Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:46])([CH:43]([F:45])[F:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[CH:40][NH:39][C:38]4=[O:42])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:39]1[CH:40]=[CH:41][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:46])[CH:43]([F:45])[F:44])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[CH:36][CH:35]=2)[C:38]1=[O:42])[CH3:13]
Reactant: O=c1[nH]ccn1-c1ccc(N2CCN(c3ccc(OCC(F)(F)C(F)F)cc3)CC2)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(N3CCN(c4ccc(OCC(F)(F)C(F)F)cc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 16.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.44 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.48 g of 1-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)imidazolone, 0.11 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)-imidazolone was obtained as a colorless powder.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:15]([NH:18][C:19]1[S:20][C:21]([C:25](=[O:28])[CH2:26]Br)=[C:22]([CH3:24])[N:23]=1)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:26][CH:25]([OH:28])[C:21]2[S:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:23][C:22]=2[CH3:24])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(CCN)cc1
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCNCC(O)c2sc(NC(C)=O)nc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carboethoxyphenyl)ethylamine and stoichiometric amounts of triethylamine with 2-acetylamino-4-methyl-5-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=19:1 as eluant and trituration with ether.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH3:32])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2.[CH:38](OC1C=CC=CC=1)=[O:39]>C1COCC1>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH2:32][CH:38]=[O:39])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2
Reactant: COCOc1ccc(-c2c(C)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Reactant: O=COc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(-c2c(CC=O)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a clean dry 200 ml flask purged with nitrogen was added diisopropylamine (2.7 ml, 19.5 mmol, 3 eq), dry THF (50 mL) and 3-(2,4-Bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (8.1 mL, 16.25 mmol, 2.5 eq.) at −78° C. After 30 minutes, to this solution was added drop-wise, a solution of 3-(2,4-bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (2.7 g, 6.5 mmol, 1 eq.) in dry THF (13 mL). The solution was warmed to −10° C. and stirred at this temperature for 30 minutes. Phenyl formate (3.6 ml, 33 mmol, 5 eq) was then added slowly into the reaction mixture. The reaction mixture was then stirred for 30 mins, quenched with saturated aqueous NH4Cl, extracted with ethyl acetate and then concentrated to yield th title product as a crude solid which was purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2cc(OC)cc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (3.9 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3,5-dimethoxyphenylboronic acid (10.0 g), copper acetate (10.0 g) and pyridine (8.9 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.0 g, 40%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1

Procedure:
(E)-2-(4-Phenylphenyl)ethenylpyridine-4-carboxylic acid (3.60 g) and a mixture of concentrated sulfuric acid/ethanol (9:1) were refluxed under heating for 2 hr, and neutralized under ice-cooling. The reaction mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-4/1) to give the objective compound (3.14 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:14]=[C:13]([C:15](Cl)=[O:16])[O:12][N:11]=1)[CH3:9].O.Cl>ClCCl>[CH2:8]([C:10]1[CH:14]=[C:13]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[O:12][N:11]=1)[CH3:9]
Reactant: CCc1cc(C(=O)Cl)on1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(=O)Nc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
11.7 g of aniline are added dropwise to 10.0 g of 3-ethylisoxazole-5-carbonyl chloride in 150 ml of dichloromethane, while cooling with ice. The mixture is stirred overnight at room temperature, water and concentrated hydrochloric acid are added and the organic phase is separated off, washed with sodium bicarbonate solution and evaporated down to give 11.8 g of 3-ethylisoxazole-5-carboxanilide as colorless crystals of melting point 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35](Br)[CH3:36])(=[O:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30]([NH:33][C:34](=[O:38])[CH:35]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[CH3:36])(=[O:31])=[O:32]
