Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2C=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1.ClCCCl>[CH3:34][N:33]1[C:31](=[O:32])[CH:19]2[CH:18]([CH2:22][CH:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:25]=3)[CH2:20]2)[C:16](=[O:17])[NH:15][C:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH:11]([CH2:12]2)[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: C1COCCN1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3ccnc(N4CCOCC4)n3)CC2C1=O
Temperature: 150 °C

Procedure:
Compound 10f (31 mg, 0.052 mmol) and morpholine (0.1 ml) in THF was left at ambient temperature for 20 hrs, volatiles were stripped of and the residue was dissolved in DCE (15 ml) to which Hoyeda-Grubbs II catalyst (7 mg) was added. The mixture was heated in a microwave oven at 150° C. for 10 min under an atmosphere of nitrogen, then concentrated to dryness and purified by column chromatography on silica gel eluted with DCM-MeOH 2% followed by prep. HPLC-MS-UV to give pure title compound, (4.7 mg), (M+H)+616.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([O:25]COC)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCOC1CCN(c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc(Oc2ccc(N3CCC(O)CC3)cc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-(methoxymethoxy)piperidine (5.50 g, 11.0 mmol) in ethanol (110 mL) was added 2 M hydrochloric acid (55 mL, 110 mmol), and the resulting solution was stirred for 8 hours at 60° C. To the resulting reaction solution was added potassium carbonate (16 g) at room temperature, and the solvent was evaporated under reduced pressure. Water (200 mL) was added to the residue. Precipitated crystals were collected by filtration, to thereby yield 5.0 g of the title compound.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:34]=[CH:33][C:22]2[O:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:21]=2[CH:20]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10](=[O:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:34]=[CH:33][C:22]2[O:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:21]=2[CH:20]=1
Reactant: O=C(CCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1CO2)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1CO2)NO

Procedure:
400 mg (0.845 mmol) 8-(11-Oxo-6,11-dihydro-dibenzo[b,e]oxepin-2 yloxy)-octanoic acid benzyloxyamide in 50 ml methanol was hydrogenated in the presence of palladium on calcium carbonate at ambient temperature and pressure. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by column chromatography (methanol/water 75:25). There was thus obtained 90 mg (28%) of the title compound as an amorphous solid. MS: 382 (M−H+); 384 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COC(CBr)OC
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C=O)c1OCC(OC)OC

