Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])=[O:16].Cl>C(O)C.O>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(C(=O)C=Cc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 3-formylbenzoic acid (2.0 g, 13.3 mmol) and sodium hydroxide (1.32 g, 33 mmol) in 400 mL of ethanol/water (1:1) is added 2,5-dimethoxyacetophenone (2.4 g, 13.3 mmol) and the resulting solution is stirred overnight at room temperature. The mixture is acidified with concentrated hydrochloric acid and the resulting solid is collected by filtration after diluting the mixture with water (200 mL) to provide 2.9 g of the title compound; mp 152°-155° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:23][C:24]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].O>CN(C)C=O>[Br:23][C:24]1[CH:31]=[C:30]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C#N)c(Br)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C

Procedure:
500 mg 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol were dissolved in 5 ml dimethylformamide. 108 mg sodium hydride were added and the mixture stirred at room temperature. After thirty minutes commercially available 2-bromo-4-fluorobenzonitrile were added and the reaction mixture stirred at room temperature for one hour. Then 5 ml water were added and the mixture extracted three times with portions of 30 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 375 mg 2-Bromo-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[NH:8][C:9](=[O:11])[CH3:10].C(O)(=O)C>S(=O)(=O)(O)O>[F:5][C:6]1[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[C:13]([F:16])=[CH:12][C:7]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cc(F)ccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of nitric acid (21.85 mL) and sulfuric acid (28.5 mL) is added dropwise to a mixture of 2',5'-difluoroacetanilide (44.2 g, 0.281 mol) and acetic acid (19 mL) in sulfuric acid (190 mL) while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at 0° C. for one hour and poured onto cracked ice (2 L). The aqueous mixture is filtered to obtain a solid. The solid is air dried and recrystallized from ethanol to give the title product as a yellow, crystalline solid, mp 188°-189° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (164.0 mg, 0.47 mmol) and triphenylphosphine (184.2 mg, 0.70 mmol) in methylene chloride (1.2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (141.6 mg, 0.80 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (140.6 mg, 1.40 mmol). The resulting reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (47.9 mg, 24%) as a cream solid: mp 189–191° C.; EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0791.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[C:21](=[N:23][OH:24])[CH3:22].[H-].[Na+].CO>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:22][C:21]1[C:3]2[CH:4]=[C:5]([N:8]3[CH2:12][CH2:11][N:10]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:18]=4[CH3:19])[C:9]3=[O:20])[CH:6]=[CH:7][C:2]=2[O:24][N:23]=1
Reactant: CC(=NO)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3onc(C)c3c2)C1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 13.6 %

Procedure:
1-[4-Fluoro-3-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (220 mg, 0.670 mmol) in DMF (5 mL) was added to a stirred mixture of NaH (19 mg, 0.804 mmol) in DMF (2 mL) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 21 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 28 mg of the product (14.5% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]([SH:17])[CH:14]([SH:16])[CH3:15].[CH3:18][C:19](=[CH:21][CH2:22][CH2:23][C:24](=[CH:26][CH:27]=O)[CH3:25])[CH3:20]>C1CCCCC1>[CH3:25][C:24]([CH2:23][CH2:22][CH:21]=[C:19]([CH3:20])[CH3:18])=[CH:26][CH:27]1[S:17][CH:13]([CH3:12])[CH:14]([CH3:15])[S:16]1
Reactant: CC(S)C(C)S
Reactant: CC(C)=CCCC(C)=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)=CCCC(C)=CC1SC(C)C(C)S1
Reaction time: 0.5 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus, is placed 0.5 grams para-toluenesulfonic acid, 5.0 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 30 minutes with stirring is added to the reaction mass 7.6 grams (0.05 moles) of citral having the structure: ##STR23## After the citral is added, the reaction mass is heated to reflux and refluxed (with removal of water of reaction) over a period of 9 hours. At the end of the 9 hour period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate, filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[ClH:12].[Cl:12][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccnc1CO
Solvent: ClCCl
Product: Cc1cccnc1CCl
Product: Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
To 2-hydroxymethyl-3-methylpyridine (90 mg, 0.73 mmol) in dry DCM (10 mL) at ambient temperature, add with stirring thionyl chloride (0.53 mL, 7.3 mmol). Continue stirring overnight, concentrate in vacuo, and azeotrope three times with chloroform. Triturate the residue with dry ether, filter, and dry under vacuum to obtain the title compound as a beige solid (130 mg, 100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3dione (10.0 g, 36.6 mmol) in anhydrous DMF (180 ml) were added DBU (8.2 mL, 54.9 mmol) and methyl bromoacetate (5.1 mL, 54.9 mmol). After stirring at rt for 45 min, the reaction mixture was quenched with water (600 mL) and HCl (1N, 100 mL). Extraction with EtOAc (3×500 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Recrystallization from AcOEt 150 mL) gave the title compound as an orange powder (6.45 g, 51%) in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC1CCCC1
Yield: 60 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclopentane (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclopentyloxy pyridine (480 mg, yield: 60%) was obtained as an oil phase.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[C:18]([OH:20])[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[C:18]([O:20][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=2[F:12])[CH:19]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3,4-difluorophenyl methyl sulfone and the product of example 18 step (iv).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:22]([OH:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:22]([OH:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCCc1ccc(Br)cc1)c1cc2ccccc2cc1O
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
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1cc2ccccc2cc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound N-2-(4-Bromophenyl)ethyl-3 hydroxyl-2-naphthamide in 2.0 mL of DME were added 36.6 mg (0.3 mmol) of phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 22 mg (60%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.C1COCC1>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5.6 mmol) and catalytic amount of DMF (5 drops) in THF (25 ml) was added oxalyl chloride (0.53 ml, 6.1 mmol). After stirring the solution for 1 h at room temperature, methanol (20 ml) and TEA (7.0 ml) were added. The reaction mixture was stirred overnight at room temperature, then concentrated and dissolved in ethyl acetate (100 ml) and washed with aqueous sodium bicarbonate solution (100 ml). The organic layer was dried over sodium sulfate and concentrated to provide crude methyl 3-methylbenzofuran-2-carboxylate (1.0 g, 5.3 mmol) as a tan solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]c(Sc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cccc(C(F)(F)F)c2)c1

