Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].[CH3:20][O:21][C:22](=O)[O:23]C>C1COCC1.CCCCCC.O>[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([C:22]([O:21][CH3:20])=[O:23])[C:15]1=[O:19]
Reactant: COC(=O)OC
Reactant: CN1CCCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a solution of diisopropylamine (11.3 g, 0.11 mol) in THF (150 ml), at -78° was added n-butyl lithium (60 mls of a 1.6M solution in hexane). The solution was stirred for 0.5 hours before adding N-methyl-2-pyrrolidone (10.1 g; 0.1 mol) in THF (50 ml) over a period of 5 minutes. After 0.75 hours. a solution of dimethylcarbonate (10.8 g: 0.12 mols) in THF (30 ml) was added and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/methanol (2:1) as eluant to afford the title product as a clear liquid (4 g). δ(CDCl3) 1.90-2.70 (2H, m, CH2); 2.80 (3H, s, CH3) 3.20-3.60 (3H, m, CH and CH2); 3.70 (3H, s, CO2CH3).
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([C:11]1[C:12]([NH:18][CH2:19][CH3:20])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:35]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][C:47]([OH:49])=O)[CH2:42][CH2:41]1)=[O:39])[CH3:36].C[O-].[Na+]>CN(C)C1C=CN=CC=1.C(O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:9]2[C:11]3[C:12](=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:18]([CH2:19][CH3:20])[C:47](=[O:49])[C:46]=2[CH:43]2[CH2:42][CH2:41][N:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])[CH2:45][CH2:44]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)N1CCC(CC(=O)O)CC1
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)N1CCC(c2c(-c3cccc(Br)c3)c3ccc(C)nc3n(CC)c2=O)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a dichloroethane solution of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine were added p-toluenesulfonyl chloride, (1-ethoxycarbonylpiperidin-4-yl)acetic acid and 4-dimethylaminopyridine, followed by stirring at 80° C. for 12 hours. Ethanol and sodium methoxide were added to the product obtained by working up the reaction mixture, and the whole was heated under reflux for 1 hour. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-bromophenyl)-3-(1-ethoxycarbonylpiperidin-4-yl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one as a pale brown solid. MS: 498.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:24][NH2:25].O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:25][CH3:24])=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: CN
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccc(NCc3cccc(F)c3)n2)c(Cl)cn1
Reaction time: 0.25 h

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (Intermediate B) (15 mg, 0.045 mmol) was added DMSO (0.4 ml) and methyl amine 40% in water (200 μl, 2.293 mmol) in a microwave tube was micro waved at 145° C. for 900 seconds and the reaction progress was followed by LCMS. Most of the amine was removed under vacuum, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lypholization 13.9 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 343.0 (MH+), retention time=0.67 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 2.97 (s, 3 H) 4.62 (s, 2 H) 6.81 (d, J=8.50 Hz, 1 H) 6.91-7.02 (m, 3 H) 7.09 (d, J=9.96 Hz, 1 H) 7.17 (d, J=7.62 Hz, 1 H) 7.27-7.39 (m, 1 H) 7.69 (dd, J=8.50, 7.33 Hz, 1 H) 8.03 (s, 1 H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:17][C:18]([OH:20])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.ClC(OCC)=O.[CH3:27][NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[CH3:27][N:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:18](=[O:20])[CH2:17][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cn1ccc2ccccc21)[C@@H]1CCCC[C@H]1N1CCCC1
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 1H-indole-1-acetic acid (175 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C. with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue dissolved in ethyl acetate (50 ml), and washed with saturated sodium biocarbonate solution (3×50 ml). The organic extract was drige (MgSO4), evaporated under reduced pressure, and recrystallized from diethyl ether/methylene chloride to yield the amide (100 mg, 32%); Vmax C=0 1635 cm-1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3N=N[N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[K+]>ClCCl.C(OCC)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCC#Cc1ccccc1
