Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.7 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodium cyanoborohydride (22.8 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (71.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: CN.[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[N:11]=1)[C:7]#[N:8].ClC1C=C(C=C(N2CCC(O)CC2)N=1)[C:23]#[N:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:24][CH3:23])[CH2:14][CH2:13]2)[N:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)nc(N2CCC(=O)CC2)c1
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Reaction time: 0.5 h

Procedure:
Methylamine (2.65 ml, 5.3 mmol) was added to a solution of 2-chloro-6-(4-oxopiperidin-1-yl)isonicotinonitrile (Intermediate 26; 500 mg, 2.12 mmol) in anhydrous THF (4 ml). The mixture was stirred for 30 minutes and sodium triacetoxyborohydride (674 mg, 3.18 mmol) was added. The mixture was stirred at room temperature for 18 h, then concentrated in vacuo, diluted with EtOAc and washed with 1 N NaOH, water and brine. The organic phase was dried over Na2SO4 then concentrated in vacuo to give a brown oil which was dried under vacuum to yield the title compound (507 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][N:5]2[CH:15]=1.CN(C)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:19]>>[CH:12]([O:11][C:9]([CH:8]1[CH2:7][CH2:6][N:5]2[C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:19])=[C:2]([CH3:1])[CH:3]=[C:4]12)=[O:10])([CH3:13])[CH3:14]
Reactant: Cc1cc2n(c1)CCC2C(=O)OC(C)C
Reactant: Cc1ccc(C(=O)N(C)C)cc1
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)C)cc1

Procedure:
In accordance with the method of Example 8, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethyl-p-toluamide, to produce isopropyl-5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XI, R = CH3, R1 = p-CH3, R2 = iC3H7).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:23])([CH2:21][NH2:22])[CH2:19][OH:20].O>C1(C)C=CC=CC=1>[OH:20][CH2:19][C:18]([CH3:23])([CH3:17])[CH2:21][N:22]=[C:12]([C:8]1[CH2:9][CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[C:7]=1[C:15]([OH:14])=[O:16])[OH:13]
Reactant: O=C1OC(=O)C2=C1CCCc1ccccc12
Reactant: CC(C)(CN)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)CN=C(O)C1=C(C(=O)O)c2ccccc2CCC1
Temperature: 25 °C

Procedure:
21.4 g (0.1 mol) of 6,7-dihydro-5H-benzocycloheptene-8,9-dicarboxylic acid anhydride and 10.3 g (0.1 mol) of 2,2-dimethyl-3-aminopropanol are dissolved in 60 ml of toluene and the solution is refluxed for 1 hour, the water formed being separated off by means of a water separator downstream of the reaction vessel. After cooling to room temperature, the crystals which have precipitated out are filtered off. This yields 28.9 g (96.6% of theory) of N-(3'-hydroxy-2',2'-dimethylpropyl)-6,7-dihydro-5H-benzocycloheptene-8,9-dicarboxylic acid imide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][CH2:21][CH:22](O)[CH2:23][CH2:24][CH3:25].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:22]([CH2:21][CH3:20])[CH2:23][CH2:24][CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC(O)CC
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC(CC)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and 3-hexanol (0.150 ml, 1.35 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was separated and purified by flash silica gel chromatography (hexane:ethyl acetate=200:1), whereby obtained were the title Isomer 293-A (low polarity) (37 mg, 0.096 mmol, 15%) and the title Isomer mixture (44 mg, 0.11 mmol, 17%), each as a white powder.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:6]1[C:18]2[N+:9](=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[CH:8]=[CH:7]1.COC1C=CC(CN2C=CC(C(C3C=CN(CC4C=CC(OC)=CC=4)N=3)=C)=N2)=CC=1>C(O)C.C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:6]1[C:18]2[CH2:17][C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][N+:9]=2[CH:8]=[CH:7]1
Reactant: c1ccc2c[n+]3ccsc3cc2c1
Agent: C=C(c1ccn(Cc2ccc(OC)cc2)n1)c1ccn(Cc2ccc(OC)cc2)n1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCO
Product: c1ccc2c(c1)Cc1scc[n+]1C2
Temperature: 25 °C

Procedure:
A reaction mixture containing thiazolo[3,2-b]isoquinolinium perchlorate (2.4 g; 8.4 mmol) and 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene (4 g; 0.01 mol) in 125 ml of ethanol and 25 ml of acetonitrile was refluxed for 12 h under nitrogen. The reaction mixture was cooled to room temperature, the solid product was filtered, washed with ether, and dried in vacuo to afford 4.65 g (81.6%) of 11,11-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)]-5,10-ethano-5,10-dihydrothiazolo[3,2-b]isoquinolinium perchlorate (Formula I: A=thiazolo;R1 =R2 =R3 =R6 =H;R4 =R5 =1-p-methoxybenzyl-3-pyrazolyl;X- =ClO4-).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[NH:6]1)=O.[NH3:16]>CO>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]([C:3]([NH2:16])=[O:2])[CH2:13]2
Reactant: N
Reactant: COC(=O)C1Cc2cc(OC)ccc2N1
Solvent: CO
Product: COc1ccc2c(c1)CC(C(N)=O)N2
Temperature: 25 °C

