Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][CH:35]=[N:34][C:33]=2[C:37](Cl)=[O:38])[CH:29]=[CH:30][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:37]([C:33]1[N:34]=[CH:35][S:36][C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[O:38])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ncsc1-c1cccc(F)c1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncsc2-c2cccc(F)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.06 min, [M+H]+=487.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in CH2Cl2 (30 mL) was stirred for 1 h at 0° C. and at ambient temp for 2 h. The solution was diluted with CH2Cl2 (40 mL) and the organic phase was washed with 0.1 N HCl and brine, dried over Na2SO4 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (5.3 g, 86.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=2)[C:38](O)=[O:39])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cccc(C(=O)O)c2)cc(OC)c1OC
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(C(=O)c2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzoic acid (577 mg) were condensed in the same manner as described in Example 1 to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:55][CH2:54]1
Reactant: O=C(O)c1cn(-c2ccccc2)nn1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2ccccc2)nn1
Reaction time: 0.03 h
Yield: 76.6 %

Procedure:
DIPEA (200 mg, 0.27 mL, 1.55 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47.6 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (107 mg, 0.35 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate formed was collected to afford 108 mg (76.6% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 95.71%. 1H NMR (300 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.5 (t, 1H), 8.02 (d, 2H), 7.68 (m, 3H), 7.48 (d, 1H), 7.36-7.22 (m, 2H), 7.0 (t, 1H), 4.8 (m, 1H), 4.3 (d, 2H), 3.8 (t, 2H), 3.6 (s, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[N:17]=1.P(Cl)(Cl)Cl.ClC1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: Clc1ccccc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cs1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol), 2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole (312.2 mg, 1 mmol), phosphorus trichloride (44 μL, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (109.8 mg, 23.5%) as a pale yellow white powder.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:70]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:70]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(COC(=N)C(Cl)(Cl)Cl)c1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(CO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (230 mg in 3 ml 33% methylene chloride in cyclohexane) was added m-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate (198 μl neat) and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (165 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[C:40]([C:43]1[CH:44]=[C:45]([N:49]2[C:53]([SH:54])=[N:52][N:51]=[N:50]2)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41].BrN1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH:9]([S:54][C:53]2[N:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:40]([OH:42])=[O:41])[CH:44]=3)[N:50]=[N:51][N:52]=2)[C:8](=[O:10])[N:7]([C:11]2[C:12]([Cl:19])=[CH:13][C:14]([Cl:18])=[CH:15][C:16]=2[Cl:17])[N:6]=1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Sc2nnnn2-c2cccc(C(=O)O)c2)c1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
15 g of 3-(2-chloro-5-tetradecanamidoanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 5.4 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole were dissolved in 100 ml of DMF and to the solution was added dropwise at room temperature 20 ml of a DMF solution containing 4.9 g of N-bromosuccinimide. After stirring for 30 minutes, 500 ml of water was added to the mixture which was extracted with ethyl acetate. The ethyl acetate was distilled off under reduced pressure and the residue was crystallized from a solvent mixture of ethyl acetate and acetonitrile to obtain 14 g of 3-(2-chloro-5-tetradecanamidoanilino)-1-(2,4,6-trichlorophenyl)-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-pyrazolin-5-one. Yield: 68%. Melting Point: 155° to 165° C.
Reaction SMILES: C[O-].[Na+].[OH:4][N:5]1[C:9](=[O:10])[CH:8]2[CH2:11][CH2:12][CH:13]=[CH:14][CH:7]2[C:6]1=[O:15].[CH2:16](Cl)[CH3:17].O>CO>[CH2:16]([O:4][N:5]1[C:6](=[O:15])[CH:7]2[CH2:14][CH2:13][CH:12]=[CH:11][CH:8]2[C:9]1=[O:10])[CH3:17]
Reactant: CCCl
Reactant: O=C1C2C=CCCC2C(=O)N1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
In an autoclave a solution of 3.5 g of sodium methoxide (0.065 mol) in 40 ml of methanol, 11.0 g of N-hydroxytetra-hydrophthalimide (0.066 mol) and 4.6 g (0.072 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was held at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction mixture comprised a large quantity of solid material. This was dissolved by the addition of water and the whole was afterwards extracted with toluene to obtain the product. Gas chromatographic analysis of the toluene extract showed that the yield was 74% of N-ethoxytetra-hydrophthalimide (0.049 mol).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[CH2:4][C:3]1([CH3:24])[CH3:23].C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH:20]([CH3:21])[CH3:22])[CH:11]=2)[CH2:4][C:3]1([CH3:23])[CH3:24]
Reactant: CC(C)Oc1cc(C2=CC(C)(C)N(C)C(C)(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc(C2CC(C)(C)N(C)C(C)(C)C2)ccc1N
Temperature: 80 °C
Yield: 57 %

