Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:16]=3)[C:7]2=[N:6][C:5]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:16]=3)[C:7]2=[N:6][C:5]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=c1c([N+](=O)[O-])c(-c2ccccc2)nc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1c(-c2ccccc2)nc2n(c1=O)CCCN2c1ccnc(NCCc2ccccc2)n1

Procedure:
A suspension of 3-nitro-9-(2-phenethylamino-pyrimidin -4-yl)-2-phenyl -6,7,8,9tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (40 mg, 0.09 mmol) in methanol (10 mL) was stirred with 10 % palladium on carbon (5 mg) under an atmosphere of hydrogen for 4 h. Reaction mixture filtered through a bed of Celite, and final product isolated as a white solid after removal of solvent under vacuum. M+1=440 1NMR (CDCl3) t (2H, 2.20 ppm), t (2H, 2.91 ppm), dd (2H, 3.67 ppm), s (2H, 4.07 ppm), m (4H, 4.15 ppm), s (1H, 5.10 ppm), d (1H, 7.17 ppm), m (3H, 7.24 ppm), m (2H, 7.31 ppm), m (1H, 7.36 ppm), t (2H, 7.46 ppm), d (2H, 7.79 ppm), d (1H, 8.03 ppm).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:29])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:37][CH2:38][C@H:39]1[CH2:43][O:42][C:41]([CH3:45])([CH3:44])[O:40]1>CN(C=O)C>[CH3:44][C:41]1([CH3:45])[O:40][C@@H:39]([CH2:38][CH2:37][O:13]/[N:12]=[C:11]2\[NH:10][C@@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:29])[C:5]\2=3)[CH2:43][O:42]1
Reactant: CC1(C)OC[C@H](CCI)O1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC[C@H]3COC(C)(C)O3)N2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (86g or Compound 61, 10.0 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs2CO3 (12.2 mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperature for 30 minutes. Then, (5)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (86d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirred overnight. LCMS showed complete consumption of starting material. The reaction mixture was poured onto crushed ice and the resulting solid was filtered, rinsed with cold water, and dried to afford (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (86h, 8.2 mg, 63%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3H) 1.39 (s, 3H) 1.91-2.01 (m, 4H) 2.72 (s, 3H) 3.07 (dd, J=16.55, 10.48 Hz, 1H) 3.26 (dd, J=17.05, 4.93 Hz, 1H) 3.55 (dd, J=7.96, 7.20 Hz, 1H) 3.90 (s, 3H) 4.05 (dd, J=7.96, 5.94 Hz, 1H) 4.10-4.21 (m, 3H) 4.89 (dd, J=10.61, 3.79 Hz, 1H) 6.74 (d, J=8.84 Hz, 1H) 7.01 (d, J=8.08 Hz, 1H) 7.11-7.22 (m, 2H) 7.61-7.69 (m, 2H)MS (ES) [M+H] calculated for C27H32FN6O4, 523.24; found 523.50.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.[CH3:16][S-:17].[Na+].[I-].[Na+].CN(C)C=O>O>[CH3:16][S:17][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: FC(F)=C(F)CCSc1nc(CCl)co1
Reactant: C[S-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1coc(SCCC(F)=C(F)F)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 23.9 %

Procedure:
1.2 g of 4-chloromethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole, 0.5 g of sodium thiomethoxide and 0.1 g of sodium iodide were added to 20 ml of dimethylformamide (hehydrated) and stirred at 80° C. for 10 hours. After cooling, 200 ml of water were added to the reaction mixture and extracted with 100 ml of diethyl ether twice. The extracted diethyl ether layers were put together, washed with 200 ml of water, dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=2:1) to obtain 0.3 g of 4-methylthiomethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 23.9%). n20D=1.5099.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[O:13].C(O)(=O)C.C([BH3-])#N>CO.ClCCl>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:12][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1)#[N:19].[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1ccc(N)cc1
Agent: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(NCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 4-aminobenzoate (0.2 g, 1.323 mmol) and 4-formylbenzonitrile (0.177 g, 1.350 mmol) in methanol (2 ml) and dichloromethane (4 ml) was treated with acetic acid (0.379 ml, 6.62 mmol) followed by MP-cyanoborohydride (1.151 g, 2.65 mmol) and the reaction was slowly stirred at room temperature. After 16 hours, the mixture was filtered and concentrated and the concentrate was partitioned between 2 N sodium hydroxide and dichloromethane. The organic phase was concentrated to give the title compound with 30% of remaining 4-formylbenzonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26]Cl)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCN1CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid [2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methylamide (45 mg) in acetonitrile (2 mL) was added morpholine (38 μL), potassium carbonate (18 mg) and potassium iodide (2 mg). the reaction mixture was heated at 80° C. for 72 h and allowed to cool to room temperature before quenching with water (30 mL) and extracting into dichloromethane (2×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 186 as an off-white solid (27 mg). NMR: CDCl3: 1.97 (m, 2H), 2.36-2.43 (m, 6H), 2.87 (s, 3H), 3.07 (m, 2H), 3.63 (t, J=4.6, 4H), 3.84 (t, J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.61 (s, 2H), 7.39 (s, 1H), 7.43 (t, J=8.2, 1H), 7.51 (d, J=8.3, 1H), 8.20 (d, J=6.8, 1H), 8.94 (s, 1H), 10.30 (brs, 1H). MS: ESI+: MH+ 572.09
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13]>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1CCO
Temperature: 900 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Triton B (4 ml, 35% in MeOH) was added to a mixture of 4-chloro-2-nitrotoluene (50 g, 291 mmol) and paraformaldehyde (3.8 g, 120 mmol) in DMSO (40 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) and stirred for 2.5 h at 900° C. It was neutralized with a few drops of conc. HCl, diluted with H2O (100 ml) and extracted using EtOAc (5×150 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The oily residue was purified by sublimation in a high vacuum (p=0.1 torr, oil bath temperature 1100° C.). 2-(4-chloro-2-nitrophenyl)ethanol (13.23 g, 55%) was obtained in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([C:15]2[N:16]=[C:17]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:30][N:18]3[C:19](=[O:29])[C:20]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=O)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[CH2:22]([O:21][C:20]1[C:19](=[O:29])[N:18]2[CH:30]=[C:31]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:32]=[CH:33][C:17]2=[N:16][C:15]=1[C:13]1[O:14][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:11][N:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1c(OCc2ccccc2)c(-c2nnc(Cc3ccc(F)cc3)o2)nc2ccc(CN3CCOCC3)cn12
Reaction time: 8 h
Yield: 80.4 %

