Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.C(OC([C:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])=O)C>O1CCOCC1>[O:12]=[C:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(CC2CCCC2=O)cc1
Yield: 93.3 %

Procedure:
Into a mixture of 20 ml of 47% hydrobromic acid and 15 ml of dioxane was dissolved 9.2 g of ethyl 4-(1-ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenylacetate and the solution was refluxed for 6 hours. The solvent was then removed by distillation from the reaction mixture, the residue was poured into ice-water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, the solvent removed by distillation to give an oily substance, which was subjected to a vacuum distillation to yield 6.0 g of an oily product, b.p. 185°-195° C. at 0.7 mm Hg (bath temp.).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:25]([Zn]C#N)#[N:26]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([C:25]#[N:26])=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: N#C[Zn]C#N
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C#N)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 140 °C
Yield: 63.9 %

Procedure:
In a heavy-walled sealed tube with a stir bar were added (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.010 mmol), and dicyanozinc (0.012 g, 0.10 mmol) in DMA (1.2 mL). The tube was sealed, flushed with argon, and heated under microwave irradiation at 140° C. for 90 min. Ice water (10 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (4 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (EtOAc/Hexanes) to give the title compound (0.011 g) as a white solid. LCMS m/z=338.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.8 and 3.5 Hz, 1H), 1.26-1.33 (m, 1H), 1.43 (s, 6H), 2.27-2.35 (m, 1H), 2.79-2.86 (m, 1H), 2.92 (d, J=16.5 Hz, 1H), 3.02 (dd, J=16.7 and 6.4 Hz, 1H), 3.71 (s, 2H), 6.88-6.94 (bs, 1H), 8.03-8.09 (m, 2H), 8.74-8.77 (m, 1H).
Reaction SMILES: C(OC(NC1C(=O)N2C(C)(C(O)=O)CCC2=NC=1)=O)C1C=CC=CC=1.C([O:30][C:31]([C:33]1([CH2:54][CH:55]=[CH2:56])[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)=[O:32])(C)(C)C>>[CH2:54]([C:33]1([C:31]([OH:32])=[O:30])[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)[CH:55]=[CH2:56]
Reactant: C=CCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: C=CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 86.3 %

Procedure:
According to the procedure for the preparation of intermediate 19b, intermediate 20a (127 mg, 0.298 mmol) was deprotected to afford 95 mg (86%) of intermediate 20b. MS (ESI) 368.2 (M−H+).
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>C1COCC1>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 2 h
Yield: 126.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (5.0 ml, 15.0 mmol) was added dropwise to a solution of 4-iodo-1-trityl-1H-imidazole (4.44 g, 10.2 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1, 17:3, and 4:1 hexane:ethyl acetate as the eluant to yield 7.72 g of impure 4-(tributylstannyl)-1-trityl-1H-imidazole as a yellow solid. Method [7] Retention time 10.89 min by HPLC (MH+ 601).
Reaction SMILES: [C:1]1(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:18]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: OCCO
Reactant: O=C1CCCCCCCC(=O)CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCC2(CCCCCCC1)OCCO2

Procedure:
To a solution of 44.0 g (175 mmol) of 1,9-cyclohexadecanedione in 125 ml of toluene is added 13.1 g (210 mmol) of ethylene glycol and 500 mg (2.5 mmol) of p-toluenesulphonic acid. The mixture is then heated with a water separator until visible amounts of water are no longer eliminated. Washing with sat. NaHCO3 solution is then carried out, the phases are separated, the organic phase is dried over Na2SO4, filtration is carried out, and the solvent is removed on a rotary evaporator. This gives 57.7 g of a solid comprising 3 components having the following GC content: 1,9-cyclohexadecanedione (33.7%); 1,4-dioxaspiro-[4.15]-eicosan-13-one (52.5%); 1,4,14,17-tetraoxadispiro-[4.7.4.7]-tetracosane (13.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]>COC(OC)N(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:22])[C:10]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])=[CH:10][N:11]([CH3:19])[CH3:12]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1cc(Cl)ccc1Cl
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1cc(Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Yield: 1541.5 %

