Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 116.5 %

Procedure:
A mixture of N-(4-bromophenyl)-4-fluoro-3-nitrobenzamide (400 mg; 1.18 mmol) and 2-dimethylamino ethylamine (208 mg; 2.36 mmol) in EtOH (5 mL) was stirred over night at 50° C. The mixture was then poured into aqueous NaHCO3 and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Recrystallization from EtOAc/petroleum ether gave the crude sub-title compound (560 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromo-N-isobutyl-benzenesulfonamide (0.25 g, 856 μmol) in anhydrous dimethylacetamide (5 mL) was added NaH (60% dispersion in mineral oil, 37.7 mg, 942 μmol) and the mixture was stirred at room temperature for 15 minutes. 4-Fluorobenzyl bromide (117 μL, 942 μmol) was added and reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water added and then extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give 4-bromo-N-(4-fluoro-benzyl)-N-isobutyl-benzenesulfonamide (267 mg, 78%) 1H NMR (300 MHz, CDCl3): δ 7.65-7.66 (m, 4H), 7.23 (m, 2H), 6.99 (t, 2H), 4.27 (s, 2H), 2.89 (d, 2H), 1.64 (dt, 1H), 0.74 (d, 6H).
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[I:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(#N)C>[CH2:8]([NH:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[I:12])[CH:9]=[CH2:10]
Reactant: O=C(Cl)c1ccccc1I
Reactant: C=CCN
Solvent: CN1CCOCC1
Solvent: CC#N
Product: C=CCNC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
470 ml (4.28 mol) of N-methylmorpholine, followed by 224 ml (2.98 mol) of allylamine are added under ice cooling to 750 g (2.81 mol) of 2-iodo-benzoic acid chloride in 7.5 l of acetonitrile, and stirred for 60 min at RT. The precipitate is filtered off and the filtrate concentrated by evaporation on a RE. The residue of evaporation is dissolved in 4 l of EtOAc and 4 l of water, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water, sat. Na2CO3, water and brine, dried (Na2SO4) and concentrated by evaporation. Stirring of the residue in 2.5 l of hexane and filtering yields 2-iodo-benzoic acid allylamide; m.p. 105-106° C.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].O=[CH:20][C:21]([Cl:24])([Cl:23])[Cl:22]>>[Cl:22][C:21]([Cl:24])([Cl:23])[CH:20]1[O:12][C:3]([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Product: O=C(c1ccccc1)C1(c2ccccc2)COC(C(Cl)(Cl)Cl)O1
Yield: 63 %

Procedure:
The procedure of Example 1 was repeated except that the starting materials were α-methylolbenzoin and chloral. The product was a 63% yield of 2-trichloromethyl-4-benzoyl-4-phenyl-1, 3-dioxolane, analyzed as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(C(CCn2ccnc2)c2ccc(Br)cc2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Clc1ccc(C(CCn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 363.28. 1H NMR (Me-d3-OD) δ 2.55-2.70 (2H, m), 3.85-3.95 (1H, m), 3.95-4.10 (2H, m), 7.05 (1H, s), 7.10-7.60 (9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:14](=[O:16])[O:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[NH:15][C:14](=[O:16])[O:13][C:8]4([CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCC2)O1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C2(CCCC2)O1

Procedure:
Prepared from 6-bromo-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2-(1H)-one and 3-chlorophenyl boronic acid according to Procedure A. Off-white solid: mp 140-145° C. 1H-NMR (DMSO-d6) δ10.27 (s, 1H), 7.75 (t, 1H, J=1.8 Hz), 7.53-7.63 (m, 3H), 7.44 (t, 1H, J=7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H, J=8.6 Hz), 2.09-2.15 (m, 4H), 1.81-1.89 (m, 4H). MS (ESI) m/z 314 [M+H]+. Anal. Calc. For C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46. Found: C, 60.94; H, 4.94; N, 3.78.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].CO.[CH3:16][C:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:16][C:17]1([CH2:23][NH:1][C@@H:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc([C@@H](C)N)cc1
Reactant: CC1(C=O)CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc([C@@H](C)NCC2(C)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (R)-methyl 4-(1-aminoethyl)benzoate (0.12 g, 0.67 mmol) in methanol (2.97 mL, 73.33 mmol) was added 1-methylcyclohexane-1-carboxaldehyde (0.093 g, 0.74 mmol) and acetic acid (0.152 mL, 2.67 mmol). The reaction was stirred for 1 hour at room temperature whereupon sodium cyanoborohydride (63.1 mg, 1.00 mmol) was added and the mixture further stirred at room temperature overnight. The solvent was evaporated and the residual sodium cyanoborohydride quenched with saturated aqueous NaHCO3. The mixture was extracted into ethyl acetate, the organic layer washed with brine and the solvent evaporated to dryness. The residue obtained was purified via silica chromatography (0-5% MeOH/DCM) to afford the title compound as a colorless oil (123.0 mg, 63%). LC-MS: (FA) ES+ 290.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24]>N12CCCN=C1CCCCC2.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[O:15][C:23](=[O:24])[NH:22][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)ON(Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of N-(4-benzyloxybenzyl)acetohydroxamic acid (1.35 g), methyl isocyanate (0.65 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene catalyst (1 drop) in tetrahydrofuran (10 ml) was stirred for 3 hours then left overnight to provide N-(4-benzyloxybenzyl)-O-methylcarbamoylacetohydroxamic acid (1.35 g) m.pt. 101°-102°[from ethyl acetate-light petroleum (b.pt. 60°-80°)].
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([S:29]([CH3:32])(=[O:31])=[O:30])[N:17]=2)[CH2:9]1.[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)=[O:38])[CH3:35]>>[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH:42]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=4)[N:18]([S:29]([CH3:32])(=[O:31])=[O:30])[N:17]=3)[CH2:9]2)[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: CS(=O)(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(S(C)(=O)=O)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methanesulfonyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)C.C(O)CCC>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCO
Solvent: CCO
Product: c1ccc(Cn2ccnc2)nc1