Procedure:
2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid methyl ester (0.084 mole) and 2M NH3 in methanol (500 ml) were combined and stirred at room temperature under argon over the weekend. The solution was concentrated to 100 ml, cooled in an ice bath, and filtered. The solid was rinsed with a small amount of cold methanol and dried. The residue was triturated in methanol/ACN and filtered, yielding 4.56 g of 2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 21, mp. 228-229° C.). b) Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196-197° C.). c) To a suspension of intermediate (22) (0.022 mole) in DCM (150 ml), cooled in an ice bath under argon, was added triethylamine (0.066 mole) then trichloroacetyl chloride (0.033 mole). The mixture was allowed to slowly warmed to room temperature overnight. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic phase was dried, concentrated and triturated in ether and the solid collected, yielding 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carbonitrile (intermediate 23, mp. 108-110° C.). d) To a solution of intermediate (23) (0.0154 mole) and ethanol (0.0231 mole) in 1M HCl/diethylether (200 ml), cooled in an ice bath was bubbled HCl (gas) for 60 minutes. The ice bath was maintained for 45 minutes, and the mixture was concentrated at room temperature under vacuum to 200 ml of an oily precipitate. The residue was triturated to a brown solid that became an oil after decanting off the diethylether. The residue was washed with diethylether twice, dissolved in methanol, and used without further purification for further synthesis, yielding ethyl 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboximidate monohydrochloride (intermediate 24).
Reaction SMILES: [NH2:1][C:2]([CH2:12][CH3:13])([CH2:8][CH:9]=[CH:10][CH3:11])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[NH2:1][C:2]([CH2:12][CH3:13])([CH2:8][CH:9]=[CH:10][CH3:11])[CH2:3][OH:4]
Reactant: CC=CCC(N)(CC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CCC(N)(CC)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A solution of the product from step (d) (116.7 g) in THF (100 ml) was added to a 1M solution of lithium aluminium hydride in THF (800 ml) at about 0° C. When addition was complete, the mixture was stirred overnight at room temperature, then 50% w/v aqu. NaOH (200 ml) was added. The organic phase was separated, washed with brine, dried and evaporated in vacuo. The residue was distilled to give the desired product as an oil (29.3 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][C:23]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[O:25][N:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:26]2[O:25][N:24]=[C:23]([CH3:22])[N:27]=2)[CH:29]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: Cc1noc(-c2cccc(N)c2)n1
Product: Cc1noc(-c2cccc(Nc3ccc4ccccc4c3[N+](=O)[O-])c2)n1

