Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>N1C=CC=CC=1>[N:1]1([C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(N2CCOCC2)c2cccnc12
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(N2CCOCC2)c2cccnc12
Yield: 77.8 %

Procedure:
In a similar fashion using route 18 general procedure 26, 5-morpholin-4-yl-quinolin-8-ylamine 581 (154 mg, 0.67 mmol), 2-nitrobenzenesulfonyl chloride (148.86 mg, 0.67 mmol), and pyridine (1 ml) gave the title compound (216 mg, 78%) after purification by column chromatography with DCM/MeOH (100%-98:2 gradient) as the eluent.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=4)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.04 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), anhydrous potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.25 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 195-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12]C)=[C:6]([CH2:8][C:9](=O)[CH3:10])[CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]([CH3:10])=[CH:8][C:6]=2[CH:7]=1
Reactant: COc1ccc(Br)cc1CC(C)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc2cc(Br)ccc2o1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
(5-Bromo-2-methoxyphenyl)acetone (6.6 g, 28.6 mmol) was dissolved in methylene chloride (50 ml) and cooled to −70° C. Thereto was dropwise added a 1 M solution (28.6 ml, 28.6 mmol) of boron tribromide in methylene chloride over 15 min. After the dropwise addition, the mixture was heated to room temperature and stirred for 1.5 hr. Then, the reaction mixture was ice-cooled and water (50 ml) was added. The insoluble matter was filtered off and the filtrate was partitioned. The aqueous layer was extracted with methylene chloride. The organic layers were combined, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1) to give the objective compound (3.45 g, 57%) as a colorless liquid.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[CH2:37])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]2[O:1][N:2]=[C:3]([C:4]3[N:5]=[C:6]([CH:9]4[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]4)[S:7][CH:8]=3)[CH2:37]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C=Cc1ccccc1OCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OCC4CCCCC4)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.90 g) and 1-(cyclohexylmethoxy)-2-vinylbenzene (2.40 g) in ethyl acetate (300 ml) were added, at room temperature, potassium hydrogencarbonate (4.60 g) and N-chlorosuccinimide (1.48 g), and then one drop of water. The reaction mixture was stirred at 60° C. for 6 h, then admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate (3.40 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:49][CH2:50][N:51]([CH3:59])[C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>C1COCC1>[CH3:59][N:51]([CH2:50][CH2:49][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:57])[CH3:56]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.8 mmol), bis(1-methylethyl) (E)-1,2-diazenedicarboxylate (5.73 g, 28.3 mmol), triphenylphosphine (7.43 g, 28.3 mmol) and 1,1-dimethylethyl (2-hydroxyethyl)methylcarbamate (4.52 g, 25.8 mmol) were dissolved in THF at 0° C. under nitrogen and the resulting mixture was stirred at this temperature for 4 h, then evaporated in vacuo and the residue triturated with MTBE. The precipitated solid was removed by filtration and the filtrate evaporated in vacuo, then purified by chromatography on silica gel (gradient:0-100% EtOAc in Hexanes) to give 1,1-dimethylethyl methyl{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}carbamate (4.85 g, 13.81 mmol, 53.6% yield) as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[ClH:23].[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH2:39][NH:1][CH:2]4[CH2:3][CH2:4][N:5]([CH2:8][C:9]5[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])=[CH:11][CH:10]=5)[CH2:6][CH2:7]4)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC(N)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(CN2CCC(NCc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 168 h
Yield: 42.4 %

Procedure:
4-[(4-Amino-1-piperidinyl)methyl]-N,N-diethylbenzamide (3.81 g, 13.16 mmol) and 4-[(7-chloro-4-quinolinyl)amino]benzaldehyde hydrochloride (13.16 mmol, 4.20 g) are refluxed for 28 hours in 52 mL of toluene under nitrogen with azeotropic removal of water. The toluene is poured off the thick oil, which is then rinsed once with fresh toluene. The remaining traces of solvent are removed in vacuo and the resulting gum is dissolved in 55 mL of ethanol and treated with NaBH4 (14.6 mmol, 552 mg). The reaction mixture is refluxed for 50 minutes, treated with another 200 mg of NaBH4 and refluxed an additional 10 minutes. The reaction mixture is poured over 100 mL of ice, which results in the formation of an orange oil. After stirring rapidly for seven days, the water is decanted and the oil is purified by flash chromatography on silica gel (65 mm column, 5% ammonia saturated methanol in methylene chloride eluent) which affords 1.55 g (2.79 mmol, 21% yield) of the title compound as the free base. Of this, 0.95 g (1.7 mmol) are dissolved in 5 mL of methanol and treated with 1.7 mL of 1N ethereal HCl. The resulting solution is concentrated in vacuo and the residue is triturated with ether for 23 hours. The resulting yellow powder is filtered, washed with ether and dried in vacuo at 60° C. for 16.5 hours, affording 896 mg of the title compound: mp 166°-190° C. (softens slowly over this range); 1H NMR (Me2SO-d6, 400 MHz) δ9.37 (br s, 1H), 8.5 (m, 2H), 7.91 (d,J=2.2 Hz, 1H), 7.6 (m, 3H), 7.28-7.42 (m, 6H), 6.96 (d,J=5.4 Hz, 1H), 4.12 (s, 2H), 2.9-3.6 (m, 10H), 2.1 (m, 4H), 1.7-1.8 (m, 2H), 1-1.2 (m, 6H);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7]C1C=C2C(=CC=1)N=CN=C2NC1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)=[O:6].C(OC(=O)NCCCC([C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH3:71])=[CH:69][CH:70]=2)=[C:60]([CH3:72])[CH:59]=1)=O)(C)(C)C>>[NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH3:71])=[CH:69][CH:70]=2)=[C:60]([CH3:72])[CH:59]=1)=[O:6]
Reactant: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C(=O)CCCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCN)cc34)cc2C)cn1
Yield: 98 %