Procedure:
A solution of 2-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol) in ethanol (50 ml) was added dropwise to a stirred, boiling solution of potassium tert-butoxide (22.4 g, 0.2 mol) and imidazole (6.8 g, 0.1 mol) in dry butan-1-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 5 h. After removal of the solvents under reduced pressure, the resulting oil was dissolved in hydrochloric acid (150 ml, 2M), and the acid solution was washed with ether (100 ml). The acid solution was then basified with sodium hydroxide solution (10M), and the basic solution was extracted with chloroform (3×100 ml). The chloroform solutions were combined, dried (MgSO4), and the chloroform was then removed under reduced pressure. The residue was purified by using a silica-gel column and by elution with chloroform/methanol (9:1). The resulting solid was recrystallised from ethanol/light petroleum affording 1-(2-pyridylmethyl)imidazole as white cubes m.p. 79°-80°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].Cl[C:32]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@H]2O)=NC=1CC.ICC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[O:27][CH2:28][CH3:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1OC
Solvent: CCI
Product: CCO[C@@H]1Cc2ccccc2[C@@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodoethane and making non-critical variations provided the title compound as a solid: MS (ESI+) for C25H27Cl2N3O m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([O:21]C)=[O:20])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1.[OH-].[Na+].C1COCC1.Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([OH:21])=[O:20])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cccc3cccnc23)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2cccc3cccnc23)nc(C(=O)O)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a suspension of methyl 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylate (5.00 g, 16.1 mmol) in MeOH (64 mL) were added 1 M NaOH aqueous solution (64 mL) and THF (64 mL) at 0° C. The mixture was heated to 80° C. The homogeneous mixture was cooled to 0° C. To the mixture was added 1 M HCl aqueous solution (64 mL) at 0° C. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (3.59 g, 75% yield) as a fresh-colored solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 7.73 (1H, dd, J=8.4, 4.3 Hz), 7.81-7.89 (1H, m), 8.12 (1H, dd, J=7.4, 1.4 Hz), 8.30 (1H, dd, J=8.4, 1.2 Hz), 8.61 (1H, dd, J=8.5, 1.6 Hz), 8.96-9.05 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:6]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: COc1cccc(C=O)c1OCCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=NCCc2ccccc2)c1OCCCN1CCOCC1
Yield: 85.9 %

Procedure:
3-Methoxy-2-[3-(4-morpholinyl)propoxy]-benzaldehyde (42.5 g) and 18.5 g of phenethylamine are reacted in 150 ml of toluene following the procedure described in Example 1B, yielding 50.0 g of the title compound, boiling point 229°-234° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>CCCCCC>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Product: C1CCC(N2CCCC2)CC1

