Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([N:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(ccn3CC3CCN(C(=O)OC(C)(C)C)C3)c2)CC1
Temperature: 110 °C
Yield: 39.3 %

Procedure:
A mixture of 21.7 mg (0.08 mmol) (1H-indol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone (intermediate 1), 24.1 mg (0.12 mmol) 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available), 38.6 mg (0.16 mmol) cyanomethylenetri-n-butylphosphorane in 1.5 mL toluene was heated to 110° C. for an extended period of time. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 14.3 mg of the title compound. MS(m/e): 455.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13](OS(C)(=O)=O)[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:21]([O-:24])(=S)[CH3:22].[K+]>CN(C)C=O>[C:21]([C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: CCOC(=O)c1csc(N2CC[C@@H](OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC[C@H](C(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 104.8 %

Procedure:
To a solution of (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (1.0 g, 3.12 mmol) (obtained as described in Reference Example 20(1)) in dimethylformamide (30 ml) was added potassium thioacetate (919 mg, 9.36 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 5.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1→1:1) as the eluant to afford (3S)-3-acetyl-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (877 mg, yield 99%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[C:21]1([CH2:27][C:28](OC)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:27]([C:28]1[NH:20][C:18](=[O:19])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccccc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccccc3)nc21

Procedure:
Analogously to the procedure of Example 1, the title compound is prepared from 566 mg (2 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.16 g (7.7 mmol) of methyl phenylacetate.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]=3[CH:17]=[CH:18][CH:19]=2.O.[OH-].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:22]([N:14]1[CH2:13][CH2:12][N:11]([C:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[C:3]4[C:4]=3[C:8](=[CH:9][CH:10]=[C:2]4[Br:1])[N:7]=2)[CH2:16][CH2:15]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1ccc2c3c(cccc13)C(N1CCNCC1)=N2
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CCN(C2=Nc3ccc(Br)c4cccc2c34)CC1
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.1 g. of 1-(6-bromobenz-[cd]indol-2-yl)piperazine, 75 ml. of water, and 75 ml. of chloroform is stirred vigorously as 10 ml. of 5 N soidum hydroxide is added, followed by 5 g. of benzoyl chloride, in six portions over a period of 10 minutes. The reaction mixture is stirred an additional 30 minutes after the completion of the benzoyl chloride addition. The chloroform layer is separated and dried over sodium sulrate. After separation from impurities by chromatography on an alumina column, the title compound is recrystallized from benzene-chloroform to yield orange flakes, melting at 237.5°-239° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:4]=[CH:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: Cn1cnc(-c2sccc2N)c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C)cn2)cc1

Procedure:
The title compound was prepared from 2-(1-methyl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B and was purified by HPLC. Method [8] Retention time 3.55 min by HPLC (MH+ 328). 1H NMR (300 MHz, DMSO) δ 10.37 (s, 1H), 8.33 (s, 1H), 7.48 (3m, H), 7.26 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), (s, 6H), 3.60 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([N:8]([C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[CH:20])=[CH:17][CH:18]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(N(C)Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-methylamine (Intermediate 131, 80.0 mg, 0.24 mmol) in methanol (5 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight at ambient temperature. The crude alkyne (60 mg, 99%) was used directly in the next reaction.
Reaction SMILES: COC(=O)[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].CC(C)([O-])C.[K+].Cl.[Cl-].[Li+]>C1COCC1.[Cl-].[Na+].O>[CH:15]([O:14][C:12]([N:11]1[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[C:4]2[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]1=2)=[O:13])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(F)c1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)N1CCCC(=O)c2c(F)cccc21
Temperature: 160 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Add a solution of 2-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-6-fluor-benzoic acid methyl ester (2.96 g, 8.01 mmol) in THF (123 mL) to a solution of potassium tert-butoxide (16 mL, 16 mmol, 1 M in THF) in THF (123 mL) at room temperature under an atmosphere of nitrogen. After 2 h, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the former crude in DMSO (58 mL) and add water (4 drops) followed by addition of lithium chloride (773 mg, 18.23 mmol) and heat the resulting solution at 160° C. for 2 h. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous magnesium sulfate, filter the mixture and evaporate the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (1.0 g, 47% over two steps): MS (ES+): 266 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1)[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[N:8]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1nccc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCc1nccc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
This compound was obtained according to example 2, step B] from 2-ethyl-pyrimidin-4-ylamine (0.25 g), and 3-chloro-2-methyl-benzenesulfonyl chloride (0.55 g) as a colorless solid (86 mg). MS (ESI−): 310.0 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(C(O)c2ccc[nH]2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(Cc2ccc[nH]2)c1
Temperature: -5 °C
Reaction time: 9.5 h

