Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:32][CH2:31][O:30][C:28](=[O:29])[CH2:27][CH2:26]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CI>O1CCCC1.CCCCCC>[CH3:1][CH:27]1[CH2:26][CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:32][CH2:31][O:30][C:28]1=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CCOC(=O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 14.3 ml (0.1 mole) of diisopropylamine in 170 ml dry tetrahydrofuran is added dropwise 37 ml (93 mmol) of a 2.5M solution of n-butyllithium in hexane. The solution is stirred for 15 min and then a solution of 13.86 g (46.1 mmol) of 4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone in 68 ml dry tetrahydrofuran is added slowly. The yellow solution is stirred at room temperature for 0.5 h and 19 ml (0.3 mole) methyl iodide is added rapidly. The exothermic reaction is controlled by cooling in a water bath. The reaction mixture is stirred for 3 h and quenched using saturated aqueous ammonium chloride solution. The mixture is extracted with ether and the organic layer is washed with water and brine. The organic phase is dried, filtered, concentrated and purified by chromatography using 3:2 hexane/ether as eluent to yield 2-methyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone; NMR (CDCl3): delta 4-4.4 (m,2H), 3.6 (t,2H), 1.2 (d,3H), 0.88 (s,9H). This is converted to methyl 8-amino-2-methyl-4-[3-(3-pyridyl)propyl]-octanoate in a similar fashion as described below for the 2,2-dimethyl analog.
Reaction SMILES: C([O:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[C:4]([OH:11])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1

Procedure:
A suspension of 4-(7-methyl-2,4-bis-pyrrolidin-1-yl-7H-pyrrolo 2,3-d!pyrimidin-6-yl)benzoic acid ethyl ester (EXAMPLE 180, 2.04 g) in ethanol (95%, 80 ml) is treated with 240 ml of a 0.1N aqueous mixture of potassium hydroxide. The mixture is heated at reflux for two days and then partially concentrated under reduced pressure. The resulting mixture is poured onto 300 ml of 5% aqueous hydrochloric acid and extracted with 5 portions of chloroform. The combined organics are dried and concentrated, the concentrate is chromatographed over silica gel, eluting with methanol/chloroform/acetic acid (5/94/1) to give the title compound, mp 290°-295°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[C:5]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1cccc2[nH]ncc12
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1cccc2[nH]ncc12

Procedure:
[3-(1H-Indazol-4-yl)-3-phenyl-propyl]-methyl-amine was prepared as a hydrochloride salt from 3-(1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=266.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]2[NH:16][CH:17]=[C:18]([CH3:20])[N:19]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:3][C:4]=1[C:15]1[NH:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: Cc1c[nH]c(-c2sc(Br)nc2-c2ccc(Cl)cc2Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nc(C)c[nH]3)s2)ccn1
Temperature: 90 °C
Yield: 23.9 %

Procedure:
2-bromo-4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)-1,3-thiazole (55 mg, 0.141 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (64 mg, 0.214 mmol) were dissolved in 1,4-dioxane (3.4 mL). Lithium chloride (18.1 mg, 0.427 mmol), copper(I) iodide (8.14 mg, 0.0427 mmol) and tetrakis(triphenylphosphine)palladium(0) (8.23 mg, 0.00712 mmol) were added under atmosphere of argon. The reaction mixture was heated at 90° C. for 7 hours. LCMS indicated complete conversion. Solvent was evaporated and the residue was purified using preparative HPLC to afford 15 mg of the title compound (24%). LCMS: (AA) ES+ 444, 446. 1H NMR (400 MHz, d1-chloroform) δ: 8.79-8.70 (m, 1H), 8.43 (s, 1H), 8.35-8.28 (m, 1H), 7.62-7.59 (m, 2H), 7.50 (d, J=8.25 Hz, 1H), 7.43 (dd, J=8.23, 2.01 Hz, 1H), 2.24 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2ccc(OCc3ccccc3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of the product from Step A (44 g, 0.185 mol) in 500 mL of MeOH was added NaBH4 (7.1 g, 0.186 mol) in portions at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 20 hours. The reaction mixture was concentrated and charged with 200 mL of aqueous NaOH (20%). The resulted mixture was extracted with EtOAc (200 mL×3). The combined organic extracts was washed with brine (200 mL×3), dried, and concentrated to give the title compound (32.0 g, 72%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.46-7.42 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.15 (d, J=8.2 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.2, 2.5 Hz, 1H), 5.20 (t, J=6.2 Hz, 1H), 5.07 (s, 2H), 3.01-2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.55-2.47 (m, 1H), 2.01-1.87 (m, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-])=O>[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCCCOc1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: COC(=O)CCCCCOc1cc(OC)ccc1N