Procedure:
The structure-directing agent (SDA) is synthesized using the reaction sequence described in the scheme below. A three neck 3000-ml flask is charged with 100 gm (1.4 mole) of pyrrolidine, 50 gm of cyclohexanone (0.51 mole) and 1000 ml anhydrous hexane. To the resulting solution, 122 gm (1.022 mole) of anhydrous magnesium sulfate is added and the mixture is mechanically stirred and heated at reflux (the reaction is monitored by NMR analysis) for 96 hrs. The reaction mixture is filtered through a fritted glass funnel. The filtrate is concentrated under reduced pressure on a rotary evaporator to give 75 gm of a clear (yellow-tinted) oily substance. 1H-NMR and 13C-NMR spectra are acceptable for the desired product 1-(1-pyrrolidino)cyclohexene. Saturation of 1-(1-pyrrolidino)cyclohexene, to give N-cyclohexylpyrrolidine, is accomplished in quantitative yield by hydrogenation in ethanol at a 55 psi pressure of hydrogen gas in the presence of 10% Pd on activated carbon.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O.Cl.[NH2:26]/[C:27](/[NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[N:28]/[H].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:28]=[C:27]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]4)[N:26]=2)[CH:13]=[CH:12][S:11]3)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2nc3sccn3c2C(=O)C=CN(C)C)ccc1F
Reactant: [H]/N=C(/N)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)ccc1F
Yield: 86 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (0.6 g, 1.74 mmol) and tert-butyl (3R)-3-{[(Z)-amino (imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.726 g, 2.61 mmol) was diluted with 13 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (875 μl) to form a reaction mixture. The reaction mixture was heated to reflux for 24 hours. HPLC revealed remaining starting enaminone. More tert-butyl (3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.243 g, 0.87 mmol) was added followed by a 21% w/w solution of sodium ethoxide in ethanol (270 μl). The mixture was kept at reflux for an additional 15 hours. Volatiles were removed in vacuo and the residue was taken up in 50 ml of ethyl acetate and 50 ml of water. The phases were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product was purified by flash chromatography on silica gel (gradient 50% to 75% ethyl acetate in hexanes) to yield 0.785 g of a pale yellow solid (86%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.5 Hz, 1H), 7.41 (d, J=4.7 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.7, 8.6 Hz, 1H), 7.18-7.08 (m, 2H), 6.41 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.85-3.75 (m, 1H), 3.72-3.63 (m, 1H), 3.00-2.88 (m, 2H), 2.04-1.94 (m, 1H), 1.82-1.73 (m, 1H), 1.62-1.50 (m, 1H), 1.50-1.38 (m, 1H), 1.34 (s, 9H). LCMS: 525 [M+H].
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:15]2[C:16]3[C:21](=[CH:20][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[CH:22]=[C:14]2[C:12]([N:9]2[CH2:8][CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:11][CH2:10]2)=[O:13])=[CH:39][CH:40]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 2-chloropyridine-5-boronic acid to afford the desired product as a colorless foam (33%). MS (ISP): 563.5 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:24])[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[S:26]>O1CCCC1.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][C:25]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[S:26])[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(OC(=S)n2ccnc2)c2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
1.0 g (2.87 mmol) of tert-butyl 3-(benzothiazol-2-ylhydroxymethyl)piperidine-1-carboxylate were dissolved in 30 ml of tetrahydrofuran at room temperature. 0.35 g (2.87 mmol) of dimethylpyridin-4-ylamine and 1.53 g (8.61 mmol) of 1,1′-thiocarbonyldiimidazole were subsequently added. The reaction mixture was then stirred at room temperature for 18 h. Conventional work-up gave 1.08 g of tert-butyl 3-[benzothiazol-2-yl(imidazole-1-carbothioyloxy)methyl]piperidine-1-carboxylate; HPLC/MS (M+H)+=459 as oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:53][C:54](=[O:67])[C@H:55]([OH:66])[C@H:56]([NH2:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])[CH2:50][CH2:51][CH3:52]>C(Cl)Cl>[CH2:49]([O:53][C:54]([C@H:55]([OH:66])[C@H:56]([NH:65][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:64])=[O:67])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (335 mg, 1.6 mmol, 1.0 eq.) was combined with DIPEA (897 μL, 3.2 eq.) and HATU (0.612 g, 1.61 mmol, 1.0 eq.) in DCM (40 mL). The resulting mixture was stirred for 10 minutes and (2R,3R)-3-amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid butyl ester (HCl salt, 519 mg, 1.6 mmol, 1.0 eq.) was added. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. The product was dissolved into AcOH (5 mL) and purified using preparative HPLC. The clean fractions were combined and lyophilized to yield 2-{3-[(1R,2R)-2-butoxycarbonyl-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-propyl}-benzoic acid (150 mg).
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][C:2]1([C:14]([O:16][CH3:21])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CO
Reactant: NC1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 70 °C

Procedure:
To a heterogeneous mixture of (3S)-1-amino-3-(4-bromophenyl)cyclopentanecarboxylic acid (I-1C, 14 g, 49.3 mmol) in MeOH (250 mL) was added thionyl chloride (36.0 mL, 493 mmol) dropwise over a period of 20 minutes at room temperature via an additional funnel (exothermic). The reaction mixture was placed in an oil bath and heated to 70° C. for 4 hours. The solvent was removed under vacuum, with the residue being dissolved in ethyl acetate (200 mL) and washed twice with 1N NaOH. The organic layer was then dried over Na2SO4 and concentrated to give 10.8 g of (3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate. HPLC retention time=0.68 min (Condition G); LC/MS M+1=298/300.