Reactant: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Br)c1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)c1
Temperature: 45 °C

Procedure:
To a stirred solution of 0.75 g (0.0026 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.89 g (0.0026 mole) of N-(2,5-dimethoxyphenylsulfonyl)-2-bromopropionamide in 50 mL of acetone was added 1.04 g (0.0026 mole) of potassium carbonate. After complete addition the mixture was heated at 45° C. for two days. The resultant mixture was cooled and the solvent was removed by evaporation under reduced pressure to leave a residue. This residue was dissolved in 100 mL of water. The aqueous solution was acidified by the dropwise addition of concentrated hydrochloric acid producing a precipitate. The precipitate was collected by filtration. The filter cake was washed with water and then dried under reduced pressure to leave 1.23 of N-(2,5-dimethoxyphenylsulfonyl)-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide (mp 168°-172° C.) Compound C90.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:10]=[C:9]([N:8]2[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]=[C:4]2[CH:1]([CH3:2])[CH3:3])[N:17]=3)[CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32]
Reactant: CC(C)N1CCNCC1=O
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.37 mmol), 1-isopropylpiperazin-2-one (0.078 g, 0.44 mmol) and 4 Å molecular sieves (0.372 g) in DCE (3 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 555 as an off-white solid (0.168 g, 84%). LCMS (Method I): RT=3.43 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d6): δ 7.93-7.89 (m, 1 H); 7.68-7.63 (m, 1 H); 7.28-7.23 (m, 2 H); 4.64-4.58 (m, 1 H); 4.29-4.21 (m, 4 H); 3.97-3.90 (m, 1 H); 3.90 (d, J=4.6 Hz, 2 H); 3.80 (s, 3 H); 3.78 (t, J=4.6 Hz, 4 H); 3.21-3.15 (m, 4 H); 2.78-2.75 (m, 2 H); 1.36 (d, J=6.8 Hz, 6 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:16]([F:19])([F:18])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:22])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4 H), 3.20-3.80 (m, 4 H), 7.29-7.36 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]1([CH:13]=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][CH2:13][CH:10]2[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1N
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc(Cl)ccc1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a dry flask, 6-chloro-2-methylpyridin-3-amine (200 mg, 1.40 mmol) and cyclopropanecarbaldehyde (116 μl, 1.54 mmol) were taken up in 1,2-dichloroethane (5.6 ml) under argon. The resulting clear solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.47 g, 2.10 mmol) and acetic acid (160 μl, 2.81 mmol) were sequentially added to the reaction mixture, which was stirred as such for 24 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted three times with dichloromethane. All organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)[CH3:2].[C:34]([O-])([O-])=[O:35].[K+].[K+].C(Cl)(Cl)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:34]1=[O:35])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc2c(c1)OCC2
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2-11 (11.8 mmol), CH2Cl2 (3 mL) and 20% K2CO3 was added phosgene (1.93 M toluene, 6.7 ml, 13.0 mmol) dropwise over 20 minutes. After stirring for 30 minutes, the organic layer was separated and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 5-10% methanol/ethyl acetate) to give 2-12 as a yellow oil. TLC Rf =0.25 (silica, 70:20:10 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 6.34 (d, J=7.3 Hz, 1H), 5.46 (t, J=7.9 Hz, 1H), 4.74 (s, 1H), 4.55 (t, J=8.9 Hz,2H), 4.10 (q, J=7.3 Hz, 2H), 3.41 (m, 2H), 3.21 (m, 6H), 2.95 (m,3H), 2.67(t, J=6.1 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 1.88 (m, 5H), 1.20 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(OCC)(=O)C>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][S:29][C:24]1[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=1)=[O:6])#[N:2]
Reactant: Fc1ccc(S)cc1F