Procedure:
6-(2-isothiocyanoto-5-methoxphenoxy)hexanoic acid, represented as TB595 and shown in FIG. 3L was prepared by a number of steps. The first step involves the reaction of 2-nitro-5-methoxyphenol (1.69 g, 10 mmol) with methyl 6-bromohexanoate (2.08 g, 10 mmol) in dry dimethylformamide and anhydrous potassium carbonate (2.0 g, 14.5 mmol) at 60° C. for 12 hours to produce the intermediate ester, methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate. Hydrogenation of methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate using palladium-on-carbon as catalyst afforded the isolation of methyl 6-(2-amino-5-methoxyphenoxy)hexanoate which was saponified in 10% water/ethanol (1:1) solution of potassium hydroxide to give 6-(2-amino-5-methoxyphenoxy)hexanoic acid in 95% yield. Finally, the reaction of 6-(2-amino-5-methoxyphenoxy)hexanoic acid (1.0 g, 3.9 mmol), thiophosgene (0.8 ml, 4.2 mmol), and pyridine (1.0 g, 7 mmol) in tetrahydrofuran at room temperature gave 0.9 g (78% yield) of the desired product as a colorless powder. The structure of the product was confirmed by NMR. Anal. Calcd for C14H17NO4S: C, 56.92; N, 4.74; S, 10.86.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>CN(C)C=O.O>[CH3:15][N:16]([CH3:20])[C:17]([NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\NC(=O)N(C)C)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to a stirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl-formamide (60 mL) at 5° C. under nitrogen over a 60 minute period. The reaction mixture is allowed to warm to and held at room temperature for 15 minutes, cooled to 5° C., and treated with dimethylcarbamoylchloride (21.6 g, 200 mmol) over a 60 minute period. The resultant solution is then warmed to and held at room temperature for 2 hours, diluted with water (150 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers are dried, filtered and concentrated, and the mineral oil layer is removed to obtain a residue. Flash column chromatography of the residue on silica gel using a 85:15 hexanes/ethyl acetate solution gives the title product as a yellow liquid (18.1 g, 71% yield): 1H NMR (DMSO-d6) δ9.18 (s,1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H); 19F NMR δ−65.7 (s).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2,6-dichloropyrazine (150 mg, 1.007 mmol) in 1,4-dioxane (1.0 mL) was added 1-methylpiperazine (121.0 mg, 0.13 mL, 1.208 mmol) followed by triethylamine (203.8 mg, 0.281 mL, 2.014 mmol). The reaction mixture was stirred at room temperature for 24 h then concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C9H14ClN4 (M+H+): 213.1; Found: 213.2 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([Cl:26])[C:16]=2[N:15]=[CH:14]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([Cl:26])[C:16]=2[N:15]=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCn1cnc2c(Cl)nc3ccccc3c21
Yield: 61.4 %