Procedure:
A 2-(3'-amino-α-hydroxybenzyl)pyrrole is dissolved in an inert organic solvent (such as a lower alkanol, preferably methanol), cooled to about -20° to 10° C., preferably -5° C., and treated with a molar excess of a reducing agent (such as sodium cyanoborohydride in glacial acetic acid). The reaction mixture is allowed to warm to about ambient temperature and is stirred for a period of about 0.5 to 36 hours, preferably 1 to 18 hours, and most preferably about 2 hours. The reaction is then quenched (e.g., with saturated sodium carbonate) and extracted with ethyl acetate. The extract is washed with water, dried and evaporated in vacuo, and then purified, e.g., by column chromatography over slica gel, to obtain the 2-(3'-aminobenzyl)pyrrole of Formula 11.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A stirred solution of methyl 5-[bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate [Palmer et al., J. Med. Chem 1994, 37, 2175] (5.50 g, 16.7 mmol) and Et3N (5.82 mL, 41.8 mmol) in dry CH2Cl2 (50 mL) was treated dropwise at 0° C. with MsCl (3.14 mL, 40.0 mmol). After 30 min, 10% aqueous KHCO3 (100 mL) was added, and the mixture was stirred for a further 30 min at 0° C. and then diluted with pet. ether (500 mL). The precipitated product was collected and washed with water and iPr2O to give methyl 5-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoate (7) (7.44 g, 92%):
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[N:19]=[CH:18][C:17]=3[N:34]=2)=[CH:10][CH:9]=1.Cl.[C:37](OCC)(=O)C>C(OCC)(=O)C>[F:35][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:37])[CH3:25])[N:19]=[CH:18][C:17]=3[N:34]=2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-(2-(2,2-difluorocyclopropyl)ethoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (239 mg), 4M hydrogen chloride/ethyl acetate (3 mL) and ethyl acetate (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with acetic anhydride (0.138 mL) and pyridine (3 mL), and the obtained mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (155 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O1CCOCC1.O.[OH-].[Na+].Cl>C(OCC)(=O)C>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a mixture of N-benzyloxycarbonyl-L-leucine (2.7 g, 10.2 mmol), L-phenylalanine methyl ester hydrochloride (2.2 g, 10.2 mmol), and triethylamine (1.4 mL, 10.2 mmol) in dry THF (150 mL) was added N-ethyl-N'-dimethylaminopropyl-carbodiimide (EDCI) (2.2 g, 11.2 mmol) with stirring at room temperature. After the mixture was stirred overnight at room temperature, it was rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give a white solid residue. Recrystallization (EtOAc-hexane) gave 2.9 g (66%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine methyl ester, m.p. 91°-93° C. A mixture of this ester (2.8 g, 6.6 mmol) in 2:1 dioxane-water (150 mL) was treated at 0° C. with 1N NaOH solution (7.3 mmol). After stirring the solution for 2-3 hours at room temperature, it was acidified at 0° C. by the addition of 1N HCl, and then rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give 2.7 g of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine as a white solid, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:23][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:7]([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:8])=[CH:22][C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: Cc1ccoc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccoc1C(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Reaction time: 3 h
Yield: 47.1 %

Procedure:
A solution of 3-methyl-2-furancarbonyl chloride (9.5 g, 0.066 mole) in toluene (20 ml) was added to 1-methylethyl 5-amino-2-chlorobenzoate (14 g, 0.066 mole) and triethylamine (10 g) in toluene (20 ml). After about three hours at ambient temperature, the mixture was washed with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate and finally water. With cooling, the product (m.p. 99°-100° C., 10 g, 47% yield) was crystallized from toluene.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.COC(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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccco1
Reactant: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccco2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 80 °C
Yield: 33.1 %

