Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][Br:21])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)c2occ(CBr)c2c1F
Yield: 43 %

Procedure:
the compound (2.6 g, 10.5 mmol) of Step 1 of Example 21, NBS (2.06 g, 11.58 mmol), BPO (catalytic amount), and carbon tetrachloride (120 mL) were added, and heated under reflux overnight. After cooling, the solvent was distilled away. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([CH2:20][C:21]4[NH:22][C:23]5[C:28]([CH:29]=4)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=5)[CH2:15][CH:14]3[C:31]([OH:33])=O)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:34][N:35]1CCOCC1.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:34][NH:35][C:31]([CH:14]1[CH2:15][N:16]([CH2:20][C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=3)[CH2:17][C:18](=[O:19])[N:13]1[CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)=[O:33]
Reactant: CN1CCOCC1
Reactant: Nc1ncnc2cc(CN3C(=O)CN(Cc4cc5cc(Cl)ccc5[nH]4)CC3C(=O)O)ccc12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1CN(Cc2cc3cc(Cl)ccc3[nH]2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Reaction time: 3 h
Yield: 153.4 %

Procedure:
To a solution containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acid (25 mg, 0.03 mmol), EXAMPLE 785, and N-methylmorpholine (36 mg, 0.36 mmol) in anhydrous DMF (1 mL) is added methylamine hydrochloride (10 mg, 0.14 mmol) followed by HATU (40 mg, 0.10 mmol) at ambient temperature. After 3 h, the solvent is removed under high vacuum and the residue is dissolved in CH3CN/water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 22 mg (88%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=[C:2]1[N:14]([CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:8]
Reactant: CNc1ccccn1
Reactant: CCn1c(Br)nc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCn1c(N(C)c2ccccn2)nc2ccccc21

Procedure:
To a flask were added 1.0 g of 2-bromo-1-ethyl-1H-benzimidazole, 0.48 2-(methylamino)pyridine, 0.64 g of sodium tert-butoxide, and 25 ml toluene. The mixture was purged thoroughly with nitrogen and 250 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and 64 mg of palladium acetate were added. The reaction mixture was heated to 90 C for 16 hours, and then cooled to 22 C. After quenching with 50 ml water, the product was extracted with 20 ml ethyl acetate. The product was extracted with 30 ml of 1M hydrochloric acid, and then basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using a gradient from 40% ethyl acetate in hexane to 70% ethyl acetate in hexane, resulting in 0.6 g of a yellow oil which crystallized on standing. The product was recrystallized from a mixture of 5 ml hexane with 1.5 ml 2-propanol. After filtration and drying of the product, a 0.44 g of a yellow solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[F:25][CH2:26][CH2:27][NH2:28]>>[F:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCF
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCF)cn1
Yield: 95 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-fluoroethylamine hydrochloride instead of methylamine, to the title compound (109 mg, 95%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[C:30]([O:31][CH3:32])=[C:29]2[C:24]([CH2:25][CH2:26][NH:27][CH2:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([O:31][CH3:32])[C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:28]2)[N:3]=1
Reactant: COc1ccc2c(c1OC)CNCC2
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Product: COc1ccc2c(c1OC)CN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)CC2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline as the reagent of choice on the same molar basis as before. In this particular instance, the final product was isolated as the free base compound, m.p. 190° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][C:4]2[NH:3][C:2](=[O:1])[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH:12]=1
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 7.00 g (33.9 mmol) of ethyl 2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (IV) and 3.02 ml (37.3 mmol) of sulfuryl chloride in acetic acid (90 ml) was stirred at 90° C. for 1 h. The cooled reaction mixture was poured into ice-water. The precipitated solid was filtered off, washed with water, dried in vacuo and recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:6]1=[O:24].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:7]2[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]2=[O:24])=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Br
Reactant: Nc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccccc1
Yield: 81 %

Procedure:
To prepare the compound of example 23, the procedure may be according to process “A”. Analogously to the method for example 1, stage 3, compound 23.2 was reacted with aniline. Compounds 23 was obtained in a yield of 81%. Molecular weight 471.14 (C25H21F4N3O2); retention time Rt=2.34 min. [B]; MS (ESI): 472.11 (MH+).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.Cl.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18]2[N:19]([CH2:32][CH2:33][CH3:34])[N:20]=[C:21]3[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=[C:22]3[NH2:31])[CH2:11][CH2:10]1.C(N(CC)CC)C.CN(C)C=O>ClCCl>[NH2:31][C:22]1[C:21]2=[N:20][N:19]([CH2:32][CH2:33][CH3:34])[C:18]([NH:17][CH2:16][CH2:15][CH:12]3[CH2:13][CH2:14][N:9]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:10][CH2:11]3)=[C:30]2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCN(C(=O)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
Isopropyl isocyanate (0.29 g, 0.33 mL, 3.39 mmol) was added to a stirring suspension of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride (1.2 g, 2.83 mmol) and triethylamine (2.9 g, 3.9 mL, 28.3 mmol) in dichloromethane (100 mL). After 10 minutes, N,N-dimethylformamide (15 mL) was added and the resulting suspension was stirred at ambient temperature 16 hours. The dichloromethane was removed under reduced pressure and water (100 mL) was added to the resulting oil. A solid formed which was removed by filtration and discarded. The filtrate was transferred to a separatory funnel and extracted with dichloromethane (50 mL). The aqueous layer was saturated with solid sodium bicarbonate and extracted with dichlioromethane (3×50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown oil was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 3-15% methanol in dichloromethane). The resulting oil was crystallized from acetonitrile and isolated by filtration to yield 132 mg of 4-{2-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 168-170° C. Anal. calcd for C24H35N7O: C, 65.88; H, 8.06; N, 22.41. Found: C, 65.89; H, 8.24; N, 22.67.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1

