Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH2:33][CH2:34][OH:35])[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH2:33][CH2:34][OH:35])[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C1c2ccc(Cl)nc2CN1CCO
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4c(n3)CN(CCO)C4=O)s2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (90 mg, 0.29 mmol), 2-chloro-6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (61 mg, 0.29 mmol), Pd2dba3 (26.4 mg, 0.029 mmol), K2CO3 (43.8 mg, 0.317 mmol) and X-Phos (68.7 mg, 0.144 mmol) were added to a 2 mL microwave vial. Degassed tert-amyl alcohol (0.7 mL) was added and the vial evacuated and back-filled with nitrogen (3×). The resulting mixture was stirred at 100° C. overnight. Room temperature was attained, MeOH was added and the resulting mixture filtered through Celite. The filtrate was concentrated in vacuo while loading onto silica. Purification of the residue by silica gel chromatography (0-20% MeOH/EtOAc) gave the title compound as a pale yellow solid after triturating in EtOH. LRMS (APCI) calc'd for (C23H23F2N4O4S) [M+H]+, 489. found 489.
Reaction SMILES: Cl.[C@H:2]12[CH2:18][C@H:5]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][CH:9]=3)[CH2:7]1)[CH2:4][NH:3]2.C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33]>ClCCl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:6]2[CH2:7][C@@H:2]3[CH2:18][C@H:5]2[CH2:4][N:3]3[C:28](=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=1
Reactant: CCC/C=C/C(=O)Cl
Reactant: c1ccc2c(N3C[C@@H]4C[C@H]3CN4)ccnc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC/C=C/C(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To 4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinoline hydrochloride (26.2 mg, 0.1 mmol), dissolved in 0.5 ml anhydrous dichloromethane, polymer-supported diisopropylethylamine (80 mg, 3-4 mmol/g) was added followed by (E)-hex-2-enoyl chloride (19.9 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 ml). The mixture was shaken at room temperature for 20 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 9 mg of a solid (0.028 mmol, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:32]3[C:33]4[C:29](=[CH:28][C:27]([F:26])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: Fc1ccc2[nH]ccc2c1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3cc(F)ccc32)cc1)c1ccccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 5-fluoroindole, the title compound was isolated as a yellow solid in 72% yield (96% purity by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH:23]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:14])=[O:15])=[C:5]3[N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(C3CC3)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 22.2 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-4-morpholin-4-yl-quinoline (compound of example 6) (0.5 g, 1.3 mmol), cyclopropyboronic acid (0.167 g, 1.95 mmol), potassium phosphate tribasic (0.826 g, 3.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039) were mixed together in dioxane (7 mL) and heated at reflux under argon for 8 h. After extraction with dichloromethane and half-saturated NaCl solution, the crude product was purified chromatography on silica gel in dichloromethane/ethyl acetate with a gradient from 100:0 to 90:10. One obtained 0.1 g (21%) of white crystals. MS: m/z=347 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([Cl:15])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: O=S(=O)(Cl)Cl
Product: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl

Procedure:
In a first step, 2,4,6-trichloro-pyrimidine-5-carbaldehyde (I) is reacted with sulfuryl chloride to form 2,4,6-trichloropyrimidine-5-carboxylic acid chloride (II). The acyl chloride (II) is reacted, by a Friedel-Crafts-reaction, with an appropriately substituted benzene to form a 2,4,6-trichloro-pyrimidine-5-yl-aryl-ketone (III). Compound III is reacted with an aromatic amine in the presence of a tertiary amine to form a 2,4-dichloro-5-aroyl-6-arylamino-pyrimidine (IV).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[CH:4]=[N:3][CH:2]=1
Reactant: Nc1cncnc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of pyrimidine-5-amine (100 mg, 1.05 mmol) and pyridine (0.255 ml, 3.15 mmol) in tetrahydrofuran (3 ml) was added 2,2,2-trichloroethyl chloroformate (0.217 ml, 1.58 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (100 mg, 35.2%) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([S:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:23])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Yield: 100 %