Procedure:
1-Nitronaphthalen-2-yl triflate and 3-(3-methyl-[1,2,4]oxadiazol-5-yl)aniline were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]=2[C:13]([O:32][CH3:33])=[CH:12][C:11]=1[CH2:34]OS(C)(=O)=O>CN(C=O)C>[Br:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]=2[C:13]([O:32][CH3:33])=[CH:12][C:11]=1[CH2:34][N:6]1[CH:5]=[C:4]([CH3:3])[CH:8]=[N:7]1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cn3cc(C)cn3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
NaH (7 mg, 0.3 mmol) is added to a solution of 23 μl (0.30 mmol) 4-methylpyrazole in 2 ml DMF. The resulting mixture is stirred at room temperature for 1 h, then 119 mg (0.23 mmol) methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester is added. Stirring is continued for 20 h. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (dichloromethane:isopropanol=95:5) to afford 80 mg of the title compound as a white foam.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:9])[CH3:7].CN([CH:20]=[O:21])C>>[CH2:6]([N:8]([C:10]1[CH:11]=[C:12]([OH:16])[C:13](=[CH:14][CH:15]=1)[CH:20]=[O:21])[CH3:9])[CH3:7]
Reactant: CN(C)C=O
Reactant: CCN(C)c1cccc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C)c1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
6.14 g (0.066 mol) of phosphorus oxychloride are cautiously added to 19 ml of dry DMF at −5° C. within a period of 5 minutes, during the course of which the temperature of the reaction solution should not exceed 10° C. Subsequently, a solution of 9.9 g (0.066 mol) of 3-(N-ethyl-N-methylamino)phenol in 14 ml of dry DMF is added thereto within a period of 10 minutes, during the course of which the temperature of the reaction solution should not exceed 20° C. When the addition is complete, the reaction solution is heated for 2 hours at 90° C. and then immediately poured onto 100 g of ice. The crude mixture is stirred for 30 minutes. The reaction solution is extracted three times with 100 ml of chloroform. The combined organic phases are concentrated under a high vacuum. The oily residue which remains is purified by column chromatography on silica gel (eluant n-hexanelchloroform 95:5). Yield: 5.8 g (26%), colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2.Cl>CO.[Fe]>[Cl:1][C:2]1[C:3]([NH2:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2cn1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cc1cc2c(N)c(Cl)ccc2cn1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To a solution of 6-chloro-3-methyl-5-nitroisoquinoline (8.00 g, 36 mmol) in methanol (200 mL) was added iron powder (6.68 g, 119 mmol), followed by careful addition of a concentrated aqueous HCl solution (18 mL). The resulting reaction mixture was heated for 1 h at 50° C. and concentrated at reduced pressure using a rotary evaporator. The residue was dissolved in water and basified (pH=9) using a 25% aqueous ammonia solution. The resulting brown suspension was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a brown solid (6.09 g, 31.6 mmol, 88%). MS (ES+): 193 (M(C10H935ClN2)+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:30]2[CH2:31][CH2:32][CH2:33][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.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.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:33][CH2:32][CH2:31][C:30]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC4)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 33.6 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (184 mg, 446 μmol) and 1-methyl-3-(tributylstannyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (293 mg, 714 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (25.8 mg, 22.3 μmol) and CuI (17.0 mg, 89.2 mmol) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (68 mg, 150 μmol, 34%) as a light yellow solid. MS (M+Na)+=477; 1H NMR (CDCl3) δ: 9.06 (s, 1H), 8.28 (s, 1H), 8.13 (d, J=8.3 Hz, 1H), 5.68 (s, 2H), 4.44 (dq, J=14.5, 6.6 Hz, 1H), 3.89 (s, 3H), 3.47-3.64 (m, 2H), 3.04 (t, J=7.0 Hz, 2H), 2.62-2.86 (m, 4H), 1.34 (d, J=6.8 Hz, 6H), 0.86-0.96 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Ic1ccccc1
Product: c1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Following General Procedure A (90° C., 30 hours), 1,1-diphenyl-methanimine (272 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol) to give 94% N-(diphenylmethylene)aniline.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][C:11]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[N:12][CH:13]=1.[OH:19][C:20]1[C:25]2[CH:26]=[C:27]([CH3:29])[O:28][C:24]=2[CH:23]=[C:22]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:21]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I>[CH3:17][N:16]([CH3:18])[C:14]([C:11]1[N:10]=[CH:9][C:8]([O:19][C:20]2[C:25]3[CH:26]=[C:27]([CH3:29])[O:28][C:24]=3[CH:23]=[C:22]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:21]=2)=[CH:13][N:12]=1)=[O:15]
Reactant: CN(C)C(=O)c1ncc(Br)cn1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: I[Cu]I
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
A mixture of Cs2CO3 (62.1 g, 191 mmol), 5-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-2: 24 g, 104 mmol) and ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 20 g, 91 mmol); 1,10-phenanthroline (1.64 g, 9.07 mmol) and copper iodide (864 mg, 4.54 mmol) in dimethylformamide (200 ml) was purged with N2 gas and then heated to 90° C. using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 35° C. and diluted with ethyl acetate (300 ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500 ml) and ethyl acetate (500 ml); however, no separation was observed. Concentrated HCL (20 ml) was added to the mixture. When the aqueous phase was about pH1, the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2×500 ml). All organics were combined and back extracted with water (200 ml) and brine (500 ml). The organics were separated and treated with activated charcoal (10 g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 mL). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 mL). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 mL). The solid was dried in the vacuum oven at 55° C. for 12 hours to afford ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a) as a yellow solid (18.2 g, 54%)
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+:23].C(C(C)=O)C(C)C>O>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6]([O-:8])=[O:7])([CH3:3])[CH3:2].[Na+:23]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)O)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(C)c1cc(C(C)C)c(C(=O)[O-])c(C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A 1-L eggplant shaped flask was charged with 39.7 g of 2,4,6-triisopropylbenzoic acid (prepared in Synthesis Example 1-1), 13.4 g of sodium hydrogencarbonate, 160 g of methyl isobutyl ketone, and 40 g of water, which were stirred at room temperature for 24 hours. At the end of stirring, the reaction solution was concentrated, followed by twice of azeotropic dehydration with 100 g of methyl isobutyl ketone. To the solid precipitate, 300 g of diisopropyl ether was added, whereupon solid-liquid washing was conducted for 30 minutes. The solid was filtered and dried, obtaining the target compound, sodium 2,4,6-triisopropylbenzoate as white crystal. Amount 30.7 g, yield 80%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([NH2:38])[CH:32]=1>>[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]2[C:32]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:38]2
Reactant: CCOC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1Cl)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-3-oxopentanoic acid ethyl ester and (3-amino-4-fluorophenoxy)acetic acid methyl ester.