Procedure:
Reaction of the commercially available 2,6-dichloropurine (3) with benzylamine gave 2-chloro-6-benzylaminopurine (4) using a reported procedure. Under our conditions, the reaction was complete in 15 min at 60° C. instead of the reported time of 3 h at 110° C. Propargylation of compound 4 using propargyl bromide in DMSO under mild conditions gave 2-chloro-6-benzylamino-9-(2-propynyl) purine (5) regioselectively in high yield. The Cu(I) catalyzed azide-alkyne click reaction (the Sharpless-Huisgen 1,3-dipolar cycloaddition) of the alkyne 5 with fluorinated benzyl azides, prepared in situ from their corresponding benzyl bromides, gave exclusively 1,4-disubstituted triazoles, 7-9. The isomeric homogeneity of the product triazoles was readily verified through their 19F NMR spectra. The pentafluorophenylmethyl-triazole, 9, showed relatively shielded δ19F absorptions as compared to the o-fluorophenylmethyl- and the 2,6-difluorophenylmethyl-triazoles, 7 and 8 respectively, in accordance with similar observations for the monofluoro-, difluoro-, and pentafluorotoluenes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH2:11](Cl)[C:12]#[CH:13]>CN(C)C=O>[CH2:13]([O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]#[CH:11]
Reactant: C#CCCl
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOCc1cccnc1
Yield: 45.3 %

Procedure:
While maintaining the reaction mixture at 5°-10° C., 3-pyridylcarbinol (50.0 g., 0.45 mol) was slowly added to a mixture of sodium hydride (24.0 g of a 50% suspension in mineral oil, 0.5 mol) in 250 ml dry N,N-dimethylformamide. Propargyl chloride (37.0 g, 0.5 mole) was then slowly added to this mixture at 15° C. Following the addition, the reaction mixture was warmed to 35° and maintained for 15 mins at this temperature. The reaction was then cooled to 15°-20°, carefully quenched by dropwise addition of water and extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 45 g crude product. Distillation gave 30.0 g of 3-(2-propynyloxymethyl)pyridine. Yield 44% theory; b.p. 95° C. (0.9 mm).
Reaction SMILES: C([O:4][C:5]1[C:6]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][C:8]([OH:14])=[C:9]([C:11]([CH3:13])=[O:12])[CH:10]=1)(=O)C.Cl(O)(=O)(=O)=O.[CH:25](OC(C)C)(C)C>C([O-])([O-])OCC>[OH:4][C:5]1[C:6]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][C:8]2[O:14][CH:25]=[CH:13][C:11](=[O:12])[C:9]=2[CH:10]=1
Reactant: CC(C)OC(C)C
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)cc1NS(C)(=O)=O
Agent: CCOC([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1O
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2.0 g of methyl 5-acetoxy-2-hydroxy-4-methylsulfonylaminophenyl ketone was suspended in 14 ml of ethyl orthoformate. Thereto was dropwise added 2.0 g of 70% (w/w) perchloric acid in 10 minutes with ice-cooling. The mixture was stirred for 1.5 hours at 20°-25° C. The reaction mixture was mixed with 20 ml of diisopropyl ether. The resulting crystal was collected by filtration and mixed with 20 ml of water. The mixture was refluxed for 5 minutes and then cooled. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 14 ml of a 1N aqueous sodium hydroxide solution. The mixture was stirred for 30 minutes at 20°-25° C. The reaction mixture was adjusted to pH 2 with 6N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a mixed solvent of N,N-dimethylformamide and water to obtain 1.0 g (yield: 59%) of 6-hydroxy-7-methylsulfonylamino-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH2:28]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:38][CH:39]=3)=[O:20])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1nnc(-c2ccc(C(=O)O)cc2)s1
Reactant: CCCCCCCCOc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCc1nnc(-c2ccc(C(=O)Oc3ccc(OCCCCCCCC)cc3)cc2)s1