Procedure:
Methyl 5-(3-trifluoromethylphenylthio)pyrrole-3-carboxylate (2.9 g.) was combined with 30 ml. of methanol and 30 ml. of 1 N sodium hydroxide and refluxed for 2.5 hours. The methanol was allowed to evaporate and the aqueous residue washed twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and the crude product (2.3 g.) which precipitated, was recovered by filtration. Recrystallization of the crude from methanol/water gave purified 5-(3-trifluoromethylphenylthio)pyrrole-3-carboxylic acid (1.47 g., m.p. 138°-140° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[Cl:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[CH:34]=[CH2:35]>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:35]=[CH:34][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:28]=2[Cl:27])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: C=Cc1cnccc1Cl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(I)cc1-c1ccccc1C
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Yield: 46.5 %

Procedure:
N-[4-iodo-2-(2-methylphenyl)benzoyl]methionine methyl ester (2.1 g, 4.34 mmol), 4-chloro-3-vinylpyridine (1.4 g, 10 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with methylene chloride 1:1, 177 mg, 0.22 mmol) were combined in NMP (9 mL) and TEA (3 mL) and heated at 100° C. for 5 hours. The mixture was concentrated and purified by flash chromatography (50% EtOAc in hexanes) to give 1.0 g of the title compound. MS m/e 495 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.61 (m, 2H), 1.90 (m, 2H), 2.15 (m, 6H), 3.69 (s, 3H), 4.65 (m, 1H), 5.95 (m, 1H), 7.3-7.5 (m, 9H), 7.69 (m, 1H), 8.05 (m, 1H), 8.45 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>C(OC(=O)C)(=O)C>[OH:20][C:19]1[CH:21]=[CH:22][C:14]([CH:13]=[CH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: Cc1ccnc2ccccc12
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=Cc2ccnc3ccccc23)ccc1O
Yield: 56 %

Procedure:
In 62.9 g of acetic anhydride, 26.73 g of 4-methylquinoline and 31.25 g of vanillin were refluxed overnight. The resultant reaction mixture was treated with an alkali. The product thus obtained was recrystallized via butyl cellosolve, to afford 29 g of 4-[2-(4-hydroxy-3-methoxyphenyl)-ethenyl]-quinoline having a melting point of 217°-219° C. From 0.55 g of this product, 1.75 g of triethylamine, 1.66 g of methacrylic acid chloride, and 16 cm3 of N,N-dimethylacetamide, there was obtained 4.70 g (80.3% in yield) of 4[2-(4-methacroyloxy-3-methoxyphenyl)-ethenyl]-quinoline having a melting point of 134°-135° C. This product was recrystallized via ethyl acetate and assayed by infrared absorption spectrometry and elementary analysis for its chemical structure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH-].[K+].[CH3:22]I>C(O)C>[CH3:1][C:2]1[N:3]([CH3:22])[C:4](=[O:19])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1
Reactant: CI
Reactant: Cc1nc2c(c(C)c(C)n2-c2ccccc2)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C)n(-c2ccccc2)c2nc(C)n(C)c(=O)c12
Yield: 78.5 %

