Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8](Br)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1B1OCC(C)(C)CO1.N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:37]3[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Reactant: COc1ccc([N+](=O)[O-])cc1B1OCC(C)(C)CO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (4S,5R)-3-{[6-azetidin-1-yl-3-bromopyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.2 g, 2.229 mmol) and 2-(2-methoxy-5-nitrophenyl)-5,5-dimethyl-1,3,2-dioxaborinane in THF (20 mL) was degassed with N2 at 25° C. 1N K2CO3 (20 mL) was added followed by 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.073 g, 0.111 mmol) and the reaction was stirred vigorously at 25° C. under N2 for 4 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 2240 mL) to give (4S,5R)-3-{[6-azetidin-1-yl-3-(2-methoxy-5-nitrophenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=610.2. found=611.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][NH:4][C:3]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([C:17]([O:19][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])=[N:4][CH:5]=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[O:8][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1[nH]cc(OCc2ccccc2)c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ncc(OCc2ccccc2)c(OCc2ccccc2)c1Br
Reaction time: 18 h
Yield: 178.5 %

Procedure:
12.96 g of the title compound of Example 1, 5.52 g potassium carbonate and 10.40 g benzylbromide were dissolved in 200 ml DMF and kept at 80°-90° C. for 18 hours. The solvent was then distilled off in vacuo and the oil residue dissolved in 100 ml ethyl acetate and 100 ml water. The organic layer was separated and washed again with 50 ml water. The solvent of the dried organic phase was then stripped off to afford an oily residue (18 g). The oil was dissolved in 30 ml ethyl acetate/cyclohexane (1:1). 4.1 g 3-bromo-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)- 2-pyridinecarboxylic acid, phenylmethyl ester crystallized from the solution. The filtrate was chromatographed on silica gel using ethylacetate/cyclohexane (1:1) as eluent. Fractions 33-35 contained 4 g pure title compound M.P.=98°-100° C.; another 1.9 g title compound with 10% 3-Bromo-1,4-dihydro-4-oxo-5 -(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, phenylmethyl ester were obtained from fractions 57-104.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:10]>>[ClH:10].[CH2:4]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH2:9])=[O:8])=[CH:3][CH:4]=1)[CH2:3][CH2:2][CH2:7][CH3:6]
Reactant: NC(=O)c1ccccc1
Agent: Cl
Product: CCCCCc1ccc(C(N)=O)cc1
Yield: 94 %

Procedure:
A solution of the benzamide of part E (2.09 g, 3.4 mmol) in 4N HCl (20 mL) was stirred for 72 hours. The solution was concentrated in vacuo and the residue was dissolved into ethyl acetate (5 mL) and dropped into ethyl ether. The resulting precipitate was collected by vacuum filtration to provide R-N-[4-[[[1-carboxyl]-2-methylpropyl][2-(4-orpholinyl)ethyl]amino]-sulfonyl]phenyl]-4-pentylbenzamide monohydrochloride as white solid (1.9 g, 94%).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:34](Br)[CH:35]=[CH2:36]>>[CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:5]([CH2:36][CH:35]=[CH2:34])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: C=CCBr
Product: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
In a manner analogous to that described in Example 45(i), from 7.28 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate and 3.88 g of allyl bromide there were obtained 7.234 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1-yl)-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 495 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23]CC)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+:37]>O1CCOCC1.CO>[Na+:37].[C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O-:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)OCC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)[O-])CC2
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of ethyl 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate in dioxane (3.5M solution) was treated with 2N NaOH (3.0 eqv) and stirred at room temperature. After stirring for 4 hours, the dioxane was removed from the reaction, and the remaining solution was diluted with water and acidified with 5N HC1. The resulting milky solution was extracted with EtOAc. The ethyl acetate extract was dried over MgSO4 and filtered. Solvent removal gave a white solid. The free acid was stirred in methanol and treated with 3 eqv. of NaOH(aq). The solvent was removed from the reaction and the product was purified by CHP-20 reverse phase chromatography eluting with a water/methanol gradient. The pure product was obtained in 68% yield by lyophilization of the product containing fractions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([F:13])[CH:15]=1)[N:8]=[CH:7]2
Reactant: COc1ccc(F)c2[nH]ncc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Yield: 25.9 %

Procedure:
7-Fluoro-4-(methyloxy)-1H-indazole (D26) (500 mg, 3.01 mmol), the {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (1.48 g, 6.02 mmol), copper (II) acetate (820 mg, 4.51 mmol), powdered molecular sieves (550 mg) and pyridine (0.49 mL, 6.02 mmol) in DCM (15 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM (3×) and the combined organics were washed with brine and dried over MgSO4. The crude (1.71 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc (0 to 20%) in hexane to afford 286 mg of title compound (D27).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15].C([O-])([O-])=O.[K+].[K+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1>CC#N.[Na+].[I-]>[CH2:28]([O:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15])[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(ccn2C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 70 °C
Yield: 64.1 %

