Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][NH:15][C:14]1=[S:23])[CH2:7]2.[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][NH:15][C:14]1=[S:23])[CH2:7]2
Reactant: CCOC(=O)c1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A mixture of ethyl 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate (4.6 g, 13.6 mmol), prepared as in Example 24, and potassium hydroxide (3.14 g, 47.6 mmol) in 130 mL of ethanol/water (10:3) was stirred at 85°-90° C. for 5 hours. The solvent was removed by evaporation and the residue was dissolved in water. The solution was acidified with 1N hydrochloric acid to a pH of 1 giving a crystalline material. Isolation of the material by filtration gave 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (3.86 g, 12.5 mmol), m.p. 250°-252° C.
Reaction SMILES: C(O)(=O)C(O)=O.[NH2:7][CH:8]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:9]1[CH2:18][CH2:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1.[C:25]1([CH2:31][C:32](OC)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>O>[C:25]1([CH2:31][C:32]([NH:7][C@@H:8]2[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:9]2[CH2:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CN1C(=O)C(N)C1CCc1ccco1
Reactant: COC(=O)Cc1ccccc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1CCc1ccco1
Temperature: 28 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A 100 mg sample of cis(racemic at 2 and 3 position) 3-amino-2-[2-(2-furanyl)ethyl]-4-oxo-1-azetidine acetic acid, methyl ester oxalate and 121 mg of methyl phenylacetate was added to 0.1 M potassium phosphate buffer(100ml) at pH=6.0, and the temperature maintained at 28° C. Milli-Q™ H2O washed Sclavo penicillin G amidase (0.035 I.U./%mole of substrate; 0.100 I.U./mg of substrate) was added and the reaction allowed to proceed overnight. The reaction mixture was then extracted two times with ethyl acetate and dried over anhydrous sodium sulfate. The ethyl acetate portion was evaporated to dryness in vacuo and the residue was purified by column chromatography using a Kiesegel 60™ column eluted with toluene/ethyl acetate (50/50), to obtain 45.7 mg (42.2% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:18])[CH2:15][CH:16]=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[ClH:19].[CH3:20][NH2:21].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC#N.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:21][CH3:20])=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CC=O)Cc1c[nH]nc1-c1ccc(F)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC#N
Solvent: O
Product: CNCCN(C)Cc1c[nH]nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a stirred solution of 2-([[3-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl](methyl)amino)acetaldehyde (200 mg, 0.81 mmol, 1.00 equiv), methylamine hydrochloride (1 g, 14.81 mmol, 18.31 equiv) and acetic acid (126 mg, 2.10 mmol, 2.59 equiv) in 1,2-dichloroethane (20 mL) was added NaBH(OAc)3 (670 mg). The resulting solution was stirred at room temperature overnight and then quenched by the addition of 10 mL of water. The pH value of the solution was adjusted to 7 with saturated sodium carbonate solution. The resulting mixture was extracted with 2×50 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was initially purified on a silica gel column eluted with 10% MeOH in CH2Cl2 and the partially purified product was repurified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase, Water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm. The fractions containing the pure product were concentrated and then redissolved in 5 mL of 12N hydrochloric acid. The resulting solution was concentrated under vacuum to afford 100 mg (47%) of N1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-N1,N2-dimethylethane-1,2-diamine hydrochloride as a white solid. 1H NMR (300 MHz, D2O) δ: 7.91(s, 1H), 7.50-7.45 (m, 2H), 7.25-7.19 (m, 2H), 4.41 (s, 2H), 3.21 (s, 4H), 2.60 (s, 3H), 2.57 (s, 3H) ppm. LCMS (method J, ESI): RT=1.01 min, m/z=263.1 [M+H]+.