Procedure:
A solution of 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (0.10 g, 0.30 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (8 mL) was heated at reflux for 2 hours. The resultant mixture was then concentrated. Purification by flash column chromatography afforded 2-(3-(2,5-dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione as a solid (0.90 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N)c(Cl)cc1C#N
Temperature: 65 °C
Yield: 78.6 %

Procedure:
To 5-chloro-2-methyl-4-nitrobenzonitrile (192 mg, 1 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (903 mg, 4 mmol) and the mixture was heated to 65° C. for 5 h. DCM (10 mL) and 2M NaOH(aq) (10 mL) were added, and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 4-amino-5-chloro-2-methylbenzonitrile (131 mg, 81%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=163 at 3.37 min. 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.52 (s, 1H), 4.21 (br s, 2H), 3.84 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].N1C=CC=CC=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[N:18]1([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1Cl)N1CCOCC1
Reaction time: 0.25 h

Procedure:
To a solution of a 2-chlorobenzene sulfonyl chloride (10 g, 47.4 mmol) in DCM (100 ml) cooled to 0° C. was added pyridine (5.7 ml, 71.1 mmol) and morpholine (6.2 ml, 71.1 mmol) dropwise. Stirring was continued for 15 minutes after which time no sulfonyl chloride was evident by LC-MS. The reaction was quenched by the addition of 2N HCl, washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound without need for additional purification. (11.2 g, 100%). δH (400 MHz, DMSO-d6) 7.97 (1H, dd, 7.8, 1.5 Hz), 7.66-7.77 (2H, m), 7.58 (1H, ddd, 8.1, 6.7, 1.8 Hz), 3.57-3.64 (4H, m), 3.11-3.18 (4H, m); TR=1.25 min.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:39]1C=CC=C[N:40]=1)CCC>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[N:22]=[CH:23][N:40]([CH3:39])[CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc2cc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: Cc1cc2cc(-c3cn(C)cn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-4-yl)naphthalen-2-yl)acetic acid (64) was prepared in a similar fashion to compound 63 with the substitution of 1-methyl-4-(tributylstannyl)-1H-imidazole for 2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H28ClN2O3: 463.98; found: 463.86. 1H-NMR: 400 MHz, (CD3CN) δ: 6.46 (br s, 1H); 8.24 (br s, 1H); 7.73 (br s, 1H); 7.65 (s, 1H); 7.62-7.51 (m, 4H); 7.36-7.25 (m, 2H); 5.21 (s, 1H): 3.85 (s, 3H); 2.56 (s, 3H); 0.97 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[N:6][N:7]2[C:12](I)=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:12]1[N:7]2[N:6]=[CH:5][C:4]([N:3]([CH2:14][CH3:15])[CH2:1][CH3:2])=[C:8]2[CH:9]=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCN(CC)c1cnn2c(I)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCN(CC)c1cnn2c(-c3ccc(Cl)cc3Cl)cccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of 3-diethylamino-7-iodopyrazolo[1,5-a]pyridine (0.20 g, 0.63 mmol) and Pd(PPh3)4 (0.037 g, 0.03 mmol) in DME (5.0 mL) was stirred at room temperature for 10 minutes then treated with 2,4-dichlorophenylboronic acid (0.19 g, 1.27 mmol) and 2M Na2CO3 (3.0 mL). The reaction was heated at 80° C. for 16 hours and cooled down to room temperature. Additional Pd(PPh3)4 (0.037 mg, 0.03 mmol) and 2,4-dichlorophenylboronic acid (0.19 g, 1.27 mmol) were added and heating was continued at 80° C. for 2 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic solutions was washed with brine, dried over MgSO4, and concentrated in vacuo to dryness. The residue was subjected to column chromatography (5% ethyl acetate/hexane) to give 0.17 g (79%) of a light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.66–7.63 (m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.14–7.09 (m, 1H), 6.71 (d, J=6.7 Hz, 1H), 3.15 (q, J=7.1 Hz, 4H), 1.09 (t, J=7.1 Hz, 6H); IR (diffuse reflectance) 2968, 2935, 2814, 1487, 1461, 1377, 1334, 1314, 1149, 1096, 921, 881, 867, 827, 791 cm−1; MS (EI) m/z 333 (M+); Anal. Calcd for C17H17Cl2N3: C, 61.09; H, 5.13; N, 12.57. Found: C, 60.97; H, 5.02; N, 12.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH2:13])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc([C@H](C)N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1cc(OC)cc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3,5-dimethoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 563 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: Clc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1c(Cl)ccc2[nH]c3ccccc3c12
Yield: 86.4 %

