphere) leaving 2.5 g (0.062 mole) of potassium hydride which was covered with dry tetrahydrofuran (25 ml). To the slurry of potassium hydride (at room temperature) was added dropwise a solution of 8-aminoquinoline (5 g, 0.035 mole) in dry tetrahydrofuran (25 ml), with stirring, followed by addition of dry hexamethylphosphoric triamide (25 ml). After stirring for 1 hour at room temperature, the reaction was cooled in an ice bath and a solution of γ-butyrolactone (2.8 ml, 0.036 mole) in dry tetrahydrofuran (10 ml) was added and the reaction stirred for 1 hour. The reaction was warmed to room temperature and a solution of p-toluenesulphonyl chloride (8 g, 0.042 mole) in dry tetrahydrofuran (10 ml) was added. The reaction was poured into ice water, filtered and the pH was adjusrted to pH 3.5. The product was extracted with methylene chloride and washed with cupric chloride to remove traces of 8-aminoquinoline. The product organics were dried, concentrated under reduced pressure and the residue was crystallized from ether/pentane affording 1-(8-quinolyl)-2-pyrrolidinone, yield 5.4%, which was identical by tlc and NMR in comparison with the product of Example 1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.ClCCl>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium triacetoxyborohydride (0:30 g, 1.42 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.71 mmol), 2-thiazolecarboxaldehyde (0.12 ml, 1.42 mmol), and dichloromethane (3.5 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with ethyl acetate, washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. Water is added to the residue, and the solution loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted with 2M ammonia in methanol (30 ml). The filtrate is concentrated and the crude material purified on silica gel eluting with 0-50% ethyl acetate/hexanes to yield (0.20 g) of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=368 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.23 (1H, d), 4.17 (2H, brs), 3.93 (2H, s), 2.72-2.54 (5H, m), 1.78 (2H, brd), 1.7-1.57 (2H, m), 1.45-1.41 (10H, m), 1.40-1.32 (2H, m), 0.87 (6H, d).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:1][C:2]2[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH3:16])[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (6.00 g, 25.7 mmol) in CH2Cl2 (120 mL) and AcOH (6 mL) was added N-Boc piperidinone (6.70 g, 33.4 mmol) and sodium triacetoxyborohydride (13.6 g, 64.3 mmol). The reaction mixture was stirred at 23° C. for 20 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/EtOAc=4/1) to give the titled compound (10.6 g, 98% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.37 (s, 1H), 6.88 (s, 1H), 4.05 (m, 2H), 3.90 (s, 3H), 3.01 (m, 3H), 2.32 (s, 3H), 1.71 (m, 2H), 1.48-1.61 (m, 2H), 1.45 (s, 9H); MS (ES) [M−H] 415.1.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH3:17])(C)C>ClCCl>[CH3:12][N:15]1[C:18]2[C:20](=[CH:3][CH:4]=[CH:5][CH:19]=2)[C:17]([C:8]2[C:9](=[O:10])[O:10][C:9](=[O:11])[C:8]=2[C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16]1
Reactant: O=C(O)Cc1ccncc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: Cn1cc(C2=C(c3ccncc3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 21.5 %

