Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=1[CH3:12])[CH2:4][CH3:5]>CC(O)=O>[CH2:3]([C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=1[CH2:12][Br:1])[CH2:4][CH3:5]
Reactant: CCCc1c(C)ncnc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1c(Cl)ncnc1CBr
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Br2 (1.28 g, 8 mmol) is added dropwise to a stirred solution 101 in HOAc (20 ml) heated at 85° C. After addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and EtOAc (25 ml) and NaHCO3 (25 ml) are added to the residue. The layers are separated and the organic layer is washed with Na2S2O3 solution (sat. 15 ml) followed by brine (20 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by flash column (6:1 EtOAc, hexane) to afford the product (102) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[Br:18].[O:19]1[CH2:24][C:23](=O)[CH2:22][C:21](=[O:26])[CH2:20]1>C(O)C>[Br:18][C:11]1[CH:12]=[C:13]([CH:14]2[C:22]3[C:21](=[O:26])[CH2:20][O:19][CH2:24][C:23]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)[CH:16]=[CH:17][C:10]=1[CH3:9]
Reactant: Cc1ccc(C=O)cc1Br
Reactant: O=C1COCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Solvent: CCO
Product: Cc1ccc(C2C3=C(COCC3=O)Nc3c2c(=O)on3C)cc1Br
Temperature: 80 °C
Yield: 17.9 %

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 4-methyl-3-bromobenzaldehyde (0.2 g, 1 mmol), prepared as described in (Pearson et al., J.Org. Chem.(1958),23,1412-1416) and 2H-pyran-3,5(4H,6H)-dione (0.11 g, 1 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was chromatographed eluting with 19:0.5:0.5 ethylacetate:formic acid: water to provide the title compound (0.07 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:44][NH:45][C:46](=[O:49])[CH2:47]Br.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:47][C:46]([NH:45][CH3:44])=[O:49])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CNC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (60 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added 60% sodium hydride/mineral oil dispersion (4 mg, 0.1 mmol). The mixture was stirred for 10 min at ambient temperature under nitrogen atmosphere and a solution of N-methyl-2-bromoacetamide (17 mg, 0.11 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added. After 2 h, an additional portion of 60% sodium hydride/mineral oil dispersion (4 mg, 0.1 mmol) was added. After 15 min, acetic acid (0.1 mL) was added and the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate/water, dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, ethyl acetate) to provide the title compound as a white solid (10 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.15-1.22 9 (1H, m), 1.2 (1H, quintuplet), 1.9-2.0 (1H, m), 2.35 (1H, t), 2.6 (3H, d), 2.65-2.80 (3H, m), 2.9 (1H, d), 2.95 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.4 (2H, s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.2 (2H, s), 6.8 (2H, d), 7.0-7.2 (3H, m), 7.22 (1H, s), 7.25 (1H, d), 7.3 (1H, d), 8.0 (1H, br s); MS: 664 (MH+);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11]C(O)=O.C([N:17]([CH2:20]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:17]=[C:20]=[O:29]
Reactant: CCN(CC)CC
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN=C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 298.9 %

Procedure:
To 2,4-dimethoxyphenylacetic acid (3.92 g, 20 mmol) in dry toluene (100 mL) was added dry triethylamine (2.93 mL, 4.2 mmol) and diphenyl phosphorylazide (4.31 mL, 4 mmol). The mixture was stirred at room temperature for 0.5 hours, and then heated at reflux for a further 3 hours. After cooling, the mixture was concentrated under reduced pressure and purified by distillation using an oil pump to give 2,4-dimethoxybenzyl isocyanate (2.31 g, 60%). IR vmax/cm−1 2243.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]#[N:12].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:13][OH:14])[C:11]#[N:12]
Reactant: O=N[O-]
