Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH2:3])=[CH:11][CH:10]=1
Reactant: CON=C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxime geometric isomers 7 (840 mg, 3.23 mmol) in 30 ml dry THF (freshly distilled from sodium/benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran complex (1.0M in THF, 16.2 ml, 16.2 mmol) by syringe at room temperature. The resulting pale yellow solution was refluxed overnight, and cooled in an ice bath. Water (25 ml) was carefully added to quench, followed by 20% NaOH (25 ml). The resulting bi-phasic solution was refluxed with vigorous magnetic stirring overnight. After cooling to room temperature, hexanes (40 ml) were added, and the layers were separated. The aqueous portion was extracted with hexanes (1×40 ml). The combined organic portions were dried over potassium carbonate and concentrated in vacuo to a cloudy, pale yellow syrup. This syrup was purified by column chromatography on 18 g neutral alumina (activity I) using chloroform as eluant to afford the amine as 455.6 mg of a colorless, slightly cloudy syrup (61% yield): Rf 0.36 (5% ET2 NH/CHCl3); IR (CDCl3) 3376 (w), 3316 (w), 3031 (w), 2928 (m), 2856 (w), 1602 (m), 1493 (m), 1451 (m); 1H NMR (CDCl3) δ7.38-7.28 (m, 5H), 7.26 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 4.18 (dd, J=8.3, 5.4 Hz, 1H), 2.98 (dd, J=13.4, 5.4 Hz, 1H), 2.84 (dd, J=13.4, 8.4 Hz), 1.50 (br s, 2H); low resolution mass spec. 232 (M+, 22), 215 (37), 125 (54), 106 (100), 89 (49), 79 (100).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.[OH-:19].[K+]>O>[CH2:8]1[O:7][C:12]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of potassium permanganate (3.31 g) in water (100 mL) was added over 30 min to a stirred solution of 1,4-benzodioxan-6-carboxaldehyde (2.50 g) in water (40 mL) at 90° C. Stirring was continued at 90° C. for an additional 45 min and the mixture was then cooled to ambient temperature. The mixture was made basic (pH 10) with aqueous 1M KOH solution, filtered, and the filtrate was cooled in an ice-bath and acidified to pH 3 with concentrated HCl. The precipitated solid was collected by filtration, washed with water, and dried. The solid was dissolved in dichloromethane, washed with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to furnish 2H,3H-benzo[e]1,4-dioxane-6-carboxylic acid as a white powder. A portion of this material (1.05 g) was dissolved in thionyl chloride (10 mL) and the mixture heated at 50° C. under a nitrogen atmosphere for 7 h. After cooling to room temperature, the excess thionyl chloride was removed under reduced pressure and the residue dried under high vacuum for 1 h. The solid was cooled in an ice-bath and treated with ammonium hydroxide solution (10 mL, 28-30% ammonia). The mixture was stirred at 0° C. for 5 min, and at room temperature for an additional 1 hr. The product was collected by filtration, washed with water and dried under high vacuum to provide 2H,3H-benzo[e]1,4-dioxane-6-carboxamide as a white powder. A portion of this material (0.90 g) was suspended in anhydrous dichloromethane under nitrogen and treated with oxalyl chloride (3.8 mL of a 2M solution in dichloromethane). The mixture was heated at reflux for 15 h, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL), cooled in an ice-bath, and treated with 3-iodoaniline (604 μL). The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 45 min. The resulting solid was filtered, washed with dichloromethane and methanol, and dried under high vacuum to produce the title compound as a white powder.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]O)[CH3:2].[ClH:10]>O>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][Cl:10])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: Cl
Solvent: O