Procedure:
A mixture of 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoic acid (Example 7, 0.1 g), 2-furylboronic acid (0.031 g), tri-tert-butylphosphinium tetrafluoroborate (0.0074 g), cesium carbonate (0.253 g) and tris-(dibenzylideneacetone)dipalladium (0.012 g) in dioxane (3 ml) and water (0.4 ml) was sealed in a vial under nitrogen and heated at 80° C. for 2 hours. After cooling, the mixture was diluted with t-butyl methyl ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified twice by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 25-98% to give 6-(benzenesulphonylmethyl)-3-(furan-2-yl)-2-methoxybenzoic acid (0.032 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH:13][CH2:14][CH3:15])[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[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>[CH2:14]([NH:13][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:27])[F:16])[CH:19]=2)[N:7]=[C:6]([C:8]#[N:9])[C:5]=1[N+:10]([O-:12])=[O:11])[CH3:15]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
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: [K+]
Solvent: C1COCCO1
Product: CCNc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)c1[N+](=O)[O-]
Yield: 64.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (2.78 g) was added under a nitrogen atmosphere to a mixture of 6-chloro-4-ethylamino-3-nitro-pyridine-2-carbonitrile (10.9 g), 4-trifluoromethyl-phenylboronic acid (10.0 g) in degassed dioxane (500 mL) and a 2M aqueous solution of potassium carbonate (60 mL). The mixture was refluxed for 4 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: DCM then DCM/acetone 95/5) to afford the title compound (10.4 g, 64%). 1H NMR (DMSO-d6) δ: 8.59 (br. s, 1H); 8.50-8.40 (m, 2H); 7.91 (d, J=8 Hz, 1H); 7.79 (t, J=7 Hz, 1H); 7.74 (s, 1H); 3.65 (q, J=7 Hz, 2H); 1.24 (t, J=7 Hz, 3H). MS m/z: 337 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29]C(=O)OCC1C=CC=CC=1.C(O)C>O1CCCC1.[C].[Pd]>[NH2:29][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:7][C:2]=1[F:1]
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of benzyl (2-fluoro-4-{2-[(4-pyrrolidin-1-ylpiperidine-1-carbonyl)amino]pyridin-4-yloxy}phenyl)carbamate (91 mg) in tetrahydrofuran (10 ml) was 10% palladium carbon (36.4 mg), followed by stirring under a hydrogen atmosphere at room temperature for 3.5 hrs. Ethanol (5.0 ml) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 1.5 hrs. The reaction mixture was filtered to remove the catalyst, and washed with a small amount of tetrahydrofuran to give a solution of the titled compound in tetrahydrofuran. The solution was concentrated to almost dryness, which was then used for succeeding reactions without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.ClCCl.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>N1C=CC=CC=1>[CH:31]([O:30][C:28](=[O:29])[NH:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)([CH3:33])[CH3:32]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N)C1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)NC1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Temperature: 5 °C
Yield: 56.9 %

Procedure:
Add (±)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (35 g, 108 mmol) to a mixture of dichloromethane (350 mL) and pyridine (70 mL). Stir the mixture under nitrogen and cool to 5° C. Add isopropyl chloroformate (1M solution in toluene, 162 mL, 162 mmol). Remove the ice bath and stir the mixture at 22° C. After 16 h evaporate the solvent. Add the resulting residue to water (350 mL) and stir 2 h. Filter and dry the collected solid under vacuum at 45° C. Add the solid to ethyl acetate (400 mL) and heat the mixture to reflux. Then cool to 22° C. and filter the solid. Add the wet solid to ethyl acetate (200 mL) and heat to reflux for 30 min. Cool the mixture to 22° C. over one hour and then cool to 0-5° C. during 5 min. Filter the mixture and dry the isolated solid under vacuum to constant weight to provide 23 g (62%) of the title compound. MS (m/z): 374 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)/C=C/c1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ester 9 (4.9 g, 18.0 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (5 g, 36.0 mmol) and benzyl bromide (3.38 g, 19.8 mmol). The reaction mixture was stirred overnight at room temperature, filtered and the solvent was removed under reduced pressure. The resulting crude reaction product was suspended in water and extracted with AcOEt. The combined organic layers were dried oved Na2SO4, filtered, and the volatiles were removed in vacuo to give 6.06 g of bromoaryl 10 as a white solid. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.94 (d, J=15.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1), 7.38-7.25 (m, 5H), 7.14 (d, J=3.0 Hz, 1H), 6.81 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 6.29 (d, J=15.9 Hz, 1H), 5.00 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 166.2, 158.0, 142.8, 136.1, 135.1, 133.9, 128.6, 128.2, 127.4, 121.1, 118.3, 116.1, 113.6, 70.2, 60.6, 14.2; HRMS (EI) m/z: calcd for C18H17BrO3: 360.0361. found: 360.0361; mp: 72-74° C.