Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12](Cl)[O:13][CH3:14]>CN(C=O)C>[CH3:12][O:13][CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To the suspension of NaH (3.25 g, 0.135 mol) in DMF (150 mL) was added 4-hydroxy-benzaldehyde (15.0 g, 0.123 mol) in DMF (10 mL) at 0° C., 5 min. later the reaction mixture became a cake. The heterogeneous mixture was stirred at 0° C. for 30 min. MOMCl (9.96 g, 0.123 mol) was added slowly and the reaction mixture was allowed to warm up to r.t. After stirring at r.t. for 16 h, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the water layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:4) to afford 4-methoxymethoxy-benzaldehyde (19.0 g, 93%): 1H NMR (300 MHz, CDCl3): δ 9.94 (s, 1H), 7.88 (m, 2H), 7.18 (m, 2H), 5.29 (s, 2H), 3.53 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:4); Rf=0.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH3:23])[CH3:20].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[C:7]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[CH:36][CH:35]=3)[C:6]=2[CH:18]=1
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-chloro-2-(4-methoxyphenyl)benzofuran (1 g, 3.9 mmol) in DCM (100 mL) was stirred at 0° C. under nitrogen. The compound of Example 2(iii) (1.68 g, 6.9 mmol) was added followed by the drop-wise addition of tinIV chloride solution (1M DCM, 11.6 mmol). The colour became a deep red and the reaction was stirred at RT. for 3 hrs. The resulting suspension was poured onto ice-water (250 mL) and the organic portion separated. The aqueous layer was extracted with DCM and the organic portions were combined, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography to give the title compound as a yellow tar (1.34 g, 72%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1.O1CCOCC1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:15]=[C:5]=[O:11])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 1 h
Yield: 144.1 %

Procedure:
21.16 g of triphosgene are dissolved in 100 mL of anhydrous toluene in a 500 mL four-neck bottle equipped with a nitrogen intake, a magnetic stirrer, a condenser and a guard filled with 2 N sodium hydroxide. A solution of 20 g of 4-amino-2-trifluoromethylbenzonitrile in 125 mL of anhydrous dioxan is added dropwise at ambient temperature in 1 hour 30 min. The mixture is heated to 110° C. Pronounced release of gas for 1 hour then appearance of an insoluble brown substance. After 2 hours under reflux, stirring is maintained overnight at AT. The insoluble matter is filtered and rinsed with toluene. The filtrate is concentrated in order to obtain 21.8 g of expected product (Yd=96%). The product is stored in solution in THF (2 M) in a refrigerator.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)N(CCCl)CCCl
Reactant: COC(=O)[C@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 44.1 %

Procedure:
A solution of 6 g (23.6 mmol) of methyl (R)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 5.2 g (23.6 mmol) of N,N-bis(2-chloroethyl)methanesulphonamide in 80 ml of N,N-diisopropylethylamine is heated at 125° C. with vigorous stirring for 18 h. After addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 3.8 g (44%) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: COC1C=CC(CO[C:9](=O)[C@H:10]([N:17]2[CH2:21][C@H:20](C3C=CC=CC=3)[C@@H:19]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:31][CH2:30]3)[CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14]C[CH2:12]2)=CC=1.[CH:47]([OH:49])=[O:48]>>[CH2:37]([O:36][CH2:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C@@H:19]2[C@@H:20]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:21][N:17]([C@@H:10]3[CH2:9][CH2:14][CH2:15][CH2:16][CH:11]3[CH2:12][C:47]([OH:49])=[O:48])[CH2:18]2)[CH2:30][CH2:31]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(COCc4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Reactant: O=CO
Product: O=C(O)CC1CCCC[C@H]1N1C[C@H](CN2CCC(COCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of α-(R)-(3-(S)-((4-(benzyloxymethyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid para-methoxybenzyl ester (30 mg, 0.048 mmol) in 96% formic acid (2.0 mL) was stirred at RT. After 2 h, the formic acid was evaporated at reduced pressure. Toluene was added and evaporated, and this was repeated with a second portion of toluene. The crude product was purified by flash column chromatography on silica gel packed in CH2Cl2. Elution with 5% CH3OH/1% conc. aq. NH4OH/CH2Cl2 followed by 10% CH3OH/2% conc. aq. NH4OH/CH2Cl2 gave 19 mg of the title compound as a colorless brittle glass. 1H NMR (400 MHz, CD3OD): δ 7.39-7.22 (m, 10H), 4.45 (s, 2H), 3.59 (dd, J=11, 8 Hz, 2H), 3.48 (d, J=4 Hz, 1H), 3.46-3.35 (m, 1H), 3.28 (d, J=6 Hz, 2H), 3.12 (td, J=10, 8 Hz, 1H), 2.93 (bd, J=11 Hz, 1H), 2.81-2.71 (m, 2H), 2.49 (dd, J=12, 10 Hz, 1H), 2.33 (dd, J=12, 3 Hz, 1H), 2.03 (bt, J=11 Hz, 1H), 1.92-1.12 (m, 18H); ESI−MS 505 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([NH2:14])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=[O:28]>C1C=CC=CC=1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]([NH:14][C:12]1[O:11][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH:13]=1)=[O:28]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)no1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(-c2cccc(C(F)(F)F)c2)no1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3-(Trifluoromethyl)phenyl)-5-aminoisoxazole (2.5 grams), triethylamine (1.5 grams) and 50 ml. benzene were placed in a 100 ml. flask. Next, 2,6-difluorobenzoylchloride (2.6 grams), dissolved in 5-10 ml. benzene, was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 2 hours and was then warmed to 60° C. for about 18 hours. Following this, the mixture was washed with dilute sodium bicarbonate, water, brine, and then dried over MgSO4. The final product was first filtered, recrystallized from benzene/pentane, and then dried, m.p. 123°-126° C.
Reaction SMILES: N1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2C=CC=N1.[H-].[Na+].[Br:14][CH2:15][C:16]([CH2:18]Br)=[O:17]>>[CH:6]1([CH2:18][C:16]([CH2:15][Br:14])=[O:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: O=C(CBr)CBr
Agent: [H-]
Agent: [Na+]
Product: O=C(CBr)CC1CCCCC1
Yield: 231.9 %