Reaction SMILES: [ClH:1].ClC1C=CC([CH:9]([NH:20][NH2:21])[C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=CC=1.[OH-].[Na+]>ClCCl.O>[Cl:1][C:10]1[CH:11]=[CH:12][C:13]([NH:21][NH:20][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=[CH:14][CH:19]=1
Reactant: Cl
Reactant: Cn1nnc2ccc(C(NN)c3ccc(Cl)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Reaction time: 0.25 h

Procedure:
To a suspension of 8.1 g of intermediate 2-b in 60 ml of dichloromethane was added a solution of 1 g sodium hydroxide in 15 ml of water. The whole was stirred for 15 min., then the organic layer was separated and evaporated. The residue and 1.4 g of potassium hydroxide were refluxed in 50 ml ethanol for 3 hours, yielding (-)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole (interm. 2-c); enantiomeric excess: 20%.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[CH:7]1([CH:12]([NH:16][C:17]([O:19][CH3:20])=[O:18])[C:13](O)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>[CH:7]1([CH:12]([NH:16][C:17](=[O:18])[O:19][CH3:20])[C:13]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: OC1CNC1
Reactant: COC(=O)NC(C(=O)O)C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC(O)C1)C1CCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 155.7 %

Procedure:
TBTU (0.373 g, 1.16 mmol) was added to azetidin-3-ol hydrochloride (1.960 g, 17.89 mmol), 2-cyclopentyl-2-(methoxycarbonylamino)acetic acid (Compound J2.1) (3 g, 14.91 mmol) and DIPEA (10 mL, 57.3 mmol) in DCM (60 mL) at rt. The resultant mixture was stirred for 2 h. Additional azetidin-3-ol hydrochloride (0.45 g, 4.11 mmol) was added and the mixture was heated at 50° C. for 1.5 h. The mixture was cooled to rt and the pH was adjusted to 2 using KHSO4 (1.5 M). The mixture was extracted with DCM and the combined DCM layers were washed with brine and concentrated under reduced pressure. The residue was diluted with MeOH (15 mL) and KOH (1.56 g) in water (30 mL) was added. The resultant mixture was stirred at rt for 5 h. Part of the solvent was removed under reduce pressure. The remaining mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduce pressure. The residue was purified via Biotage (gradient: 10-100% of DCM/MeOH (1:0.05) in DCM, KP-SIL 100 g column) to give the title product (5.95 g, 50%). 1H NMR (600 MHz, CDCl3) 1.15-1.40, 1.45-1.81, 2.04-2.20, 2.33, 2.50, 3.65, 3.84, 3.92, 4.04, 4.14-4.28, 4.32, 4.37-4.44, 4.65, 5.25. Total no of protons: 20.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:24](/B(O)O)=[CH:25]/[CH3:26]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:11]1[S:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:17])[N:4]=[CH:3][C:2]=1/[CH:24]=[CH:25]\[CH3:26]
Reactant: C/C=C\B(O)O
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C/C=C\c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 87.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (320 mg, 1.015 mmol)[prepared in Example 99], potassium carbonate (702 mg, 5.08 mmol), bis(tri-t-butylphosphine)palladium(0) (25.9 mg, 0.05 mmol) and (1Z)-1-propen-1-ylboronic acid (87 mg, 1.01 mmol) in 1,4-dioxane (5.3 ml) and water (1.3 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol, 87% yield) as a yellow oil: LCMS (ES) m/z=277 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.C1COCC1>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4′-Nitro-biphenyl-4-sulfonic acid (1.12 g, 4 mmol) was mixed with tin (II) chloride (5.2 g, 32 mmol) and 40 ml of THF. The mixture was refluxed overnight. The reaction mixture was poured into 80 ml of water and stirred at room temperature for 8 h. The mixture was filtered and the solid was dried under vacuum to provide 0.73 g (73%) of 4′-amino-biphenyl-4-sulfonic acid, obtained as an off-white solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 4-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E11 (75 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.70 (2H, d), 8.57 (1H, d), 8.17 (1H, s), 7.72 (2H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.20 (2H, dt), 1.90 (2H, m), 1.60 (2H, m), MS(ES+) 323 [M+H]+.
