Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.Cl>O1CCCC1>[CH3:6][CH2:9]/[C:10](/[C:11]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[C:9](\[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[CH2:11][CH3:10]
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C(/CC)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 85 %

Procedure:
A slurry of titanium trichloride (1.54 gm, 10.0 mmol) in 30 ml dry tetrahydrofuran was prepared under an inert atmosphere, and powdered lithium aluminum hydride (190 mg, 5.0 mmol) was cautiously added. The resulting solution was stirred for two hours at room temperature to form the Ti(II) reagent, and a solution of para-methoxypropiophenone (820 mg, 5 mmol) in 5 ml dry tetrahydrofuran was added. The reaction was refluxed for four hours, and then poured into 50 ml 2 N aqueous hydrochloric acid. The solution was extracted several times with ether, and the ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was purified by chromatography on alumina to give 630 mg (85% yield) dimestrol; mp 124°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Reflux a mixture of 53.5 mL (0.504 mol) of 1-fluoro-4-nitrobenzene, 99.14 g(0.555 mol) of 1-benzylpiperazine, and 76.7 g (0.555 mol) potassium carbonate in acetonitrile for about 17 h. Cool the mixture to room temperature and dilute with methylene chloride and filter. Concentrate thefiltrate in vacuo. Dissolve the residue in methylene chloride and wash withwater. Dry the organic layer with anhydrous sodium sulfate and concentrate in vacuo to give the title compound. NMR (DMSO-d6): δ=2.59(t,4),3.42(t,4), 3.57(s,2), 6.80(d,2) 7.34(m,5) and 8.11(d,2) ppm.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].N1CCCCC1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:17][C:16]=1[CH:34]=O.C(OC(C)C)(C)C>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:17][C:16]=1[CH:34]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC#N
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
0.97 ml of methyl cyanoacetate and 0.3 ml of piperidine were added to a solution of 3.3 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 100 ml of tetrahydrofuran. After the mixture had been stirred for 5 hours at the reflux temperature, a further 0.97 ml of methyl cyanoacetate was added and refluxing was continued for a further 5 hours. The reaction mixture was evaporated down and the oil obtained was chromatographed (dichloromethane). The solid obtained was stirred with diisopropyl ether, isolated, washed with petroleum ether and dried.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].C(=O)(O)[O-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1.O>[C:14]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.S1C2C=C(C=O)N=CC=2OC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=Cc1cc2c(cn1)OCS2
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC1CCN(C[C@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (100 mg, 0.332 mmol) was stirred with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (45 mg, 0.811 eq.) in chloroform:methanol (9:1, v:v, 5 ml) at room temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (211 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The mixture was quenched by addition of saturated aqueous sodium hydrogen carbonate (1 ml). DCM (10 ml) was added and vigorous stirring was continued for 10 mins, followed by separation of the phases (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (eluting with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure and dried on the vacuum line over the weekend to give the free base of the title compound as a pale yellow foam (70 mg, 44.3%)
Reaction SMILES: [CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(CC(=O)O)cc2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 123, 0.1 g, 0.23 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a white solid (0.068 g, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 69 %

Procedure:
Using the general method of Example 245 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with p-toluenesulfonyl chloride (1.08 g, 5.55 mmol) to provide 1.57 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamide as an off white powder, m.p. 197.0-198.5° C. Analysis: Calculated for C24H29N5O2S: % C, 63.83; % H, 6.47; % N, 15.51; Found: % C, 63.68; % H, 6.40; % N, 15.51.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Br:13].[H-].[Na+].[CH2:17]1OCCOCCOCCOCCO[CH2:18]1.[CH2:32](I)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:4]([CH2:32][CH3:33])([CH2:17][CH3:18])[C:3]([OH:2])=[O:14]
Reactant: C1COCCOCCOCCOCCO1
Reactant: CCI
Reactant: COC(=O)Cc1cc(OC)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(C(=O)O)c1cc(OC)ccc1Br
Temperature: 140 °C