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1240 mg, 5.59 mmol) in toluene (10 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2114 mg, 8.38 mmol) at 0° C., followed by the additions of tributylphosphine (2.09 mL, 8.38 mmol) and 4-bromo-thiophenol (1267 mg, 6.7 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid methyl ester. 393 mg of the ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:28]([C:32]1[CH:33]=[C:34]([CH:40]=[C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37](Cl)=[O:38])([CH3:31])([CH3:30])[CH3:29]>C1C=CC=CC=1>[C:44]([C:41]1[CH:40]=[C:34]([CH:33]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37]([N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH2:5]1)=[O:38])([CH3:46])([CH3:47])[CH3:45]
Reactant: CC(C)(C)c1cc(C=CC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 16.8 g. (50 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate dihydrochloride and 200 ml. anhydrous pyridine is added dropwise at 5°-10° C., in the course of 40 minutes, a solution of 14.8 g. 3,5-di-tert.-butyl-4-hydroxycinnamoyl chloride and 50 ml. anhydrous benzene. The reaction mixture is stirred for 4 hours at 20° C., the benzene and pyridine are substantially distilled off in a vacuum and the residue is stirred into about 1 liter ice water. The separated, greasy precipitate is taken up in methylene chloride and the methylene chloride phase is washed with aqueous sodium carbonate solution, dried with anhydrous sodium sulphate and evaporated to dryness in a vacuum. The crude base is dissolved in ethanol, gassed with hydrogen chloride and finally precipitated as the hydrochloride by the addition of diethyl ether. The yield is 17.3 g. (62% of theory) of the desired product which, after stirring up with diethyl ether, melts at 193°-195° C. (decomp.).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (32.3 g, 193 mmol) was added to 80 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (11.6 g, 77.3 mmol) in 10 mL of tetrahydrofuran to the reaction solution was followed by addition of 1-bromo-3,3-dimethyl-butane (20.4 g, 124 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 250 mL of 1 N NaOH, washed with 250 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 17.3 g (96%) of clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: C(#Cc1cnc(NC2CCCCC2)nc1)c1ccccc1

Procedure:
The title compound, white solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cyclohexanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@@H:10]([CH:15]=O)[CH2:9]2)=[CH:5][CH:4]=1.[C:19](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:15]([C@H:10]1[CH2:9][N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@H:13]([CH3:14])[CH2:12][CH2:11]1)#[CH:19]
Reactant: COc1ccc(CN2C[C@H](C=O)CC[C@H]2C)cc1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CC[C@@H](C)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (3R,6R)-1-(4-methoxybenzyl)-6-methylpiperidine-3-carbaldehyde (3.01 g, 12.2 mmol) and potassium carbonate (3.36 g, 24.3 mmol) in MeOH (150 mL) was treated with dimethyl (1-diazo-2-oxopropyl)phosphonate (2.19 mL, 14.6 mmol) and allowed to stir at ambient temperature for 3 d. The reaction was concentrated in vacuo and the residue taken up in sated, aqu. NaHCO3 and extracted twice with EtOAc. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo, providing (2R,5S)-5-ethynyl-1-(4-methoxybenzyl)-2-methylpiperidine as an orange oil. The material gave a mass ion (ES+) of 244.2 for M+H+. 1H NMR δ (ppm) (CDCl3): 7.21 (2H, dm J=8.4 Hz), 6.83-6.87 (2H, m), 3.98 (2H, d, J=13.4 Hz), 3.80 (3H, s), 3.11 (1H, d, J=13.6 Hz), 3.11 (1H, s), 2.91-2.96 (1H, m), 2.39-2.44 (1H, m), 2.18-2.25 (1H, m), 1.89-1.98 (2H, m), 1.64-1.69 (2H, m), 1.31-1.40 (2H, m), 1.18 (3H, d, J=6.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(C(F)(F)F)c4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-trifluoromethylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-3′-trifluoromethylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (7 mg, 4%): m/z (ES+) 433 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.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:8][C:5]1[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)=[CH:3][C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][N:6]=1
Reactant: C#Cc1cccnc1
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2ccc(F)cc2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3cccnc3)cnc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a 15 ml sealable vial was added a mixture of (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(4-fluorophenyl)oxazolidin-2-one (270 mg, 0.760 mmol) in triethylamine (15 mL). To this suspension was added 3-ethynylpyridine (94 mg, 0.912 mmol), triphenylphosphine (59.8 mg, 0.228 mmol) and copper(I) iodide (2.90 mg, 0.015 mmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (10.67 mg, 0.015 mmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy 2% MeOH/98% CH2Cl2 affording (4R,5R)-4-(2-fluoro-5-(pyridin-3-ylethynyl)pyridin-3-yl)-5-(4-fluorophenyl)oxazolidin-2-one (210 mg, 0.540 mmol, 71.0% yield) 1H-NMR (CDCl3, 400 MHz) δ 8.82 (s, 1H), 8.64 (d, J=4.0, 1H), 8.44 (s, 1H), 8.14 (d, J=8.0, 1H), 7.86, (d, J=8.0, 1H), 7.44-7.40 (m, 2H), 7.38-7.36 (m, 1H), 7.19-7.15 (m, 2H), 5.64 (brs, 1H), 5.38 (d, J=4.0, 1H), 5.05 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=1.78 min. Mass=378.16 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:25](OCC)(OCC)OCC>>[N:12]1([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:25]1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccccc3c21

