Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C(NN)=O.[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25].[Br:27]NC(=O)CCC(N)=O>C(O)C>[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([Br:27])[C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: NNC(=O)c1cc2ccccc2[nH]1
Solvent: CCO
Product: COC(=O)c1cc(Br)c(N)cc1OC

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme V or VI to form a compound of the invention
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][N+:18]([O-])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][N:18]=[C:19]([Cl:24])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc[n+]([O-])cc2OCCN1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C1c2ccnc(Cl)c2OCCN1Cc1ccccc1
Yield: 94 %

Procedure:
A solution of the compound (0.23 g) obtained in step 4 in phosphorus oxychloride (1.0 mL) was stirred at 80° C. for 30 min. The reaction mixture was poured into water, and the resultant product was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give 4-benzyl-9-chloro-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (0.23 g, 94%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[N:18]=[C:17]([O:32][CH3:33])[N:16]=2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CO.C1COCC1.O>[CH3:33][O:32][C:17]1[N:16]=[C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:34])=[O:3])[CH:20]=[C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:18]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(OC(C)(C)C(=O)O)c3)nc(OC)n2)cc1
Reaction time: 5 h
Yield: 68.6 %

Procedure:
A solution of 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [330 mg, 0.7 mmol, Example 22(a)] in a 2 M solution of sodium hydroxide (5 mL, 10 mmol) in MeOH (4 mL), THF (2 mL) and water (4 mL) is heated to 60° C. for 30 minutes. After an additional 5 hours at room temperature, the mixture is concentrated, and diluted with water and ethyl acetate. The solution is acidified with dilute hydrochloric acid to pH, 2.0, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid [0.21 g, 72%, Example 23(a)]. LCMS: RT=2.47 minutes, MS: 438 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[O:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C.[OH-].[Li+].C1COCC1.CO>O>[CH:22]1([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:5]([O:6][CH:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[C:4]([OH:25])=[O:3])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid ethyl ester (23.2 gm, 62.87 mmol) was added a solution of lithium hydroxide (13.0 gm, 314.36 mmol) in water (150 ml) followed by THF (200 ml) and methanol (10 ml) and stirred for 2 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified 1N HCl, extracted with ethyl acetate (3×200 ml), organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and washed concentrated under reduced pressure to provide (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (18.49 gm)
Reaction SMILES: [C:1]([P:5](C(C)(C)C)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C([Mg][Cl:19])(C)(C)C.[Mg].C(Cl)(C)(C)C.P(Cl)(Cl)Cl>>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)[Mg]Cl
Agent: [Mg]
Solvent: CC(C)(C)Cl
Solvent: ClP(Cl)Cl
Product: CC(C)(C)P(Cl)C(C)(C)C

