Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:18](N)=[NH:19]>CCO>[OH:5][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:8]=2)[N:1]=[CH:18][N:19]=1
Reactant: COCCOc1ccc(N)c(C(=O)OC)c1
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: COCCOc1ccc2ncnc(O)c2c1
Temperature: 130 °C
Yield: 95.2 %

Procedure:
To methyl 2-amino-5-(2-methoxyethoxyl)benzoate (964 mg, 4.2 mmol) in absolute EtOH (25 mL) was added formamidine hydrochloride (1.4 g, 17.2 mmol) and the mixture heated in a sealed tube at 130° C. overnight. The mixture was cooled to room temperatureand filtered to give 4-hydroxy-6-(2-methoxyethoxy)quinazoline (871 mg, 4.0 mmol, 95%). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (br s, 1H), 7.99 (s, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.43 (dd, 1H), 4.21 (dd, 2H), 3.70 (dd, 2H), 3.32 (s, 3H); LC-MS (ESI) m/z 221 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C1COCC1.CCCCCC>[O:8]1[C:4]2[CH:3]=[C:2]([CH:19]=[O:20])[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 1 g of 6-bromo-2,3-dihydro-1-benzofuran (prepared as described by Z. J. Song, M. Zhao, L. Frey, J. Li, L. Tan, C. Y. Chen, D. M. Tschaen, R. Tillyer, E. J. J. Grabowski, R. Volante, P. J. Reider, Y. Kato, S. Okada, T. Nemoto, H. Sato, A. Akao, T. Mase, Organic Letters, 2001, Vol. 3, No. 21, 3357-3360) in 20 mL of anhydrous THF was added 4 mL of 2.5 M n-butyllithium in hexane. After stirring 10 min at −78° C., 0.5 mL of anhydrous DMF was added and the mixture allowed to warm to −20° C., quenched with 20 mL of 3N HCl and extracted into 2×50 mL of ether. Combined extracts dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (0-20% ethyl acetate in hexanes) gave the product as white crystalline solid. MS (m+1)=149.1; 1H NMR (400 MHz, CDCl3) 9.9 (s, 1H), 7.4 (m, 2H), 7.3 (s, 1H), 4.62 (t, 2H), 3.28 (t, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:5]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:4](=[O:25])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:7][C:6]=2[N:5]([CH2:14][CH2:15][CH2:16][OH:17])[C:4](=[O:25])[CH:3]=1
Reactant: NC1CCCCC1
Reactant: CSc1ncc2c(N)cc(=O)n(CCCO[Si](C)(C)C(C)(C)C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Nc1cc(=O)n(CCCO)c2nc(NC3CCCCC3)ncc12
Reaction time: 0.67 h
Yield: 23.9 %

Procedure:
To a solution of 5-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.395 mmol) in DCM (9 mL) was added 3-chloroperoxybenzoic acid (77% max., 106 mg, 0.474 mmol) at RT under argon atmosphere and the resulting mixture was stirred for 40 min. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in anhydrous dimethyl sulfoxide (ca. 9 mL). Cyclohexylamine (0.226 mL, 1.975 mmol) was then added at RT and the resulting mixture was stirred at 80° C. for 1.5 h. The reaction mixture was then quenched with water (70 mL) and an aqueous saturated solution of ammonium chloride (30 mL). The resulting mixture was extracted with EtOAc; the organic extracts were washed twice with water (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. To the residue, dissolved in THF, was added a solution of tetrabutylammonium fluoride (1 M in THF, 0.59 mL) at RT and the resulting mixture was stirred overnight. The solid formed was collected by filtration, washed with hexane and purified by preparative TLC (DCM/MeOH, 90/10) to give 30 mg of 5-amino-2-cyclohexylamino-8-(3-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow powder. MS=318 [M+H]+; MP=131.0-132.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: [C-]#[N+]CC(=O)OC(C)C
Reactant: Oc1cnc2ccccc2n1
Product: CC(C)OC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 205°-206° C., from 2-quinoxalinol and isopropyl isocyanoacetate. (Compound 3)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(N)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CN1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 40.9 %

