Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[Cl:12][C:13]([Cl:17])=[C:14]([F:16])[F:15]>CC(C)=O.[OH-].[K+]>[Cl:12][CH:13]([Cl:17])[C:14]([F:16])([F:15])[O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: FC(F)=C(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(OC(F)(F)C(Cl)Cl)c1
Temperature: 0 °C
Yield: 27 %

Procedure:
In a 500 ml stirred reaction flask equipped with thermometer, air condenser, dropping funnel and ice water bath was placed 76.57 g (0.5 mol) of 5-methyl-2-nitrophenol in 150 ml of acetone and 5.5 g of powdered KOH (85 percent). The mixture was vigorously stirred at 10° C, whereupon 73 g of 2,2-dichloro-1,1-difluoroethene was gradually introduced. After stirring overnight, the reaction mixture was poured into ice water, and the lower organic layer separated by methylene chloride extraction. The extract was washed with diluted bicarbonate of soda solution, decolorized with charcoal, and dried over desiccant-grade magnesium sulfate. Evaporation of the solvent left an oily residue which was vacuum distilled at 5 mm to give 38.6 g of 2-(2,2-dichloro-1,1-difluoroethoxy)-4-methyl-1-nitrobenzene distilling at 156° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11]
Reactant: CN(C)c1c(Cl)cc(CC#N)cc1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1c(Cl)cc(C(C#N)C(=O)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.41 g (35.3 mmol) of sodium hydride are initially charged in absolute THF (50 ml), and 4.05 g (17.6 mmol) of [3,5-dichloro-4-(dimethylamino)phenyl]acetonitrile in 20 ml of absolute THF are added dropwise at 0° C. The mixture is stirred at 0° C. for 20 minutes, and 5.02 g (35.3 mmol) of ethyl trifluoroacetate are then added dropwise at 0° C. The reaction mixture is warmed to room temperature and then carefully added to water. After washing with n-hexane, the aqueous phase is acidified with 1 N HCl. A colourless solid precipitates out and is, after filtration with suction and air-drying, used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1])(=[O:32])=[O:33]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (75 mg, 0.262 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (84 mg, 0.236 mmol) were dissolved in 2.5 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-yl idene)methyl)-3-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 66 (117 mg, yield 79.6%) as an orange solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][C:7]=3[OH:11])[N:4]=[CH:3][CH:2]=[N:1]4)[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2nccnc2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2nccnc2cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred solution of quinoxalin-6-ol (King et al.; J. of the Chem. Society 1949:3012.) (11.2 g, 76.66 mmol) in tetrahydrofuran (800 mL) was added isopropylmagnesium chloride (38.3 mL, 2.0 M THF solution, 76.60 mmol) at −40° C. to −30° C. The mixture was allowed to stir at 0° C. for 2 h, followed by the addition of 1-(diphenylmethyl)-1H-indole-2,3-dione (20.00 g, 63.84 mmol) in tetrahydrofuran (400 mL). The mixture was stirred at ambient temperature for 20 h, and quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×1000 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (dichloromethane/methanol, 100/1) to give 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one (10.0 g, 34%): 1H NMR (300 MHz, CDCl3) δ 10.21 (s, 1H), 8.47 (s, 1H), 7.97-7.92 (m, 2H), 7.60-7.58 (m, 2H), 7.54-7.49 (m, 4H), 7.46-7.35 (m, 6H), 7.14 (s, 1H), 7.05-7.00 (m, 1H), 6.89-6.87 (m, 1H), 6.56-6.52 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)CCCCOc1cc(-c2ccc([N+](=O)[O-])cc2)cc(-c2ccccc2)n1
Solvent: CCO
Product: CCOC(=O)C(C)CCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 12 is followed but using ethyl 2-methyl-6-{[4-(4-nitrophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (2.5 g), stannous chloride (5.3 g) and ethanol (100 cc). The residue, after extraction and concentration of the organic phases to dryness, is used as it is in the next stage. (yellow oil)
Reaction SMILES: Br[C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.[CH2:8]([Mg]Br)[CH:9]([CH3:11])[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: OC1CCC=C1Br
Reactant: CC(C)C[Mg]Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1=CCCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate D3, 16 mmol) in THF (30 mL) at 0 EC was treated with isobutyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 h. (see: Organ et al. J. Org. Chem. 1997, 62, 1523, incorporated herein by reference). The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-isobutyl-cyclopent-2-enol (Intermediate D4). Use of 2-isobutyl-cyclopent-2-enol (Intermediate D4) in Method A produced 4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 20).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([OH:16])=O.C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([Cl:1])=[O:16]
Reactant: CC1=C(C(=O)O)SC2=NCC(C)(C)CN21
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Cl)SC2=NCC(C)(C)CN21
Yield: 198.1 %

