Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]Cl>C(O)C>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: CN(C)CCCl
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCN(C)C)CC4)CO6)cc3)c(C)c2)o1
Yield: 13.1 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477, 500 mg, 0.99 mmole) in ethanol (40 ml) was treated with sodium carbonate (419 mg, 3.9 mmole) and 2-dimethylaminoethyl chloride hydrochloride (287 mg, 1.98 mmole) and heated under reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-8% methanol/chloroform to afford the title compound as a yellow/beige solid (75 mg, 13%). This was converted to its hydrochloride salt and crystallised from acetone/ether m.p. 246-248° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:15]2[C:16]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)[CH:13]=[CH:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccccc1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: c1ccc(COc2ccc3ccn(-c4ccccc4)c3c2)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-(benzyloxy)-1H-indole and iodobenzene: ESMS m/e: 300.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[Cl:3][C:4]1[N:5]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Reactant: ClCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COCCOCc2ccccc2)c1Cl
Yield: 38.4 %

Procedure:
NaH (0.033 g, 1.52 mmole, 90% oil dispersion) was added to a stirred suspension of 2,4,5,6,7-pentachlorobenzimidazole (14) (0.3 g, 1.03 mmole) in dry CH3CN (35 mL) under a N2 atmosphere. The solution was stirred until H2 evolution had ceased and a clear solution was obtained (20 min.). (2-Benzyloxyethoxy)methylchloride (0.31 g, 1.54 mmole) in CH3CN (10 mL) was then added dropwise. The reaction mixture was stirred for an additional 15 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil. The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions followed by crystallization from hexane:EtOAc afforded 0.18 g (38.4%) of blocked product: m.p. 95° C.; 1H NMR (CDCl3): d 7.22-7.34 (m, 5H, C6H5), 5.93 (s, 2H, C-1'), 4.47 (s, 2H, CH2C6H5), 3.70-3.73 (m, 2H, C-3'), 3.45-3.57 (m, 2H, C-4'), 1.83 (s, 3H, Ac). Anal. Calcd. for C17H13NCl5O2 : C, 44.88; H, 2.86; N, 6.16. Found: C, 44.95; H, 2.59; N, 6.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH3:14])[CH:10]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:15][CH:10]1[CH:11]([O:13][CH3:14])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: [H][H]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC1CN(C(=O)OC(C)(C)C)CC1N
Yield: 81.4 %

Procedure:
0.13 g of 20% w/w palladium-on-carbon was added to a solution of 0.99 g (0.0025 mole) of 1-t-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine dissolved in 15 ml of ethanol, and the mixture was stirred vigorously at 50° C. for 4 hours in an atmosphere of hydrogen. The catalyst was filtered off from the reaction mixture, after which the filtrate was concentrated by evaporation under reduced pressure, to give 0.44 g of 3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[O:21])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[O:21])=[C:9]([CH:32]([CH3:33])[CH3:34])[N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc2n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1

Procedure:
General Procedure S. A solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 124, 300 mg, 0.65 mmol) in EtOAc (5 ml) was treated with 10% Pd—C (6.8 mg, 0.065 mmol) and hydrogen gas under atmospheric pressure at room temperature for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[O:20]=[C:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(CCCc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 14 h
Yield: 72 %

Procedure:
(Method J15A) A solution of 4-phenyl-butyric acid (1/95) (6.570 g, 40 mmol) and N-hydroxysuccinimide (4.830 g, 42 mmol) in acetonitrile (100 ml) was treated with N,N′-dicyclohexylcarbodiimide (8.650 g, 42 mmol) at 0° C. The resulting suspension was allowed to stand for 14 hours at 4° C., the precipitate was filtered off and washed with ethyl acetate (3×30 ml). The solvents were removed in vacuum and the residue was crystallized from isopropanol (50 ml) to give the activated ester 15/95 (7.520 g, 72%) as colorless crystals. 1H NMR (DMSO-d6, HMDSO) δ: 1.78-2.20 (2H, m); 2.53-3.00 (8H, m); 6.84-7.67 (5H, m); 10.80 (1H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1
Reactant: OCCON=Cc1ccc2ccccc2c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc4ccccc4c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 69.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 430 mg of 2-(2-naphthylmethyleneaminooxy)ethanol (prepared as described in Preparation 7), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 712 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[C:9]=2[CH:10]=1>N.CO.[Ni]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][NH2:12])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C#N)cccc2[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc2c(CN)cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of 2-methyl-1H-indole-4-carbonitrile (408 mg, 2.61 mmol) in NH3/MeOH (7 M, 20 mL) was added Raney nickel (100 mg). The mixture was stirred under hydrogen at 1 atmosphere at RT for 3 h. The mixture was filtered with Celite® and the filtrate was concentrated in vacuo to afford (2-methyl-1H-indol-4-yl)methanamine (105) as a yellow solid (398 mg, 95.1%). MS (ESI): m/z=144.3 [M−16]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 28.2 %

Procedure:
A solution of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.5 g, 4.5 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.12 g, 5.0 mM) in 25 mL of toluene was stirred between 80-90° C. for 6 h. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 420 mg (28%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 3.8 (s, 3H). IR (CHCl3, cm−1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11](=[O:16])[NH:10][C@@H:9]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@H:8]3[C:7]=2[CH:6]=1)[CH3:4].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>C1COCC1>[CH2:3]([C:5]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11](=[O:16])[N:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C@@H:9]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:19][C@H:8]3[C:7]=2[CH:6]=1)[CH3:4]
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CC(=O)OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of sodium hydride (33 mg of 60% dispersion in mineral oil, hexane-washed, 0.87 mmol) in 4 mL of THF was added (±)-trans-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 74, Part A (191 mg, 0.58 mmol) in 10 mL of THF. The resulting mixture was stirred at ambient temperature for 30 min, at which time gas evolution has ceased. Then there was added methyl bromoacetate (0.082 mL, 0.87 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction was quenched with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 15-25% EtOAc/hexane) to afford 180 mg (77%) of the title compound. LRMS (ESI): 403.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:16])[CH2:14][OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCC(C)(C)c1ccc(C=C(C)CO)cc1
Agent: [Pd]
Product: CCC(C)(C)c1ccc(CC(C)CO)cc1