Procedure:
This was prepared following the method of Example 1B, using the Bock benzodiazepine (250 mg, 0.62 mmol), sodium hydride (26 mg of an 80% dispersion in oil, 0.87 mmol) and the bromomethylketone of Example 32A (219 mg, 1 mmol). The crude product was purified by flash chromatography on silica gel eluant (EtOAc:hexane fr 35:65 v/v) to afford the title compound as a colourless crystalline solid (315 mg, 97%).
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].BrC[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH:1]=[O:4])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1cc(I)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(I)cc1[N+](=O)[O-]
Temperature: 86 °C
Reaction time: 19 h
Yield: 60.9 %

Procedure:
NaHCO3 (3.32 g, 39.48 mmol) was added to a solution of 1-bromomethyl-4-iodo-2-nitrobenzene (2.25 g, 6.58 mmol) in anhydrous DMSO (150 mL). The mixture was stirred at 86° C. for 19 hours under a nitrogen atmosphere, then cooled down to room temperature, diluted with water (300 mL), and extracted with methylene chloride four times (250 mL). The combined organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 4-iodo-2-nitrobenzaldehyde (1.11 g, 61%). 1HNMR (400 MHz, CDCl3): δ 10.38 (d, 1 H, J=1.6 Hz, CHO), 8.45 (d, 1 H, J=1.5 Hz, Ph-H), 8.15 (dd, 1 H, J=1.5 and 8.0 Hz, Ph-H), 7.67 (d, 1 H, J=8.1 Hz, Ph-H); 13C NMR (100 MHz, CDCl3): δ 187.28 (CH), 143.18 (CH), 133.29 (CH), 130.67 (CH), 130.28 (C), 109.60 (C), 99.78 (C).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[CH:15][CH:14]=1.[Cl:29]CCl>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:29])=[O:22])=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
To (0.05 mol) of 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid in dichloromethane solution (500 mol) and chilled in an ice bath is added thionyl chliride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10][CH3:11].C([Li])CCC.CON(C)[C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]>C1COCC1.CCCCCC>[CH3:11][O:10][CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][C:6]([C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[CH:7][CH:2]=1
Reactant: COC=Cc1ccccc1Br
Reactant: C=CCCCCCCCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)c1ccc(C=COC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-bromo-(2-methoxyethenyl)benzene (2.13 g) in THF (20 ml) at -78° is added dropwise a 2.5M solution of n-butyllithium in hexane (4.2 ml). The temperature is not allowed to rise above -55°. After 90 min, a solution of N-methoxy-N-methyl-10-undecenamide (2.3 g) in THF (5 ml) is added dropwise, and the mixture stirred an additional 60 min at -78°. The mixture is not allowed to warm, but is immediately quenched by the addition of 10% aqueous citric acid. The mixture is extracted with dichloromethane, and the extracts are dried, filtered, and concentrated. The crude product is chromatographed with 1:1 dichloromethanehexane, to provide 1-(4-(2-methoxyethenyl)phenyl)-10-undecen-1-one as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]=[CH:5][C:4](=[O:8])[CH2:3]1>[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1
Reactant: CC1(C)CC=CC(=O)C1
Agent: [Pd]
Product: CC1(C)CCCC(=O)C1