Procedure:
A heterogeneous solution of 31 g (0.134 mol) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde, 28 g (0.166 mol) of 2-bromo-1,1-dimethoxyethane and 49 g (0.150 mol) of caesium carbonate in 150 ml of dimethylformamide is heated at 160° C. for 3 hours. After returning to room temperature, the mixture is filtered. The filtrate is then evaporated under reduced pressure. The solid so obtained is taken up in 250 ml of dichloromethane and filtered again. The homogeneous solution is then washed twice with 200 ml of 0.1N hydrochloric acid each time and subsequently with 200 ml of a saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and subsequently evaporated under reduced pressure, yielding the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14]I)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].II.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH2:47]([O:54][C:55]1[CH:60]=[C:59](Br)[CH:58]=[CH:57][C:56]=1[CH3:62])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>[Zn].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].O.CCOC(C)=O.CN(C=O)C>[CH2:47]([O:54][C:55]1[CH:60]=[C:59]([CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH3:13])=[O:11])[CH:58]=[CH:57][C:56]=1[CH3:62])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(Br)cc1OCc1ccccc1
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
Dry DMF (100 mL) was added to zinc dust (7.00 g, 108 mmol) in a flame dried flask under N2. (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (9.7 g, 29 mmol) and a catalytic amount of iodine (0.7 g, 2 mmol) were added. The mixture was stirred at ambient temperature for 0.5 h, then Pd2(dba)3 (1.9 g, 2.0 mmol), S—Phos (1.6 g, 4.0 mmol) and 2-(benzyloxy)-4-bromo-1-methylbenzene (7.40 g, 27.0 mmol) were added. The reaction mixture was stirred at 60° C. for 6 h then cooled to ambient temperature. EtOAc (500 mL) and water (500 mL) were added and the organic phase was separated, washed with water (300 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=10:1) to afford (S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (4.0 g, 37% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[O:27][C:28]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12.NC1ON=C2C=CC=CC=12>>[N:26]1[O:27][C:28]([NH:35][C:36]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:37])=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1onc2ccccc12)Oc1ccccc1
Agent: Cl
Agent: Nc1onc2ccccc12
Product: O=C(Nc1onc2ccccc12)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl benzo[c]isoxazol-3-ylcarbamate (113 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-2,1-benzisoxazole) were combined to provide the title compound (168 mg). MS (APCI 10V) AP+ 495.2, 376.2, 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.56 (dt, J=50.88, 5.69 Hz, 4H) 3.66 (dt, J=37.31, 5.71 Hz, 4H) 6.48 (s, 1H) 6.98-7.07 (m, 2H) 7.13 (ddd, J=8.75, 0.68, 0.56 Hz, 1H) 7.16 (d, J=7.77 Hz, 1H) 7.30 (ddd, J=8.05, 6.80, 1.16 Hz, 1H) 7.41 (t, J=7.99 Hz, 1H) 7.49-7.66 (m, 2H) 7.85 (dt, J=8.13, 1.03 Hz, 1H) 8.09 (ddd, J=8.72, 2.67, 0.38 Hz, 1H) 8.43 (td, J=1.82, 0.93 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Br[CH2:33][O:34][C:35](=[O:37])[CH3:36].CC([O-])(C)C.[K+].O>CN(C=O)C>[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)(=[O:37])[CH3:36]
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Reactant: CC(=O)OCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
To a solution of 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (50 mg, 0.12 mmol, Example 137) in DMF (5 mL) was added acetic acid bromomethyl ester (20 mg, 0.12 mmol), t-BuOK (27 mg, 0.24 mmol) and KI (40 mg, 0.24 mmol) at 0° C., then the mixture was stirred for 72 hr at rt, H2O was added, extracted with EA, dried, concentrated and purified by HPLC to give the title compound (5 mg, 8.6%). 1H NMR (300 MHz, CD3OD): δ 2.13 (3H, s), 5.38 (2H, s), 6.55 (2H, s), 6.97-6.98 (1H, m), 7.23-7.49 (7H, m), 7.85 (1H, s), 8.10 (1H, d, J=6.0 Hz), 8.28 (1H, m), 8.64 (1H, m). [M+H] Calc'd for C25H19ClFN7O2, 504. Found, 504.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:25][OH:26]>CCCCCCC.O>[Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH2:18][O:26][CH3:25])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Reactant: CO
Solvent: O
Solvent: CCCCCCC
Product: COCCS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a 0° C. solution of 3-chloro-6-(4-(vinylsulfonyl)piperazin-1-yl)-2,2′-bipyridine (68 mg, 0.190 mL) in methanol (1.8 mL), Na metal (47.5 mg, 2.05 mmol) washed in heptane was added and stirred for 15 min at 0° C. The reaction mixture was heated to 50° C. and stirred for 2 h and was cooled to RT, diluted with H2O (20 mL), extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by column chromatography (30 to 75% ethyl acetate/heptane) to obtain pure product (29 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=4.80 Hz, 1 H) 7.92 (td, J=7.71, 1.77 Hz, 1 H) 7.75 (d, J=9.09 Hz, 1 H) 7.69 (d, J=7.83 Hz, 1 H) 7.44 (ddd, J=7.52, 4.86, 1.01 Hz, 1 H) 7.00 (d, J=8.84 Hz, 1 H) 3.57-3.70 (m, 8 H) 3.35 (t, J=5.94 Hz, 2 H) 3.30 (s, 3 H) 3.22-3.27 (m, 2 H). LCMS (M+H)+: 397.0.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[CH:28][C:27]=2[CH:38]=1>CCOCC>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:36])[CH3:37])[C:32]([O:14][CH2:13][C:9]3[NH:10][CH:11]=[CH:12][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:33])=[CH:28][C:27]=2[CH:38]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about15 ml), under nitrogen, is added a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in either. The mixture is stirred for about 60 minutes and then quenched with saturated aqueous NaHCO3. The ether phase is washed with aqueous NaHCO3, water and brine, dried over sodium sulfate and solvent evaporated to give 3-benzylpyrrolylmethyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][OH:8].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[C:22]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=1[O:2][CH3:1])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenoxy)ethanol (5.5 g, 26 mmol) and pyridine (2.35 g, 30 mmol) in THF (140 mL) at 0° C. was acetyl chloride (2.33 g, 30 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuSO4 solution, brine, dried over MgSO4, and concentrated to give 2-(2-methoxy-4-nitrophenoxy)ethyl acetate as a yellow solid (6 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C@@H:10]2[O:13][C@@H:11]2[CH3:12])=[CH:5][CH:4]=1.[H-].[Na+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([CH2:25][N:8]([CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9](=[O:14])[C@@H:10]1[O:13][C@@H:11]1[CH3:12])=[O:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(CNC(=O)[C@@H]2O[C@@H]2C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2O[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.21 g of (2R,3R)-2,3-epoxybutyric acid p-methoxybenzylamide in 100 ml of THF is added dropwise to a mixture, stirred at 0° under an argon atmosphere, of 550 mg of sodium hydride dispersion (55-60% in oil) and 1.52 ml of bromoacetic acid tert.-butyl ester in 25 ml of THF. The reaction mixture is heated to room temperature and stirred for a further 1 hour (reaction monitored by thin-layer chromatography). Total reaction time: 90 minutes. The insoluble portions are filtered off and washed with THF and the combined filtrates are concentrated by evaporation. The resulting crude product is purified by chromatography over 150 g of silica gel (system: toluene, toluene/ethyl acetate 80:20). Concentration of the pure fractions by evaporation yields the amorphous title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:31][CH2:30][CH:21]3[N:22]([C:26](=O)[CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH:20]3[C:18]=2[CH:19]=1>O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:31][CH2:30][CH:21]3[N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH:20]3[C:18]=2[CH:19]=1
Reactant: CCC(=O)N1CCCC2c3cc(OC)ccc3OCC21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN1CCCC2c3cc(OC)ccc3OCC21
Temperature: 25 °C