Procedure:
To a solution of methyl 4-hydroxy-1-methyl-1H-indole-5-carboxylate (7.70 g, 37.52 mmol), prepared according to the literature (Bioorg. Med. Chem. 2005, 13, 1497-1505), in CH3CN (150 mL) was added K2CO3 (8.80 g, 63.67 mmol), NaI (200 mg, cat.) and BnBr (6.70 mL, 56.41 mmol). The mixture was heated at 70° C. overnight. The solids were filtered off and the mother liquor was concentrated. The residue was purified by column chromatography using EtOAc/hexanes (gradient 10-30%) to afford methyl 4-(benzyloxy)-1-methyl-1H-indole-5-carboxylate (7.10 g) in 85% yield based on recovered starting material (1.90 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]3[C:27]([CH:31]=1)=[N:28][O:29][N:30]=3)=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[N:30]1[O:29][N:28]=[C:27]2[CH:31]=[C:23]([C:9]3[C:10](=[O:22])[N:11]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:12]4[C:7]([CH:8]=3)=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][CH:13]=4)[CH:24]=[CH:25][C:26]=12
Reactant: COC(=O)c1ncc2c(cc(-c3ccc4nonc4c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc4nonc4c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of 3-benzo[1,2,5]oxadiazol-5-yl-1-benzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (33 mg, 0.077 mmol), β-alanine (687 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After stirring the mixture for another 24 h at r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a brown solid. MS: (+) m/z 486.26 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Yield: 25 %

Procedure:
To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216 (M+3)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:7][CH2:6]2.O.NN>[Fe](Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[NH2:13])[CH2:9][N:8]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:7][CH2:6]2
Reactant: CCCN1CCC(N2CCc3cc(OC)c([N+](=O)[O-])cc3C2)CC1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCCN1CCC(N2CCc3cc(OC)c(N)cc3C2)CC1
Temperature: 65 °C
Yield: 41.7 %

Procedure:
A suspension of 6-(methyloxy)-7-nitro-2-(1-propyl-4-piperidinyl)-1,2,3,4-tetrahydroisoquinoline (1.43 g, 4.35 mmol), hydrazine hydrate (1.0 mL, 30.5 mmol), iron(III)chloride (0.180 g, 1.09 mmol), activated carbon (2 g), and methanol (50 mL) was maintained at 65° C. for 12 hours, cooled, and filtered through celite (rinsed with additional methanol). Filtrates were concentrated, redissolved in ethyl acetate, and washed twice with saturated aqueous sodium chloride and sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 6-(methyloxy)-2-(1-propyl-4-piperidinyl)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.550 g, 42%). 1H NMR (400 MHz, CDCl3) δ ppm 6.49 (s, 1 H), 6.37 (s, 1 H), 3.80 (s, 3 H), 3.64 (s, 4 H), 2.99-3.15 (m, 2 H), 2.70-2.85 (m, 4 H), 2.49 (s, 1 H), 2.33 (s, 2 H), 2.01 (s, 2 H), 1.89 (s, 2 H), 1.77 (s, 2 H), 1.56 (s, 2 H), 0.91 (t, J=7.33 H, 3 H).
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O-:4])=[O:3]>C1(C)C=CC=CC=1.C(O)CC>[N+:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH2:1])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: N
Solvent: CCCO
Solvent: Cc1ccccc1
Product: Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 70 °C

Procedure:
Compound 7 was prepared as described elsewhere [Van Galen, P. J. M. et. al. (1991) ibid.]. In brief, ammonia gas was passed, while stirring, through a solution of 3-nitro-4-chloroquinoline 6 (7.0 g, 30 mmol) in toluene (95 ml) and propanol (15 ml) till the product was formed. During the course of the reaction, the temperature was gradually raised till 70° C. After cooling, the solid was separated by filtration and washed successfully with toluene/2-propanol (70:30), ether and cold water until Cl− could no longer be detected. The solid was filtered off and dried at 80° C. Yield: 6.1 g (95%). Mp.: 255-257° C. 1H NMR (DMSO-d6): δ 7.50-7.66 (m, 1H, Ar); 7.81-7.92 (m, 2H, Ar); 8.59 (d, 1H, J=8.0 Hz, Ar); 9.03 (broad s, 2H, NH2); 9.18 (s, 1H, Ar)
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].O.[OH-].[Li+:12]>O>[NH:1]([CH2:6][C:7]([O-:9])=[O:8])[CH2:2][C:3]([O-:5])=[O:4].[Li+:12].[Li+:12]
Reactant: O=C(O)CNCC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CNCC(=O)[O-]