Procedure:
180 μl of formaldehyde and 3.4 ml of formic acid are added to a solution of 500 mg of 2,2,6,6-tetramethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine (obtained according to method 2) in 15 ml of DMSO. The tube is microwave-heated at 100° C. for 5 minutes. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel, elution being carried out with a mixture of dichloromethane and methanol (95/5), so as to obtain 230 mg of 1,2,2,6,6-pentamethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine in the form of a yellow oil. In a microwave tube, 230 mg of 1,2,2,6,6-pentamethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine are introduced into 11.5 ml of methanol. 262 mg of ammonium formate and 221 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by flash chromatography on alumina, elution being carried out with a dichloromethane/methanol (98/2) mixture, so as to obtain 120 mg of 4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: Cc1cccc(B(O)O)c1
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: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 83.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH2:12]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH2:12]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (4.05 g, 23.5 mmol), 1-n-butyl-piperazine (10.0 g, 70 mmol) and anhydrous potassium carbonate (3.6 g, 26 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(4-butyl-piperazin-1-yl)-2-nitro-phenylamine (4.4 g, 67%) as a yellow powder, and used in the next step without further purification.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1.Cl.O>[OH-].[Na+].C(O)C>[C:14]([C:12]1[CH:13]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N(C(=O)/C=C\C(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 2.97 g (0.01 mole) of 4-anilino-2,6-di-t-butylphenol and 4.90 g 0.05 mole) of maleic anhydride was heated at 140° C. for 2 hours. The cooled reaction mixture was suspended in 10% sodium hydroxide, and was then acidified with 10% hydrochloric acid. The resulting precipitate was collected, rinsed with water, air dried, and recrystallized from a mixture of ethyl acetate and hexane to give a yellow solid. This material was dissolved in hot ethanol. The ethanol solution was acidified with 6N hydrochloric acid, and then saturated with water. The resulting precipitate was collected, rinsed with water and air dried. This material was purified by silica gel chromatography, eluting with ethyl acetate, followed by recrystallization from a mixture of ethyl acetate and hexane to give 0.5 g of yellow crystalline N-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenylmaleamic acid, m.p. 154°-157° C. Analysis: Calculated for C25H29NO4 :% C, 72.9; % H, 7.9; % N, 3.5. Found: % C, 73.2; % H, 7.7; % N, 3.3.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][N:14]=2)=[N:11][CH:12]=1)(C)C.[F-].[K+]>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][N:11]=2)=[N:14][CH:15]=1)#[CH:20]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2ccc(C#C)cn2)nc1
Yield: 85.7 %

Procedure:
Subsequently, the obtained 5,5′-bis(trimethylsilylethynyl)-2,2′-bipyridyl (120 mg, 0.34 mmol) and potassium fluoride (KF: 42 mg, 0.72 mmol) were added with dist. methanol (MeOH: 12 mL). The resultant mixture was then stirred under a nitrogen atmosphere at room temperature for 11 hours to obtain a reaction mixture. After that, an organic layer in the reaction mixture was then concentrated to obtain a crude product (II). Subsequently, the obtained crude product (II) was separated and purified by silica gel column chromatography (CH2Cl2=100) to obtain 5,5′-diethynyl-2,2′-bipyridyl (59.5 mg, 85% yield (in two steps)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].Cl.[CH3:12][S:13]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CCN(C(C)C)C(C)C>C(#N)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:17][CH2:18]2)[C:3]=1[CH:4]=[O:5]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=Cc1c(F)cccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)C1CCN(c2cccc(F)c2C=O)CC1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
In a 250 mL round bottom flask, 2,6-difluorobenzaldehyde (7.12 g, 5.4 mL, 50.1 mmol), 4-methanesulfonylpiperidine hydrochloride (10 g, 50.1 mmol) and DIPEA (7.77 g, 60.1 mmol) were combined with acetonitrile (75 mL). The mixture was stirred and heated at 80° C. overnight. The mixture was evaporated and extracted with dichloromethane and citric acid solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The crude solid was triturated with cold ethyl acetate to afford 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (12 g, 84% yield). LC-MS calcd for C13H16FNO3S (m/e) 285.08, obsd 286.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C(COC)OC.C(OCC)(=O)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]>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH:7]=1)([O-:10])=[O:9]
Reactant: NC(=O)C1CC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-Chloro-4-nitro-pyridine (476 mg, 3 mmol), cyclopropanecarboxylic acid amide (306 mg, 3.6 mmol), and tripotassium phosphate (892 mg, 4.2 mmol) are mixed in dimethoxyethane under an argon atmosphere. (2′-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (118 mg, 0.3 mmol) and Pd2(dba)3 (275 mg, 0.3 mmol) are added and the mixture is stirred for 3 h at 90° C. Further 0.5 equivalent cyclopropanecarboxylic acid amide (128 mg, 1.5 mmol) is added and the mixture is stirred for 1 additional hour. After cooling at RT the reaction mixture is taken in ethyl acetate, washed with a solution of saturated sodium hydrogen carbonate and brine. The combined organic phases are dried (Na2SO4), concentrated under reduced pressure and the residue is purified by column chromatography (ethyl acetate/hexane) to afford the title compound as a brown solid. M-H−=206.1, HPLC tR: 4.62 min.
Reaction SMILES: [O:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][NH2:14]>C(O)(C)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][CH2:6][C:7]([NH:14][CH3:13])=[O:8]
Reactant: CN
Reactant: O=C1CCCc2ccccc2O1
Solvent: CC(C)O
Product: CNC(=O)CCCc1ccccc1O
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 4,5-dihydro-3H-benzo[b]oxepin-2-one and 40 ml of 10% methylamine in isopropanol is heated in an autoclave at 100° C. over 16 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation. The title compound is obtained as white crystals from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (4:1 EtOAc-heptane); Rt=2.66.