Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.Cl>C(OCC)(=O)C>[OH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:12]=[C:11]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCO)CC1
Yield: 79.5 %

Procedure:
Combine tert-butyl 4-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (6.88 g, 14.84 mmol), tetrahydrofuran (136 mL) and 1 N aqueous hydrochloric acid (25 mL). Stir the reaction at room temperature overnight. Dilute with ethyl acetate and wash with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate. Extract the combined aqueous layers with 9:1 dichloromethane:isopropyl alcohol. Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a white solid (4.48 g, 79%). MS (ES) m/z=380 [M]+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:16][C:15]=1[C:23]([O:25]C)=O)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C-]#N.[Na+].O>CO>[CH3:1][NH:2][C:23]([C:15]1[S:16][C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:18][C:14]=1[NH:13][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:25]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 20 %

Procedure:
To a saturated solution of methylamine in MeOH (200 mL) in a screw top vessel was added methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate (13.6 g, 39.2 mmol) and NaCN (0.98 g, 20 mmol). The vessel was sealed and the reaction mixture was heated to 50° C. for 8 h. The resulting solution was poured into water (500 mL) and extracted with EtOAc. The organic layer was washed with water and a concentrated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexane) affording N-methyl-3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxamide (2.76 g, 20%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][C:6]=1[C:26]([OH:28])=[O:27])(=O)C.C(O)C.Cl>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:7][C:6]=1[C:26]([OH:28])=[O:27]
Reactant: CC(=O)Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 4.0 g. (0.011 mole) of 1-(4-acetamido-3-carboxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole, 50 ml. of ethanol, 10 ml. of water, and 2 ml. of conc. hydrochloric acid was heated under reflux under nitrogen for 4 hours, concentrated to 10 ml., diluted with 100 ml. of water, adjusted to pH 4 and filtered. Recrystallization of the collected solid from 75% ethanol gave 0.83 g. (23%) of crystals, m.p. 205.5°-206.5°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:41])[CH2:38][C:37](=[O:39])[O:36][C:35](=[O:40])[CH2:34]1.C(N(CC)CC)C>CS(C)=O>[CH3:32][C:33]([CH3:41])([CH2:38][C:37](=[O:39])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[CH2:34][C:35]([OH:40])=[O:36]
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CC(=O)O)CC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1
Yield: 55.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (46.2 mg, 0.107 mmol), 4,4-dimethyl-dihydro-pyran-2,6-dione (18.3 mg, 0.128 mmol) and triethylamine (30 uL, 0.214 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 3,3-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid as a white solid (34 mg, 55%). ES-MS calcd for C29H30F3N3O6 (m/e) 573.57, obsd 574 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.Cl>CO>[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: CN(C)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
Dimethyl-piperidin-4-yl-amine dihydrochloride (Aldrich, 2.0 g, 9.95 mmol) and 4-fluoro-nitrobenzene (Aldrich, 2.5 g, 17.7 mmol) were added to methanol (30 mL). The mixture was heated to 90° C. and stirred for 3.5 hours. The mixture was treated with 1 N HCl to pH=1 and then extracted with diethyl ether (2×10 mL). The aqueous layer was treated with saturated sodium carbonate to pH=10 and then extracted with methylene chloride (2×20 mL). The organic layer was dried with sodium sulfate and the solvent was removed to give the desired product. 1.25 g, 50%. MS (m+H)+: 250.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:26]([N:39]1[CH2:42][C:41](=O)[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH:26]([N:39]1[CH2:42][C:41](=[CH:4][O:5][CH3:6])[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (60% mineral oil dispersion, 0.10 g, 2.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added (methyoxymethyl)triphenylphosphonium chloride (0.80 g, 2.3 mmol) at 0° C. The mixture was stirred at 0° C. for 40 minutes, then a solution of 1-benzhydryl-azetidin-3-one (0.50 g, 2.1 mmol) in tetrahydrofuran was introduced at 0° C. The resulting mixture was refluxed for 2 hours. The reaction was quenched with water and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude oil was column chromatographed on silica gel (20% ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 0.29 g (52%) of the title compound as a light yellow solid, m.p. 56-58° C.
Reaction SMILES: Cl.Cl.[OH:3][C:4]([CH3:21])([CH3:20])[CH2:5][NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:16]2[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]3/[C:7]([NH:6][CH2:5][C:4]([OH:3])([CH3:21])[CH3:20])=[N:8][C:9](=[O:19])[S:10]/3)[CH2:14][CH2:15]2)=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: O=Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Cl)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of (5Z)-4-[(2-hydroxy-2-methylpropyl)amino]-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (2 mL) was added a solution of triethylamine (0.32 mL) and 4-chloro-2-(trifluoromethyl)benzaldehyde (117 mg) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (501 mg) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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 (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (82 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:10](=[O:30])[CH2:11][CH2:12][C:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)(C(O)=O)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(C)=O>[CH2:1]([O:8][N:9]([CH2:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:10](=[O:30])[CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC(Cc2ccc(C(=O)O)cc2)(C(=O)O)C(=O)O)c(OC)c1
Solvent: CS(C)=O
Product: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC(Cc2ccc(C(=O)O)cc2)C(=O)O)c(OC)c1
Temperature: 130 °C
Yield: 71.7 %

