Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[CH:11]=1)[C:7]#[N:8].[CH3:19]I>C1COCC1.CCOC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]([CH3:19])[C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH:11]=1)[C:7]#[N:8]
Reactant: CI
Reactant: N#Cc1cc(F)cc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cc(F)cc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
NaH (23 mg, 0.96 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.1 mL) was added. The slurry was cooled to 0° C. and compound 11 (185 mg, 0.864 mmol, 1.00 eq) was added as a solution in THF (2.1 mL). After stirring at 0° C. for 30 minutes methyl iodide (59.3 μL, 0.958 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 163 mg (83%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.71 (s, 2H), 7.32-7.27 (m, 2H), 7.19 (dt, J=11.7, 2.3 Hz, 1H), 3.35 (s, 3H); [M+1]+: 229.2.
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13](C)([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]=1)#[C:2][CH3:3]>Cl>[C:1]([C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1)#[C:2][CH3:3]
Reactant: CC#CC1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC#CC1=CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
tert-Butyl 4-(1-propynyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (410 mg) prepared in 3) of Example 7 was dissolved in 10% methanolic hydrochloric acid followed by stirring at room temperature for 3 hours and the solvent was evaporated in vacuo. The resulting residue was dissolved in 10 ml of methylene chloride and cooled down to 0° C. and 0.56 ml of triethylamine and 354 mg of isopropyl chloroformate were dropped thereinto. After raising its temperature to room temperature, the reaction was stopped by a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted with ethyl acetate and the organic layer washed with a saturated aqueous solution of ammonium chloride and dried over sodium sulfate. After the solvent was evaporated, the residue was separate and purified by a silica gel column chromatography (hexane/ethyl acetate=4/1) to give 384 mg of a crude product of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:21]([OH:28])[C@@H:22]([C@@H:24](CO)[OH:25])[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:21]([C@@H:22]([CH2:24][OH:25])[OH:23])[OH:28])=[O:7]
Reactant: OC[C@@H](O)[C@@H](O)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OC[C@H](O)[C@H](O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.1 %

Procedure:
1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate was slowly added dropwise to a solution of erythritol 0.86 g (7.1 mmol) and 0.59 g (4.3 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 275 mg of the title compound (21% yield).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C.C(OCC)(=O)C>[CH:13](=[N:8]/[C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]1[NH:1][CH:2]=[N:3][CH:4]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1-c1cnc[nH]1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C(=N/c1ccccc1-c1cnc[nH]1)\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
2-(1H-imidazol-5-yl)aniline 965 mg, 0.410 mmol) was dissolved in acetic acid (2 mL) and benzaldehyde (43 mg, 0.410 mmol) was added. The reaction was stirred for 1 h at room temperature, diluted with 30 mL ethyl acetate, and extracted with 5% HCl (56 mL from 50 mL water+6 mL 12N HCl). The aqueous layer was basified with K2CO3 (add solid portionwise until PH=7), then extracted with ethyl acetate (30 mL×2). The organic layer was evaporated under reduced pressure and the residue was separated by column chromatography to afford the desired product (9 mg, 0.036 mmol, 9%). 1H NMR (MeOH-d4): 7.11-7.25 (m, 3H), 7.41-7.48 (m, 2H), 7.61-7.67 (m, 2H), 7.78 (s, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 8.83 (s, 1H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]=[CH2:54])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]=[CH2:39])[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14].[OH-].[Na+].Cl>C(O)C.O>[CH2:41]([O:40][C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]=[CH2:39])[C:19]([OH:21])=[O:20])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]=[CH2:54]
Reactant: C=CC=CCCCCCCCCCCOc1cc(C(=O)[O-])cc(OCCCCCCCCCCC=CC=C)c1OCCCCCCCCCCC=CC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC=CCCCCCCCCCCOc1cc(C(=O)O)cc(OCCCCCCCCCCC=CC=C)c1OCCCCCCCCCCC=CC=C
Temperature: 80 °C