Procedure:
70 g of 3-(p-tert.amyl-phenyl)-2-methyl-allyl alcohol are dissolved in 700 ml of alcohol, treated with 7 g of 5% palladium/carbon and hydrogenated until the hydrogen uptake has been completed. The catalyst is subsequently filtered and the alcohol is evaporated. By distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propanol of boiling point 124°-129° C./0.04 Torr.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:39][C:4]1[CH:3]=[C:2]([C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C@@H:28]1[C@H:30]([C:31]([OH:33])=[O:32])[C:29]1([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)cc3)cc2F)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (4-fluorophenyl)boronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.5 Hz, 1H), 8.12-8.09 (m, 1H), 7.84-7.81 (m, 1H), 7.76-7.72 (m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.58-7.53 (m, 1H), 7.51-7.46 (m, 2H), 7.34-7.30 (m, 2H), 7.28 (d, J=8.9 Hz, 1H), 7.25-7.23 (m, 1H), 7.16-7.10 (m, 3H), 6.92-6.88 (m, 1H), 5.49-5.38 (m, 4H), 2.34 (d, J=8.2 Hz, 1H), 2.14 (d, J=8.2 Hz, 1H), 1.31 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH2:35])=[CH:26]1>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:26]1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1csc2ccccc12
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3csc4ccccc34)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 476.4. HPLC (Condition A), Rt: 4.82 min (HPLC purity: 77.5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>O1CCOCC1.CO>[CH3:12][CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,1-dimethylethyl 5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 4, 512 mg, 1.11 mmol) and 4M HCl in dioxane (20 ml) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to give a pale yellow solid, which was redissolved in MeOH. This solution was applied to an SCX-3 cartridge (10 g), and the product eluted with 1% NH3 in MeOH. Concentration gave a yellow oil, that became a solid on standing overnight (366 mg, 91%). 1H NMR (400 MHz, d6-DMSO) δ 8.38 (1H, d), 8.32 (1H, dd), 7.94 (1H, d), 7.32-7.17 (2H, m), 7.13 (1H, m), 4.80 (1H, sept), 4.10 (2H, s), 3.20-3.14 (4H, m), 1.48 (6H, d); m/z (ES) 361 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CCO)cc1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(CCOCCCCCBr)cc1
Yield: 76.1 %

Procedure:
4-(methylthio)benzeneethanol (7.44 g) and 1,5 dibromopentane (30.48 g) were stirred rapidly at room temperature with TAB (1.0 g) and 12.5M aqueous sodium hydroxide (35 ml) for 64 h. The mixture was diluted with water (170 ml), extracted with ER (3×200 ml), and the combined organic extracts were washed consecutively with water (170 ml) and brine (170 ml), dried and evaporated. The residual oil (29.29 g) was purified by FCC eluting with ER-CX (0:100→3:97) to give the title compound as a colourless oil (10.68 g). T.l.c. (ER-CX 1:79) Rf 0.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (171 mg, 0.44 mmol) (from example 49, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. Sodium hydroxide (0.117 mL, 0.44 mmol) dissolved in water (0.200 mL) was added dropwise and the solution stirred for 20 min. Hydroxylamine (50% by weight in water, 0.024 mL, 0.44 mmol) was then added and stirring was continued for 3.5 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (2.290 mL, 13.74 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated in vacuo and DCM (50 mL) and water (50 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 19 mL/min. (2S,4S)-Methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (49.0 mg, 31.2%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.58-1.70 (m, 1H), 1.85-2.06 (m, 2H), 2.60 (d, 1H), 2.73-2.96 (m, 2H), 3.73 (s, 3H), 4.04-4.44 (m, 1H), 5.42-5.78 (m, 2H), 6.92-7.05 (m, 2H), 7.38 (t, 1H). MS m/z 355 (M+H)+
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:33]1[CH2:35][CH2:34]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[CH:20]=[C:19]1[CH:33]1[CH2:34][CH2:35]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-cyclopropyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 266, 2.64 g, 5.18 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an orange foam (2.33 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(C)c1OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1OCc1ccccc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-(benzyloxy)-3-methylbenzoate (40 g, 156.07 mmol, 1.00 equiv) and tetrahydrofuran (300 mL). This was followed by the addition of LiBH4 (15.6 g, 5.00 equiv) in several batches with stirring. The resulting solution was stirred overnight at 60° C. The reaction was then quenched by the addition of 1.5 L of water/ice. The resulting solution was extracted with 2×800 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×1000 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 30 g (84%) of [2-(benzyloxy)-3-methylphenyl]methanol as light brown oil. 1H NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 4.55-4.57 (m, 2H), 4.83 (s, 2H), 5.05-5.09 (m, 1H), 7.02-7.51 (m, 8H).
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OP([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+]>C1COCC1>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1ccc(/C=C/C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 4-pentylbenzaldehyde (25 g, 142 mmol) and ethyl diethylphosphonoacetate (30 ml, 150 mmol) in THF was added sodium hydride (60%, 6 g, 150 mmol), and the mixture was stirred at room temperature for 12 hours and poured into ice water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure to give the object compound as an oily substance. 39.6 g, (yield 100%)