Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>O>[N:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g), sodium azide (10.7 g) and dimethyformamide (260 ml) is heated with stirring at 75°-80° C. overnight. After cooling, the mixture is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from hexane to give 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g).
Reaction SMILES: Cl[C:2]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:5].[CH2:28](OB(C=C)OCCCC)[CH2:29]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:22]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[O:5])=[C:2]([CH:28]=[CH2:29])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
Under nitrogen, the mixture of tert-butyl 4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate (Step 1, 1.52 g, 3.88 mmol), vinylboronic acid dibutyl ester (0.86 mL, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.2 mmol) and sodium carbonate (2.9 g, 27.2 mmol) in THF (40 mL) and water (10 mL) was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine. The organic extracts were dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/Hexanes:1/4) to afford tert-Butyl 4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate; ESMS m/z 394.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:21][Mg]I>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:19]([OH:20])[CH3:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C[Mg]I
Reactant: CCCCCCCOc1ccc2cc(C=O)cnc2c1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2cc(C(C)O)cnc2c1
Yield: 79.6 %

Procedure:
To a solution of 7-(heptyloxy)quinoline-3-carbaldehyde (1.6 g, 5.9 mmol) in THF (30 mL) at 0° C. was added CH3MgI (2 g, 12 mmol, 2 eq.) dropwise over 10 min. The mixture was warmed to it over 8 h. Then, the reaction mixture was quenched (water), extracted (ethyl acetate), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (pet. ether:ethyl acetate, 1:5) to give 1-(7-(heptyloxy)quinolin-3-yl)ethanol as yellow oil (1.35 g, yield 80%). ESI-MS: 288 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:45][NH:46][O:47][CH3:48]>ClCCl>[CH3:48][O:47][N:46]([CH3:45])[C:31]([C:17]1[C:18]2[C:23]([CH3:24])=[N:22][N:21]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:19]=2[N:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[F:34])[CH:16]=1)=[O:32]
Reactant: CNOC
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.00 g) was dissolved in dichloromethane (50 mL), DIPEA (3.34 mL), N,O-dimethylhydroxylamine hydrochloride (0.63 g) and finally BEP (3.92 g) were added. The mixture was stirred at r.t. overnight, then extracted with sat. sodium carbonate solution, washed with 1N HCl and finally again with sodium carbonate solution. The solvent was evaporated and the residue was crystallized from methanol and filtered off giving 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methoxy-methyl-amide (2.28 g, 70%) as a solid.
Reaction SMILES: [N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][N:34]1[C:38]([CH:39]=[O:40])=[CH:37][N:36]=[C:35]1[CH3:41]>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:39]([C:38]4[N:34]([CH3:33])[C:35]([CH3:41])=[N:36][CH:37]=4)[OH:40])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ncc(C=O)n1C
Reactant: FC(F)(F)c1ccc(Cc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)n1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.00 g, 2.19 mmol, Intermediate 69: step a) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (0.30 g, 2.4 mmol) in THF (20 mL) was added via cannula and the resulting mixture stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and the mixture stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1.N1C=CC=CC=1>ClC(Cl)C>[C:35]([O:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(Oc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2)c1cccnc1
Yield: 95 %

Procedure:
Heat at reflux for 8 hours, under a nitrogen atmosphere, a solution of 1.37 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin, 4.5 mmol of nicotinoyl chloride and 3.42 mmol of anhydrous pyridine in 25 cm3 of dichloroethane. After cooling, the reaction mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is then purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 70:30). 6-Nicotinoyloxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 95%. Melting point: 142° C. ##STR77##
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[F:34][C:35]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][C:36]=1[CH2:37]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:37][C:36]3[CH:39]=[C:40]([O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:41]=[CH:42][C:35]=3[F:34])=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: Fc1ccc(Oc2ccccc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1cc(Oc2ccccc2)ccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 2-fluoro-5-phenoxybenzyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hours and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on prep. TLC plates developing with 10% ether/hexane to yield 2-fluoro-5-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([SH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Fc1c(F)c(F)c(S)c(F)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Sc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (4.96 g) in dry dichloromethane (20 ml) was added dropwise over 15 minutes to a stirred solution of pentafluorothiophenol (5.00 g), pyridine (2.1 ml) and 4-N,N-dimethylaminopyridine (50 mg) in dry dichloromethane (75 ml), the mixture being maintained close to 5° C. by immersion in an ice-bath. The reactants were allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester (8.79 g).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:6](F)=[N:7][C:8]([F:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.O>C(O)CC>[Cl:4][C:5]1[C:6]([NH:2][NH2:3])=[N:7][C:8]([F:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: Fc1nc(F)c(C(F)(F)F)cc1Cl
Reactant: NN
Solvent: O
Solvent: CCCO
Product: NNc1nc(F)c(C(F)(F)F)cc1Cl
Reaction time: 2 h