Procedure:
By way of example, the preparation of tri-tert-butylphosphine is described in Chem. Ber., 100(2), 692-3 (1967). Tertiary butyl magnesium chloride is first prepared from magnesium metal and t-butyl chloride, then this is allowed to react with PCl3 to form di-tert-butylchlorophosphine. This product is then treated with tert-butyl lithium to yield tri-tert-butyl phosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[NH:29][CH2:30][CH2:31][N:32]=5)[CH:23]=4)[CH:18]=3)[CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].C=O.[C:39]([BH3-])#N.[Na+].[C:43]([O-:46])(O)=[O:44].[Na+]>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[NH:29][CH2:30][CH2:31][N:32]=5)[CH:23]=4)[CH:18]=3)[CH2:13][N:12]2[CH3:39])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35].[CH3:16][C:17]([CH2:18][C:43]([OH:46])=[O:44])=[O:21]
Reactant: O=C([O-])O
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1Cc2cc(Oc3ccnc(C4=NCCN4)c3)ccc2CN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)CC(=O)O
Product: CN1Cc2ccc(Oc3ccnc(C4=NCCN4)c3)cc2CC1C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-54) (70.0 mg, 0.11 mmol), in acetonitrile (1.0 mL), was added formaldehyde (37% solution in water, 42 μL, 0.56 mmol) and sodium cyanoborohydride (28.8 mg, 0.46 mmol). A few drops of MeOH were added and the reaction was allowed to stir for 1 h. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc (2×). The combined organic solutions were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography and then further purified by HPLC (250 mm C18 column) eluting with acetonitrile containing 30% to 100% 10 mM ammonium acetate in water (20 min gradient), to give N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]-oxy}-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-11) as the diacetate salt (12 mg, 17%). 1H NMR (300 MHz, CD3OD): δ 8.58 (d, 1H), 8.17 (d, 1H), 7.85-7.81 (m, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.26 (d, 1H), 7.16-7.13 (m, 1H), 6.99-6.97 (m, 2H), 4.07 (d, 1H), 4.04 (s, 4H), 3.71 (d, 1H), 3.46-3.41 (m, 1H), 3.24-3.06 (m, 2H), 2.53 (s, 3H), and 1.91 (s, 6H). LCMS: (FA) ES+ 530.3, ES− 528.2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH3:26]>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:25][CH3:26])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CCBr
Product: CC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 67.6 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and bromoethane (0.025 mL, 0.335 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0456 g, 68.1%). EI-MS m/z 331 (M+) Rt (1.80 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a stirred solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (16.82 g, 52.23 mmol) in 522 mL of anhydrous THF cooled to 0° C. with an ice bath was added NaH [60% dispersion in mineral oil] (3.76 g, 156.7 mmol). The reaction mixture was stirred for 20 min at 0° C., after which p-toluenesulfonyl chloride (14.88 g, 78.3 mmol) was added. The resulting mixture was stirred at 0° C. for 1.5 hr, after which cold 0.5 M HCl (20 mL) was added. The mixture was partitioned between EtOAc and 0.5 M HCl, after which the organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to yield a residue that was triturated with 20% CH2Cl2 in hexanes to yield the title compound (0.84 g, 81%) as a light yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 8.00 (d, J=5.1 Hz, 2H), 7.44 (dd, J=8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 477.0/479.0 (M+1)+, calc. 476.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([F:24])([F:23])[F:22])=[N:6][CH:7]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH2:30])=[O:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.C(N)CN>O1CCOCC1.O.[Cu]I>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:30][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([F:22])([F:24])[F:23])=[N:6][CH:7]=1)=[O:29]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: COC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: NCCN
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Reaction time: 0.75 h
Yield: 4.2 %

Procedure:
Into a 50 mL 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 1-(5-bromopyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (xii) (200 mg, 0.50 mmol) in 1,4-dioxane (10 mL). To this was added 2,6-difluorobenzamide (235.5 mg, 1.50 mmol), followed by addition of K3PO4.H2O (500 mg, 1.48 mmol). CuI (11.7 mg, 0.06 mmol) was then added to the mixture, followed by ethane-1,2-diamine (EDA) (3.2 mg, 0.05 mmol). The resulting solution was allowed to stir for 45 minutes under reflux then diluted with 50 mL of H2O and extracted three times with 300 mL of EtOAc. The organic layers were combined then dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system to provide the final product methyl 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (10 mg, 4% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[H][H].[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][C:16]=1[Cl:23])=[O:13]>CN(C)C=O>[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:17][C:16]=1[Cl:23])=[O:13]
Reactant: CC(C)(C)C(=O)Oc1ccc(CBr)cc1Cl
Reactant: [H][H]
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1ccc(Cn2nccn2)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A mixture of 2.26 g of 2H- 1,2,3-triazole, 1.31 g of sodium hydride (60% oil dispersion) and 100 ml of anhydrous N,N-dimethylformamide was stirred at 60° to 70° C. under a nitrogen atmosphere for 2 hours. After the evolution of hydrogen gas ceased, the mixture was cooled to 10° C. To this mixture was added dropwise an anhydrous N,N-dimethylformamide (150 ml) solution of 10 g of 4-bromomethyl-2-chlorophenyl 2,2-dimethylpropanoate at room temperature under stirring over 1 hour, and the mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1([CH3:28])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:26]=O)[CH:22]=2)[O:17]1.N1CCCCC1>O>[CH3:15][C:16]1([CH3:28])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:26]=[C:9]3[C:8]4[C:12](=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=4)[NH:11][C:10]3=[O:14])[CH:22]=2)[O:17]1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: O
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
A mixture of 6-acetamido-2-oxindole (285 mg), 2,2-dimethylchroman-6-carboxaldehyde (285 mg) and piperidine (0.2 ml) was stirred at 90° C. overnight. The reaction mixture was cooled and diluted with 20 ml of water. The sticky solid which formed was filtered and chromatographed (2% ethanol in ethyl acetate) to give 240 mg (44%) of N-[3-(2,2-dimethylchroman-6-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-6-yl]acetamide as an orange red solid.
Reaction SMILES: NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1.C(OC([NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36])=O)C1C=CC=CC=1.CCO>CCOC(C)=O>[NH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1cccc(OCCCNC(=O)OCc2ccccc2)c1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OCCCN)c1