Procedure:
2-{3-[Benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2-(4-carboxyphenyl)methyl-malonic acid (9.30 g, 15.6 mmol ) was taken up in DMSO (10 mL). This solution was heated at 130° C. for 1.5 h. The reaction mixture was then allowed to come to room temperature. The solvent was then removed under reduced pressure. EtOAc was used as an azeotrope to remove the DMSO. The residue was partitioned between 50 mL of 10% KHSO4 and 100 mL of EtOAc. The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated to give 6.17 g of 4-[5-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-2-carboxy-5-oxopentyl]benzoic acid as an off white powder (76% yield). 1H NMR (CDCl3): d 0.88-0.96 (m, 2H), 1.26-1.91 (m, 2H), 2.02-2.32 (m,2H), 2.47-2.83 (m, 2H), 3.01-3.60 (m,2H), 4.70 (s, 1H), 7.14-7.29 (m,9H), 7.93-7.96 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].CSC.B.O.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CSC
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.6 %

Procedure:
78.78 g of 2-chloroisonicotinic acid are added, under argon, portionwise, to 300 mL of a 2M solution of dimethyl sulphide-borane in tetrahydrofuran. The reaction mixture is stirred for 17 hours at room temperature and then treated successively with 20 mL of water dropwise and 20 mL of 5N hydrochloric acid. 300 mL of ethyl acetate are then added, the phases are separated and the organic phase is washed with three times 100 mL of saturated sodium chloride solution, dried over magnesium sulphate and filtered. The filtrate is then concentrated under reduced pressure to give 68.6 g of 2-chloro-4-hydroxymethylpyridine in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:20]([O-:22])=[O:21])[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7].[CH2:23]([O:30][C:31]([NH:33][C@H:34]1[CH2:38][O:37][NH:36][C:35]1=[O:39])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:23]([O:30][C:31]([NH:33][C@H:34]1[CH2:38][O:37][N:36]([C:5]2([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)=[O:7])[CH2:4][CH:3]([O:2][CH3:1])[C:20](=[O:21])[O:22]2)[C:35]1=[O:39])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: COC(CC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC1CC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In 10 ml of dichloromethane was dissolved 896 mg of Compound (93). To the solution were added 680 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 593 mg of DCC, and the mixture was stirred at room temperature for one hour. Then, precipitating crystals were filtered off, and the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane--ethyl acetate (3:2) to give 723 mg of the subject Compound (94) as an oily product.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2[CH3:43])(=O)C1C=CC=CC=1.O(C)[Na].C(O)(=O)C>CO>[CH3:43][C:39]1[N:38]=[CH:37][N:36]=[C:35]2[C:40]=1[N:41]=[CH:42][N:34]2[C@@H:11]1[O:12][C@@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CO[Na]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1c (453 mg, 0.78 mmol) in MeOH (7 ml) at 5° C. is added dropwise 0.5 N NaOCH3 in MeOH (0.78 ml) over 5 min. After being stirred at room temperature for 2 h, the reaction solution is chilled to 5° C. and neutralized with glacial acetic acid. Pure 1d crystallized in two crops from this neutral solution as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:27][CH2:28][CH3:29])[N:7]2[N:30]=[C:31]([CH3:33])[N:32]=[C:6]12.[BH4-].[Na+]>CO>[OH:34][CH:3]([C:2]([CH3:1])([CH3:36])[CH3:35])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:27][CH2:28][CH3:29])[N:7]2[N:30]=[C:31]([CH3:33])[N:32]=[C:6]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution (10 mL) of 4′-{[4-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.4 g) in methanol was added sodium borohydride (0.017 g), and the mixture was stirred at room temperature for 2 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 84%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-11.62 (c=0.45, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9]C(=O)C)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CC(=O)OCc1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc(Cl)nc1Cl

