Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:30](=[O:31])[CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COCCOCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COCCOCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2-methoxy-ethoxy)-acetic acid to yield (3aR,4S,7aR)-4-[2-(2-methoxy-ethoxy)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 430; RT=7.850 min; HPLC Method I
Reaction SMILES: CO.C([CH:10]([OH:34])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])C1C=CC=CC=1.CCCCCC>[Pd].CC(OC)(C)C>[CH2:32]([OH:33])[CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:34]
Reactant: OCCOCCOCCOCCOCCOCCOCCOCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CCCCCC
Product: OCCOCCOCCOCCOCCOCCOCCOCCO
Reaction time: 17 h
Yield: 51 %

Procedure:
10% Pd/C (11.2 g) was added to MeOH (50 mL) at −15° C. in hydrogenation bottle under agron. BnO-dPEG8-OH (69.0 g, 0.15 mole) was added to the bottle along with MeOH (150 mL). The bottle was placed on the Parr shaker for 17 h at 50 psi of H2. The reaction was monitored by tlc on silica gel plates, eluting with 10% MeOH/CH2Cl2. The reaction is about 50% complete. The reaction was worked up. The reaction mixture was filter through glass fiber, used MeOH as needed to make a clean transfer. The filtrate was concentrated in vacuo to give an oil. A column was prepared with 600 g of silica gel and hexane. The crude product was placed onto column with hexane and minimum of TBME (100 mL). The column was eluted as follows: (2 L) 20% TBME/hexane; (2 L) 50% TBME/hexane; (4 L) TBME; (2 L) 5% MeOH/TBME; (2 L) 10% MeOH/TBME. Like fractions containing product were combined and concentrated in vacuo to give 28.5 g (51% yield). The product was characterized by nmr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1.CC1(C)CCC(C)(C)C2C=C(COC3C=CC(C(O)=O)=CC=3C3C=CC=CC=3)C=CC1=2>>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]2[CH:12]=[C:11]([CH2:10][O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Reactant: Oc1ccccc1Br
Agent: CC1(C)CCC(C)(C)c2cc(COc3ccc(C(=O)O)cc3-c3ccccc3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(COc3ccccc3Br)ccc21
Yield: 88.7 %

Procedure:
2-Bromophenol (1.50 g., 8.70 mmol) is alkylated with 2-chloromethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) (18a) (2.05 g., 8.70 mmol) in a similar manner as described in Example 26 (for the synthesis of 44) to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-bromobenzene (50) (2.88 g., 7.72 mmol, 89%): chromatographed on silica gel using EtOAc/hexane to afford a clear oil; 1H NMR (300 MHz, CDCl3) δ 7.57 (dd, J=2, 8 Hz, 1H, ArH), 7.45 (d, J=2 Hz, 1H, ArH), 7.32 (d, J=8 Hz, 1H, ArH), 7.25 (m, 2H, ArH, 6.98 (dd, J=2, 8 Hz, 1H, ArH), 6.83 (dd, J=8, 8 Hz, 1H, ArH), 5.09 (s, 2H, ArCH2O), 1.70 (s, 4H, CH2CH2), 1.29 (s, 6H, 2×CH3), 1.28 (s, 6H, 2×CH3) .
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH2:39]([O:41][C:42]([C:44]1[C:45](=[O:61])[C:46]([C:58](O)=[O:59])=[CH:47][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[CH:49]=1)=[O:43])[CH3:40]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:58]([C:46]1[C:45](=[O:61])[C:44]([C:42]([O:41][CH2:39][CH3:40])=[O:43])=[CH:49][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[CH:47]=1)=[O:59])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)O)c1=O
Reactant: CCNCC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)N(CC)CC)c1=O
Reaction time: 5 h

Procedure:
Diethylamine (130 μl) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (528 mg) were added to a solution of the compound obtained in Step 2 (270 mg) in dichloromethane (3.0 ml) at room temperature, and the mixture was stirred for five hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 160 mg of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1)[CH3:2]>C(CN)O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: NCCO
Product: CCc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 190 °C
Yield: 127 %