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To an ice-cooled stirred solution of 10 g of 2-benzimidazolylacetonitrile (63.6 mmol, 1 eq) in 50 ml of glacial acetic acid is added dropwise a solution of 4.83 g of sodium nitrite (70 mmol, 1.1 eq) dissolved in a minimum amount of water (10 mL). When the addition is completed, the reaction mixture is allowed to stir at room temperature for 1 h. The precipitate formed in the course of the reaction is filtered and washed with 2×20 ml of cold water and 2×30 ml of diethylether to provide 11.8 g of the product as light yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[C:14]#[N:15].Cl>CS(C)=O>[C:14]([C:13]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=1[O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)#[N:15]
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)ccc1Oc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
66 g of resorcinol are added to 220 ml of dimethyl sulphoxide. With stirring, 37.4 g of potassium hydroxide (powder) are added, whereupon the temperature rises to 55° C. The mixture is kept for 30 minutes at 60° C. and the 51.6 g of 2,5-dichlorobenzonitrile are added in portions. The reaction mixture is then stirred for 7 hours at 90° C. and, after cooling, poured into ice-water. The pH is adjusted to 6 with conc. hydrochloric acid and initially a brown oil precipitates, which soon becomes crystalline. Crystallisation from ethanol/-water yields 49.6 g of 3-(2'-cyano-4'-chlorophenoxy)-phenol with a melting point of 118°-120° C.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH2:11]([Si:15](OC)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]>O1CCCC1>[CH2:11]([Si:15]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: CCNCC
Reactant: CO[Si](CC(C)C)(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCN(CC)[Si](CC(C)C)(OC)OC
Temperature: 42.5 °C
Yield: 79 %

Procedure:
Following the same general procedure described in Example 1, a flask was charged with one mol of isopropylmagnesium chloride in 500 ml of tetrahydrofuran under a dry nitrogen atmosphere and stirred. To this was added 1.05 mol (76.8 g) of diethylamine over a period of one hour. During the addition of the diethylamine to the reaction mixture, the pot temperature was maintained at 40-45° C. After the addition was complete, the reaction mixture was refluxed for 30 minutes to complete the evolution of the gas. The reaction mixture was cooled to a pot temperature of 50° C. and one mol (178 g) of isobutyltrimethoxysilane was added over a period of one hour. The reaction mixture was refluxed at a pot temperature of 75° C. for four hours to complete the reaction. The isobutyl(diethylamino)dimethoxysilane was filtered under a nitrogen atmosphere from the magnesium methoxychloride salt. The salt cake was washed with ether (2×200 ml) to obtain the residual isobutyl(diethylamino)dimethoxysilane. The combined filtrate was distilled to a pot temperature of 100° C. to remove the lighter fraction and the residue distilled under reduced pressure to yield 153 g of isobutyl(diethylamino)dimethoxysilaie as a colorless oil (purity>98%); bp 104° C./30 mm. The total yield was 79% of theoretical.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31]([N:33]2C=N[CH:35]=[CH:34]2)=[O:32])C=1.[Cl:38][C:39]1[CH:40]=[C:41](C(N)C)[CH:42]=[CH:43][C:44]=1[Cl:45].O>CN(C)C=O>[Cl:38][C:39]1[CH:40]=[C:41]([CH:34]([NH:33][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])[CH3:35])[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Yield: 17.2 %

Procedure:
A stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and CDI (0.18 g, 1.10 mmol) in N,N-dimethylformamide (10 mL) was heated to 40° C. under nitrogen overnight. 