Procedure:
Following the procedure described for methyl 3-(4-aminophenyl)cyclopentanecarboxylate, replacing methyl 3-(4-nitrophenyl)cyclopentanecarboxylate (Intermediate 84 (i)) with methyl 3-(3-{[(benzyloxy)carbonyl]amino}propoxy)benzoate and using EtOAc as solvent instead of EtOH the title compound was obtained; 1H NMR δ 1.77-1.83 (2H, m), 2.70 (2H, t), 3.86 (3H, s), 4.09 (2H, t), 7.21-7.23 (1H, m), 7.43 (2H, t), 7.54 (1H, d); MS m/e MH+ 210.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[N:27]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:24])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NCCCN1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NCCCN3CCOCC3)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using 3-morpholin-4-yl-propylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 10%) which was obtained as an off-white solid. MS: m/e=472.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of p-aminobenzoic acid (5.0 g, 36 mmol) and HBTU (14 g, 36 mmol) in DMF (50 mL, 600 mmol) at 0° C. were added N,N-diisopropylethylamine (19 mL, 110 mmol) and 4-(trifluoromethyl)benzylamine (6.2 mL, 44 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo (8.2 g, 70%).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CO>[C:20]([NH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](NC(C)=O)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-3 (155 mg) in methanol (10 mL), was added acetic anhydride (30 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo and chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (153 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@@H:11]([CH3:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:31]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[C@H:34]([CH3:39])[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:47]([O-:50])([OH:49])=[O:48].[Na+]>O1CCOCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:47](=[O:48])[O:49][C:25]([CH3:30])([CH3:26])[CH3:24])[C@@H:11]([CH3:16])[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:40]([N:31]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:47](=[O:48])[O:50][C:2]([CH3:7])([CH3:3])[CH3:1])[C@H:34]([CH3:39])[CH2:33]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@H]1N
Reactant: O=C([O-])O
Reactant: C[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@@H]1N
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To (1S,3S ,4S)—N1,N1-dibenzyl-3-methylcyclohexane-1,4-diamine/(1R,3R,4R)—N1,N1-dibenzyl-3-methylcyclohexane-1,4-diamine (1.851 g, 6 mmol) in dioxane (200 mL) and saturated aqueous NaHCO3 solution (100 mL) was added BOC-anhydride (2.438 mL, 10.50 mmol), dissolved in dioxane (˜5 mL). The resulting white suspension was stirred vigorously for 18 hr. The mixture was extracted with DCM (4×300 mL) and EtOAc (1×100 mL). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered of and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 120 g, DCM/MeOH= 100/0 to 95/5]. Fractions containing product were combined, concentrated in vacuo providing tert-butyl (1S,2S,4S)-4-(dibenzylamino)-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-(dibenzylamino)-2-methylcyclohexylcarbamate. Yield: 778 mg. LCMS (m/z): 409.2 [M+H]+; Retention time=0.84 min.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C@@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1)=[N+:20]=[N-:21]
Reactant: CCC(CC)COc1cccc(C[C@H](O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC(CC)COc1cccc(C[C@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol with sodium azide following the method used in Example 6 gave (S)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(F)c(Cl)c1
Yield: 88 %

Procedure:
To 130 ml. of toluene was added, with stirring, 24.0 g. (0.165 mole) of 3-chloro-4-fluoroaniline and 13.5 ml. (0.166 mole) of pyridine. The resulting solution was cooled to ca 0° C. and 13.2 ml. (0.166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml. of 1N hydrochloric acid, followed by 100 ml. of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate, and then it was concentrated in vacuo to give 32.6 g. (88% yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.