Product: CCCCC(CC)CCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer, an immersed tube for reactant metering and an attached water separator is initially charged with 200 g of N-n-butylalkylpyridinium chloride (prepared according to Example 1 as catalyst and adjusted to a temperature of 135° C. 519.8 g of 2-ethylhexanol are introduced uniformly via the immersed tube within 5 h. Over the entire reaction time, gaseous hydrogen chloride is likewise metered in via the immersed tube in a slight stoichiometric excess (223 g). The water of reaction is distilled off azeotropically with the target product and removed as the lower phase in the water separator, while the upper phase is recycled into the reactor. After a total reaction time of 22 h, the conversion based on the 2-ethylhexanol is 99.3%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[CH:15][N:16]3[C:22]4[CH:23]=[CH:24][S:25][C:21]=4[C:20](=[O:26])[N:19]4[CH2:27][CH2:28][C@H:18]4[C:17]=23)[N:9]=1>CN(C)C=O>[CH2:1]([N:3]([CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[CH:15][N:16]3[C:22]4[CH:23]=[CH:24][S:25][C:21]=4[C:20](=[O:26])[N:19]4[CH2:27][CH2:28][C@H:18]4[C:17]=23)[N:9]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1c2sccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
0.36 ml (3.45 mmol) of diethylamine was added to a suspension of 400 mg (1.1 5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepin-8-one in 10 ml N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried with magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, ethyl acetate/methanol 10:1). There were obtained 410 mg (92%) of (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.31 (silica gel, ethyl acetate/methanol 10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39].O>C(#N)C.[Cu](I)I>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:11][C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 504.6 %

Procedure:
(5-[(4-Methoxybenzyl)oxy]-4-{[(trifluoromethyl)sulfonyl]oxy}pyridin-2-yl)methylacetate (1.2 g, 2.78 mmol) was dissolved in acetonitrile (9.3 mL), added copper iodide (53 mg, 278 μmol), ditriphenylphosphine palladium (II) dichloride (98 mg, 139 μmol), triethylamine (8.0 mL) and trimethylsilyl acetylene (819 mg, 8.34 mmol) under an argon atmosphere, and under ice-cold conditions, and the mixture was stirred at 45° C. overnight. This operation was conducted for 4 lots, and the following treatments were conducted as a whole. The reaction solution was added water, and filtered through a pad of celite. The obtained filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. A crude product of the title compound (5.38 g) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(N)nc(OC2CCCCC2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, cyclohexanol and DBU in DME. EI-MS m/e (%): 308 (M+, 12), 226 ([M—C6H10]−, 100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31]>>[OH:32][CH:29]([CH2:30][CH3:31])[CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CCC(O)CN
Product: CCC(O)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 1-amino-2-butanol in a manner similar to that described in Example 11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:9]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]4[CH3:24])=[CH:7][CH:6]=3)[CH2:12][CH2:11][C:10]2=[O:13])=[CH:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C2C(=O)CCC2c2ccc(N)cc2)cc1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(C2CCC(=O)C2c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A mixture of Example 7H (300 mg, 0.976 mmol), hexane-2,5-dione (134 mg, 1.171 mmol) and p-toluenesulfonic acid (1.856 mg, 9.76 mol) in toluene (2 mL) was stirred at 110° C. for 1 hour. The mixture was concentrated in vacuo. The residue was directly used in the next step without further purification. LC/MS (ESI) m/z 386 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:22])=[C:13]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:22])=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1