Procedure:
(a') A catalytic hydrogenation of 3,3-dimethyl-cyclohex-5-en-1-one was carried out according to the usual techniques in the presence of palladium on charcoal and yielded 3,3-dimethyl-cyclohexanone. The subsequent ethylination by means of acetylene in a basic medium gave 1-ethynyl-1-hydroxy-3,3-dimethyl-cyclohexane in about 50% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (10.2 g, 67 mmol) in acetonitrile (250 mL) was added potassium carbonate (27.6 g, 200 mmol) and methyl iodide (4.1 mL, 66 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the solid was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (250 mL). The solution was washed with 2N NaOH (aq.) (200 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to yield 1-methoxy-2-methyl-4-nitrobenzene (9.5 g, 57 mmol, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH3:14]>O1CCOCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:14])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cc(S(N)(=O)=O)ccc1F
Reaction time: 0.5 h

Procedure:
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) in 1,4-dioxane (10 mL) at 0° C. was treated dropwise with a 7 M ammonia solution in methanol (3.57 mL) and stirred for 30 minutes. A small amount of solid was removed by filtration and discarded. The filtrate was concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and triturated with diethyl ether to give the product.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(OC(F)F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)F)c1
Yield: 46.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 520 mg of 3-(difluoromethoxy)aniline in place of the 2,4-difluoroaniline. 135 mg of N-[3-(difluoromethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1[N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[SH:38].O>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH:2]([S:38][C:34]2[NH:35][CH:36]=[CH:37][N:33]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Sc1nccn1-c1ccccn1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Solvent: O
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1C(Sc1ncc[nH]1)c1ccccn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
2.3 g (5.6 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine and 1.0 g (5.6 mmol) of 1-pyridin-2-yl-1H-imidazole-2-thiol in 100 ml of isopropanol are heated under reflux for 2 h under a nitrogen atmosphere. The mixture is then cooled to room temperature, treated with 1 l of water and extracted with 4×200 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia=19:1:0.6). The fractions of Rf =0.35 are concentrated and crystallized from methanol. 0.45 g of the title compound is isolated as a pale beige solid. M.p. 146-149° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[C:4]=1[CH3:33].[H-].[Na+].[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)[CH2:38][CH2:37]1>CS(C)=O>[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2/[CH:43]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[C:4]([CH3:33])[N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:37][CH2:38]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1sc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n2c1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.00 mmol) in dry DMSO (12 ml) was treated with NaH (89 mg, 2.240 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (462 mg, 2.240 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 600 mg of the desired compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.32-0.35 (m, 2H), 0.54-0.58 (m, 2H), 1.15-1.21 (m, 1H), 2.26 (s, 3H), 2.59 (s, 3H), 3.73-3.75 (m, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 6.99-7.00 (m, 3H), 7.29-7.31 (m, 1H), 8.03 (d, J=16.2 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:14]=[C:15]1[O:18][C:17](=[O:19])[CH2:16]1>ClCCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:19])[CH2:16][C:15](=[O:18])[CH3:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Solvent: ClCCCl
Product: CC(=O)CC(=O)Nc1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirred solution of 10 parts of 4-[(1H-imidazol-1-yl)methyl]benzenamine in 180 parts of 1,2-dichloroethane were added dropwise 3.9 parts of 4-methylene-2-oxetanone. After stirring for 1/2 hour at room temperature, the precipitate was filtered off, washed with 1,2-dichloroethane and dried, yielding 9.8 parts (74.8%) of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide; mp. 175° C.(interm. 57). In a similar manner there were also prepared the intermediates listed in Table 4:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=O)[NH:10][C:11]=2[CH:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=[S:26])[NH:10][C:11]=2[CH:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)NC(=O)C1CCCC21
Product: COc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 77.5 %

Procedure:
Analogously to Example 4, 7-methoxy-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (180 mg, 0.83 mmol) is reacted with Lawesson's reagent (370 mg, 0.91 mmol) to form 150 mg (78%) of product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCSc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCSc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenylthiopropyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenylthio)propyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][NH:23][OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]=[C:28]=[O:29]>O1CCOCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][N:23]([C:28]([NH:27][CH3:26])=[O:29])[OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccccc1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Reaction time: 12 h

Procedure:
2-(3-Phenylpropyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (498 mg, 1.5 mmol) is dissolved in dioxane (15 mL) and methyl isocyanate (0.22 mL, 3.7 mmol) is added. After 12 hours, the reaction mixture is diluted with EtOAc (150 mL) and the organic phase washed with 2N HCl (2×200 mL), H2O (4×200 mL), saturated NaHCO3 solution (2×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes and recrystallized from CH2Cl2 /hexanes to give 2-(3-phenyipropyl)-6-{2-[N-(methylaminocarbonyl)-N-hydroxyamino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-139°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]2([CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]2([CH2:55][CH2:54][N:53]([C:32]([N:12]3[C@@:13]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[C@@:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([CH3:16])[N:15]=[C:11]3[C:8]3[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=3[O:35][CH2:36][CH3:37])=[O:33])[CH2:52][CH2:51]2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (Syntech Labs) to give the title compound. HR-MS (ES, m/z) calculated for C43H56Cl2N5O4 [(M+H)+] 776.3704, observed 776.3699.