Procedure:
In 6 ml of thionylchloride was suspended 1.0 g of 3,6,6-trimethyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained in Example 120, followed by reflux under heating for 30 minutes. After dissolving completely, the mixture was cooled. Under cooling with ice, to the mixture was added anhydrous diethylether. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.06 g of 3,6,6-trimethyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride. The total amount of this compound and 610 mg of 3,5-dimethylaniline was dissolved in the mixture 60 ml of pyridine and 10 ml of dimethylformamide, followed by stirring at 60° C. for 17 hours. The reaction mixure was concentrated and to the concentrate was added 5% sodium hydrogencarbonate aqueous solution. The precipitated crystals were collected by filtration and washed diethylether. The obtained powder was suspended in diethylether. To the suspension was added 0.2 ml of saturated hydrogenchloride dioxane solution, followed by stirring at room temperature. The precipitated crystals were collected by filtration. The crystals were recrystallized from a mixed solvent of ethanol and diethylether to obtain 810 mg of the titled compound.
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](I)[CH:26]=1>>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:25]3[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[CH:26]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cncc(I)c1
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Product: CC(C)(C)c1nc2ncc(C#Cc3cncc(Cl)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=312.2/314.1 (M+H+), can be prepared in accordance with the general method of example 43, step 2 from 2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3-chloro-5-iodopyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][N:19]=[N:18]1.CN(C)C=O>C(#N)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[NH:17][N:18]=[N:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Nc1cccc(-c2nnn[nH]2)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3nnn[nH]3)c2)[C@@H]1O
Yield: 60 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.003 mol, from Example 1, part B) and [3-(1H-tetrazol-5-yl)phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol, from part A) in acetonitrile (35 mL) and dimethylformamide (20 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 0.5M HCl and water. The organic layer was concentrated in vacuo, and the residue was azeotroped with toluene and triturated with ethyl acetate/hexane (1:1). The product was purified by flash chromatography (EM-60 flash silica gel, 300 mL) and eluted with EtOAc/MeOH/HOAc (20:1:0.06). The solvent was removed in vacuo, acetic acid was azeotroped with toluene and the product was triturated in hexane (40 mL) and ethyl acetate (0.5 mL) and dried in vacuo to give 0.72 g (60%) of the title compound, m.p. 204°-208° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:0.2), Rf =0.58; 1H-NMR (DMSO-d6) δ1.3 (s, 3H), 1.5 (s, 3H), 3.7 (d, J=9.4 Hz, 1H), 4.8 (dd, J=8.8 & 8,8 Hz, 1H), 5.8 (s, 1H), 6.8 (d, J=8.2 Hz, 1H), 7.0 (d, J=8.8 Hz, 1H), 7.5 (m, 5H), 8.4 (s, 1H), 9.0 (s, 1H); 13C-NMR (DMSO-d6) δ5 156.6, 156.0. 141.6, 132.9, 132.8, 130.2, 126.2, 125.0, 120.7, 120.1, 119.4, 118.2, 116.5, 103.0, 80.7, 71.6, 49.8, 26.9, 21.4, 19.3; IR (KBr) 2980, 2932, 2228, 1663 cm-1. M.S., (M+H)+ at 406, M.W. 405; [60 ]D=-41.6° (c=0.76 DMSO).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](B(O)O)=[C:19]([F:27])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:21]1[CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:18]=[C:19]([F:27])[C:20]=1[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Reactant: Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)c(-c3ccc(C)s3)c(F)c2)cc1