Procedure:
The procedure of (87-1) of Example 87 was repeated except for using 1.51 g of the compound obtained in Example 99 instead of the compound obtained in example 86 to obtain the title compound (1.21 g, 98%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl.[OH2:19]>[Fe]>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:19])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O
Reactant: CC(=Cc1cccc(OC(F)(F)F)c1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: CC(=O)Cc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
29 g (117 mmols) of 1-(3'-trifluoromethoxyphenyl)-2-nitro-propene, 46g (0.82 g atom) of iron powder, 0.6 g of ferric chloride and 120 ml of water are introduced into a 500 ml three-necked flask equipped with a mechanical stirrer, a condenser and a dropping funnel, and this mixture is heated at 80° C. 29 ml of concentrated hydrochloric acid are added dropwise, via the dropping funnel, with stirring, over the course of 5 hours, while the temperature is kept at 80° C. The reaction mixture is allowed to cool overnight. The ketone is then steam distilled. The distillate is extracted twice in succession with 100 ml of diethyl ether each time. The two ether extracts are combined, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate in vacuo on a water bath, and the residue is rectified. 14, 15 g (55 % yield) of 1-(3'-trifluoromethoxy-phenyl)-2-propanone are thus obtained as a liquid, b.p. 112° -118° C/18 mm.Hg, nD21°5 = 1.448.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1I
Yield: 63.7 %

Procedure:
Under the conditions of example 2A, 25 g of 2-iodophenol and 22.16 g of 4-bromobutyric acid ethyl ester are reacted in 100 ml of dimethylformamide in the presence of 74 g of cesium carbonate, worked up, and 24.2 g of 4-(2-iodophenoxy)butyric acid ethyl ester with a boiling point of 200° C./0.02 mbar is obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(O[CH2:26][CH:27]=[C:28]([C:34]#[N:35])[C:29](OCC)=[O:30])C>CCO>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:29](=[O:30])[C:28]([C:34]#[N:35])=[C:27]([CH3:26])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOCC=C(C#N)C(=O)OCC
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: CCO
Product: Cc1nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c(=O)c1C#N
Temperature: 25 °C
Yield: 44 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (14.16 g, 46 mMol) in EtOH (50 mL) was added Ethyl 2-ethoxyethylidene-cyanoacetate (8.4 g, 46 mMol). The reaction was refluxed for 18 h, cooled to RT and concentrated under vacuum. Purification by flash chromatography on silica gel (5% EtOAc, CH2Cl2) followed by crystallization from EtOAc, hexane and Et2O, pet. ether gave the title compound (8.03 g, 44%) as a white solid: MS (ES) m/e 397.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[N:5]/[C:6]1[S:7][C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=1)[CH3:3].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:11]([C:8]2[S:7][C:6](/[N:5]=[CH:4]/[N:2]([CH3:1])[CH3:3])=[N:10][CH:9]=2)=[O:13])[CH2:27][CH2:26]1
Reactant: CN(C)/C=N/c1ncc(C(=O)O)s1
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)/C=N/c1ncc(C(=O)NC2CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL flask was charged 2-{[(1E)-(dimethylamino) methylidene]amino}-1,3-thiazole-5-carboxylic acid 23-2 (0.56 g, 2.37 mmol) and thionyl chloride (5 mL). This suspension was refluxed for 75 minutes. At the end of this time the homogeneous solution was evaporated to dryness and the residue was flushed 2 times with CCl4. This residue was then dissolved in methylene chloride and triethylamine (1.20 g, 11.8 mmol) was added followed by cyclopropylamine (0.47 g, 8.29 mmol). The reaction was stirred overnight at 25° C. A precipitate was filtered off. Hi-Res MS: calc: 239.0961 found: 239.0959. 1H-NMR (DMSO): 8.36 ppm (s, 1H); 8.27 ppm (s, 1H); 7.83 ppm (s, 1H); 3.12 ppm (s, 3H); 2.98 ppm (s, 3H); 2.72 ppm (m, 1H); 0.67 ppm (m, 2H); 0.52 ppm (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1>C(O)(C)C>[ClH:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:23]([F:28])[CH:22]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C#N
Yield: 98 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg 1 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (0.5 ml, 3.4 mmol) in isopropanol (20 ml) was heated at reflux for 3 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoroanilino)-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (400 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24](=[O:29])[CH2:23]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)ccc2N1
Temperature: 90 °C