Procedure:
To a suspension of 3.8 g of lithium aluminium hydride in 100 ml of tetrahydrofuran, 3.6 g of concentrated sulfuric acid is added dropwise at -5° to -10°, then 5.0 g of 9-methoxy-4-propionyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine is added slowly with stirring. The reaction mixture is allowed to warm to room temperature, stirred for 18 hours and finally heated under reflux for 1 hour. After cooling the reaction mixture is quenched with ethyl acetate, then treated with a small volume of water and 3N sodium hydroxide, filtered and concentrated in vacuo. The residue is redissolved in ethyl acetate and the ethyl acetate solution is washed with water, dried and evaporated to yield 9-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine. The starting material is prepared by treatment of 9-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine in the presence of two mole equivalents of powdered potassium carbonate in methylene chloride solution with 1 mole of propionyl chloride at room temperature overnight.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].I[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(CC(C)C)=O>C(O)C.O>[CH:1]1([S:7][C:21]2[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: Ic1cccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(SC3CCCCC3)cccc2c1
Temperature: 90 °C
Reaction time: 11 h
Yield: 68.9 %

Procedure:
33.5 g of cyclohexanethiol, 37.4 g of sodium ethoxide, and 70 g of 1-iodonaphthalene was dissolved in 1 l of ethanol in a reaction flask, in which the atmosphere was replaced with nitrogen. 3.2 g of tetrakis(triphenylphosphonium)palladium was added. The mixture was stirred for 11 hours at 90° C. Ethanol was condensed under reduced pressure and 1 l of methyl isobutylketone and 1 l of distilled water were added. The mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 1 l of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting solution was dried with anhydrous magnesium sulfate and filtered. After further drying using an evaporator, methyl isobutylketone was evaporated from the dried solution. The residual liquid was dried under reduced pressure and was purified by a silica gel column using n-hexane as a developing solvent. The n-hexane was evaporated under reduced pressure to obtain 46 g of 1-cyclohexylthionaphthalene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CC(C)(CO)n1cc(N)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 41.3 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (11.5 g) obtained in Step E of Example 103, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (7.1 g) obtained in Step H of Example 103 and acetic acid (2.6 mL) in ethanol (200 mL) was stirred in a sealed tube reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (6.9 g).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O-:9])=[O:8].[Na+:10].N1C(=[O:16])CC[C@@H]1C([O-])=O.[Na+]>>[OH2:6].[OH2:16].[OH2:6].[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O-:9])=[O:8].[Na+:10]
Reactant: O=C1CC[C@H](C(=O)[O-])N1
Agent: O=C1CC[C@@H](C(=O)[O-])N1
Agent: [Na+]
Product: O

Procedure:
A mixture of 85 mole % sodium L-pyroglutamate and 15 mole % sodium D-pyroglutamate crystallized in a manner analogous to Example 6. 12% of theory sodium L-pyroglutamate trihydrate was obtained at a concentration of 60% in the solution during cooling to -10° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[CH2:10][C:11]#[N:12]>>[CH2:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]#[N:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNCC1
Reactant: N#CCCl
Product: CCC1CCN(CC#N)CC1

Procedure:
The title compound was prepared according to general procedure G described in Scheme 3 from 4-ethylpiperidine and 2-chloroacetonitrile. The crude solution was used directly without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[O:23][CH:24]=1>>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:31]=[CH:32][C:27](/[CH:26]=[CH:25]/[C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]3[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)[CH:14]=[CH:13][CH:12]=3)[N:21]=2)=[CH:28][CH:29]=1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)cc1
Yield: 90.2 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (123 mg), 65% oily sodium hydride (24 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl)-1,3-oxazole (183 mg), the same reaction as Example 2 was carried out to yield the titled compound (248 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][C@@H:45]([CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:44]1>CN(C)C=O>[C:53]([O:52][C:51](=[O:57])[NH:50][CH2:49][C@@H:45]1[O:46][CH2:47][CH2:48][N:43]([C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH2:44]1)([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.432 g), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl(2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g).