Reactant: N#CCNC(=O)C1CCCCC1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#CCNC(=O)C1CCCCC1CSc1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of N-cyanomethyl 2-bromomethylcyclohexanecarboxamide (3.0 g, 11.58 mmol) in acetone (100 mL) at room temperature were added, in two portions, cesium carbonate (5.77 g, 17.5 mmol) and the crude 3,4-difluorothiophenol (2.69 g, 18.4 mmol). After 16 h, ethyl acetate (100 mL) was added. The solution was washed with 1M HCl (40 mL), brine (20 mL), evaporated, and purified on a short plug of silica gel (30% ethyl acetate/hexane to elute non-polar impurities, then 20-30% ethyl acetate/dichloromethane to give N-cyanomethyl 2-(3,4-difluorophenylsulfanylmethyl)-cyclohexanecarboxamide.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[Cl:23])(=O)C1C=CC=CC=1.[CH:24]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)CCC.Cl>C(OCC)(=O)C>[ClH:23].[CH:24]1([N:29]([C:19]2[N:18]=[CH:17][N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Reactant: Cc1ccc(C)c(CNC2CCCC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(C)c(CN(c2ncnc3c2ncn3COCCO)C2CCCC2)c1
Yield: 75 %

Procedure:
A mixture of 9.0 g. (27 mmole) 9-[(2-benzoyloxyethoxy)-methyl]-6-chloropurine, 16.5 g. (81 mmole) N-cyclopentyl-(2,5-dimethylbenzyl)-amine and 130 ml. butanol is heated under reflux for 16 hours. The reaction mixture is evaporated, the residue is taken up in dichloromethane, washed with dilute acetic acid and subsequently with water, dried over anhydrous sodium sulphate, evaporated, mixed with a solution of 3.3 g. sodium in 200 ml. methanol, heated under reflux for 3 hours, evaporated and the residue taken up in water, extracted with dichloromethane, dried over anhydrous sodium sulphate and evaporated. After chromatography on silica gel with an elution mixture of 95% dichloromethane and 5% methanol, there are obtained 8.0 g. of the title compound (75% of theory) in the form of an oily base, the hydrochloride of which, prepared in ethyl acetate, melts at 132°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[NH:10][C:9]([C:14]([O:16]C)=O)=[CH:8]2.[NH3:18].CO>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[NH:10][C:9]([C:14]([NH2:18])=[O:16])=[CH:8]2
Reactant: COC(=O)c1cc2cccc(OC)c2c(=O)[nH]1
Reactant: N
Solvent: CO
Product: COc1cccc2cc(C(N)=O)[nH]c(=O)c12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a vessel containing NH3/MeOH (20 mL) was added methyl 8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (800 mg, 3.43 mmol). The vessel was sealed and the solution was stirred at 50° C. for 16 hours. The reaction mixture was subsequently concentrated in vacuo to give the title compound, which was used without further purification (800 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.80 (s, 1H), 7.66 (t, 1H, J=8.0 Hz), 7.19-7.22 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 3.85 (s, 3H); ESI-MS m/z [M+H]+219.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:14]([S:11]([C:4]1[CH:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])(=[O:13])=[O:12])[CH3:15]
Reactant: CCS(=O)(=O)c1cc(Cl)cc(C)c1C#N
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 150 °C
Yield: 96 %

Procedure:
4-Chloro-2-(ethylsulfonyl)-6-methyl-benzonitrile (0.43 g, 1.77 mmol), morpholine (0.46 ml, 5.31 mmol) and potassium carbonate (0.32 g, 2.30 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 150° C. for 2 d. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.50 g, 1.70 mmol, 96%).
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:11][C@H:3]([CH3:2])[CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
Reflux a mixture of (R)-1-methyl-2-morpholin-4-yl-ethylaminehydrochloride (0.04 mol, 8.7 g), 5-bromo-2-fluoronitrobenzene (0.048 mol, 10.5 g), triethylamine (0.20 mol, 20.2 g) and dimethylaminopyridine (0.0004 mol, 0.048 g) in ethyl acetate (220 mL) for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 10% ethyl acetate in hexanes as eluent to obtain the title compound (12.8 g, 95%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 1.29 (d, 3H), 2.47-2.51 (m, 5H), 2.53-2.58 (m, 1H), 3.64-3.69 (m, 4H), 3.72-3.78 (m, 1H), 6.78 (d, 1H), 7.46 (dd, 1H), 8.30 (d, 1H), 8.33 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 53 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.63 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.38 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)[CH:27]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: Br
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3cccc(-c4ccccc4)c3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 496.5. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 87.7%).