Procedure:
5 g of 4-pyridyl-acetic acid hydrochloride and 3.72 g of diisopropylethylamine in 50 ml of dichloromethane were treated at 0° C. firstly with 6.37 g of 1-methylindole-3-glyoxylyl chloride in 50 ml of dichloromethane and then with 7.5 g of diisopropylethylamine. The mixture was allowed to warm to room temperature and was then stirred for 65 hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and chromatographed on silica gel with ethyl acetate. The product-containing fractions were concentrated. Crystallization from ethyl acetate/hexane yielded 940 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione, m.p. 217°-219° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccncc1I
Reactant: COc1ccc2c(c1)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Yield: 28 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-26b: 400 mg, 2.259 mmol) was reacted with 3-iodo-4-methyl-pyridine (495 mg, 2.259 mmol), 1,4-dioxane (25 mL), copper iodide (43 mg, 0.225 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (96.23 mg, 0.677 mmol) and potassium phosphate (1.197 g, 5.647 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 170 mg of the product (23% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=2)=[O:25])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 20 mg (37%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.30 (m, 1H), 7.55 (m, 2H), 7.80 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.08 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=1.C(Cl)(=O)C(C)(C)C.Br.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>ClCCl>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][N:39]([CH3:40])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: CNCC(=O)c1ccc(OC)c(OC)c1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CN(C)C(=O)/C=C/c2cccnc2)cc1OC
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
Dichloromethane (50 ml) and triethylamine (2.69 ml, 19.30 mmol) were sequentially added to trans-3-(3-pyridyl)acrylic acid (1.44 g, 9.65 mmol) and stirred for 10 minutes. Then, pivaloyl chloride (1.18 ml, 9.65 mmol) was added and stirred for 13 minutes. 1-(3,4-Dimethoxyphenyl)-2-(methylamino)ethanone hydrobromide (2.79 g, 9.65 mmol) was dissolved in dichloromethane (4 ml) and triethylamine (1.34 ml, 9.65 mmol), added to the reaction mixture and stirred at room temperature for 30 minutes. After the reaction mixture was washed with water and aqueous saturated sodium bicarbonate solution, the organic phase was dried over magnesium sulfate and the solvent was distilled out under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield a crude product. The crude product was recrystallized to yield the titled compound (1.84 g, 5.41 mmol, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1CC1OC(N)=NC=1.ClC(CC1C=CC=CC=1OC)C=O.[NH2:29]C(N)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[NH2:29]
Reactant: COc1ccccc1Cc1cnc(N)o1
Reactant: NC(N)=O
Agent: COc1ccccc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccccc1N

Procedure:
5-(2-methoxy-benzyl)-oxazol-2-ylamine. A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product, (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1, found 205.1 (M+1)+ 1H NMR(CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[CH3:19][N:20]([C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)[C:16]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([C:8]([F:9])([F:11])[F:10])[C:12]([F:14])([F:13])[F:15])[C:2]=1[CH3:1])=[O:18]
Reactant: CNc1ccnnc1
Reactant: Cc1c(C(=O)O)cnn1C(C(F)(F)F)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N(C)c2ccnnc2)cnn1C(C(F)(F)F)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
A mixture of 300 mg 5-methyl-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyrazole-4-carboxylic acid, 127 mg N-methylpyridazin-4-amine, 710 mg O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate [HATU] and 220 mg triethylamine in 30 ml THF was stirred at 20-25° C. for about 24 h, then evaporated. The residue was taken up in 21 ml CH2Cl2, washed with 3×14 ml water, dried over Na2SO4, then evaporated. Purification by flash chromatography (CH2Cl2/MeOH) gave 130 mg of the title compound (90% purity).
Reaction SMILES: [K].[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH:26]([F:28])[F:27])[C:19](Cl)=[O:20])[CH2:13][CH2:12]1.Cl>CN(C=O)C.O>[CH:22]1[C:18]([C:19]([NH:2][C:3]2[C:4]([Cl:10])=[CH:5][N:6]=[CH:7][C:8]=2[Cl:9])=[O:20])=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13]2)=[C:24]([O:25][CH:26]([F:27])[F:28])[CH:23]=1
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C

Procedure:
The potassium salt suspension of the anion of 4-amino-3,5-dichloropyridine in DMF (2-2.5 equivalents) is introduced into a reaction vessel. A solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (1 equivalent) in DMF is slowly added to this suspension while stirring vigorously at a temperature of 15 to 40° C., preferably 20 to 30° C. After the reaction is complete, water is slowly added while stirring at 15-25° C., and the pH is adjusted to 2-3 with hydrochloric acid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=C(C(O)=O)[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:1]([C:2]([Cl:4])=[O:3])[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(Cl)cnc(Cl)c2c1

