Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+].CCOCC>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCCc1ncccn1
Reaction time: 20 h

Procedure:
A mixture of 2-pyrimidinebutanol (1.31 g), 1,6-dibromohexane (5 ml), 50% aqueous sodium hydroxide solution (5 ml) and TAB (140 mg) was vigorously stirred under nitrogen at 23° for 20 h. Ether (25 ml) and water (20 ml) were added, the organic phase separated, washed with brine (20 ml), dried and evaporated in vacuo. The residue was purified by FCC. Elution with hexane and hexane-ether (9:1) followed by ether afforded the title compound as a colourless oil (1.67 g)
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][CH3:12])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][OH:17])[C:6](=[O:18])[N:5]([CH3:19])[C:4]=2[N:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:37]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Br:1][C:2]1[N:10]([CH2:11][CH3:12])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)[C:6](=[O:18])[N:5]([CH3:19])[C:4]=2[N:3]=1
Reactant: C1=COCCC1
Reactant: CCn1c(Br)nc2c1c(=O)n(CCCO)c(=O)n2C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1c(Br)nc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 1.2 mmol) in DCM (10 mL) was added PPTS (27 mg, 0.1 mmol); then dihydropyran (0.15 g, 1.8 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by a column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 8-bromo-7-ethyl-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.38 g, 76.9% yield) as white solid. LCMS retention time 1.871 min; LCMS MH+-THP 331.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>CO.CCOCC.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
5-Nitro-1H-indazole (20 mg) was dissolved in methanol (1 ml) and to the solution was added a catalytic amount of palladium/carbon, followed by stirring at room temperature under hydrogen gas atmosphere for 30 minutes. The resulting mixture was diluted with ether, filtered through celite, and then concentrated under reduced pressure to yield 5-amino-1H-indazole (16 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:15]([O:14][C:10]1[C:11]([F:13])=[CH:12][C:2]([NH:1][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1N
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 10.5 g of the compound obtained in Step 4.2, 29.07 g of tetrahydro-4H-pyran-4-one and 51.56 g of Na2SO4 in 360 ml of acetic acid is stirred overnight at room temperature. 34.62 g of sodium triacetoxyborohydride are then added and the mixture is stirred for 3 hours at room temperature. The resulting mixture is evaporated under reduced pressure and the residue is taken up in EtOAc. This solution is washed with water and then 4 times with saturated aqueous NaHCO3 solution. The resulting solution is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (50/50, v/v) to give 10.55 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 2-bromobenzonitrile (34.6 g, 190 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (76.1 g, 285 mmol) and potassium fluoride (36.4 g, 627 mmol) in tetrahydrofuran (600 ml) was degassed with nitrogen for 30 min then treated with tris(dibenzylideneacetone)dipalladium(0) (1.74 g, 1.9 mmol) followed by tri-tert-butylphosphine (38 ml of a 0.1M solution in 1,4-dioxane, 3.8 mmol) and then the reaction was stirred at ambient temperature for 30 min before heating at 50° C. for 1 h to complete the coupling. The slurry-like reaction mixture was then diluted with water (3 l) and stirred at ambient temperature for 90 min. The resulting solid was collected by filtration, washed with water then with isohexane and finally dried under vacuum over phosphorus pentoxide to afford 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a beige solid (46 g, 100%): δH (360 MHz, CDCl3) 7.37-7.42 (1H, m), 7.53 (1H, d, J 8), 7.59 (1H, td, J 8 and 1), 7.75 (1H, td, J 8 and 1), 7.83 (1H, dd, J 8 and 1), 8.35-8.39 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)CCc1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)CCc1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1
Yield: 41.57 %

Procedure:
Compound 20 was synthesized from 19 (3.26 mmol) and LiOH.H2O (32.6 mmol) using the procedure according to Method E described above.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[O:7][CH:8]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:5]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(-c2nc(CCN)co2)cc1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(-c2nc(CCNC(=O)c3cncc(-c4noc(C(F)(F)F)n4)c3)co2)cc1
Yield: 23 %