Yield: 13.7 %

Procedure:
The general method described in Part D of Example 109 was followed using 8-ethoxymethyl-5,6-dimethyl-7-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (6.47 g, 16.0 mmol) as the starting material. The reaction with triphenyl phosphine (4.61 g, 17.6 mmol) required 41 hours, and the hydrolysis of the intermediate required 18 hours. The crude product (11.6 g) was dissolved in dichloromethane and treated with a 1 M solution of hydrochloric acid in diethyl ether (80 mL). The volatiles were removed under reduced pressure, and the resulting solid was recrystallized from acetonitrile. The crystals were dissolved in water (20 mL), and the solution was adjusted to pH 14 with the addition of 50% aqueous sodium hydroxide to provide a solid that was isolated by filtration. The solid was stirred wtih 1 M aqueous potassium hydroxide for one hour, isolated by filtration, dried for three days under reduced pressure at 70° C. to provide 0.828 g of 2-ethoxymethyl-6,7-dimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 129–130° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 70.6 %

Procedure:
To a stirred solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (713 mg, 4.91 mmol, 1.0 eq) in DMF (20 mL) was added Na2CO3 (1.56 g, 14.8 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 35 min, then isopropyl bromoacetate (1.07 g, 5.90 mmol, 1.2 eq) was added and the reaction stirred at room temperature overnight. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:6) to give the title compound (intermediate IV(b)) as an oil (850 mg, 71%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=1[CH2:45][C:46]([OH:48])=[O:47].C(=O)(O)[O-].[Na+]>[N+](CC)([O-])=O>[F:34][C:35]1[C:36]([CH2:45][C:46]([OH:48])=[O:47])=[C:37]([C:41]([F:42])([F:43])[F:44])[C:38]([N+:1]([O-:4])=[O:2])=[CH:39][CH:40]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC[N+](=O)[O-]
Product: O=C(O)Cc1c(F)ccc([N+](=O)[O-])c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.33 g (100.62 mmol) of fuming nitric acid (100%) and 25.80 g (91.44 mmol) of trifluoromethanesulfonic anhydride are mixed under ice bath cooling. 200 ml of nitroethane and 12.93 g (91.44 mmol) of phosphorus pentoxide are added to this mixture. 20.31 g (91.44 mmol) of 2-fluoro-6-trifluoromethylphenylacetic acid, suspended in 40 ml of nitroethane, is now instilled under cooling. It is stirred for 1 hour at 0° C. and then allowed to reach room temperature and stirred overnight at room temperature. The thin-layer chromatogram no longer shows starting material. The suspension is poured on 350 ml of cooled, saturated sodium bicarbonate solution. It is extracted three times with dichloromethane. Then, it is acidified with 4N hydrochloric acid, extracted five times with ethyl acetate. The organic phase is washed with water, dried on sodium sulfate and evaporated to dryness in a vacuum. The residue is crystallized from ether/pentane.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([C:11]1[N:12]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]=[CH:14][C:15]=1[C:16](O)=[O:17])[CH3:10].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:10][C@@H:9]1[C:11]2[N:12]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:13]=[CH:14][C:15]=2[C:16](=[O:17])[NH:8]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@@H](C)N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](C)NC3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105 %

Procedure:
To a slurry of (R)-2-(1-aminoethyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (702d; 22.83 g, 54.1 mmol) in 150 mL EtOAc at 0° C. was added DIPEA (28.2 mL, 162 mmol). A portion of the slurry seemed to dissolve. After 10 min, 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in EtOAc; Matrix Scientific; 35.0 mL, 59.5 mmol) was added and much of the solid dissolved. After 10 min, the still heterogeneous reaction was warmed to RT. After 4 h, the reaction was dark brown and homogeneous. The reaction was treated with 400 mL sat'd aq. NaHCO3 and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 1× sat'd aq. NaHCO3 then 1× brine, dried over anhydrous Na2SO4, filtered through a glass frit and concentrated in vacuo to give (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (16.5 g, 56.8 mmol, quantitative yield) as a tan foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.70-7.77 (2H, m), 7.35 (2H, d, J=8.0 Hz), 7.16 (1H, d, J=3.3 Hz), 6.48 (1H, d, J=3.1 Hz), 5.75 (1H, br. s.), 4.68 (1H, q, J=6.5 Hz), 1.62 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 291.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][CH:29]=1)[O:26][C:7]1=[N:8][C:9]([F:25])=[C:10]([Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:11]=[C:6]1[C:5]2=[O:30].CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+].[F:51][C:52]1[C:57](B(O)O)=[CH:56][CH:55]=[CH:54][N:53]=1>CCO.O.C(OCC)(=O)C>[F:25][C:9]1[N:8]=[C:7]2[O:26][C:27]3[C:4]([C:5](=[O:30])[C:6]2=[CH:11][C:10]=1[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:3][C:2]([C:57]1[C:52]([F:51])=[N:53][CH:54]=[CH:55][CH:56]=1)=[CH:29][CH:28]=3
Reactant: OB(O)c1cccnc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(=O)c3cc(Br)ccc3oc2nc1F
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(=O)c3cc(-c4cccnc4F)ccc3oc2nc1F
Temperature: 85 °C

Procedure:
7-Bromo-2-fluoro-3-(tributylstannyl)-5H-chromeno[2,3-b]pyridin-5-one (0.240 g, 0.412 mmol), AmPhos (0.015 g, 0.021 mmol), potassium acetate (0.077 mL, 1.235 mmol), and 2-fluoro-3-pyridineboronic acid (0.070 g, 0.494 mmol) were suspended in a mixture of EtOH (20 mL) and water (2 mL) and heated to 85° C. After 30 minutes water (250 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was washed with 10% saturated sodium bicarbonate (100 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to ethyl acetate gradient) to give 2-fluoro-7-(2-fluoropyridin-3-yl)-3-(tributylstannyl)-5H-chromeno[2,3-b]pyridin-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 10.4 g (55.2 mmol) of 4-bromothiophenol and 6.49 g (55.4 mmol of ethyl acrylate in 5 mL of dichloromethane was added 4.13 g (41 mmol) of triethylamine at 0 ° C. under argon. The resulting solution was warmed to room temperature and stirred for 12 hours. The solution was then treated with 50 mL 10% aqueous NaOH and the product extracted into 3×100 mL ether.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[O:12][N:11]=2)=[CH:6][CH:5]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:18])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A suspension of 448 g of tetrahydrofuran and 95 g (0.70 mol) of zinc chloride was stirred at 20-30° C. for 1 h. 23.6 g (0.62 mol) of sodium borohydride were added in portions at 20-38° C. and the mixture subsequently stirred at 60-65° C. for 3 h. A solution of 69 g (0.31 mol) of 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid in 220 g THF was added dropwise and the resulting mixture stirred at 60-65° C. for 16 h. The reaction was then quenched by the drop wise addition of mixture of 93 g of HCl in 202 g of water at 5-10° C. The mixture was stirred at this temperature for 2 h to dissolve the solids completely. The solvent was removed under reduced pressure with a jacket temperature of 35-40° C. To the residue were added 510 g of water. The resulting suspension was cooled to 20-30° C. and the crystals were filtered off and washed with water. The crude wet product was stirred for 1 h in a mixture of 150 g of water, 31 g of HCl and 419 g of MTBE. The lower aqueous phase was removed and organic phase was dried with 25 kg of anhydrous sodium sulfate, stirred for 0.5 h and filtered under nitrogen. The filtrate was almost completely concentrated under reduced pressure at 40-45° C. The residue was treated at 20-25° C. with 100 g of MTBE. The mixture was stirred at 55-60° C. for 2 h, cooled to 0° C. and subsequently stirred at this temperature for additional 2 h. The crystals were filtered off and dried at 45-50° C. in vacuum over night to afford 42 g (66% yield) of the title alcohol as an off-white solid with a purity of 99.9% (HPLC).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([OH:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].[CH:17]([N:30]1[CH2:33][CH:32](I)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>COCCOC.O>[CH:17]([N:30]1[CH2:33][CH:32]([O:6][C:4]2[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[S:1][CH:5]=2)[CH2:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1csc2ccccc12