Procedure:
Anal. Found: C, 49.59; H, 2.08; N, 5.74. Calc for C10H5Cl2NO2 : C, 49.62; H, 2.08; N, 5.78. ##STR170## Oxalyl chloride (144 μL, 1.65 mmol) was added to a suspension of 1,4-dichloro-7-isoquinolinecarboxylic acid (200 mg, 0.83 mmol) at room temperature in CH2Cl2 (10 mL), followed by DMF (1 drop). After 30 min the resultant clear solution was evaporated in vacuo to afford 1,4-dichloro-7-isoquinolinecarbonyl chloride which was used without further purification.
Reaction SMILES: C1([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:16][C:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:18][CH:19]=2)C=CC(C(OCCCC)=O)=CC=1.IC1C=C(C=CC=1)[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38]>>[C:27]1([C:15]2[CH:14]=[CH:19][CH:18]=[C:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:16]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:32]=[CH:31][CH:30]=[C:29]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38])[CH:28]=1
Reactant: CCCCOC(=O)c1ccc(-c2ccc(C(=O)OCCCC)cc2-c2ccccc2)cc1
Reactant: CCCCOC(=O)c1cccc(I)c1
Product: CCCCOC(=O)c1cccc(-c2cccc(C(=O)OCCCC)c2-c2ccccc2)c1

Procedure:
This compound was prepared by the procedure for dibutyl 4,4′-terphenyl dicarboxylate (CS-13). The intermediate, butyl 3-iodobenzoate, was prepared and purified by vacuum distillation, collecting the fraction bp 104-108° C./0.2 mm. A colorless oil was obtained, mass: 26.17 g (85% of theory). 1H NMR (CDCl3): δ 0.98 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.32 (q, 2H), 7.18 (t, 1H), 7.88 (d, 1H), 8.00 (d, 1H), 8.36 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].Cl>CN(C=O)C.O>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinedione was dissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[CH3:17][C@@H:18]1[CH2:23][O:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:19]1[CH2:20][CH2:21][O:22][CH2:23][C@H:18]1[CH3:17]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 75 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.32 g, 1.44 mmol), (3R)-3-methylmorpholine hydrochloride (0.4 g, 2.9 mmol) and triethylamine (0.9 g, 8.9 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 3-methyl-2-((3R)-3-methylmorpholin-4-yl)-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.31 g, 1.08 mmol, 75%) as white crystals.
Reaction SMILES: CC1C=NN([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[S:25])=[CH:19][CH:18]=3)[CH:8]=2)C=1.CC1C=NNC=1.[CH3:42][C:43]1[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=1>>[CH3:42][C:43]1[CH:47]=[C:46]([CH3:48])[N:45]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[S:25])=[CH:21][CH:22]=3)[CH:8]=2)[N:44]=1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Reactant: Cc1cc(C)[nH]n1
Agent: Cc1cn[nH]c1
Product: Cc1cc(C)n(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)n1

Procedure:
Following the procedures described above for the synthesis of compound 258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in the step 1 with 3,5-dimethyl-1H-pyrazole, title compound 258c was obtained. Characterization of 258c is provided in the table 23.
Reaction SMILES: C(O[C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)CCCCCCCCCCC.[C:78]([OH:81])(=[S:80])[CH3:79].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:78]([S:80][C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:81])[CH3:79]
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](OC(=O)CCCCCCCCCCC)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reactant: CC(O)=S
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reaction time: 20 h
Yield: 7.2 %

Procedure:
To compound 1 (25.0 g, 22.9 mmol) and thioacetic acid (8.5 mL, 114.5 mmol) in dry dichloromethane (100 mL) under argon, was added trimethylsilyl trifluoromethanesulfonate (5.6 mL, 45.8 mmol) at room temperature. After 20 h, the mixture was diluted with dichloromethane (600 mL), washed with saturated sodium hydrogen carbonate (250 mL) and water (2×200 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography three times (SiO2, pentane/EtOAc 20:1, 30:1, 40:1) to give 1-S-acetyl-2,3,4,6tetra-O-lauroyl-1-thio-α-D-galactopyranose (1.59 g, 7.2%).