Procedure:
This compound was synthesized from 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (30 mg, yield 23%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 9.69 (m, 1H), 9.47 (m, 1H), 9.18 (m, 1H), 8.18-8.16 (d, J=8.3 Hz, 2H), 7.78-7.76 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 3.92-3.91 (m, 2H), 3.05-3.02 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H13F3N6O3: 454.10. found: 453.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][C:30]([O:33][C:34]([NH:36][C@H:37]([C:44](O)=[O:45])[CH2:38][C:39]1[S:43][CH:42]=[CH:41][CH:40]=1)=[O:35])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:44](=[O:45])[C@@H:37]([NH:36][C:34](=[O:35])[O:33][C:30]([CH3:29])([CH3:31])[CH3:32])[CH2:38][C:39]5[S:43][CH:42]=[CH:41][CH:40]=5)[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: COc1ccc(NC(=O)c2ccc3nc(N4CCNCC4)sc3c2)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)[C@H](Cc5cccs5)NC(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Reaction time: 8 h

Procedure:
N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide (1.00 g, 2.51 mmol), Boc-L-2-thienylalanine (0.68 g, 2.551 mmol), diisopropylethylamine (1.75 ml, 10.04 mmol) and HBTU (1.24 g, 3.26 mmol) were dissolved in DMF (71 ml) and stirred overnight. The resulting mixture was diluted with ethyl acetate (154 ml), washed with 1N HCl (3×77 ml), washed with brine (77 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed, eluting with dichloromethane/methanol (97:3) to yield (S)-tert-butyl 1-(4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:17][CH:16]=3)[C:11]2=[O:29])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])=[CH:19][CH:20]=3)[C:11]2=[O:29])=[CH:8][CH:9]=1
Reactant: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(-n2ccn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Reaction time: 14 h
Yield: 95.2 %

Procedure:
Ferric chloride (0.2 g) and activated carbon (2.0 g) were added to a solution of 1-(4-nitrophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (20.5 g) in methanol-tetrahydrofran (75 ml:75 ml), to which hydrazine hydrate (8.0 ml) was added dropwise over the period of 10 minutes. After the mixture was refluxed with stirring for 14 hours, ferric chloride (0.2 g), activated carbon (2.0 g) and hydrazine hydrate (8.0 ml) were added thereto and the reaction mixture was refluxed with stirring for further 6 hours. The activated carbon was filtered off and washed with methanol (100 ml). The filtrate and the washing were combined and distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (700 ml). The ethyl acetate layer was washed with water (200 ml×4), dried over anhydrous magnesium sulfate and distilled off under reduced pressure to give 1-(4-aminophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (18.1 g, 95%) as a pale yellow powder.
Reaction SMILES: COC(=O)[C:4]1[C:9]([NH:10][NH:11][C:12](OC(C)(C)C)=[O:13])=[CH:8][C:7]([F:19])=[C:6]([F:20])[C:5]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:5]1[C:6]([F:20])=[C:7]([F:19])[CH:8]=[C:9]2[C:4]=1[C:12](=[O:13])[NH:11][NH:10]2
Reactant: COC(=O)c1c(NNC(=O)OC(C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH][nH]c2cc(F)c(F)c(Nc3ccccc3Cl)c12
Reaction time: 2 h