Reactant: IC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: c1ccc(C(c2ccccc2)N2CC(Oc3csc4ccccc34)C2)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophen-3-ol (215 mg, 1.43 mmol) and potassium carbonate (237 mg, 1.72 mmol) were successively added to a solution of 1-benzhydryl-3-iodoazetidine (500 mg, 1.43 mmol) in a mixture of 1,2-dimethoxyethane (12 mL) and water (6 mL) at room temperature. The reaction mixture was then heated up to 95° C. and stirred for 3 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (5×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (1:0 to 9:1) as eluent. The title compound was obtained as a yellow oil (220 mg, 21%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:18]=1[C:19]#[N:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[C:18]=2[C:19]#[N:20])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: CN1CCN(c2cccc(N)c2C#N)CC1
Product: CN1CCN(c2cccc(NC(=O)c3nnnn3Cc3ccccc3)c2C#N)CC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-methyl-1-piperazinyl)benzonitrile to give 1-benzyl-N-[2-cyano-3-(4-methyl-1-piperazinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([CH:39]=O)[S:36][C:35]=2[CH:41]=1>O1CCCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([CH2:39][CH:2]=[O:4])[S:36][C:35]=2[CH:41]=1
Reactant: O=Cc1cc2ccc(Br)cc2s1
Reactant: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCc1cc2ccc(Br)cc2s1
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a 0° C. solution of potassium tert-butoxide (2.50 g, 21.4 mmol) in tetrahydrofuran (100 mL) is added (methoxymethyl)triphenylphosphonium chloride (7.49 g, 21.4 mmol). The reaction mixture is stirred for 20 minutes. 6-Bromo-benzo[b]thiophene-2-carbaldehyde (2.58 g; 10.7 mmol) is added and the ice-bath is removed. The mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with AcOH (5 mL). The mixture is treated with water (50 mL) and concentrated to a residue under reduced pressure. The residual aqueous solution is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to a residue. The residue is dissolved in THF (50 mL) and treated with HCl (5 N, 5 mL). The mixture is stirred at 70° C. for 60 minutes and neutralized with NaOH (5 N, 5 mL). The mixture is concentrated to a residue under reduced pressure. The residual aqueous mixture is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (2.25 g, 82%). ES/MS m/e 254.8, 252.8 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[CH:10][C:5]2=[CH:4][C:3]=1[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[H-].[Na+].I[CH2:41][CH3:42].O>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[C:3]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH:4]=[C:5]2[CH:10]=[C:9]1[C:11](=[O:28])[NH:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:14]([F:15])([F:16])[F:17])[CH3:42]
Reactant: Cc1nc2[nH]c(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2cc1CNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(=O)OC(C)(C)C)c(C)nc21
Reaction time: 2 h

Procedure:
tert-Butyl {[6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate (410 g, 0.77 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (7.9 ml). Sodium hydride (60%; 37 mg, 0.92 mmol) was added and the mixture was stirred with ice cooling for 2 h. Iodoethane (145 g, 0.92 mmol) was added and the reaction mixture was thawed with stirring over 18 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (3/1) and gave 300 g (68% of theory) of tert-butyl a {[1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate. HPLC-MS: log P=4.67; mass (m/z): 559.2 (M+H)+; 1HNMR (D6-DMSO): δ 1.21 (t, 2H), 1.40 (s, 9H), 3.32 (s, 3H), 4.21 (m, 2H), 4.57 (q, 2H), 6.28-6.32 (m, 1H), 7.29 (s, 1H), 7.37 (m, 1H), 7.70-7.87 (m, 2H), 8.06 (d, 1H), 8.20 (s, 1H), 9.67 (m, 1H).