Procedure:
A mixture of 5.50 g (31.0 mmol) of 2-bromo-5-methylthiophene, 9.0 g (32.6 mmol) of 4′-propyl-3,5-difluoro-4-biphenylboronic acid, 1.83 g (1.58 mmol) of tetrakis(triphenylphosphine)palladium(0) and 36 ml of 2 N sodium carbonate soln. in 90 ml of toluene/ethanol (1:2) is heated under reflux for 16 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to completion. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). Further purification is carried out by recrystallisation from ethanol and n-heptane; 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-methylthiophene (PUS-3-1) is obtained as a colourless solid (m.p. 75° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:32][O:31][C:27]1[CH:26]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([S:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:28]=1[O:29][CH3:30]
Reactant: C=CC(=O)Nc1cccc(Sc2ccnc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Product: C=CC(=O)Nc1cccc(Sc2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)c1
Yield: 13.4 %

Procedure:
In a procedure analogous to Example 8, reaction of N-(3-(2-chloropyrimidin-4-ylthio)phenyl)acrylamide (100 mg, 0.34 mmol) and 3,4,5-trimethoxyaniline (75 mg, 0.41 mmol) furnished the product (20 mg, 14%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: C[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol) in methanol (1 mL) was added a solution of sodium methoxide (5.4 M in MeOH, 23.5 μL, 0.13 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (27 mg, 55%) which was obtained as a yellow solid. MS: m/e=391.1 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:3]=O.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=1[I:18]>CCO>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]2[C:2]([CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:3][N:17]=[C:13]2[C:12]=1[I:18]
Reactant: Nc1nccc(Cl)c1I
Reactant: O=CC(Br)CC(F)(F)F
Solvent: CCO
Product: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Temperature: 150 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A 2.0-5.0 mL microwave vial was charged with 2-bromo-4,4,4-trifluorobutanal (403 mg, 1.965 mmol) dissolved in EtOH (2500 μl). To that stirring solution was added 4-chloro-3-iodopyridin-2-amine (250 mg, 0.982 mmol). The vial was sealed and heated in the microwave for 1 h at 150° C. After 1 hour, LCMS showed clean and complete consumption of the starting material to a single peak with the desired mass (m/z=260 [M+H]+; Methanol/Water/TFA Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The mixture was transferred into a round bottom flask and the ethanol was removed under reduced pressure. The crude mixture was diluted with EtOAc and sat'd sodium bicarbonate. The contents of the flask were transferred into a separatory funnel where the aqueous was extracted twice with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography: (25 g, equilibrated with hexanes, loaded with DCM, initial waste: mL, fraction size: 9 mL 13×100 mm, and eluted with EtOAc in hexanes 0% [115 mL], 10% [150 mL], 20% [400 mL], 30% [400 mL]). Collected fractions to give 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (261 mg, 73.7% yield) as a sticky yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=7.3 Hz, 1H), 7.70 (s, 1H), 6.98 (d, J=7.3 Hz, 1H), 3.72 (q, J=9.9 Hz, 2H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:13][C:12]1=[O:24])(C)(C)C>Cl.O1CCOCC1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][OH:6])[C:12](=[O:24])[N:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCn1ccc(-c2ccccc2F)nc1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1nc(-c2ccccc2F)ccn1CCCCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
1-[4-(tert-Butyl-dimethyl-silanyloxy)-butyl]-4-(2-fluoro-phenyl)-1H-pyrimidin-2-one (370 mg, 0.98 mmol) was dissolved in 4N HCl in dioxane (15 ml). The mixture was stirred at room temperature for 15 minutes, then basified with 30% NH4OHaq and finally extracted with DCM. The organic layer was dried (Na2SO4), filtered and evaporated, to give 258 mg of the title compound as a yellow solid (95% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[C:30]([CH3:35])([CH3:34])[CH2:29][C:28]3([CH3:37])[CH3:36])O1.C([O-])=O>>[CH3:36][C:28]1([CH3:37])[C:27]2[C:31](=[CH:32][C:33]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)=[CH:25][CH:26]=2)[C:30]([CH3:35])([CH3:34])[CH2:29]1
Reactant: CC1(C)CC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Agent: O=C[O-]
Product: CC1(C)CC(C)(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described above starting from 110 mg (0.29 mmol) of 2-[1-(4-bromothiazol-2-yl)piperidin-4-ylamino]ethanol and 98 mg (0.29 mmol) of 4,4,5,5-tetramethyl-2-(1,1,3,3-tetramethylindan-5-yl)-1,3,2-dioxaborolane. The product is in the form of the formate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>>[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccccc3[nH]2)cc1