Procedure:
1-(2-Ethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(801 mg, 2.0 mmol) was dissolved in ethanolamine(10 ml), and the reaction mixture was refluxed at 190° C. for 3 hours. The excess solvent was removed by distillation under reduced pressure, and the residue was diluted in dichloromethane(20 ml), then washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 530 mg of desired compound as solid in 62% of yield.
Reaction SMILES: COC1C=CC(C([O:9][CH2:10][C@H:11]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=O)=CC=1.CC(C[AlH]CC(C)C)C.CO.[K].[Na]>C(Cl)Cl>[Si:22]([O:21][C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][OH:9])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COc1ccc(C(=O)OC[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [K]
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a 1.0 L RB flask containing (S)-2,3-bis(tert-butyldimethylsilyloxy)propyl 4-methoxybenzoate (9.200 g, 20 mmol) was added DCM (100 mL) and the mixture was allowed to stir at −78° C. for 5 minutes. At this time, DIBAL-H (1.0 M, hexanes) (61 ml, 61 mmol) was added via a syringe. The reaction was allowed to stir for 30 min and then quenched with MeOH (4.1 ml, 101 mmol). Sodium potassium tartate (sat, 200 mL) and DCM (100 mL) was added and the solution was allowed to warm to 23° C. and stirred for 3 h. The aq. layer was extracted with DCM (3 100 mL). The combined organics were washed with brine and dried with sodium sulfate and concentrated to give a residue.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]1([CH3:30])C=CC=C[CH:25]=1.C1([B-](F)(F)F)CC1.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([CH:30]2[CH2:24][CH2:25]2)[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Temperature: 120 °C

Procedure:
In a 50 mL two-necked flask, methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1 g, 3.18 mmol, Eq: 1.00, CAN 1211589-51-3) and cesium carbonate (3.11 g, 9.55 mmol, Eq: 3) were combined with toluene (25 ml) and water (2.8 ml) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon, then palladium(II) acetate (14.3 mg, 63.7 μmol, Eq: 0.02), potassium cyclopropyltrifluoroborate (518 mg, 3.5 mmol, Eq: 1.1) and butyldi-1-adamantylphosphine (68.5 mg, 191 μmol, Eq: 0.06) were successively added and the reaction mixture was heated to 120° C. for 5 h when TLC indicated that the reaction was complete. The mixture was cooled to rt, poured into 50 ml H2O and extracted with AcOEt (2×50 ml). The organic layers were washed with H2O/NaCl sol, combined, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 70 g, 0% to 20% EtOAc in heptane) yielded eventually 836 mg of the title compound as light yellow semisolid; MS (EI) 276.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH:5]1Cl)[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C(Cl)C(=O)N1C(C(=O)OC)=C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Yield: 87 %

Procedure:
A mixture of methyl 2-[(4R)-4-allyl-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (600 mg), tributyltinhydride (0.97 ml) and 2,2'-azobis-(2-methylpropionitrile) (40 mg) in benzene (6 ml) was refluxed for 1.5 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 ml) and dilute aqueous sodium bicarbonate. The organic layer was separated, and washed with brine, dried over magnesium sulfate and evaporated in vacuo. The oily residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (10:1-10:3) to give methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (452 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10]C1C=CC(S(O)(=O)=O)=CC=1.CC(OO)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:10]=[N:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(Cl)ccc1O
Agent: CC(=O)OO
Solvent: C1CCOC1
Product: Clc1ccc2ocnc2c1
Temperature: 60 °C

Procedure:
To a 250 mL 3-neck round bottom flask equipped with a distillation head, glass stopper, septum, thermocouple and magnetic stir bar was charged 2-amino-4-chlorophenol (20.00 g, 0.139 mol). The solid was dissolved in THF (60 mL) and p-TsOH (0.265 g, 1.39 mmol) was added. The brown solution was warmed to 60° C. over 10 min and aged for 90 min. HPLC assay of the reaction mixture showed 1 LCAP unreacted starting material. The temperature was increased from 60° C. to 74° C., and at 63° C. solvent distillation began. A total of 58 mL was collected during the first distillation. The mixture was diluted with THF (60 mL) and a total of 67 mL of solvent was removed between 71 and 84° C. The mixture was again diluted with THF (60 mL) and 61 mL of solvent was removed between 74 and 114° C. The dark brown solution was cooled to room temperature. The final mass of the solution was 27.96 g. Analysis of the crude stream by 1H NMR showed 0.1 wt % MeOH present in the sample. 1H NMR (500 MHz, CDCl3): δ=8.10 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.36 ppm (dd, J=8.7, 1.7 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[N:23](COCC[Si](C)(C)C)[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:14][CH:13]=2)[C:4]1=[O:36])[CH3:2].[ClH:37]>CCO>[ClH:37].[NH:20]1[C:21]2[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=2[N:23]=[C:19]1[O:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[C:4]2=[O:36])=[CH:17][CH:16]=1
Reactant: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF (dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1>>[Cl:9][C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[C:10]1([OH:14])[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCC1
Reactant: Clc1cc(Cl)c(Br)cn1
Product: OC1(c2cnc(Cl)cc2Cl)CCC1

Procedure:
The title compound was synthesized in analogy to Example 123a, using 5-bromo-2,4-dichloropyridine (CAN 849937-96-8) and cyclobutanone (CAN 1191-95-3) as starting materials and isolated (5.1 g, 76%); MS (ESI, m/z): 218.4 (M+H+).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:3][CH:2]=1.C1C(=O)N([Br:32])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>>[Br:32][C:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:3]([CH3:2])[CH:24]=1
Reactant: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1NC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C