Procedure:
6-(N′-tert-Butoxycarbonylhydrazino)-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (1.00 equivalent) is treated with a 1:1 mixture of methylene chloride and TFA and stirred for 2 hours The reaction mixture is concentrated under reduced pressure and the product is purified by trituration or flash column chromatography if needed.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH3:21]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To 1.24 g (4.5 mmol) of the compound (189) obtained in Example 62, 8 ml (87 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 3 hours. After air-cooling, the solution was added to 70 ml of ice/water to which 12 g (87 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 100 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel 40g, eluent solvent; chloroform:methanol=100:1) to obtain 571 mg of the subject compound (190) in a 46% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[N:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:6](=[O:16])[CH:7](Br)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].C([O-])(=O)C.[Na+]>CO.C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([OH:16])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:17]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=NNc1ccccc1Cl)C(=O)C(Br)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCCCC1
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo4-(4-chloro-phenyl)-2-[(2-chloro-phenyl)-hydrazono]-3-oxo-butyric acid ethyl ester (12.1 g, 26 mmol) and sodium acetate (10.8 g, 130 mmol) in methanol (100 ml) was heated at reflux for 4 hours, cooled, concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a solid. A slurry of this material in cyclohexane was heated to reflux and allowed to stir at ambient temperature for 2 hours, and filtered to afford the title compound (I-1d) as a yellow solid (I-1d), 6.5 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([N:11]1[CH2:12][CH:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: Cl
Product: CC(=O)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Using the method of Example 19, 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (Example 1) is reacted with acetyl chloride to give 3-acetyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and then is converted to 1-(p-chlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane which is obtained as a brown oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=1)[C:22](=[O:28])[NH:23]2
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: Cc1cccc2c1C(=CNc1ccc(OCCCN3CCCCC3)cc1)C(=O)N2
Yield: 49.6 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.35 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (388 mg, 49%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(N(CC)CC)C>CC(N(C)C)=O>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-iodopyridin-2-yl)piperazine-1-carboxylate (1.0 g, 2.57 mmol, prepared as in Example 1), trimethylsilyl acetylene (0.73 mL, 5.14 mmol), triethylamine (1.11 mL, 7.71 mmol), and cuprous iodide (196 mg, 1.03 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (149 mg, 5 mol %). The reaction was stirred for 10 minutes. Volatiles were removed in vacuo. The residue was then dissolved in ethyl acetate (250 mL) and washed with water (100 mL). The layers were then separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to give tert-butyl 4-{5-[(trimethylsilyl)ethynyl]pyridin-2-yl}piperazine-1-carboxylate as a pale brown solid (652 mg, 1.81 mmol, 70%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]2[CH2:18][N:17]([C:19]([C@H:21]3[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22]3)=[O:20])[C@H:16]([C:36]([NH:38][C:39]3[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=3)=[O:37])[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:35][C:32]([O:31][C:29]([NH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][C@H:21]([C:19]([N:17]2[CH2:18][C@@H:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][C@H:16]2[C:36]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=2)=[O:37])=[O:20])[CH2:22][CH2:23]1)=[O:30])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(Cc4ccccc4)CC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1

Procedure:
To a flask under nitrogen was added the compound prepared in Example 49 (0.90 g), ammonium formate (2.57 g) and palladium on carbon (1.61 g). Methanol was added (45 mL) under nitrogen and the reaction heated at reflux for 2.5 h. The reaction mixture was cooled and filtered through Celite®, washing the filter cake with methanol. The solvent was removed in vacuo, diluted with water and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried and concentrated to give the title compound (0.57 g) as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:51](C1C=CC(B(O)O)=CC=1)([OH:53])=[O:52]>>[CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([C:51]([OH:53])=[O:52])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(C(=O)O)cc4)ccc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 549a using 4-carboxyphenylboronic acid instead of 4-fluorophenylboronic acid.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])=[O:2].[CH3:14][C:15]([CH3:21])([CH3:20])[CH:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1>[C:15]([CH:16]1[CH2:17][O:18][CH:1]([C:3]2[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=2[CH3:13])[O:2]1)([CH3:21])([CH3:20])[CH3:14]
Reactant: CC(C)(C)C(O)CO
Reactant: CCOC(=O)c1noc(C=O)c1C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(C2OCC(C(C)(C)C)O2)c1C
Temperature: 110 °C

Procedure:
To a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (50 mg, 0.273 mmol) in toluene (0.5 mL) was added 3,3-dimethylbutane-1,2-diol (32.3 mg, 0.273 mmol) and the mixture was heated at 110° C. for 4.5 hours. The resulting mixture was partitioned between EtOAc and water and the organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])=[O:13])=[CH:7]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([O:31][CH3:32])[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])=[O:13])=[CH:7]3)=[C:24]([O:31][CH3:32])[CH:23]=1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2c(Br)cccc2c1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)OCC(F)(F)F)ccc12
Temperature: 84 °C
Yield: 71.5 %

Procedure:
A vial was charged with 2,2,2-trifluoroethyl 5-bromonaphthalene-2-sulfonate (0.211 g, 0.572 mmol), (4-chloro-2-methoxyphenyl)boronic acid (0.128 g, 0.687 mmol), potassium phosphate (0.486 g, 2.289 mmol), and Pd(dppf)Cl2 CH2Cl2 (0.047 g, 0.057 mmol). The vial was sealed with a septum cap and flushed with N2. Dioxane (2.60 mL) and water (0.260 mL) were added and the mixture was sparged with N2 for 1 minute, then heated at 84° C. for 2 h. The resulting mixture was filtered through diatomaceous Earth® (diatomaceous earth) and concentrated to a residue for purification by MPLC. The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford 2,2,2-trifluoroethyl 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonate (0.176 g, 0.409 mmol) as a colorless amorphous solid.