Procedure:
The product of example 16 (250 mg, 0.46 mmol), carbon tetrachloride (354 mg, 2.3 mmol) and triethylamine (116 mg, 1.15 mmol) were mixed in acetonitrile (15 ml). To the above mixture was added triphenylphosphine (302 mg, 1.15 mmol) at room temperature and stirred overnight. Then water (50 ml) was added and the mixture was extracted with dichloromethane three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated into dryness. The residue was subjected to silica gel chromatography using PE-ethyl acetate (1:4 v/v) as eluent to give the titled product (195 mg, 80.7%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13]([N:41]1[CH2:42][CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40]1)=[O:14])[CH3:2]
Reactant: CN(C)C1CCCNC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCCC(N(C)C)C2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 130 mg (1.01 mmol) dimethyl-piperidin-3-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Br:11]Br>Br.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrBr
Agent: Br
Solvent: c1ccccc1
Product: N#CC(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
4-Chlorophenylacetonitrile (303.2 g., 2.0 mole) is heated to 90°C. on a steam bath and 48% hydrobromic acid (5drops) is added. Bromine (336 g., 2.1 mole) is then added dropwise to the stirred melt over a 1-hour period at 90° -95°C. The reaction mixture is heated an additional 15 minutes and then cooled. Benzene (300 ml.) is then added and 100 ml. of the benzene is removed by distillation at 80°C. The solution is cooled, filtered and the benzene removed to afford 435.5 g. of crude product which is extracted with 3 liters of hexane at 50°-55°C. Isopropanol (100 ml.) is added to the hexane solution which is then cooled to 25°C. The product is collected by filtration to afford 235.2 g. (57% yield) of 4-chlorophenyl-α-bromoacetonitrile, m.p. 46°-49°C.
Reaction SMILES: C([O:8][C:9](=[O:59])[CH2:10][CH2:11][C:12]([O:14][C:15]1([CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:51][C@H:50]([CH2:52][NH:53][C:54](=[O:56])[CH3:55])[O:49][C:48]3=[O:57])=[CH:43][C:42]=2[F:58])[CH2:20][CH2:19][N:18]([C:21]2[C:30]([F:31])=[CH:29][C:28]3[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]4[CH2:38][CH2:37]4)[C:23]=3[N:22]=2)[CH2:17][CH2:16]1)=[O:13])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].O1CCCC1.CO>[C:54]([NH:53][CH2:52][C@@H:50]1[O:49][C:48](=[O:57])[N:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH2:39][C:15]3([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([OH:59])=[O:8])[CH2:16][CH2:17][N:18]([C:21]4[C:30]([F:31])=[CH:29][C:28]5[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]6[CH2:38][CH2:37]6)[C:23]=5[N:22]=4)[CH2:19][CH2:20]3)=[C:42]([F:58])[CH:43]=2)[CH2:51]1)(=[O:56])[CH3:55]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 3 step 5 with 22 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-piperidin-4-yl ester benzyl ester (MW: 817.80, 0.026 mmol) and 2 mg of palladium hydroxide 20% on activated carbon in 20 ml of a 1/1 tetrahydrofuran/methanol mixture. Yield: 16 mg, 81%. MS: 729 (M+H)+, 727 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.P(Cl)(Cl)[Cl:17]>C(Cl)(Cl)Cl>[Cl:17][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: ClP(Cl)Cl
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Cl)CC(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (3.0 g) in chloroform(10 ml) was added phosphorus trichloride (0.62 g), and the mixture was stirred at 100° C. for 2.5 hours. To the mixture was added phosphorus trichloride (0.62 g), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ice-water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give 3-chloro-5-(2-chlorophenyl)-2-cyclohexen-1-one, which was dissolved in ethanol (3 ml). To the solution were added sodium sulfide 9 hydrate (2.0 g) and water (3 ml), and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in water, and the solution was washed with diethylether. To the aqueous layer was added 4N hydrochloric acid to make the solution acidic, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give oil of 5-(2-chlorophenyl)-3-mercapto-2-cyclohexen-1-one (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH3:12])=[CH:5][C:4]=1[N+:13]([O-])=O.[Sn].[ClH:17]>>[ClH:17].[NH2:13][C:4]1[CH:5]=[C:6]([CH3:12])[CH:7]=[C:8]([NH2:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Product: COc1c(N)cc(C)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methoxy-5-methyl-1,3-dinitrobenzene (0.050 g, 0.236 mmol) was suspended in conc. Hydrochloric acid (1.2 mL). Tin granules (0.118 g, 0.995 mmol) were added slowly to the mixture with stirring at room temperature. After 2 hours, the solution turned white (all the tin granules were dissolved), the solution was cooled to 4° C. The product was collected as a white precipitate and recrystallized from hot water-concentrated hydrochloric acid. Yield=0.037 g (70%) from 0.050 g 2-Methoxy-5-methyl-1,3-dinitrobenzene. White flakes; mp 226° C. (dec); 1H NMR (DMSO) δ: 6.57 (s, 2H), 3.91 (s, broad, 6H), 3.72 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: C(O)C.Cl.[C:5]([N:13](C)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=1)(=O)C1C=CC=CC=1>O>[CH3:5][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CN(Cc1ccc(S(C)=O)cc1)C(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCc1ccc(S(C)=O)cc1
Yield: 84.1 %