Procedure:
Using the procedure of example 1, 1-methylpiperidin-4-ylamine (30 mg) was reacted with compound 1f (30 mg) to provide compound 61 (10.2 mg, 41%). 1H NMR (300 MHz, CD3OD) δ 8.92 (d, 1 H), 8.23 (d, 1 H), 8.15 (s, 1 H), 8.10 (d, 1 H), 7.25 (m, 1 H), 7.00 (d, 1 H), 3.96 (m, 1 H), 3.05 (m, 2 H), 2.45 (m, 2 H), 2.15 (m, 2 H), 1.95 (s, 3 H), 1.75 (m, 2H). MS (ESI) m/z: 309 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([O:5][C:6]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:9]3[CH:18]=[C:19]([C:22]#[C:23][Si](C)(C)C)[CH:20]=[CH:21][C:8]=3[N:7]=2)[CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:19]1[CH:20]=[CH:21][C:8]2[N:7]=[C:6]([O:5][CH:3]3[CH2:2][O:1][CH2:4]3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:9]=2[CH:18]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1ccc2nc(OC3COC3)n(-c3ccnc(N)n3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(OC3COC3)n(-c3ccnc(N)n3)c2c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[2-(oxetan-3-yloxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (450 mg, 1.19 mmol) in dry THF (5 mL) at RT was introduced TBAF (0.88 mL of a 1M solution in THF, 0.88 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo, DCM (5 mL) added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by silica gel flash column chromatography (eluent: DCM containing a 2-10% gradient of methanol) furnished the title compound as a yellow solid: 1H (500 MHz, DMSO) delta 4.83-4.70 (2H, m), 5.04-4.93 (2H, m), 5.85-5.77 (1H, m), 7.18-7.07 (3H, m), 7.33 (1H, dd, J=8.2, 1.5 Hz), 7.45 (1H, d, J=8.2 Hz), 8.36 (1H, s), 8.40 (1H, d, J=5.5 Hz); LCMS: m/z=+307.95 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].CC(C)([O-])C.[K+].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][OH:22])=[CH:18][CH:17]=1)[CH3:14]>CN(C)C=O>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][O:22][CH2:3][CH2:4][NH2:5])=[CH:18][CH:17]=1)[CH3:12]
Reactant: NCCCl
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(COCCN)o1

Procedure:
A solution of 2-chloroethylamine hydrochloride (6.25 g) in dry dimethylformamide was added dropwise to a stirred, cooled solution of potassium tert-butoxide (8.96 g) and 5-(dimethylamino)methyl-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue basified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid. The crystalline salt was recrystallised from ethanol to give 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine, bis oxalate, m.p. 130°-133° (3.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:27]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]2[I:27])=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(C)c1oc2c(ccc3[nH]ncc32)c(=O)c1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1oc2c(ccc3[nH]nc(I)c32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-2-isopropyl-7H-pyrano[2,3-e]indazol-4-one (20 mg, 0.059 mmol) in dry N,N-dimethylformamide (2 ml) at room temperature are added potassium hydroxide (6.3 mg, 0.112 mmol) and iodine (55 mg, in three portions over 3 h, 0.217 mmol). The reaction mixture is stirred at room temperature for 20 h, then diluted with ethyl acetate and washed successively with 10% aqueous sodium thiosulfate solution (40 ml) and saturated brine (40 ml). The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The resulting solid is triturated with n-hexane/dichloromethane to give a colourless solid that is recovered by filtration and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(F)cc1

Procedure:
Using a procedure similar to that described in Example 1-A, 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene was acylated with p-fluorobenzoyl choride to afford 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 4-fluorophenyl ketone which was treated with 4-[2-(1-pyrrolidinyl) ethoxy]phenyl magnesium bromide using a procedure similar to that described in Example 1-B to afford title compound in 84% overall yield.
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]3[S:47][CH:48]=[C:49]([C:51](O)=[O:52])[N:50]=3)[CH2:42][CH2:41]2)=[O:39])[N:35]=[C:34]([C:54]([F:57])([F:56])[F:55])[CH:33]=1>O1CCCC1>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([C:46]3[S:47][CH:48]=[C:49]([C:51]([O:11][CH:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)=[O:52])[N:50]=3)[CH2:44][CH2:45]2)=[O:39])[N:35]=[C:34]([C:54]([F:57])([F:55])[F:56])[CH:33]=1
Reactant: OC1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OC3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 1,2,3,4-tetrahydronaphthalen-1-ol (155 mg) and triphenylphosphine (758 mg) are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 380 mg) in tetrahydrofuran (2.5 ml). The mixture is stirred at 0 C under argon for 5 minutes, and diethyldiazene 1,2-dicarboxylate (383 mg) is then added dropwise. The reaction mixture is slowly warmed to room temperature. After 2 hours, the solvent is removed under reduced pressure and the residue is purified chromatographically. This gives 1,2,3,4-tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (196 mg, 39%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37]>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([NH:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
2.49 g (10 mmol) N-carbobenzoxy-D-proline, 1.37 g (10 mmol) isobutyl chloroformate, 1.01 g (10 mmol) N-methylmorpholine, and 1.03 g (10 mmol) L-valinol were contacted and reacted in THF substantially according to the procedure described in Example 1. Crude product (2.82 g) was recrystallized from a mixture of 20 mL ethyl acetate and 15 mL n-hexane, to give 2.37 g (7.1 mmol, 71%) of colorless crystalline N-carbobenzoxy-D-prolyl-L-valinol; m.p. 117.5°-118.6°, α25D=+26.7° (C=1.02 g/100 mL in acetone).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[C:6]1([CH:13]=CC(O)=[CH:9][CH:8]=1)[OH:7]>C1(C)C=CC=CC=1>[C:2]([CH:3]1[CH2:4][CH2:9][CH:8]=[C:6]([CH3:13])[O:7]1)(=[O:5])[CH3:1]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C1CCC=C(C)O1
Temperature: 200 °C
Reaction time: 4 h