Procedure:
(2-Bromo-5-methoxy-phenyl)-acetic acid methyl ester (3.51 g, 13.5 mmol) was dissolved in DMF (4.5 ml), and added with NaH (2.1 g, 67.7 mmol). Subsequently, 15-crown-5 (1.38 ml, 6.8 mmol) and EtI (5.5 ml, 67.7 mmol) cooled to 0° C. were added to the mixture. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The residues obtained after concentration under reduced pressure were purified by silica gel column (hexane-ethyl acetate). Then, the resultant was dissolved in ethanol (80 ml) and water (80 ml), added with KOH (91 g), and stirred at 140° C. The reaction solution was extracted with ethyl acetate, and washed with water and saturated brine. After concentration under reduced pressure, the target compound was obtained (10.62 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([Cl:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([Cl:23])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4c(Cl)cccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a), using 2,5-dimethylindole and 4,8-dichloroquinoline.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[C:23]=1[O:24][CH3:25])[CH:19]=O.C[Si]([C:42]#[N:43])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:42]#[N:43])[CH:21]=[C:22]([CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:30])[CH3:31])[C:23]=1[O:24][CH3:25]
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After adding 1.3 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 2.605 g of 3,4-dimethoxy-5-triisopropylsilanyloxymethylbenzaldehyde, 2.2 g of MS3A and 1.5 ml of trimethylsilyl cyanide to a solution of 460 mg of Yb(OTf)3 in 18 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (3,4-dimethoxy-5-triisopropylsilanyloxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].[CH3:22][C:23](CC(C)C)=[O:24].O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[CH2:13]([N:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:1][CH2:22][C:23]1=[O:24])[CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)CC(C)C
Reactant: CCCCNc1cc(C(=O)OC)ccc1N
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 4-amino-3-(butylamino)benzoate (950 mg) and sodium bicarbonate (862 mg) in 1:1 isobutyl methyl ketone/water (20 mL) was added chloroacetyl chloride (0.41 mL), and the mixture was stirred for 1 h. The mixture was warmed to room temperature and refluxed for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 850 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.89, 7.72, 6.80, 3.97, 3.88, 3.30-3.25, 1.68-1.58, 1.47-1.35, 0.94-0.88.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C1C=CC=CC=1>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1cccc(Nc2ccccc2)c1C
Product: Cc1cccc(NCc2cccc([N+](=O)[O-])c2)c1C

Procedure:
Starting with 3-nitrobenzaldehyde (0.50 g) and 2,3-dimethylphenylaniline (0.40 mL) the method described in Step 3. of Example 1 was used to prepare the above compound. NMR (300 MHz, CDCl3) δ 8.25 (1H, s), 8.12 (1H, d, J=7 Hz), 7.72 (1H, d, J=7 Hz), 7.50 (1H, t, J=8 Hz), 6.95 (1H, t, J=8 Hz), 6.62 (1H, d, J=7 Hz), 6.36 (1H, d, J=7 Hz), 4.50 (2H, s), 4.09 (1H, s), 2.30 (3H, s), 2.13 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>>[Cl:8][C:7]1[C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1

Procedure:
A mixture of 2,3-dichloropyridine (0.74 g, 5 mmol, Aldrich) and (R)-(−)-2-methylpiperazine (0.6 g. 6 mmol, Aldrich) reacted under the conditions of Example 43a to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 212 (M+1).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][N:17]=[C:16](NC(C3CC3)=O)[CH:15]=2)[C:10](=[O:26])[N:9]2[C:27]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)C=3)(C)[NH:28][C:29](=O)[C:8]=12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40]>CO.ClCCl>[N:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[C:10](=[O:26])[N:9]3[C:27]4([CH2:32][CH2:37][CH2:36][CH2:35][CH2:34]4)[NH:28][C:29](=[S:40])[C:8]3=[CH:7][CH:12]=2)=[N:19][CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(Nc2ccncn2)ccc2n1C1(CCCCC1)NC2=S
Temperature: 50 °C

Procedure:
A vial containing tetrahydrofuran (10 mL) was charged with 6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (1, 0.6 g, 1.93 mmol) and phosphorus pentasulfide (857 mg, 3.85 mmol). Seal the vial and heat the reaction mixture at 50° C. for 16 h. After completion, the reaction mass was diluted with 5% methanol in dichloromethane (100 mL), washed with water (2×100 mL) and brine solution (100 mL), dried over anhydrous sodium sulfate, concentrated under vacuum. Crude material was purified by flash chromatography in silica gel in 3-4% methanol in dichloromethane, fraction were combined concentrated under reduced pressure. The product was triturated with methanol, filtered washed with methanol (3 mL), ether (5 mL), dried under high vacuum to obtain the desired product 6′-(pyrimidin-4-ylamino)-1′-thioxo-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one (Cpd. No. 131) as light yellow solid. Yield: 0.050 g, 8%; MS (ESI) m/z 328.41 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.80-8.77 (d, 2H), 8.39-8.38 (d, 1H), 7.39-7.38 (d, 1H), 7.07-7.06 (d, 1H), 2.97 (t, 2H), 1.78-1.72 (m, 5H), 1.59-1.56 (d, 1H), 1.26 (m, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1(=[O:16])N[C:13](=[O:15])[CH2:12][CH2:11]1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[C:13](=[O:15])[CH2:12][CH2:11][C:10]1=[O:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C1CCC(=O)N1
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1C(=O)CCC1=O
Reaction time: 2 h
Yield: 120823.5 %