Procedure:
10.5 g (0.21 mol) of hydrazine hydrate were added to a stirred mixture of 21.8 g (0.1 mol) of 3-chloro-2,6-difluoro-5-trifluoromethylpyridine in 100 ml of propanol at 50° C. in the course of 15 minutes, and stirring was continued for 2 hours at the same temperature. After cooling, the batch was poured into 1.5 l of water and the precipitate which had separated out was filtered off with suction. It was taken up in ethyl acetate for purification and extracted using water. After drying and concentration, 20.9 g (91% of theory) of the title compound of m.p. 104°-106° C. were obtained; a sublimated sample melted at 111°-113° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)[CH3:19]>CC(N(C)C)=O>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[CH2:29][CH2:30]1)[CH3:19]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(-c4ccccc4)nc4ccccc34)CC2)ccc1OC
Yield: 3 %

Procedure:
A solution of 4-chloro-2-phenyl-quinazoline (36.1 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwave irradiation to 180° C. for 10 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 469.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[C:18]([C:36]([F:39])([F:38])[F:37])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[C:18]([C:36]([F:38])([F:37])[F:39])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)OC(C)(C)C)c4)n3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)O)c4)n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of tert-butyl 3-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I29) (0.048 g, 0.088 mmol) in DCM (3 mL) was added TFA (0.5 mL); the reaction was then stirred for 35 minutes at room temperature before concentrating under reduced pressure. The residue was taken up in toluene (2×10 mL) and concentrated under reduced pressure. The resulting residue was taken up in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 1 hour then the volatiles removed by evaporation under reduced pressure. The residue was taken up in toluene (2×20 mL) and concentrated under reduced pressure to give the title compound (I30) in quantative yield; 1H NMR (400 MHz, d6-Acetone) b 9.14 (s, 1H), 8.62 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.74 (bs, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.44 (dd, J=7.6, 7.6 Hz, 1H), 7.34 (bd, J=8.0 Hz, 1H), 7.25 (dd, J=8.1, 8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.8 Hz, 1H), 3.60 (m, 4H), 3.47 (m, 4H), 3.20 (m, 4H), 2.94 (s, 3H). LCMS Method C: rt 4.93 min; m/z 486.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([O:25][C:26]([N:5]2[C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=[C:4]2[C:8]([F:11])([F:10])[F:9])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1nc(Cl)c(Cl)[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)n1c(C(F)(F)F)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
20.5 g (0.1 mol) of 4,5-dichloro-2-trifluoromethyl-imidazole were dissolved in 150 ml of dioxane, 10.1 g (0.1 mol) of triethylamine were added thereto and 16.05 g (0.1 mol) of chloroformic acid phenyl ester were then added dropwise whilst cooling at 10°-15° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had separated out was filtered off and the filtrate was evaporated in vacuo. The oily residue was distilled. The main fraction boiled at 106.5°-107° C./0.08 mm Hg. 28.6 (88% of theory) of 4,5-dichloro-2-trifluoromethyl-imidazole-1-carboxylic acid phenyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].O1CCOCC1>C1COCC1>[CH3:11][N:12]([CH3:13])[C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:8]
Reactant: CNC
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C)C)c(C)o1
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonylchloride (2.19 g; 13.8 mmol) in 10 ml of THF was added to a 2M solution of dimethylamine in dioxane (21 ml; 42 mmol) in 80 ml of THF at rt. After stirring for 1 hr, the volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 ml) and water (100 Ml). The organic layer was washed with saturated potassium bisulfate solution (100 ml), 1N NaOH (50 ml) and brine (50 ml). Drying over MgSO4 and concentration in vacuo afforded compound 866A (1.84 g, 80%) as an amber liquid. 1HNMR (CDCl3): δ 2.23 (s, 3H), 2.33 (s, 3H), 3.04 (s, 6H), 5.96 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])=[CH:4][CH:3]=1
Reactant: CNc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Yield: 51.6 %