Procedure:
A solution of 100 g of 3-buten-2-one in 100 ml of toluene stabilized with 1 g of hydroquinone was heated to 200° C. in a steel pressure vessel and held at that temperature for 4 hours. The resulting mixture was distilled under reduced pressure to give 2-acetyl-3,4-dihydro-6-methyl-2H-pyran (16A), as a liquid, b.p.: 38°-42° C., 0.02 Torr.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(O)(=O)C.BrBr.[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>C(OCC)C>[CH2:15]([O:17][P:18]([CH:8]1[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]1[CH3:1])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CN1CC(=O)NC1=O
Reactant: CCOP(OCC)OCC
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methylhydantoin (20.25 g, 180 mmole) and acetic acid (100 ml) is heated to 90° C. Bromine (10 ml, 195 mmole) is introduced dropwise at such a rate that instant decolorization occurred. After the addition is completed, the reaction mixture is stirred at 90° C. for 60 minute and at room temperature overnight. The acetic acid is decanted from white precipitate and removed in vacuo. The residue is combined with the precipitate and suspended in diethylether (200 ml). Triethylphosphite (32 ml, 180 mmole) is added portionwise with stirring and cooling. A solution resulted which on continued stirring, yield trace of white precipitate. The mixture is diluted with diethyl ether and allowed to stand overnight. Decanted the solvent, and pumped in vacuum oven to give white crystal ylide, (3-Methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester: 16.57 g (36.8%) MS(ES+): (M+H)=251.0
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[I:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.O>CN(C=O)C>[I:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(Cn2ccnc2)cc1
Reaction time: 11.5 h
Yield: 45.2 %

Procedure:
To a solution of imidazole (400 mg, 5.88 mmol) and K2CO3 (1.22 g, 8.81 mmol) in DMF (19 ml) was added 4-iodobenzyl bromide (1.83 g, 6.17 mol) at RT under protection from light. After stirring for 11.5 h, the reaction mixture was poured into water. The aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (757 mg, 2.66 mmol, 45%) as a beige solid. HPLC: EtRet=3.838 min; LC-MS: m/z 285.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.ClCCl.O.C[N:33](C)C=O>>[NH2:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCBr)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCN)cc1

Procedure:
8.0 mmol of 1-(6-bromohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methyl indole and 8.8 mmol of phthalamidepotassium are heated in 100 ml of anhydrous dimethylformamide for 2 hours under reflux. Following cooling the product is shaken with dichloromethane and H2O. The product is then dried over Na2SO4 and the solvent distilled off. The residue is chromatographed on silica gel with dichloromethane. To liberate the amine the so-obtained colorless crystals are taken up in 50 ml of ethanol (99%) and mixed with hydrazine hydrate in 20 ml of ethanol. The mixture is now heated for 2 hours under reflux; after cooling, it is acidified with 40 ml of 2N HCl solution and suctioned off from the precipitate. After distilling off the solvent the mixture is made alkaline with 40 ml of 2N NaOH and extracted three times with ethyl acetate. The mixture is then dried over Na2SO4 and chromatographed on silica gel with dichloromethane/ethyl acetate (10:1, volume/volume). A viscous colorless to yellowish oil is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][CH:24]=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[I:30][C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([CH3:1])[CH:3]=3)=[N:13][C:14]=12
Reactant: ClI
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a stirred solution of 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.12 g, 6.14 mmol) in acetic acid (15 ml) was added at room temperature sodium acetate (0.57 g, 6.95 mmol) and drop wise a solution of iodine monochloride (1.13 g, 6.96 mmol) in acetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.44 g, 84%) as a yellow solid. MS (EI) 471.0 [(M)+]; mp 160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][Si](C)(C)C)=[CH:8][CH2:7][CH2:6]2.F[B-](F)(F)F.[F:23][C:24]([F:39])([F:38])[S+]1C2C=CC=CC=2C2C=CC=CC1=2>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:24]([F:39])([F:38])[F:23])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC=C2O[Si](C)(C)C
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (6-methoxy-3,4-dihydronaphthalen-1-yloxy)-trimethylsilane (3.00 g, from step A) and 5-trifluoromethyldibenzothiophenium tetrafluoroborate (5.6 g, 16.5 mmol) in DMF (20 mL) is added slowly tetrabutylammonium difluorotriphenylstannate (7.0 g, 11.1 mmol) in DMF (40 mL) by a dropping funnel. After the addition is finished, the suspension is stirred at RT for 72 h. DMF is then removed under vacuum. Water and EtOAc are added. The organic layer is dried with MgSO4, concentrated and purified to give the title compound as a light yellow oil: 1H NMR (CDCl3) δ 2.24-2.31 (m, 1H), 2.44-2.50 (m, 1H), 3.01-3.07 (m, 2H), 3.20-3.25 (m, 1H), 3.87 (s, 3H), 6.70 (d, J=2.5 Hz, 1H), 6.86 (dd, J=2.52, 9 Hz, 1H), 8.04 (d, J=9 Hz, 1H).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=O>[OH-].[K+].C(O)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1ccccn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1C=C[NH+](C)C1C=Cc1ccccn1