Procedure:
Prepared from 3-chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.060 g, 0.22 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.10 g, 0.48 mmol) according to the procedure used for Example 2 without heating to give 0.092 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2oc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of 33 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 35 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid as a colorless resinous compound. ESI+: 624
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCCC1.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]>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([N:28]2[CH2:27][CH2:26][CH:25]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH2:20][CH2:21]3)[CH2:30][CH2:29]2)=[CH:3]1
Reactant: COc1ccccc1N1CCN(C2CCNCC2)CC1
Reactant: Brc1csc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C2CCN(c3csc4ccccc34)CC2)CC1

Procedure:
A solution of 3-bromo-benzothiophene (commercially available, 0.232 g) and 4-(4-(2-methoxyphenyl)piperazin-1-yl)piperidine (Step 2, 0.30 g) in tetrahydrofuran was added sodium tert-butoxide (0.15 g), tris-(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.10 g) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (CYMAP, 0.01 g). The reaction was heated at reflux for 24 hours. It was then cooled and filtered through celite. The filtrate was evaporated and purified by flash chromatography on silica gel using ethyl acetate/hexanes to give 0.10 g of the desired product. MP: 156-158° C.; MS (ES) m/z (relative intensity): 408 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C@H:17]4[CH2:20][C@H:19](O)[CH2:18]4)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]4[CH2:20][C@H:19]([N:58]=[N+:59]=[N-:60])[CH2:18]4)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc([C@H]2C[C@H](O)C2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc([C@H]2C[C@@H](N=[N+]=[N-])C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of trans-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]cyclobutanol (step 8, 572 mg, 1.6 mmol), triphenylphosphine (623 mg, 2.4 mmol) and diphenylphosphoryl azide (DPPA) (655 mg, 2.4 mmol) in THF (8 mL) was added diethyl azodicarboxylate (415 mg, 2.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h, then the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 506 mg (83%) of the title compound as colorless solids: MS (EI) m/z: 385 (M+); 1H-NMR (CDCl3) δ 7.84 (1H, br.s), 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.17 (1H, br.s), 3.98-3.88 (1H, m), 3.37-3.25 (1H, m), 2.89-2.75 (2H, m), 2.77 (2H, q, J=7.6 Hz), 2.34-2.23 (2H, m), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCO1
Product: O=C1CCCN1Cc1ccccc1

Procedure:
6.97 g (0.06M) of γ-butyrolactone is mixed with 6.97 g (0.065 M) of benzylamine and heated at 190° for 24 hours. Excess benzyl amine and water was distilled off and the residue was distilled to obtain 7.4 g (70%); b.p. 125°-130°/1 mm.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[C:7]1=[O:24].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:23][C:12]1([CH2:11][N:8]2[CH2:9][CH2:10][NH:6][C:7]2=[O:24])[O:16][C:15]2=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]2[CH2:13]1
Reactant: COc1ccc(CN2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)C2=O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CN2CCNC2=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 1-(2,4-dimethoxybenzyl)-3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)imidazolidin-2-one prepared in Example 594 (100 mg, 0.24 mmol), trifluoroacetic acid (2 ml) and methylene chloride (2 ml) was stirred at room temperature for 1 hour. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added for neutralization. The resulting solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether to afford 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)imidazolidin-2-one (50 mg, yield 78%) as a white powder.