Procedure:
In the next step as shown in FIG. 18, the yellow oil prepared above, 3,4,5-tris((11,13-tetradecadienyl)oxy)benzoate, was dissolved in a solution of ethanol (400 mL), H2O (80 mL), and NaOH (3.21 g, 80.2 mmol) in a round-bottom flask equipped with a reflux condenser and a magnetic stir bar. The mixture was then stirred and refluxed at 80° C. for 12 hours. After this period, the solution was cooled to 0° C. using an ice bath and acidified to pH 5.0 with hydrochloric acid (42 mL, 3M) to afford a pale brown precipitate. The precipitate was then filtered, washed with hexane (2×100 mL), and dried overnight under vacuum to collect a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (7.927 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile are initially charged in 15 ml of DMF, 2.13 g (8.720 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.99 g (23.781 mmol) of sodium bicarbonate are added and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the precipitated solid is filtered off, washed with MTBE and dried under high vacuum. This gives 3.87 g (100% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1coc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-pyridyl)ethylmercaptan and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH2:16]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Oc1ccc2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ncccc2c1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.33 g, 8.3 mmol) in anhydrous N,N-dimethylformamide (30 ml) was added 6-hydroxyquinoline (1.0 g, 6.9 mmol) at room temperature. The reaction mixture was stirred for 1 hour, then allyl bromide (0.72 ml, 8.3 mmol) was added. The reaction mixture was allowed to stir for 1 hour at room temperature, quenched with water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (50% hexanes-ethyl acetate) afforded 1.14 g (89%) of 6-allyloxyquinoline as brown oil. MS ESI m/z 185 [M+H]+.
Reaction SMILES: [C:1](C1CCC(CCC2C=CC(CCC)=CC=2)(C(OC(C)(C)C)=O)C=1)(OCC)=O.[H-].[Na+].C(C(CCC1C=CC(CCC)=CC=1)C(OC(C)(C)C)=O)=O.F[B-](F)(F)F.C(C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CC1)(OCC)=O.[CH3:84][N:85]1[CH2:90][CH2:89][CH2:88][N:87]([CH3:91])[C:86]1=O>>[CH3:86][N:87]([CH3:91])[C:88]1[CH:89]=[CH:90][N:85]=[CH:84][CH:1]=1
Reactant: CCCc1ccc(CCC2(C(=O)OC(C)(C)C)C=C(C(=O)OCC)CC2)cc1
Reactant: CN1CCCN(C)C1=O
Agent: CCCc1ccc(CCC(C=O)C(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)C1([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: F[B-](F)(F)F
Product: CN(C)c1ccncc1
Reaction time: 0.33 h

Procedure:
##STR28## tert-Butyl 3-carbethoxy-1-(2-(4-propylphenyl)ethyl)-2-cyclopentene-1-carboxylate. Sodium hydride (16 mg of 60% oil dispersion, 0.40 mmol) was added to a solution of 102 mg (0.35 mmol) of tert-butyl 2-formyl-4-(4-propylphenyl)butanoate in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 mL). After 20 min., 1-carboethoxycyclopropyl triphenylphosphonium tetrafluoroborate (193 mg, 0.42 mmol) was added to the pale yellow solution and stirring was continued overnight at room temperature. The solution was then partitioned between hexane (25 mL) and 2N aq. HCl (25 mL). The organic layer was washed with water (15 mL) and saturated aq. NaCl (15 mL), dried (Na2SO4), decanted, and evaporated. The residue was purified by flash column chromatography on silica gel (8 g), eluting with 100 mL of 5% EtOAc/hexane, to give the title compound as 52 mg (38% yield) of colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[OH:15])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C(O)c1cnc(Cl)nc1Cl
Yield: 77 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 2-methoxybenzaldehyde (Aldrich) in 77% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.75 (s,1 H), 7.34 (d.t. 1H, J=2 Hz, 8 Hz), 7.16 (d,d, 1H, J=1.8 Hz, 7.3 Hz ), 6.96 (d, 1H, J=7.3 Hz), 6.95 (d,1H, J=8 Hz), 1H), 3.85 (s, 3H), 3.148 (br. s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH3:35])[CH2:4][O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:18][C:17](=[O:19])[N:16](CC3C=CC(OC)=CC=3OC)[S:15]2(=[O:32])=[O:31])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:34]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6](=[O:33])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH2:18][C:17](=[O:19])[NH:16][S:15]2(=[O:31])=[O:32])=[CH:11][CH:12]=1)[CH3:35]
Reactant: CCC(CC)COC(=O)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)COC(=O)c1ccc(CN2CC(=O)NS2(=O)=O)cc1

Procedure:
A solution of the title C compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 2-ethyl-butyl ester (230 mg, 0.456 mmol) and 2 mL of TFA in 6 mL of CH2Cl2 is stirred at RT overnight. The solvent is evaporated and the residue is treated with MeCN and filtered. The filtrate is concentrated and the residue is treated with Et2O, filtered and the Et2O is evaporated to give 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-ethyl-butyl ester as a light pink colored solid: [M−H]−=353.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([NH:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:6][N:7]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Reaction time: 66 h
Yield: 25.2 %