Procedure:
4-fluoro-N-methylaniline (204 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03), using an analgous procedure to that described in Example 3.00, to afford 8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (96 mg, 51.9%) as a white solid. Mass Spectrum: M+H+ 454. NMR Spectrum: (DMSOd6) 1.55 (d, 3H), 2.65 (s, 3H), 2.89 (s, 3H), 3.00 (s, 3H), 3.20-3.27 (m, 2H), 3.27-3.33 (m partially hidden by H2O, 2H), 3.42-3.48 (ms, 2H), 3.48-3.56 (m, 2H), 5.48 (q, 1H), 5.54 (s, 1H), 6.83 (dd, 2H), 7.04 (dd, 1H), 7.65 (d, 2H), 7.86 (d, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)CCC>CN(C)C=O.[Cu]=O>[F:1][C:2]1[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)nc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(F)nc1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
6-Fluoro-2-iodo-3-methoxypyridine (84 mg), tetrakistriphenylphosphine palladium (0) (38 mg), and copper(II) oxide (53 mg) were suspended in N,N-dimethylformamide (2 ml). 2-Tributylstannylpyridine (244 mg) was added to the suspension, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature. The reaction solution was then filtered, the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-fluoro-3-methoxy-[2,2′]bipyridine (12 mg, yield 18%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCI
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(C2CCC(=O)CC2)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodoethane (10.5 mL, 20.5 g, 131 mmol, 5 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-ethoxyphenyl)-cyclohexanone (5.74 g, 100%). 1H NMR (CDCl3) 7.15 (dt, 2H), 6.86 (dt, 2H), 4.02 (q, 2H), 2.99 (tt, 1H), 2.46-2.54 (m, 4H), 2.16-2.24 (m, 2H), 1.83-2.00 (m, 2H) and 1.41 (t, 3H); MS (electrospray) m/e, 219 (M+1)+, Calcd for C14H18O2, 218. Step 2:
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[N:10]([CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1)=[N+:11]=[N-:12]
Reactant: N#Cc1csc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1csc(CN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
2-Bromomethyl-thiazole-4-carbonitrile (1.6 g, 7.8 mmol) was dissolved in 20 mL DMF and sodium azide (0.768 g, 11.8 mmol) was added. The reaction was allowed to stir for 16 h at room temperature and then diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were washed again with 75 ml of brine, dried with anhydrous sodium sulfate and concentrated in vacuo to yield 1.20 g (92%) of the title compound as a gummy material which was used in next step with out further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:17]1[O:18][CH:5]([C:4]2[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=2[O:2][CH3:1])[O:6][CH2:16]1
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1OC

Procedure:
A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16.0 g, 75 mM), ethylene glycol (64 g, 103 mM), and p-toluenesulfonic acid monohydrate (0.2 g) in benzene (750 ml) is refluxed in a Dean-Stark apparatus for 48 hours. The solution is then poured into water (1 l.). The organic phase is washed with saturated aqueous NaHCO3 (2×20 ml), dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane (2 l.); yield 15.2 g (78.2%); m.p. 74°-76° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:17][C:18]#[N:19])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>CO.Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:17](=[N:20][OH:21])[C:18]#[N:19])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: N#CCc1nc2cnc(Br)cc2n1-c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#CC(=NO)c1nc2cnc(Br)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
The product from Step 5 (2.5 g, 7.99 mmol) in methanol (40 mL) and 2 N hydrochloric acid (16 mL) was treated portionwise with NaNO2 (1.10 g, 16 mmol) and allowed to stir at rt for 1 h. The resulting tan precipitate was filtered and washed with methanol to give the title compound (2.7 g, 99%). MS (ES+) m/e 342/344 [M+H]+.