Reactant: CCOC(=O)C=Cc1cc(OCc2ccccc2)ccc1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cc(O)ccc1C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 3-(5-(benzyloxy)-2-methylphenyl)acrylate (1.00 g) in methanol (50 mL) was added 10% palladium-activated carbon (150 mg), and the mixture was stirred for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (500 mg) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[C:8]([N:13]=[C:14]=[S:15])(=[O:12])[O:9][CH2:10][CH3:11]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:14]([NH:13][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[S:15]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cnccn1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cnccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with pyrazin-2-amine (7.6 g, 80.0 mmol, 1.0 eq.), O-ethyl carbonisothiocyanatidate (12.5 g, 95.4 mmol, 1.2 eq.), and dioxane (150 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, it was concentrated to a volume of around 20 mL under reduced pressure and the resulting suspension was filtered. The solid was collected and washed with ethyl acetate (3×20 mL) to afford 270a (14.0 g, 77%) as a white solid. MS-ESI: [M+H]+ 227.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])[NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: NNc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: NN(C(=O)/C=C\C(=O)O)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 50 °C
Yield: 64.8 %

Procedure:
10.5 g (0.05 mol) of 3-chloro-4-trifluoromethylphenylhydrazine were dissolved in 50 ml of toluene. 4.9 g of maleic anhydride (0.05 mol) in the solid form were introduced into this solution at room temperature. This caused the temperature to rise by a few degrees, while the reaction product precipitated in the crystalline form. The mixture was then heated to about 50° C. for some time, after which it was allowed to cool and the product was filtered off. 10 g (65% of theory) of maleic acid mono-(3-chloro-4-trifluoromethyl-phenyl)-hydrazide of melting point 180°-182° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([O:26]C)=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:13]=[C:12]([C:24]([OH:26])=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Yield: 9.9 %

Procedure:
Methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole -4-carboxylate (150 mg, 0 4 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (1.0 N, 1.8 mL, 1.8 mmol) was added. After 1 hr the organic solvents were removed on the rotary evaporator and the pH of the aqueous solution was adjusted to about 3 with 6 N aqueous HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum in the presence of KOH to leave 7-methoxy-2-(4-methoxyphenyl)-5H -pyrido[3,2-b]indole-4-carboxylic acid (138 mg, 67% yield) as an orange solid. MS (ESI) m/z 349.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.47 (1H, s), 8.18 (1H, d, J=8.55 Hz), 8.16 (1H, s), 8.13 (2H, d, J=8.55 Hz), 7.29 (1H, d, J=1.83 Hz), 7.10 (2H, d, J=8.85 Hz), 6.94 (1H, dd, J=8.55, 1.83 Hz), 3.89 (3H, s), 3.85 (3H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH2:10][O:11]C)[N:7]=[C:6]([NH2:13])[N:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[NH2:13][C:6]1[N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: COCc1cc(C(C)C)nc(N)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(CO)nc(N)n1
Yield: 66 %

Procedure:
To a stirred solution of 4-isopropyl-6-(methoxymethyl)pyrimidin-2-amine (537 mg, 3.0 mmol) in CH2Cl2 (30 mL) at 0° C. was added BBr3 (3 mL of 1.0 M solution, 3 mmol) dropwise. The reaction was quenched with saturated aqueous NaHCO3 after 4 h. The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide (2-amino-6-isopropylpyrimidin-4-yl)methanol as a dark brown oil which was used for next step without further purification. 1H NMR (CDCl3): d 6.49 (s, 1H), 5.06 (br, 2H), 4.59 (s, 2H), 2.78-2.87 (m, 1H), 1.25 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.I[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: COc1ccc(I)cc1
Reactant: OB(O)c1cc2cc(Cl)ccc2o1
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: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Temperature: 100 °C
Yield: 43.8 %

Procedure:
A mixture of 1.4 g (7.13 mmol) 5-chlorobenzofuranboronic acid, 1.24 g (5.30 mmol) 4-iodoanisole, 150 mg Pd(PPh3)4, 7.1 ml 1M aqueous sodium carbonate solution, and 25 ml 1,2-dimethoxyethane were heated in a sealed tube at 100° C. under argon overnight. It was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. 600 mg of the title benzofuran were obtained by crystallization from ethyl acetate and another 250 mg were obtained from the mother liquid after chromatography on silica gel with hexane.