1-(3,4-Dichloro-phenyl)-ethylamine (0.19 g, 1.00 mmol) was then added and the mixture was heated at 40° C. overnight. Water (60 mL) was added, solid precipitated, was filtered, washed with water (30 mL) and was purified by preparative HPLC (gradient: CH3CN/H2O: 10/90 for 5 min, to 100/0 in 10 min, 100/0 for 5 min). Solvent was evaporated and the residue was triturated in ether (20 mL) for 1 h. The product was then isolated by filtration and dried in vacuo to give 1-[1-(3,4-Dichloro-phenyl)-ethyl]-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.084 g, 17% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient: CH3CN/0.1% H3PO4: 10/90 to 90/10 in 10 min, 90/10 (5 min); 8.57 min (96.68%); mp: 200-202° C.; 1H NMR (DMSO-d6) δ 1.32 (d, J=7.0 Hz, 3H, CH3), 1.88-2.13 (m, 1H, CHH), 2.28-2.47 (m, 1H, CHH), 2.55-2.70 (m, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.18-4.55 (m, 4H, CH2, CH2), 4.74 (quin, J=7.0 Hz, 1H, CH), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.51 (s, 1H, NH), 6.66 (d, J=7.9 Hz, 1H, NH), 7.20-7.46 (m, 3H, Ar), 7.48-7.62 (m, 2H, Ar), 7.65 (d, J=7.7 Hz, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 22.80, 31.20, 42.86, 47.07, 48.18, 51.55, 121.61, 122.81, 126.28, 126.70, 127.78, 128.79, 130.14, 130.38, 130.77, 142.26, 145.29, 147.41, 157.20, 167.95, 170.98, 172.85; LCMS: MH=489, 491; Anal Calcd for C23H22N4O4Cl2+0.9 H2O: C, 54.64, H, 4.75, N, 11.08; Found: C, 54.27, H, 4.66, N, 10.98.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]2([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])=[C:6]([CH3:33])[CH:5]=1.[OH-].[Li+].O>C1COCC1.CO>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:15]2([CH2:14][CH2:13][CH2:12][C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=3[CH3:33])[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])(=[O:23])=[O:24])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C#CCCCC2(S(=O)(=O)c3ccc(OC)cc3)SC(=O)NC2=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(C(=O)O)cc3C)SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic acid methyl ester (Example 160)(0.29 g, 0.536 mmol) in THF (30 ml plus sufficient methanol to dissolve the substrate) was added lithium hydroxide (0.75 ml of 1.0M in water), and this solution was stirred at room temperature for 3 days. Dilution with water and acidification gave a solid which was crystallized from hexane-ethyl acetate to give the title compound as a light yellow solid mp 182-184° C. THEORY: C, 56.66, H, 4.34, N, 2.87. FOUND: C, 56.39, H, 4.60, N, 2.80.
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]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23](O)=O)=[O:15])=[CH:4][CH:3]=1.[C:26]1([NH2:33])[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[NH:32]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:33]=[C:23]1[CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 52 %

Procedure:
(RS)-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid, D17 (110 mg, 0.3 mmol) and benzene-1,2-diamine (33 mg, 0.3 mmol) in PPA (2 g) were heated at 140° C. for 3.5 h. The cooled reaction mixture was poured onto a mixture of crushed ice and K2CO3. The basic aqueous solution was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, ethyl acetate) afforded the title compound as a dark yellow gum (72 mg, 52%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCCCCC>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:4]2[CH2:5][CH2:6][C:7]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:3]2)=[N:28][CH:29]=1
Reactant: CCOC(=O)C1(C)CCNCC1C
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of ethyl 3,4-dimethylpiperidine-4-carboxylate (0.2 g, 1.08 mmol) in EtOH (7 mL) was added DIPEA (0.6 mL, 3.24 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.21 g, 1.08 mmol) then heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow solid (0.33 g, 95% yield). MS: 341.03 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>C(#N)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][O:29][CH3:30])[CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4]
Reactant: COCCBr
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 333 (M+, 1), 289 (15), 288 (bp), 264 (4), 148 (6).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[N:25]=CN(C)C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.NN>C(O)(=O)C>[C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