Procedure:
A mixture of 2,5,6-trimethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (1.46 g, 5.8 mM) (N S Girgis et atl, Synthesis, 1985, p101-104). A mixture of potassium hydroxide flake (327 mg, 5.8 mM) and methyl iodide (0.54 ml, 8.7 mM) in ethanol (37 ml) was heated under reflux for 15 hours. A mixture of methyl iodide (0.5 ml) and potassium hydroxide flake (0.3 g) was added and the reaction mixture heated under reflux for a further 3 hours. The solvent was evaporated and the residual solid suspended in water. The solid was collected by filtration and washed with water to give 2,3,5,6-tetramethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (1.21 g, 78.5% yield) as a light foam solid, m p 215°-217° C.; NMR: DMSO-d6 2.0-2.1(3H, s, CH3), 2.3(3H, s, pyrrole CH3), 2.4(3 H, s, pyrrole- CH3), 3.4-3.5(3H, s, N--CH3), 7.3-7.6(5H, complex, aromatic).
Reaction SMILES: FC(F)(F)C(C(O)=O)=O.[NH2:10][CH:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:16][CH2:15]1)=[O:13].[CH:40]([N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]1[CH2:52][C:53](O)=[O:54])([CH3:42])[CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:11]([NH:10][C:53](=[O:54])[CH2:52][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][N:43]2[CH:40]([CH3:41])[CH3:42])[C:12](=[O:13])[N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[CH2:16][CH2:15]2)=[CH:38][CH:37]=1
Reactant: CC(C)N1Cc2ccccc2C1CC(=O)O
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1Cc2ccccc2[C@H]1CC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Reaction time: 3 h
Yield: 17.4 %

Procedure:
To a solution of 2-amino-3-(4-chloro-phenyl)-1-[4-(2-[1,2,4]triazol-1-ylmethyl-phenyl)-piperazin-1-yl]-propan-1-one trifluoroacetyl carboxylate salt(0.30 g, 0.55 mmol), (2-isopropyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (0.12 g, 0.55 mmol), HATU (0.21 g, 0.55 mmol) in DCM was added DIPEA (0.19 mL, 1.13 mmol). After about 3 hours, the solution was purified by silica gel chromatography (eluent: 3% 2.0M NH3 in MeOH/DCM). The purified fractions were combined and concentrated under reduced pressure to give the final compound as white foam (0.06 g, 18%). ES MS 626.3 (M+H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][C:21]#[N:22])=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(N)CN>CCOC(C)=O.[Cu](I)I.O1CCOCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][C:21]#[N:22])=[CH:18][N:17]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CC(C)c1ccc(I)cc1
Reactant: CCc1cccc(CC)c1-c1cc2c(CC#N)c[nH]c2cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1-c1cc2c(CC#N)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 60 °C

Procedure:
A mixture of [5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acetonitrile (800 mg, 3.1 mmol), 1-iodo-4-isopropyl-benzene (1.13 g, 4.6 mmol), copper iodide (874 mg, 4.6 mmol), Cs2CO3 (1.50 g, 4.6 mmol) and ethylenediamine (30 μL, 4.6 mmol), and dioxane (100 mL) is heated to 60° C. under nitrogen for 18 h. The mixture is diluted with EtOAc and filtered over a small pad of silica gel. The obtained solution is concentrated under reduced pressure, and the residue is purified by chromatography on silica gel (hexane-EtOAc, 5:1) to afford [5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acetonitrile as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reaction time: 4 h

Procedure:
Combine 2-methyl-5-nitrobenzoic acid (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf=0.61 (silica gel, ethyl acetate/hexane 1/1).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[N:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][OH:4].C(Cl)Cl.C(N(CC)C(C)C)(C)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([C@:2]1([CH3:5])[CH2:3][O:4][C:31](=[O:33])[NH:1]1)[N:15]=[CH:14]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2nc([C@@](C)(N)CO)ncc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2nc([C@]3(C)COC(=O)N3)ncc2c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(R)-2-Amino-2-(6-methoxy-quinazolin-2-yl)-propan-1-ol (3.10 g, 13.3 mmol) was dissolved in methylene chloride (60 mL, 900 mmol), followed by N,N-diisopropylethylamine (6.94 mL, 39.9 mmol). The mixture was then cooled down to −78° C., and triphosgene (4.34 g, 14.6 mmol) was added in small portions over for 1 hour. The reaction mixture was then warmed up to 23° C. gradually and stirred for additional for 3 hours. Quenched with K2CO3 (sat), and organic layer was separated. The aqueous layer was extracted with DCM (2×20 mL) and combined organic layers were washed with water, brine and dried over Na2SO4. The crude product was then purified via chromatography (SiO2, 40 g, 0-10% MeOH/DCM) (1.78 g, 51%). 1H NMR (CHLOROFORM-d) δ: 9.29 (s, 1H), 7.90 (d, J=9.4 Hz, 1H), 7.58 (dd, J=9.1, 2.6 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 6.29 (br. s., 1H), 5.18 (d, J=8.7 Hz, 1H), 4.49 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 1.76 (s, 3H). MS (M+1): 260.10.