Procedure:
A mixture of 12.0 g of 1,2,3-trimethyl-1H-imidazolium iodide and 12 ml of 2-pyridinecarboxaldehyde in 40 ml of 10% potassium hydroxide in absolute ethanol is refluxed for 15 minutes. The resulting solid is filtered off and crystallized from absolute ethanol to yield 3.5 g of the title compound, melting point 306° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:13])=[C:8]([CH2:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:17]([O:16][C:14]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([O:13][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[C:2]=1[CH3:1])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1oc2ccc(CC)c(O)c2c1C
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1oc2ccc(CC)c(OCc3ccccc3)c2c1C
Yield: 99.8 %

Procedure:
According to the procedure of Example 86, Step 3, 0.250 g (1.01 mmol) of 3-methyl-4-hydroxy-5-ethylbenzofuran carboxylic acid ethyl ester (Example 86, Step 2) and 0.599 mL (5.04 mmol) of benzyl bromide gave 0.341 g of 5-ethyl-4-benzyloxy-3-methylbenzofuran-2-carboxylic acid ethyl ester after chromatography on silica gel eluting with ethyl acetate/hexanes (1:20).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]#N)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@:10]1([C:16]([O:18][CH2:19][CH3:20])=C)[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([OH:26])[CH3:25]>[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C@H:9]2[C@:10]([OH:15])([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:16]([O:26][CH2:24][CH3:25])([O:18][CH2:19][CH3:20])[CH2:22][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(OCC)[C@@]1(O)CCCC[C@H]1N(CC#N)Cc1ccccc1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC1(OCC)CCN(Cc2ccccc2)[C@@H]2CCCC[C@@]21O
Reaction time: 1 h

Procedure:
To silver nitrate (125 mg, 0.735 mmol) in Ethanol (27.00 ml) at room temperature was added {Benzyl[(1R,2R)-2-(1-ethoxyethenyl)-2-hydroxycyclohexyl]amino}acetonitrile (220 mg, 0.700 mmol) in 10 ml of absolute ethanol. The reaction mixture was stirred for an addition 1 hr. Another 125 mg of Silver Nitrate was added and the reaction was stirred overnight. The reaction mixture was filtered through a pad of celite, concentrated. The residue was purified by column chromatography (dry load) on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) to give the title compound. 1H-NMR (500 MHz, CDCl3) 2-4: δ 7.20-7.36 (m, 5H), 4.07 (d, 1H), 3.74 (dt, 1H), 3.62 (dt, 1H), 3.52 (dt, 1H), 3.41 (dt, 1H), 3.28 (bs, 1H), 3.06 (d, 1H), 2.61 (m, 1H), 2.00-2.14 (m, 2H), 1.88-1.98 (m, 2H), 1.70-1.80 (m, 2H), 1.54-1.62 (m, 2H), 1.22-1.44 (m, 2H), 1.18 (t, 6H). LRMS m/z (M+H) Calcd:334.5. found: 334.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1CCCCC1>[CH2:16]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1

Procedure:
A mixture of 156 g (0.743 mole) of dimethyl 5-hydroxyisophthalate, 171 g (1 mole) of benzylbromide and 138 g (1 mole) of K2CO3 in 1 l. of acetone was refluxed for 18 hours. The reaction mixture was evaporated to a residue which was extracted with hot cyclohexane to give the crystalline product in a quantitive yield upon cooling. The analytical sample was obtained by recrystallization from cyclohexane, mp. 94-95° .