Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][C@:16]1([NH2:24])[CH2:20][CH2:19][C@@H:18]([NH2:21])[C:17]1([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CO.C(Cl)Cl>CN(C=O)C>[NH2:24][C@@:16]1([CH3:15])[CH2:20][CH2:19][C@@H:18]([NH:21][C:9]2[C:4]3[N:5]([CH:14]=[C:2]([Br:1])[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:11]([NH2:13])=[O:12])[C:17]1([CH3:23])[CH3:22]
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1(C)[C@H](N)CC[C@]1(C)N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)N
Temperature: 95 °C
Yield: 239 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 638 mg, 2.325 mmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (prepared as described in Intermediate 10, 430 mg, 3.02 mmol) in DMF (3.5 mL) was added DIPEA (1.218 mL, 6.98 mmol). The reaction vessel was purged with N2, sealed and heated to at 95° C. for 90 min. The reaction was cooled and partitioned between ethyl acetate (35 mL) and water (20 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude extracts were combined with two previous reactions and concentrated onto SiO2 and eluted onto a silica gel column with 100% ethyl acetate. After the non-polar impurities had eluted, the solvent was changed to 5% MeOH/CH2Cl2 then 10% then 15% MeOH/CH2Cl2 to afford the title compound (2.113 grams, 67% yield). HPLC (condition 0): retention time=2.61 min; LCMS: 382.08 (M+2); 1H NMR (methanol-d4, 400 MHz) δ 8.14 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 4.41 (t, J=8.4 Hz, 1H), 2.34 (m, 1H), 1.85 (m, 2H), 1.70 (m, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[C:22]([CH3:37])[O:21][N:20]=1>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>[CH3:18][C:19]1[C:23]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:15])[C:3]=2[C:16]#[N:17])=[C:22]([CH3:37])[O:21][N:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Reactant: COc1ccc(-n2nc(C)c(C#N)c2I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-n2nc(C)c(C#N)c2-c2c(C)noc2C)cc1
Reaction time: 0.5 h
Yield: 135.3 %

Procedure:
5-iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (450 mg, 1.33 mmol), 3,5-dimethyl-4-(tributylstannyl)isoxazole (907 mg, 2.35 mmol) and PdCl2(PPh3)2 (186 mg, 0.27 mmol), were mixed with 1 mL degassed dioxane and 1 mL degassed DME under nitrogen in a microwave vial. The reaction was run at 145° C. in the microwave for 30 min. Water was added, extracted with CH2Cl2, filtered through a phase separator. The organic phase was evaporated and the residue was purified using silica to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (555 mg, >100%) which was used as such in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[Cl:11][CH2:12][C:13]([NH:15][CH2:16]O)=[O:14].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:11][CH2:12][C:13]([NH:15][CH2:16][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[OH:1])=[O:14]
Reactant: O=C(CCl)NCO
Reactant: Oc1ccc2c(c1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(CCl)NCc1cc2c(cc1O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
134 g (1 mole) of 5-hydroxyindane and 100 g (0.81 mole) of 2-chloro-N-hydroxymethylacetamide are suspended in 300 ml of glacial acetic acid, and 10 ml of concentrated sulfuric acid are added. The mixture is stirred for 30 minutes at room temperature and is poured into ice water. The product is filtered off with suction and recrystallized from methanol.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([NH2:8])=[CH:6][O:5][N:4]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]([C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:51])=[CH:46][C:42]=2[C:43](O)=[O:44])=[CH:35][CH:34]=1>CN(C)C=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]([C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:51])=[CH:46][C:42]=2[C:43]([NH:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][CH:6]=2)=[O:44])=[CH:35][CH:34]=1
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
3-Methyl-4-isoxazolamine hydrochloride (44.9 mg, 0.33 mmol), 1-hydroxy-7-azabenzotriazole (41.7 mg, 0.31 mmol), diisopropylethylamine (0.10 ml, 0.56 mmol) and EDC (80 mg, 0.42 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(4-morpholinylcarbonyl)benzoic acid (100 mg, 0.28 mmol) in N,N-dimethylformamide (5 ml). The solution was stirred for 18 hours before the solvent was removed in vacuo. The residue purified by column chromatography (silica gel; 10% 7M NH3 in methanol/dichloromethane). Trituration with methanol yielded the title compound as a white solid. 21 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc2c(=O)[nH]ccc2c1
Solvent: CN(C)C=O
Product: Nc1ccc2c(=O)[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.3 %