To 3 (44.64 g, 117 mmol) was added reagent grade ethanol (1200 mL), glacial acetic acid (20.65 mL) and hydrazine (26 mL). The reaction mixture was stirred at 50° C. for 5 hrs. Solvent was removed and to the crude product was added methylene chloride (1,500 ml) and 1 N sodium hydroxide (67 ml) with stirring at room temperature for 15 minutes. The two resulting layers were separated and the organic layer was washed with brine (2×300 mL), dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to obtain 1-trityl-2-aminoimidazole, 4 (37.2 g, 97%). M.p. 196-199° C.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[CH:59]([C:61]1[CH:62]=[C:63]([CH:69]([CH2:76][CH3:77])[CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:64]=[C:65]([F:68])[C:66]=1[F:67])=[CH2:60].S([O-])([O-])=O.[Na+].[Na+].[OH2:84]>CC(O)(C)C>[OH:84][C@@H:59]([C:61]1[CH:62]=[C:63]([CH:69]([CH2:76][CH3:77])[CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:64]=[C:65]([F:68])[C:66]=1[F:67])[CH2:60][OH:22]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: C=Cc1cc(C(CC)CC(=O)OCC)cc(F)c1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)CO)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A solution of AD-mix-α (50.0 g), t-BuOH (250 mL), and H2O (280 mL) was stirred until no solid was observed and then cooled to 0° C. Ethyl 3-(3-ethenyl-4,5-difluorophenyl)pentanoate (12.58 g, 0.0469 mol) in t-BuOH (35 mL) and H2O (10 mL) was added and the reaction stirred at 0° C. for 6 h and then warmed to room temperature overnight. Sodium sulfite (64 g) was added to quench the reaction and the reaction was diluted with H2O and extracted three times with ethylacetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Column chromatography (hexane:ethylacetate, 7:3) yielded the desired product (13.02 g, 92%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCO.CCOC(C)=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a suspension of 2-aminoindane hydrochloride (5.0g, 29.5 mmol) and powdered K2CO3 (8.3 g, 60.0 mmol) in absolute EtOH (30 mL) was added tert-butyl bromoacetate (4.4 mL, 29.5 mmol). After stirring for 10 min at rt the reaction was heated to 45° C. and stirred for 2 hr. The reaction was cooled to rt, diluted with EtOAc, filtered and concentrated. Chromatography of the residue on silica gel (elution with 20% EtOAc:hexane) provided 4.7g of compound 721 as a white crystalline solid. ##STR100##
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Sn](CCCC)(CCCC)/[CH:45]=[CH:46]\[C:47]([O-:49])=[O:48])CCC.[CH3:58]N(C=O)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([CH:45]=[CH:46][C:47]([O:49][CH3:58])=[O:48])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(I)c2c(N)ncnc21
Reactant: CCCC[Sn](/C=C\C(=O)[O-])(CCCC)CCCC
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)C=Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(N)c12
Temperature: 70 °C
Yield: 81 %

Procedure:
To a solution of compound 6.3 (1.25 g, 1.726 mmol) in 10 mL of anhydrous DMF was added Z-3-tributylstannylacrylate (1.1 mL, 2 eq.) (J. Am. Chem. Soc., 1993, 115, 1619), CuI (66 mg, 0.2 eq.) and PdCl2(PPh3)2 (121 mg, 0.1 eq.) at room temperature under the argon atmosphere. The reaction mixture was heated at 70° C. for 8 hr. Then the reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated in vacuo to provide an orange-red oil as the crude product which was purified on a silica gel column with 10-30% THF in CH2Cl2 as eluent to give 995 mg 6.4 as yellow foam (yield 81%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]([Mg]Br)#[C:16][CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][C:2]1([C:15]#[C:16][CH3:17])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.99 g) was dissolved in 30 ml of tetrahydrofuran, cooled down to −78° C., 40 ml of a 0.5N solution of 1-propynyl magnesium bromide in 40 ml of tetrahydrofuran was dropped thereinto and temperature of the mixture was raised to room temperature followed by stirring for one night. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution to stop the reaction and the product was extracted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride and dried over sodium sulfate. The solvent was evaporated in vacuo and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1.41 g of the title compound as a crude product.