Reaction SMILES: [CH3:1][CH:2]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][N:23]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=2)=[CH:16][CH:15]=1)[CH2:3][C:4]([NH:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=O.[BH4-].[Na+].[Cl-].[Mg+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>C(O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][C@@H:4]([NH:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:15]2[C:14](=[CH:19][CH:18]=[C:17]([C:20]3[N:21]=[CH:22][N:23]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=3)[CH:16]=2)[NH:13]1
Reactant: CC(CC(=O)NC(=O)OC(C)C)Nc1ccc(-c2cn(CCC(=O)OC(C)(C)C)cn2)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)OC(=O)N[C@@H]1C[C@H](C)Nc2ccc(-c3cn(CCC(=O)OC(C)(C)C)cn3)cc21
Temperature: -15 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl 3-[4-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazol-1-yl]propanoate (for a preparation see Intermediate 95) (1.53 g, 3.34 mmol) in ethanol (20 mL) was cooled to −15° C. then treated with sodium borohydride (114 mg, 3.0 mmol) followed by magnesium chloride (1M in water, 3.67 mL, 3.67 mmol) maintaining the temperature below −10° C. The mixture obtained was stirred at a temperature lower than 0° C. for 1 h then at room temperature for 1 h. The suspension formed was poured onto a stirred mixture of citric acid (1.6 g, 8.34 mmol), HCl (1M in water, 25 mL) and DCM (15 mL) and the mixture obtained was stirred at room temperature for 30 min. The layers were separated and the aqueous phase was basified by the addition of solid K2CO3 then was extracted with AcOEt (3×20 mL). The combined organic phases (DCM+EtOAc) were washed with water then brine dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 2% MeOH in DCM) gave 1,1-dimethylethyl 3-{(cis)-4-[2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoate (1.46 g, 3.30 mmol, 99%) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:18]>>[F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:18])[CH:4]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1cc(C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
The procedure was derived from methods described in U.S. Pat. No. 5,756,275 and WO 02/38569. In a 250 mL round bottom flask, 6-trifluoromethyl-4-pyrimidinol (10 g, 60.9 mmol) was dissolved in 70 mL phosphorus oxychloride (0.73 mol). The solution was heated at reflux for 7 h. The cooled reaction solution was then added gradually to 200 mL 30% ammonium hydroxide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (2×100 mL), and the combined extracts were dried (MgSO4) and evaporated in vacuo to give 6-trifluoromethyl-pyrimidin-4-ylamine (1.4 g, yield 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1 H), 7.60 (broad s, 2 H), 6.90 (s, 1 H); LC-MS m/z 164.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[N:14]([C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:28])=[CH:22][C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[C:15]=[O:16]>C1COCC1>[CH3:28][C:21]1[C:20]2[C:25](=[CH:26][C:17]([NH:14][C:15](=[O:16])[O:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)=[CH:18][CH:19]=2)[O:24][C:23](=[O:27])[CH:22]=1
Reactant: OCc1ccc(-c2ccco2)cc1
Reactant: Cc1cc(=O)oc2cc(N=C=O)ccc12
Solvent: C1CCOC1
Product: Cc1cc(=O)oc2cc(NC(=O)OCc3ccc(-c4ccco4)cc3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.3 %

Procedure:
(4-(Furan-2-yl)phenyl)methanol (100 mg, 0.57 mmol) and 76 (139 mg, 0.69 mmol) were dissolved in THF (10 mL). The resulting mixture was stirred at room temperature for 15 min and then at 80° C. for 1 h. THF was evaporated off in vacuo. The residue was adsorbed on silica and purified by flash chromatography, eluting with CH2Cl2/EtOAc (1:1) to give the target compound (20 mg, 9%) as a white solid. m/z=376.11 (M+H), 751.22 (2M+H).
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:32]N1C(=O)CCC1=O.CCOC(C)=O>ClCCl>[Br:32][C:8]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][C:7]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2sccc2c1Br
Temperature: 23 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.06 g, 0.31 mmol) in dichloromethane (1 mL) was added TBAF (1M THF, 0.46 mL) followed by N-bromosuccinimide (NBS) (0.07 g, 0.4 mmol). The resulting mixture was allowed to stir at 23° C. for 16 h at which time the entire reaction mixture was placed on a silica gel column. Flash column chromatography (20% EtOAc in hexanes) affords one major peak containing a mixture of 4-bromo and 2,4-dibromo products. Separation of the desired product from the byproduct by RP-HPLC (10-100% gradient 0.1% formic acid in H2O to CH3CN over 10 min) afforded ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.03 g, 35% yield).