Procedure:
To a mixture of ethanol (40 ml), water (20 ml) and conc. hydrochloric acid (60 ml), N-benzoyl-N-methyl-N-(4-methylsulfinylbenzyl)amine (4.1 g) is added and the mixture is heated with refluxing for 12 hours. After the reaction, the solvent is distilled off under reduced pressure, and to the resulting residue is added 20 % aqueous sodium hydroxide solution, and the mixture is extracted with diethyl ether. The extract is washed successively with water and aqueous sodium chloride solution, and dried over magnesium sulfate. Diethyl ether is distilled off to give N-methyl-N-(4-methylsulfinylbenzyl)amine (2.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)C(=O)c2ccc(N)cc2)cc1
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3nc2-c2ccc(N)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 1.0 g (4.17 mmole) of 4,4′-diaminobenzil and 0.45 g of o-phenylenediamine in 250 ml glacial acetic acid was heated at 50° C. for 15 mins., then stirred for 16 hours at room temperature. The mixture was then heated to 80° C. and allowed to cool slowly. The solvent was removed under vacuum and the residue was redissolved in ethanol and that was removed under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,3-dichlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 588.7 ([M+H]+)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=[NH:32])[NH2:31])[CH:24]=1.Cl.C(CC1C=C(C=CC=1)C(N)=O)(=N)N>C1COCC1.O>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]2[NH:31][CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)[N:32]=2)[CH:24]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cccc(CC(=N)N)c1
Agent: Cl
Agent: N=C(N)Cc1cccc(C(N)=O)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cc2nc(-c3ccc(C#N)cc3)c[nH]2)c1
Yield: 129.4 %

Procedure:
Suspend 4-(2-bromo-acetyl)-benzonitrile (0.11 g, 0.48 mmol), K2CO3 (0.28 g, 2.00 mmol) and a 2:1 mixture of 3-carbamimidoylmethyl-benzoic acid methyl ester hydrochloride/3-carbamimidoylmethyl-benzamide hydrochloride (0.14 g) into 5 mL of 4:1 THF/H2O. Heat the mixture to reflux for 2 h. Concentrate the mixture to dryness and dissolve into 20 mL of H2O. Add 5% aq HCl until pH is acidic. Extract with 2×20 mL of CH2Cl2. Dry organic phase with MgSO4, filter and concentrate to give 0.13 g of crude 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzoic acid methyl ester and 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzamide as a purple residue.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39].O>CN(C=O)C>[CH2:36]([N:37]([CH2:40][CH3:41])[CH2:38][CH2:39][O:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:35]
Reactant: O=c1c2ccccc2nc(C=Cc2cccc(O)c2O)n1-c1ccccc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1c(O)cccc1C=Cc1nc2ccccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.3 %

Procedure:
To a solution of 75 (0.85 g, 0.023 mol) and K2CO3 (0.45 g, 0.003 mol) in DMF (5 mL) was added (2-chloro-ethyl)-diethyl-amine (0.37 g, 0.025 mol). The reaction mixture was stirred at RT for 10 hours, poured into water. The precipitate formed was filtered off, washed with water and purified by column chromatography on silica gel using EtOAc/hexane 1:4 as eluent to yield 76 (0.14 g, 15%). M. Wt. 455. LCMS [M+H]+=456.