Reaction SMILES: Cl.O1CCOCC1.C(=[N:15][C:16]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:22][CH:23]=[CH2:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C1C=CC=CC=1>O>[NH2:15][C:16]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:22][CH:23]=[CH2:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CCC(N=Cc1ccccc1)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C=CCC(N)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
4N HCl-1,4-dioxane (308 mL) and water (65 mL) were added to ethyl 2-(benzylidene-amino)-2-(3,4-dichlorophenyl)-4-pentenoate (518 g), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Water (1 L) and 1N aqueous hydrochloric acid (500 mL) were added to the residue, and the mixture was washed with diisopropyl ether (500 mL) three times. 25% Aqueous sodium hydroxide (250 mL) was added to the aqueous layer to adjust the pH to 9. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (231 g). The title compound was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:17])=[O:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(O)c(OC(F)(F)F)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(O)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (901 mg, 4.37 mmol) in acetone (10 ml) was added 4 ml of the Jones reagent. The ice bath was removed and the reaction was stirred at room temperature for ca. 1 h. Isopropanol was added to destroy the excess Jones reagent. The mixture was diluted with ethyl acetate, the precipitate was filtered off, and the filtrate concentrated in vacuo. The residue was diluted with 1M HCl and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound. Mass spectrum (ESI) 221.1 (M−1).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]4[CH:24]=[C:23]([C:25]([OH:27])=O)[S:22][C:16]4=[CH:17][CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:47]([NH:54][CH2:55][CH2:56][NH2:57])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C(Cl)CCl>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[NH:54][CH2:55][CH2:56][NH:57][C:25]([C:23]1[S:22][C:16]2=[CH:17][CH:18]=[C:19]3[C:14]([N:13]=[C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:3])(=[O:4])[NH2:2])[CH:6]=4)[N:21]=[CH:20]3)=[C:15]2[CH:24]=1)=[O:27])([CH3:53])([CH3:51])[CH3:52]
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3ccc4sc(C(=O)O)cc4c3n2)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carboxylic acid (150 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol), N,N-diisopropylethylamine (73 mg, 0.56 mmol) and BOC-ethylenediamine (66 mg, 0.41 mmol) were dissolved in dry DMF (2 mL) and cooled in an ice-bath. EDC (79 mg, 0.41 mmol) was added in one portion and the resultant suspension was stirred overnight allowing the ice-bath to melt. The reaction was concentrated under reduced pressure, redissolved in isopropanol (˜10 mL) and water was added (˜5 mL). The precipitate formed was isolated by filtration and washed with water (1×5 mL), dilute NaHSO4 (1×5 mL), water (1×5 mL), saturated Na2CO3 (1×5 mL), water (1×5 mL), isopropanol (1×5 mL), diethyl ether (2×5 mL) and pentane (2×5 mL) giving an ochre powder (102 mg, 51% yield). MS (ES+) 543. δH (d6 DMSO) 1.2-1.5 (9H, s), 3.3-3.5 (4H, br m), 6.6 (0.1H, br s), 7.0 (0.9H, br s), 7.1-7.4 (2H, br s), 7.4-7.6 (2H, m), 7.8-8.0 (2H, m), 8.2 (1H, m), 8.6-9.0 (3H, br m), 9.4 (1H, s), 10.3-10.6 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([CH3:11])[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]=1[CH3:14].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O>>[CH3:11][C:6]1[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]([CH3:14])=[C:2]([CH3:1])[C:7]=1[C:8](=[O:10])[CH:9]=[CH:19][C:18]1[CH:21]=[C:22]([CH3:25])[C:23]([OH:24])=[C:16]([CH3:15])[CH:17]=1
Reactant: CC(=O)c1c(C)c(C)c(C)c(C)c1C
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2c(C)c(C)c(C)c(C)c2C)cc(C)c1O

Procedure:
This compound was synthesized from pentamethylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(=O)(O)(O)O.[C@@H:15]12[N:22](C)[C@@H:19]([CH2:20][CH2:21]1)[CH2:18][C:17](=O)[CH2:16]2>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:17]2[CH2:16][CH:15]3[NH:22][CH:19]([CH2:20][CH2:21]3)[CH:18]=2)=[CH:2]1
Reactant: CN1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: c1ccc2[nH]ccc2c1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Temperature: 62.5 °C