Procedure:
Under N2 a mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine V (2.0 g, 9.08 mmol), 5-(2-chloroethyl)oxindole (0.95 g, 10 mmol), Na2CO3 (1.06 g, 10 mmol) and KI (1.0 g, 6.0 mmol) in 45 ml dry DMF was heated at 90° C. for 72 hours. The reaction mixture was then poured over 150 ml ice/water, stirred, and filtered to give 3.04 g of brown solids. Chromatography on silica gel (230-400 mesh), eluting with 95% EtOAc: 5% triethylamine provided clean product, 0.645 g (19%), light brown solid, m.p. 199°-204° C. Analysis for C22H22FN3O2.0.5H2O: C 68.03, H 5.97, N 10.82. Found: C 67.94, H 5.57, N 10.81; MS(%): 379 (1, p+), 253 (4), 234 (32), 233 (100). NMR (300 MHz, CDCl3, delta), 2.0-2.4 (m, 6H), 2.65 (m, 2H), 2.8 (m, 2H), 3.1-3.2 (m,3H), 3.5 (s, 2H), 6.75 (d, 1H), 7.1 (m, 3H), 7.2 (s, 1H), 7.7 (m, H), 8.25 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21](S(C)(=O)=O)[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1.CC1([N:35]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1.C(Cl)Cl.N>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:35])[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ncn(C)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ncn(C)c2-c2cc3c(N)ncnc3s2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-methoxyphenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 106) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 17) followed by flash chromatography on silica eluting with DCM:MeOH (0-10%) then 1% NH3. Tan solid (0.91 g, 36%);
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:28]([N:30]=C=S)[CH3:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([NH:30][C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2)[CH3:29]
Reactant: CCN=C=S
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH2Cl2 (2 mL), ethyl isothiocyanate (0.042 ml, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 ml, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])[CH:20]=[CH:19][N:18]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Cc1cccc(C#Cc2c[nH]c(C)n2)c1
Product: Cc1cccc(C#Cc2cn(-c3ccnc(Cl)c3)c(C)n2)c1

Procedure:
The title compound, light brown solid, MS: m/e=308.2, 310.1 (M+H+) was prepared in accordance with the general method of example 1b from 2-Methyl-4-m-tolylethynyl-1H-imidazole and 2-chloro-4-fluoropyridine
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16]O)=[CH:8][CH:7]=1>>[Cl:3][CH2:16][CH2:15][CH2:14]/[CH:13]=[C:12](/[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)\[C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCC/C=C(\c1ccc(F)cc1)c1cccnc1
Product: Fc1ccc(/C(=C\CCCCl)c2cccnc2)cc1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
160 Parts of thionyl chloride were added dropwise to 10 parts of (E)-5-(4-fluorophenyl)-5-(3-pyridinyl)-4-penten-1-ol while stirring (exothermic reaction, the temperature rose to 45° C.). Upon complete addition, stirring was continued for 2 hours at room temperature. The reaction mixture was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again. The residue was solidified in 2,2'-oxybixpropane. The product was filtered off and dried, yielding 11.5 parts (94.4%) of (E)-3-[5-chloro-1-(4-fluorophenyl)-1-pentenyl]pyridine hdyrochloride (int. 60).
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CN.[CH:34]([N:37](CC)C(C)C)(C)C>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]([C@@H:11]([NH:10][C:8]([C:3]1[C:2]([NH:37][CH3:34])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])[CH3:12])=[CH:22]2
Reactant: C[C@H](NC(=O)c1nccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nccnc1C(=O)N[C@@H](C)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide (12) (133 mg, 0.30 mmol) in anhydrous 1,4-dioxane (6 mL) in a sealed tube, methylamine hydrochloride (102 mg, 1.51 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.51 mmol) were added sequentially. The resulting mixture was stirred at 140° C. in a sealed tube for 14 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-8% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-3-(methylamino)pyrazine-2-carboxamide (compound 56). ESI-MS m/z: 434.0 [M+H]+.