Procedure:
4-(2-n-Nonyl-1,3,4-thiadiazole-5-yl)-benzoic acid (0.005 moles, 1.66 g) is reacted with 5 mL of thionyl chloride and heated 2 hours at the boiling point. After that, the excess thionyl chloride is distilled off in the rotary evaporator and the residue is treated with 0.006 moles (1.33 g) octyloxyphenol, dissolved in 20 mL toluene, 5 mL triethylamine and 100 mg 4-dimethylaminopyridine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.COC(OC)(C)C>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH3:14])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CC[C@H](CO)N1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
Prepared according to WO patent: 2013004290A1. To a stirred suspension of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (Sigma Aldrich Chemical Company, St. Louis, Mo., 5.36 g, 46.5 mmol) and p-toluenesulfonic acid (44 mg, 0.233 mmol) in toluene (100 mL), 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 1.5 h. The reaction was equipped with a Dean-Stark apparatus then additional 2,2-dimethoxypropane (17.1 mL, 140 mmol) was added and the reaction was refluxed for 36 h. The solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as an orange waxy solid. MS (ESI) 156.1 [M+H]+. The crude material was taken to the next step without further purification.
Reaction SMILES: C(O[C:4]([CH:6]1[NH:11][CH2:10][C:9]2[S:12][CH:13]=[N:14][C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH3:4][CH:6]1[NH:11][CH2:10][C:9]2[S:12][CH:13]=[N:14][C:8]=2[CH2:7]1
Reactant: CCOC(=O)C1Cc2ncsc2CN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1Cc2ncsc2CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In anhydrous tetrahydrofuran (500 ml), 6-ethoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (WO94/21599) (21.0 g) was dissolved, followed by the addition of a solution of lithium aluminum hydride in tetrahydrofuran (a 1.0M solution, 200 ml) under ice cooling. The resulting mixture was stirred at room temperature for 2 hours. Water (7 ml) was then added slowly to the reaction mixture. After the termination of the reaction, a 1N aqueous potassium hydroxide solution (7 ml) and anhydrous magnesium sulfate were successively added. After removal of the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by distillation under reduced pressure (1.5 mmHg, boiling point: 82 to 85° C.), whereby the title compound (6.10 g, 40%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]3[CH:18]=[N:19][CH:20]=[CH:21][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:44]([Si:41]([CH3:43])([CH3:42])[O:40][CH2:39][CH2:38][O:29][C:25]1[C:26]([CH3:28])=[CH:27][C:22]([C:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:6][CH:7]=3)[C:16](=[O:17])[C:15]3[CH:18]=[N:19][CH:20]=[CH:21][C:14]=3[N:13]=2)=[CH:23][C:24]=1[CH3:30])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCC(C)c1ccc(-n2c(-c3cc(C)c(O)c(C)c3)nc3ccncc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccncc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-sec-butyl-phenyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-pyrido[4,3-d]pyrimidin-4-one (0.25 g, 0.63 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (0.62 g, 1.9 mmol). The color changed to orange. The reaction mixture was stirred at room temperature for 10 minutes under nitrogen. Then, (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (9) (0.300 g, 1.27 mmol) was added and the reaction mixture was stirred at 80° C. for 5 hours under nitrogen, cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water (2×50 mL), then brine (50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-3-(4-sec-butyl-phenyl)-3H-pyrido[4,3-d]pyrimidin-4-one (10) as a gummy solid. Yield: 0.20 g (58%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccccc1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[CH2:15][O:14][CH2:13][C@H:12]2[CH2:11][O:10][N:9]3[C@@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[CH:7]=1.[C:26]([NH2:29])(=[O:28])[CH3:27].[I-].[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>[Cu]I.CN(C=O)C>[F:25][C:5]1[CH:4]=[CH:3][C:2]([NH:29][C:26](=[O:28])[CH3:27])=[CH:7][C:6]=1[C@:8]12[CH2:15][O:14][CH2:13][C@H:12]1[CH2:11][O:10][N:9]2[C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18]
Reactant: CC(N)=O
Reactant: CC[C@H](c1ccccc1)N1OC[C@@H]2COC[C@@]21c1cc(Br)ccc1F
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC[C@H](c1ccccc1)N1OC[C@@H]2COC[C@@]21c1cc(NC(C)=O)ccc1F
Temperature: 110 °C

Procedure:
A mixture of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)hexahydrofuro[3,4-c]isoxazole (1.0 equiv., volumes are in mL/g of this compound), acetamide (4 equiv.), copper (I) iodide (0.2 equiv.), potassium iodide (0.7 equiv.), K3PO4 (2.0 equiv.), N,N-dimethylethylenediamine (0.8 equiv.) and DMF (4 mL/g) is heated at 110° C. for about 4 hours. After cooling to 30° C., the mixture is partitioned between isopropyl acetate (3.7 mL/g) and 10 weight % NH4Cl (5.7 mL/g) in water. The layers are separated and the aqueous layer is extracted with isopropyl acetate (2 mL/g). The combined organic layers are washed twice with 10 weight % NH4Cl (1 mL/g) in water. The organic layer is mixed with xylenes (4.3 mL/g), and the mixture is distilled under vacuum to remove most of the isopropyl acetate and residual DMF. The mixture is cooled to 0° C., the solids are collected by filtration, rinsed twice with xylenes (0.7 mL/g) and dried to give the title compound. LC-MS (m/z): 385 (M+H).