Procedure:
Using the general method of Example 1 Part C, tert-butyl N-(4-[(3-aminoquinolin-4-yl)amino]butyl)carbamate (149 g, 0.451 mol) was reacted with triethyl orthoformate to provide crude product. This material was recrystallized from isopropyl alcohol to provide 84 g of tert-butyl N-[4-(1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a crystalline solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH3:14][C:15](C)([O-])C.[K+].O.Cl>C1COCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)=[CH:14][CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C1CCC(C=O)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC=CC1CCC(C(=O)OCC)CC1
Reaction time: 8 h

Procedure:
240 g of ethyl 4-formylcyclohexanecarboxylate were dissolved in 2.4 l of THF at 10-15° C. under nitrogen, and 531 g of ethyltriphenylphosphonium bromide were added. 160 g of potassium tert-butoxide were introduced in portions into the resultant suspension over a period of 1.5 hours, the temperature being held at below 20° C. After the mixture had been stirred overnight, the mixture was hydrolyzed using water the next day and rendered slightly acidic using 2 N HCl. Conventional work-up gave ethyl 4-propenylcyclohexanecarboxylate as an E/Z isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.[CH3:28][CH:29]([O:31][C:32]1[C:33](=O)[C:34](=[O:40])[C:35]=1[O:36]C(C)C)[CH3:30]>C(O)C>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:33]5[C:34](=[O:40])[C:35](=[O:36])[C:32]=5[O:31][CH:29]([CH3:30])[CH3:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: CCO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(OC(C)C)c(=O)c4=O)cc23)CC1
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-aminoindole (6) (0.208 g, 0.56 mmol) and 3,4-bis (1-methylethoxy) cyclobut-3-ene-1,2-dione4 (2) (0.112 g, 0.56 mmol) in 5 mL of absolute ethanol was stirred at room temperature for 66 h and then it was heated at ca. 80° C. (oil-bath temperature) for 4 h. The cooled mixture was filtered and the residue was washed with ethanol and then dried in vacuo to give the title compound (0.190 g, 64%) as a slightly pinkish solid, mp 140°-143° C.: IR (KBr) 3312, 1800, 1720, 1607, 1588 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 10.80 (s, 1H), 10.7 (br s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.48 (m, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.06 (m, 1H), 5.40 (m, 1H), 3.81 (s, 3H), 3.65 (br s, 4H), 3.42 (q, J=7.0 Hz, 0.6H, CH3CH2OH), 2.67 (m, 2H), 2.43 (m, 4H), 2.35 (m, 2H), 1.82 (m, 2H), 1.41 (d, J=6.1 Hz, 6H), 1.04 (t, J=7.0 Hz, 0.9H, CH3CH2OH). Anal. Calcd for C27H32N6O4. 0.5 H2O. 0.3 C2H6O: C, 62.85; H, 6.65; N, 15.94. Found: C, 62.85; H, 6.46; N, 16.17.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl>CC(O)C.ClCCl.[Fe]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]([OH:27])([C:23]([F:26])([F:24])[F:25])[C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=3)[CH2:7][CH2:6]2)=[C:2]([Br:1])[CH:31]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Yield: 90.8 %

Procedure:
Iron (94 mmol, 5.24 g) (reduced powder) was added to a suspension 2-(4-((4-(2-bromo-4-nitrophenoxy)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (9.40 mmol, 5.24 g) in 2-propanol (100 mL) containing concentrated hydrochloric acid (1 mL) and the mixture refluxed for 4.5 hours. The mixture was cooled, diluted with dichloromethane and filtered through dicalite. The filtrate was washed with sodium carbonate solution, the organic phase dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (4.5 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Clc1cnccn1
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=286.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloropyrazine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>>[N+:8]([C:7]1[C:2]([NH:14][CH2:15][CH2:16][CH:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18]([O:20][CH3:21])=[O:19])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C(CCN)c1ccccc1
Product: COC(=O)C(CCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1
Yield: 77.7 %

Procedure:
A procedure similar to the method described in step C.1 is carried out, starting from 0.8 g (3.93 mmol) of 2-chloro-3,5-dinitropyridine and 1 g (4.32 mmol) of methyl 4-amino-2-phenylbutyrate. This gives 1.1 g of expected product.