Procedure:
The mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid p-tolylamide (183 mg, 0.482 mmol), NBS (108 mg, 0.603 mmol) and 2,2′-Azo-bis-isobutyronitrile (8.08 mg, 0.0482 mmol) in carbon tetrachloride (5 ml, 50 mmol) was heated at 80° C. under an atmosphere of nitrogen for 24 h. After that time, the mixture was filtered to give the title compound as a beige solid that was used for further reaction without purification. MS (ES+): m/z 400.92/402.96 [MH+]. HPLC: tR=3.66 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15](CC(=O)NC3C=CC=CC=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].ClCC(N[C:46]1[CH:51]=CC=[CH:48][CH:47]=1)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:51]([N+:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[C@@H:13]([O:12][C:10](=[O:11])[C:9]([OH:8])([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[CH2:14]2)[C:46]#[C:47][CH3:48]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2)Nc1ccccc1
Reactant: O=C(CCl)Nc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CC#CC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2

Procedure:
This compound is made analogously to (R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 76) by replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3cccc(Cl)c3)sc2c1
Temperature: 0 °C

Procedure:
To 200 ml. of 1,2-dichloroethane were added 10.0 g. (0.042 mole) of 3-phenyl-6-methoxybenzothiophene and 6.5 g. (0.042 mole) of 3-chlorobenzoyl chloride. The mixture was stirred and cooled to 0° C., and 5.73 g. (0.042 mole) of aluminum chloride were added. The mixture was stirred for about one hour and ice then was added. The resulting organic layer was separated from the aqueous. The aqueous layer was washed with chloroform, and the chloroform was separated and added to the organic layer. The organic layer then was evaporated, and to the resulting residue were added 250 ml. of methanol and 15 ml. of 5N sodium hydroxide. The mixture was refluxed for 30 minutes and evaporated. The residue was recrystallized from methanol to obtain the title compound, m.p. 105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:11]([CH2:26][CH3:27])[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=S.[S]>[Hg]=O.CO>[CH2:26]([N:11]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[C:9]1[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:27]
Reactant: CCN(C(=S)Nc1ccccc1N)C1CCN(CCc2ccccc2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CO
Product: CCN(c1nc2ccccc2[nH]1)C1CCN(CCc2ccccc2)CC1
Yield: 43 %

Procedure:
A mixture of 39.8 parts of N-(2-aminophenyl)-N'-ethyl-N'-[I-(2-phenylethyl)-4-piperidinyl]thiourea, 15 parts of mercury oxide, 0.1 parts of sulfur and 400 parts of methanol is stirred and refluxed overnight. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 14.5 parts (43%) of N-ethyl-N-[I-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 204.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH2:26][C:27]#[N:28])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[C:22]([CH2:26][C:27]#[N:28])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: N#CCc1[nH]nc(N)c1C#N
Product: N#CCc1nn2c(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)nc2c1C#N
Yield: 58.7 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (147 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (223 mg, 59%). MS (ISP) 380.1 [(M+H)+]; mp 185° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[C:5](=[O:17])[N:4]([CH3:18])[CH:3]=1.[C:19]([C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:31]=2[CH3:45])=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].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.O>[C:19]([C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=4)[C:5](=[O:17])[N:4]([CH3:18])[CH:3]=3)[C:31]=2[CH3:45])=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cn1cc(Br)nc(Nc2ccc(C=O)cc2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C=O)cc2)n1
Temperature: 95 °C
Yield: 111.8 %

Procedure:
A mixture of 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde (3) (2.0 g; 6.51 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (3.28 g; 7.8 mmol), tetrakis(triphenylphosphine)palladium (0.75 g; 0.65 mmol), 1N sodium carbonate (16.0 mL), and 1,2-dimethoxyethane (50 mL) was heated at 95° C. in a sealed pressure vessel for 12 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×75 mL) and brine (1×75 mL), dried over solid sodium sulfate, and evaporated under reduced pressure. The resulting residue was triturated with diethyl ether/dichloromethane to give 4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (4) as a light gray solid (3.6 g), MS 495.35 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[N:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH3:29])=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[K+]>C(O)C.O>[CH2:1]([N:8]1[C:12]2=[C:13]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[N:14]=[C:15]([C:17]([NH2:18])=[O:31])[CH:16]=[C:11]2[C:10]([CH3:29])=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C#N)cc12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(N)=O)cc12
Yield: 83.3 %

Procedure:
1-Benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.76 mmol) prepared in Example 686 was diluted with a mixture of ethanol (7 ml) and water (1 ml). Potassium hydroxide (426 mg, 7.6 mmol) was added to the solution, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 260 mg of the titled compound as a white solid. (Yield: 84%)