Procedure:
31.5 ml of hexamethyldisilazane (0.15 mmole) were added to a refluxing suspension of a mixture of 50 ml of toluene and 19.80 g (0.20 mole) of succinimide and 458 mg of saccharin (2.5 mmoles) and refluxing was continued for 2 hours. Fifteen minutes after the addition of the silylating agent, a clear, light yellow solution was obtained which turned brown when refluxing was continued. The reaction mixture was cooled, filtered and after evaporation of the solvent, the residue was vacuum distilled to obtain 31.04 g (90.8%) of N-trimethylsilylsuccinimide boiling at 86°-88° C. at 1.3 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=O)=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.F[C:21]1C=CC(N)=CC=1.ClC(C(=O)C)C(=O)C.[S-]C#N.[K+]>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13](=[O:15])[CH3:21])=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)C(Cl)C(C)=O
Agent: N#C[S-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1

Procedure:
1-(1-(4-Fluorophenyl)-2-mercapto-4-methyl-1H-imidazol-5-yl)ethanone (60) was prepared in a similar manner as that described for the synthesis of compound 57 using 4-fluoroaniline (2 g, 18 mmol), 3-chloropentane-2,4-dione (2.7 g, 19.8 mmol), potassium thiocyanate (3.5 g, 36 mmol) and acetic acid (10 mL) in acetonitrile (100 mL).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][NH:10][C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCBr
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
To a solution of 0.259 g (0.64 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 2 mL of DMF were added 0.16 g (0.77 mmol) of methyl 6-bromohexanoate, 0.155 g (1.12 nmmol) of K2C03 and 2 crystals of nBu4NI. The resulting solution was heated in a 60° C. bath for 36 h, at which time a tlc indicated incomplete reaction. The bath temperature was raised to 100° C. After 3 h the reaction mixture was cooled and diluted with EtOAc. The EtOAc solution was washed with water (2×), brine and dried over Na2SO4. The filtrate was concentrated and the residue was chromatographed using 30% EtOAc/hexane to isolate 220 mg (65%) of the product. 1H-NMR (400 MHz, CDCl3): δ 1.0-1.4 (m, 4 H), 1.47 (m, J=8 Hz, 2H), 1.95 (m, 1H), 2.2 (t, J=8 Hz, 2H), 2.35 (m, 2H), 2.9 (d, J=13 Hz, 1H), 3.07 (d, J=7 Hz, 1H), 3.62 (s, 3H), 3.81 (td, J=8 Hz and 2 Hz, 1 H), 4.04 (dd, J=10 Hz and 2 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.4 (d, J=13 Hz, 1H), 4.79 (d, J=13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7](=[CH2:24])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.CCCCCC>C(OCC)(=O)C>[CH3:24][C:7](=[CH2:6])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: C=C(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: C=C(C)CN1CCN(c2ccc(N)cc2)CC1
Yield: 73.5 %

Procedure:
Tin (II) chloride dihydrate (67.0 g, 297 mmol) was added in portions to a solution of 1-(2-methyl-allyl)-4-(4-nitro-phenyl)-piperazine (prepared as described in Reference Example 40, 13 g, 50 mmol) in ethyl acetate (200 mL) at room temperature. The mixture was heated to reflux for 4 hours then the solvent was evaporated under reduced pressure. The resulting residue was diluted with water and basified with 10% sodium hydroxide solution to pH ˜10 then extracted with ethyl acetate (4×100 mL). The combined organic layers were washed twice with saturated brine then dried over sodium sulfate. Filtration and concentration in vacuo gave a gummy mass which was washed repeatedly with small volumes of 1:3 ether/hexane to afford a solid. This was slurried with hexane, filtered and dried under vacuum at room temperature to afford 1-(2-methyl-allyl)-4-(4-amino-phenyl)-piperazine (8.5 g, 74%) as light yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 91 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (117 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 190 mg (91%) of the title compound as a brown solid.