Procedure:
To a solution of [4-(6-aminopyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.035 g, 0.12 mmol) in dichloromethane (3 mL) was added benzylisocyanate (0.4 mL, 0.3 mmol). After stirring for 66 h, dichloromethane was removed in vacuo and the residue was diluted with ethyl acetate (20 mL). The organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by preparative thin layer chromatography afforded the title compound as a pale white solid (14.6 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ 9.61, 8.78, 7.73, 7.58, 7.25, 6.78, 4.59, 3.95, 3.32, 3.13, 2.94. MS (ES+) m/z 484.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH2:10][C:11](O)([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:10]=[C:11]([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(CSc3ccccc3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:19][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2cccc(Cl)c2)nc1C#N
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1nc(C#N)c(C#N)nc1-c1cccc(Cl)c1
Yield: 78.4 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-chlorophenyl)pyrazine (1.0 g; 0.0036 mole), 0.24 g (0.004 mole) of n-propylamine and 40 ml of a 0.1 N aqueous solution of sodium hydroxide were worked up in the same way as in Example 17, and recrystallized from methanol to afford 0.84 g (yield 78%) of 2,3-dicyano-5-n-propylamino-6-(m-chlorophenyl)pyrazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].CC(C)([O-])C.[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(N4CCN(S(C)(=O)=O)CC4)ncc3o2)CC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
4-(5-Chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (80 mg) is added to a flask charged with a stir bar, N-methylsulfonyl-piperazine (47 mg), potassium tert-butoxide (63 mg), Xantphos (103 mg), tris(dibenzylideneacetone)-dipalladium(0) (54 mg), and toluene (3 mL). The mixture is sparged with Ar at room temperature for 10 min and then stirred at 110° C. overnight. After cooling the mixture to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 5): tR=1.25 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH:27]([C:29]1[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=1)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[C:37]([O:36][C:35](=[O:41])[NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Br:26])[C:6]([N:11]4[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:19])[NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)[CH2:13][CH2:12]4)=[C:7]3[N:8]=2)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
To a mixture of 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.1 g, 0.22 mmol) and ethanol (5 ml) was added tert-butyl N-(4 formylbenzyl)carbamate (69 mg, 0.29 mmol) and a freshly prepared aqueous solution of Na2S2O4 (1M; 900 μL, 0.9 mmol). The reaction mixture was stirred at 80° C. for 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate 7:3+0.5% methanol to 2% methanol in ethyl acetate). The isolated product was further triturated in ether/methanol 9:1, filtered, and dried in vacuo to give the title compound as a pale yellow solid (0.049 g, 34%);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[C:17]([F:16])=[CH:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:19]=2)=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CCOC(=O)CCSc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of ethyl 3-((2-bromophenyl)thio)propanoate (5.8 g, 20 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (6.95 g, 22.1 mmol), Pd(dppf)Cl2.CH2Cl2 (1.7 g, 2.0 mmol), Na2CO3 (4.25 g, 40.1 mmol) and 1,4-dioxane/water (80 mL/10 mL) was stirred at 90° C. overnight under N2. The reaction mixture was cooled to rt, filtered, and the filtrate concentrated to dryness. The resultant residue was subjected to FCC to give the title compound (6.5 g, 82%). MS (ESI): mass calcd. for C21H20FN3O2S, 397.13; m/z found, 397.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:4]([CH2:3][CH2:2][N:30]3[CH:31]=[C:27]([CH3:26])[N:28]=[CH:29]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9]C)[C:6]([C:11]#[N:12])=[CH:5][C:4]=1[O:13]C)#[N:2].[Br-].[Br-].[Br-].[Al+3].Cl>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:11]#[N:12])=[CH:5][C:4]=1[OH:13])#[N:2]
Reactant: COc1cc(C#N)c(OC)cc1C#N
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: c1ccccc1
Product: N#Cc1cc(O)c(C#N)cc1O
Temperature: 0 °C
Yield: 41.7 %

Procedure:
In a 5 liter-reaction vessel, 100 g (5.32×10-1M) of 2,5-dicyano-1,4-dimethoxybenzene, 312.5 g (1.17M) of anhydrous aluminum tribromide and 2.5 liters of dry benzene were placed, followed by heat-refluxing for 7 hours. After the reaction, the reaction mixture as cooled and poured into a mixture of 3 kg of crushed ice and 500 ml of concentrated hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration and dissolved in 2N-sodium hydroxide aqueous solution. The resultant insoluble residue was filtered off and the filtrate was acidified with 2N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying to obtain 35.5 g of 2,5-dicyanohydroquinone (Yield: 41.7%).