Procedure:
260 g (1.18 mols) of this 2,6-dichloro-3-acetoxymethylpyridine, 520 ml (2 mols) of aqueous 2N sodium hydroxide solution and 520 ml of methanol are heated under reflux for 2 hours. The methanol is then removed on a rotary evaporator and the residual water phase is extracted by shaking with diethyl ether. After drying the organic phase over magnesium sulphate and concentrating the solution, crude crystalline 2,6-dichloro-3-hydroxymethylpyridine is obtained, which can be purified by recrystallisation from a mixture of cyclohexane/diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([O:9]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:5].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=1)=[O:9])=[O:5]
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Cl)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
A portion of 2-chloro-6-fluorobenzamidocarboxylic acid, 4-nitrophenyl ester, is combined with a portion of 5-chloro-2-aminopyridine in an inert organic solvent. The reaction mixture is stirred at elevated temperature for a period of time, and is then evaporated under vacuum. The product named in the heading above, identical to the product of Example 3, is isolated by recrystallization.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Cl:6][C:1]([CH2:2][O:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:3][CH2:2][C:1]([Cl:6])=[O:5])=[O:5]
Reactant: c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)COc1ccccc1OCC(=O)Cl
Reaction time: 96 h

Procedure:
30 g. Of the above acid are added to a mixture of 200 ml. anhydrous benzene. Then 35 g. oxalylchloride are added, the flask being protected by a calcium chloride tube. The mixture is stirred for four days and the diacid progressively dissolves as it is being transformed into the corresponding dichloride. The solution is then evaporated to dryness (without heating) leaving a brownish solid residue which is recrystallized from a mixture of chloroform-benzene giving white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[F:18][C:19]1[CH:30]=[C:23]2[C:24](OC(=O)[NH:28][C:22]2=[CH:21][CH:20]=1)=[O:25].Cl>O.O1CCOCC1>[NH2:28][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:30][C:23]=1[C:24]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:25]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: NCCCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(F)cc1C(=O)NCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
A 50% (by weight) solution of potassium carbonate (11.2 mL, 16.8 mmol, 1.02 eq), 8-aminocaprylic acid (9.5 g, 59.7 mmol, 1.00 eq), 5-fluoroisatoic anhydride (10.82 g, 59.7 mmol, 1.00 eq), dioxane (40 mL), and water (5 mL) were added to a 100 mL round bottom flask equipped with a magnetic stir bar and a condenser. The red cloudy mixture was heated to 90° C. for 2 hours (at which time the reaction was determined, by HPLC, to have finished). The deep purple solution was cooled to 25° C. and acidified to pH=4.0 with 3% (by vol.) aqueous hydrochloric acid. The dark precipitate which formed was isolated by filtration. The solid was recrystallized from 50 mL of 65% ethanol-water, recovered by filtration, and dried over 6 hours in a 50° C. vacuum oven. The N-(2-amino-5-fluorobenzoyl) -8-aminocaprylic acid was isolated as a light yellow solid (11.86 g, 67%), mp=108°-109° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:11][C@H:10]([C:12]([O:14][C@H](C2C=CC=CC=2)C)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](OC(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (S)-1-phenylethyl trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (0.4 g, 1.26 mmol) and 10% palladium-carbon (0.134 g, 1.26 mmol, 50%, wet) in MeOH (20 mL) was stirred at room temperature for 1.5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (0.261 g, 1.218 mmol, 97%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(C)=O>[CH2:21]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 55 °C
Yield: 90.9 %

Procedure:
In a 500-ml flask, place 18.9 g (0.1 m) of 2-amino-4-chloro-5-nitrophenol (1) and 120 ml of acetone, and heat to 50° C. Add 7.2 g (0.1 m×1.15@90%) of KOH flakes and stir at 55° C. to make a deep red brown solution. Add 6.9 g (0.05 m) of potassium carbonate, 0.8 g of tetrabutyl ammonium bromide and 14.6 g (0.1 m×1.15) of benzyl chloride. Stir the reaction mixture under reflux with fast stirring for 3 hrs. Cool the mixture to room temperature and add 240 ml of water slowly. Stir the resulting slurry and cool to 20° C. Collect solid, wash with water and heptane, and dry in an air oven to give 25.4 g (91%) of 2-benzyloxy-5-chloro-4-nitroaniline (2) as yellow granular solids.