Procedure:
The reaction is performed by first dissolving the indole in a suitable solvent, typically acetic acid, and then adding a suitable acid, such as hydrochloric or phosphoric acid. The 3-tropanone is then added and the reaction heated at about 60-65° C. for from about 4 to about 24 hours. The resulting 3-(indol-3-yl)-8-azabicyclo-[3.2.1]oct-2-ene is isolated by pouring the reaction mixture into an ice water slurry, adjusting the pH of the aqueous mixture to about 8 by the addition of base, typically sodium hydroxide, and extracting with a water immiscible solvent, typically dichloromethane or ethyl acetate. The product recovered may be purified by crystallization or chromato-graphy as necessary or desired.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.Cl.[CH2:40]([NH2:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:40]([NH:42][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1)[CH3:41]
Reactant: CCN
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNCCCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 64.6 %

Procedure:
In a manner similar to that of Example 1b, by reaction of 600 mg (1 mmol) of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 850 mg (10.4 mmol) of ethylamine hydrochloride and 1.44 g (10.4 mmol) of potassium carbonate in 50 ml of ethanol. 350 mg of ethyl 4′-(5-ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a colorless oil (yield=62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:13][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH3:12])(=[O:24])=[O:23]
Reactant: Cc1cc(C(C)O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Into a THF solution (35 ml) of 1-(3-methyl-4-nitrophenyl)-ethanol (5.44 g) and triethylamine (3.95 g), a THF solution (10 ml) of methanesulfonyl chloride (3.48 g) was added dropwise at 5° C. over a period of 30 minutes. Further, the mixture was stirred at room temperature for 8 hours. After finishing the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). It was washed with 2N aqueous solution of hydrochloric acid and saturated aqueous solution of sodium bicarbonate and then dried with anhydrous magnesium sulfate. After distilling off the solvent, the aimed 1-(3-methyl-4-nitrophenyl)-ethyl methanesulfonate (5.80 g) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: C[C@@H]1NCCNC1=O
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3S)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase chromatography (Biotage SP4). The relevant fractions were combined, concentrated and dried in vacuo to yield the title compound as white crystals (349 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[N+:23]([O-])=O>[Pd].C(OCC)(=O)C>[NH2:23][C:3]1[C:4]([C:21]#[N:22])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[C:10]([C:17]([F:20])([F:18])[F:19])[CH:9]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: CCOc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
To a flask containing 4-amino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (5 g, 14.2 mmol) and 10% Pd-C (wet) (5 g) under nitrogen was added ethyl acetate (500 ml). The vessel was purged with hydrogen and stirred at room temperature for 1.5 h before filtration through a cellite pad followed by concentration under reduced pressure to afford 3,4-diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (2.5 g). 1H NMR (DMSO): δ 8.02 (m, 2H), 7.31 (d, 1H), 7.14 (s, 1H), 6.1 (bs, 2H), 5.69 (bs, 2H), 4.25 (q, 2H), 1.35 (t, 3H). MS m/z 323.3 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([C:23]1[N:24]([CH3:32])[CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[N:24]([CH3:32])[CH:25]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CCCCc1nc(C(=O)OC)cn1C
Product: CCCCc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile (664 mg, 2.55 mmol) and methyl 2-butyl-1-methyl-1H-imidazole-4-carboxylate (500 mg, 2.55 mmol). The product was purified with flash chromatography. Yield 291 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.88 (t, 3H), 1.09 (t, 3H), 1.28-1.36 (m, 2H), 1.54-1.61 (m, 2H), 2.62 (t, 2H), 3.57 (s, 3H), 4.26-4.39 (m, 3H), 6.95 (bs, 1H), 7.47 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.96 (s, 2H), 8.09 (s, 1H).