Procedure:
To a solution of 0.500 g (3.12 mmol) of 6-amino-2H-isoquinolin-1-one in DMF (30 mL) was added 0.45 g (3.4 mol) of N-chlorosuccinimide. The mixture was stirred at room temperature for 15 h then poured over ice and stirred until all the ice was melted during which time a solid precipitated from solution. The tan solid was collected by filtration, washed with water and dried on the filter pad to provide 0.50 g (82% yield) of the title compound. MS calc. for C9H8ClN2O [M+H]+: 195.63. Found: 195.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2ccoc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1cccc(-c2ccoc2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
0.61 g (1.7 mmol) of methyl 5-chloro-2-({[3-(furan-3-yl)phenyl]carbonyl}amino)benzoate was dissolved in 20 mL of THF solvent, and 4 mL of 1N aqueous sodium hydroxide was added. The mixture was stirred at 50° C. for 1.5 hours. After cooling, 1N hydrochloric acid was added to acidify the reaction mixture. Thereafter, the solvent was distilled off under reduced pressure. Subsequently, water was added to the residue, and solids were collected by filtration and washed with water. The obtained crude product was recrystallized using a mixed solvent of ethyl acetate and n-hexane, thereby giving 0.24 g of the target 5-chloro-2-({[3-(furan-3-yl)phenyl]carbonyl}amino)benzoic acid (yield: 41%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][C@H:19]3[C@@H:18]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[C:24]([C:45]([O:46][CH3:47])=[O:48])([C:45]([O:46][CH3:47])=[O:48])[CH2:25][C@H:19]3[C@@H:18]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CCC(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 112.1 %

Procedure:
To a solution of (1S,8aS)-N-((R)-1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-N-methyl-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (300 mg, 0.61 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LiHMDS (2.3 mL, 1 M in THF, 2.3 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (134 mg, 1.43 mmol). After stirring for another 3 h at room temperature, the reaction was quenched with water at 0° C. and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (220 mg, yield: 59%); m/z (ES+): 610 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH:42]([NH:45][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)C1

Procedure:
3-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared was prepared starting from intermediate M and 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester. MS calcd. for C26H30ClN4O4 [(M+H)+] 497.2, obsd. 497.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[C:27]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(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.[Pd].CCCCCC.C1(C)C=CC=CC=1>[C:27]1([NH:37][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:4][CH:3]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Reactant: Nc1cccc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(C2(c3ccc(Nc4cccc5ccccc45)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 52.5 %

Procedure:
In a 200 mL three-neck flask were put 3.2 g (8.7 mmol) of 9-(4-bromophenyl)-9-phenyl-9H-fluorene, 1.2 g (8.7 mmol) of 1-naphthylamine, and 2.5 g (26.2 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen. To this mixture were added 43.0 mL of toluene and 0.2 mL of a 10% hexane solution of tri(tert-butyl)phosphine. The temperature of this mixture was set to 60° C., and 35.1 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. The temperature of the mixture was raised to 80° C., followed by stirring for 2.5 hours. After the stirring, the mixture was suction-filtered through Florisil, Celite, and alumina to give a filtrate. The filtrate was concentrated to give a solid, which was then purified by silica gel column chromatography (the developing solvent has a 1:1 ratio of hexane to toluene). Accordingly, 2.1 g of a white solid was obtained in 52% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in the following (E19-1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18]O)=[CH:14][S:13]2)([O-:3])=[O:2].[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18][N:22]1[CH2:23][CH2:24][CH2:21][CH2:20]1)=[CH:14][S:13]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CO)csc2n1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccccc1-c1cn2c(CN3CCCC3)csc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[6-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-3-yl]-methanol (110 mg, 0.4 mmol) in CH2Cl2 (5 ml) with triethylamine (56 ul, 1 eq) was cooled to 0° C. Methylsulfonyl chloride (31 ul, 1 eq) was added dropwise, stirred at 0° C. for 10 min, warmed to room temperature, and stirred for 15 min. The reaction was quenched by the addition of brine, and the mesylate was extracted with CH2Cl2, dried over Na2SO4 and concentrated. The residue was dissolved in acetonitrile (3 ml), and added triethylamine (31 ul, 1 eq), followed by pyrrolidine (66 ul, 2 eq). The reaction mixture was stirred for 2 hours, concentrated and chased with pentane. Column chromatography in CH2Cl2 (0 to 4% MeOH gradient) gave 6-(2-Nitro-phenyl)-3-pyrrolidin-1-ylmethyl-imidazo[2,1-b]thiazole. This material was dissolved in methanol (16 ml) and a solution of sodium hydrogen sulfide (112 mg, 5 eq) in water (4 ml) was added. The reaction mixture was refluxed for 2 days with additional charges of NaHS (2×112 mg). The reaction was concentrated to remove the methanol, and the aqueous solution was extracted with CH2Cl2 (3×40 ml). The organic layer was dried over Na2SO4, and concentrated to obtain the product as a yellow film, 109 mg. (MS, M++H=299.1)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.O=[CH:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:19]([O:18][C:17]([NH:16][CH2:15][CH2:14][NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](NCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (1.22 g) obtained in Reference Example 2(1) is suspended in dichloromethane (10 ml), and thereto is added triethylamine (1.76 ml) and the mixture is stirred for several minutes. After a solution of t-butyl (2-oxoethyl)carbamate (1.00 g) in dichloromethane (5 ml) and sodium triacetoxy borohydride (1.46 g) are added successively under ice-cooling, the reaction solution is warmed to the room temperature and stirred for 15 hours. Saturated aqueous sodium hydrogen carbonate solution is poured to the reaction solution, and the mixture is extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. A portion (1.71 g) of the resulting residue (2.33 g) is purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give methyl trans-4-({2-[(t-butoxycarbonyl)amino]ethyl}amino)-cyclohexanecarboxylate (793 mg).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([F:4])[F:3].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(SC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.42 g (26.3 mmol) 4-trifluoromethylsulfanyl-benzaldehyde, 3.12 g (30.0 mmol) malonic acid, 0.26 g (3.0 mmol) piperidine and 12.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (5 h). The reaction mixture was poured into a solution of 50 ml ice water and 15 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried at 50° C. Yield: 5.9 g (85%) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(C(F)(F)F)c4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.80–6.94 (m, 12H), 6.69 (d, 1H, J=3.6 Hz), 3.36 (s, 2H), 3.10–3.00 (m, 2H), 2.58–2.42 (m, 2H), 2.16–2.02 (m, 2H), 1.85–1.75 (m, 4H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:10]
Reactant: Oc1ccccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1F
Yield: 82.1 %