Procedure:
3 g of iminodiacetic acid, 27 g of water, and 1.85 g of lithium hydroxide monohydrate were placed in a 500 mL capacity three-necked flask equipped with a refluxing condenser, and stirred. Then, water was evaporated using an evaporator to provide lithium iminodiacetate as solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:26])=[O:25])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1N
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (commercially available) (2.0 g) and (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chloride (Example 1.2) (4.2 g) in dichloromethane (32 ml) was added dropwise pyridine (5.3 ml) over a period of 5 minutes at ambient temperature. The reaction mixture was stirred at ambient temperature for 23 hours. Dichloromethane (50 ml) was added to the reaction mixture and the mixture was washed with aqueous sulfuric acid (2M) (3×30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/dichloromethane from 0:10 to 1:9) to give 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as a white solid (4.728 g). 1H-NMR (400 MHz, CDCl3): 10.30 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.77 (bs, 1H), 7.54-7.60 (m, 2H), 5.15 (s, 2H), 4.04 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:14]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.S(=O)(=O)(O)O.[OH-].[Na+].Cl[CH2:32]Cl>>[CH3:32][N:9]1[CH2:10][CH:11]([C:13]2[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:2]2[C:1](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:8]1
Reactant: ClCCl
Reactant: COC(=O)Cc1cccc(C(O)CNCCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1cccc(C2CN(C)Cc3ccccc32)c1

Procedure:
1.5 g (4.8 mmol) of 2-benzylmethylamino-l-(3-methoxycarbonylmethylphenyl)ethanol are dissolved in 13 ml of dichloromethane. 3.7 ml of conc. sulfuric acid are added dropwise to this solution with cooling and stirring. It is stirred at room temperature for three hours. The reaction solution is diluted with dichloromethane and treated with ice. This solution is then adjusted to an alkaline pH using NaOH solution. The deposited organic phase is separated off. The aqueous phase is extracted twice more with dichloromethane. The combined organic phases are dried and the solvent is distilled off. The residue is taken up in ether and the solution is filtered. Methyl 3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenyl-acetate is obtained as an oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[CH:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 23 mg, 0.58 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (171 mg, 0.64 mmol) in THF (2.0 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude, prepared in accordance with example 1, step 4, ˜0.64 mmol) in THF (2.0 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (30×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel twice (1st CH2Cl2→2% MeOH/CH2Cl2, gradient and 2nd CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 51 mg (21%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)=[O:29])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1ccc(SCC2COC(c3ccccc3)=N2)cc1
Solvent: ClCCl
Product: O=S(CC1COC(c2ccccc2)=N1)c1ccc(O)cc1

Procedure:
To a solution of 2.85 q (10.0 mm) of the sulfide prepared in Example 1 in 50 ml methylenechloride at 25° C. was added 2.1 g (12 mm) of 90% MCPBA. Small portions of MCPBA were added until conversion was completed as indicated by thin layer chromatography. The soution was poured into 50 ml methylenechloride, washed with 100 ml NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give crude title compound.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.CN(C)C=O.[Cl-:36].[Li+]>O>[Cl:36][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: [Cl-]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(Cl)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 40 ml. of N,N-dimethylformamide containing 650 mg. of lithium chloride is heated on the steam bath for 18 hours. The cooled solution is diluted with water and the resulting mixture is extracted with ether. The ether extract is washed with saline, dried with saline, dried with anhydrous magnesium sulfate and evaporated to dryness to give an oil. Chromatography on silica gel affords an oil; λmax. 5.78 μ (carbonyl groups).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Product: N#Cc1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following a procedure analogous to that described in Example 508. LC-MS Method 2 tR=1.218 min, m/z=439.1; 1H NMR (CDCl3) 1.21-1.36 (m, 1H), 1.62 (m, 1H), 1.78 (m, 3H), 1.56 (m, 2H), 1.86-2.00 (m, 2H), 2.19 (m, 1H), 2.29 (m, 1H), 2.67-2.86 (m, 3H), 3.20 (m, 1H), 3.50 (t, 2H), 3.79 (m, 1H), 4.12 (m, 1H), 4.30 (d, 1H), 6.53 (m, 1H), 7.01 (t, 2H), 7.24 (m, 2H), 7.51 (d, 1H), 8.30 (s, 1H).