Procedure:
Compound 458 was prepared from 4-morpholinoaniline and 4-(1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H22N4O2: 399.17; found: 398.98.
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(O)=CC2)N1.[CH3:24][C:25]1([CH3:43])[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38](Cl)=[CH:37][CH:36]=2)[CH:32]2[C:27](=[CH:28][C:29]([OH:42])=[CH:30][CH2:31]2)[NH:26]1>>[CH3:24][C:25]1([CH3:43])[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([C:18]([F:21])([F:20])[F:19])=[CH:37][CH:36]=2)[CH:32]2[C:27](=[CH:28][C:29]([OH:42])=[CH:30][CH2:31]2)[NH:26]1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)C2CC=C(O)C=C2N1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)C2CC=C(O)C=C2N1
Product: CC1(C)CC(c2ccc(C(F)(F)F)cc2)C2CC=C(O)C=C2N1

Procedure:
2,2-dimethyl-7-hydroxy-4-(3-trifluoromethylphenyl)tetrahydroquinoline and 2,2-dimethyl-7-hydroxy-4-(4-chlorophenyl)tetrahydroquinoline.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C1(C)C=CC(S(O[CH2:22][CH2:23][Cl:24])(=O)=O)=CC=1>O1CCCC1>[Cl:24][CH2:23][CH2:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCn1ccc2ccccc21
Yield: 40.8 %

Procedure:
An oil dispersion (7.2 g) of sodium hydride (0.21 mol) and tetrahydrofuran (50 ml) were placed in a 500-ml flask equipped with a stirrer and a condenser tube, and the mixture was stirred in an ice-water bath. Indole (24.60 g, 0.21 mol) dissolved in tetrahydrofuran (100 ml) was gradually added dropwise to the mixture. After completion of addition, the ice-water bath was removed, and the mixture was stirred for one hour at room temperature. Subsequently, 2-chloroethyl p-toluenesulfonate (49.29 g, 0.21 mol) was added, and the mixture was allowed to react for 15 hours while being stirred under heat-reflux conditions. After completion of reaction, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography to obtain 1-(2-chloroethyl)indole (15.4 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:20][CH2:19][O:18][C:17]([CH3:22])([CH3:21])[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:20][CH2:19][O:18][C:17]([CH3:21])([CH3:22])[CH2:16]1
Reactant: CC1(C)CC(O)(c2csc(S)c2)CCO1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Product: CN1C(=O)CCc2cc(Sc3cc(C4(O)CCOC(C)(C)C4)cs3)ccc21
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-hydroxy-4-(2-mercaptothien-4-yl)-2,2-dimethyltetrahydropyran to give 4-hydroxy-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 72% yield as a foam;