Procedure:
2-fluorophenol 4a (6.7 g, 60 mmol) was dissolved in 66 mL acetone, followed by addition of ethyl iodide (6.3 mL, 78 mmol) and potassium carbonate (12.4 g, 90 mmol). The reaction mixture was refluxed in an oil bath for 5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 100 mL ethyl acetate and 60 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-ethoxy-2-fluoro-benzene 4b (6.9 g, red grease), yield: 82.1%. MS m/z (ESI): 280.2 [2M+1].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)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[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[N:3][CH:4]=1
Reactant: C#CCCc1cn2ccccc2n1
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#CCCc2cn3ccccc3n2)nc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.3 mL), were added 2-bromo-5-fluoropyridine (120 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.03 mmol) under N2. A yellow suspension was obtained after 5 min of stirring at room temperature. A solution of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (120 mg, 0.68 mmol) in triethylamine (0.5 mL) was then added under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 80° C. overnight. The reaction mixture was concentrated and the crude product was purified by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 15 mg of 2-(4(5-fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 8%) as a brown semi-solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](O)=[O:5]>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1CO
Temperature: 25 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
To a 0° solution of 54.30 g (0.30 moles) of 2-methyl-6-nitrobenzoic acid in 500 ml of anhydrous tetrahydrofuran was added dropwise under a nitrogen atmosphere, 380 ml (0.38 moles) of a stock IM boran/THF solution at such a rate that the temperature did not exceed 5°. Upon complete addition, the ice bath was removed, the solution allowed to stir at room temperature for 14 hours, heated to reflux for 4 hrs. and then cooled to 0° in an ice bath. The reaction was quenched by the dropwise addition of 400 ml of 10% hydrochloric acid, the solution heated to reflux on a steam bath for 0.5 hrs., the THF solvent distilled at atmospheric pressure and the insoluble precipitate extracted into methylene chloride. The methylene chloride extracts were combined, washed with satd. sodium bicarbonate solution, dried (Na2SO4) and the solvent removed in vacuo affording a reddish colored semi solid. Purification was effected from 300 ml of carbon tetrachloride resulting in 41.35 g (84% yield) of yellow flakes; mp 67°-8°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]SC>[Cu]>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: CSSC
Reactant: Cc1cccc(N)c1C1=NOCC1
Agent: [Cu]
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
40 g (0.22 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 1.5 g of copper powder are initially charged in 300 ml of dimethyl disulfide, and 26.1 g of n-butyl nitrite (0.23 mol) are added dropwise at 55-66° C. The mixture is then stirred at 60° C. for 1.5 hours. For work-up, the hot mixture is filtered through activated carbon and then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 44.5 g (88%) of a dark oil which solidifies after a while (content according to HPLC (95%). The product can be purified further by trituration with methyl tert-butyl ether.