Procedure:
0.10 g (0.267 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo-[4,5-c]quinoline was dissolved in 6 ml of methylene chloride. 0.21 ml (2.67 mmol) of trifluoroacetic acid was added thereto and the mixture was concentrated under reduced pressure. 2 ml of a 1N sodium hydroxide aqueous solution and brine were added to the residue and the mixture was extracted five times with chloroform. The extract was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride) and the precipitate thus formed was collected by filtration to obtain 45 mg (0.164 mmol) of 1-(4-aminobutyl)-4-chloro-1H-imidazo[4,5-c]quinoline (shown below) as pale orange powder. ##STR44## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3400, 2950, 1670, 1520, 1360.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]=1[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C.CC(C)([O-])C.[K+]>C1COCC1>[CH2:24]([O:23][C:21]([C:20]1[C:4]([OH:3])=[C:6]2[C:10]([Cl:11])=[C:9]([Cl:12])[N:8]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]2=[CH:18][N:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Cl)c(Cl)n1CCC(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The crude 2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-4,5-dichloro-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester (24.1 g, 48.9 mmol) was dissolved in 110 mL of anhydrous THF and cooled to −78° C. in a acetone dry ice bath. A solution of 77.0 mL of 1.0 M potassium tert-butoxide in THF was added slowly to cold solution, and the reaction was stirred at −78° C. for 30 min. and then at room temperature for 10 min. The reaction was quenched with 9.2 mL of acetic acid. The solvent was evaporated off, and the residue was dissolved in methylene chloride (184 mL). Trifluoroacetic acid (184 mL) was added, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated off, and the residue was dissolved in 100 mL of methylene chloride. Triethylamine was added until the solution was basic. After air passed the reaction mixture overnight, the solvent was evaporated off. The residue was dissolved in 350 mL of ethyl acetate, and the organic solution was washed with water and saturated sodium chloride solution, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to produce 2.23 g of a brown froth. MS: (+) m/z 345.2 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>COC(C)(C)C>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Dissolve (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g, 42.5 mmol) in anhydrous tert-butyl methyl ether (50 mL) and cool to -5° C. Treat the solution with methanesulfonyl chloride (3.6 g, 46.5 mmol, mesyl chloride), followed by triethylamine (7.2 mL, 51.7 mmol), at such a rate as to keep the temperature between -5° C. and -2° C. with an ice bath. The ice bath is removed and the solution is stirred for 2 hours. The mixture is then transferred to a separatory funnel and treated with brine/water (50 mL/50 mL). The layers are separated and the aqueous layer is extracted with tert-butyl methyl ether (2×50 mL). The organic layer and extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (12.1 g, 97% yield) as a colorless oil; 1 H NMR (CDCl3) δ5.1 (m, 1H), 4.2 (m, 1H), 2.99 (s, 3H), 2.3 (m, 1H), 2.0 (m, 3H), 1.8 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17]C(=O)C3C=CC=CC=3)[CH2:14][C@H:13]2[CH2:26][NH:27][C:28]([NH:30]C(=O)C(Cl)(Cl)Cl)=[O:29])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:26][NH:27][C:28]([NH2:30])=[O:29])=[O:11])=[CH:37][CH:38]=1)([O-:3])=[O:2]
Reactant: O=C(NC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-trichloroacetylaminocarbonylaminomethyl-4-benzoyloxypyrrolidine (431 mg) was dissolved in 10 ml of methanol, and 1.48 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at room temperature for 1.5 hours. 1N Hydrochloric acid (1.48 ml) was added thereto, followed by concentration to remove methanol. The residue was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-aminocarbonylaminomethyl-4-hydroxypyrrolidine.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].[C:9]1([CH3:21])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH2:17][C:18](Cl)=[O:19]>O>[CH3:21][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH2:17][C:18]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:19]
Reactant: CNCC(=O)O
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(CC(=O)N(C)CC(=O)O)c(C)c1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
11.25 g (0.15 mol) of sarcosine and 3 g (0.075 mol) of NaOH are dissolved in 210 ml of water. While cooking the solution in a water bath 9 g (0.225 mol) of NaOH, dissolved in 45 ml of water, and 29.6 g (0.15 mol) of mesityleneacetyl chloride are added synchronously dropwise, during which addition the temperature is kept at <40 ° C. After 1 hour the mixture is acidified with concentrated HCI at 0° to 20° C., filtered off and the filtrate is dried in vacuo over P2O5 at 70° C. 37.1 g (99.3 % of theory) of N-(2,4,6-trimethyl-phenyl-acetyl)-sarcosine of a melting point of 140° C. are obtained.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([NH:17][C:18](=[O:20])[O-:19])[CH3:16].[OH:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:26]([CH3:34])[CH:27]3[CH2:31][NH:30][CH2:29][CH:28]3[C:32]=2[CH:33]=1>CC#N>[CH2:15]([NH:17][C:18](=[O:19])[O-:20])[CH3:16].[CH2:1]([O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:26]([CH3:34])[CH:27]3[CH2:31][NH:30][CH2:29][CH:28]3[C:32]=2[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: BrCc1ccccc1
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1c2ccc(OCc3ccccc3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzyl bromide (15 μL, 0.12 mmol) and K2CO3 (70 mg, 0.5 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydro indeno[1,2-c]pyrrole (26 mg, 0.1 mmol) in CH3CN (2 mL). The resulting mixture was stirred overnight at 80° C. The reaction was cooled to room temperature, concentrated by rotary evaporation and taken up in H2O (2.5 mL). The product was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C22H25NO3+H: 352, observed: 352.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[C:11]([OH:12])=[C:10]([S:13](=[O:17])(=[O:16])[NH:14][CH3:15])[CH:9]=[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=1)(=O)C.[ClH:22]>C(O)C>[ClH:22].[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:18]([CH3:20])([CH3:21])[CH3:19])[CH:9]=[C:10]([S:13](=[O:17])(=[O:16])[NH:14][CH3:15])[C:11]=1[OH:12]
Reactant: CNS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(C)=O)c1O
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O

Procedure:
4.9 g (0.016 mole) of 6-acetamidomethyl-4-(1,1-dimethylethyl)-2-methylsulfamoylphenol in a mixture of 30 ml of ethanol and 10 ml of concentrated hydrochloric acid are heated under reflux for 8 hours. Evaporation and recrystallization from methanol/ether gives white crystals of melting point 238°-240° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C1(C2C=C(SCC(O)=O)C3C(=CC=CC=3)N=2)C=CC=CC=1>N1C=CC=CC=1>[C:12]1([C:4]2[CH:3]=[C:2]([S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Reactant: O=C(O)CCS
Agent: O=C(O)CSc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccncc1
Product: O=C(O)CCSc1cc(-c2ccccc2)nc2ccccc12
Yield: 54.9 %

Procedure:
4-Chloro-2-phenylquinoline (4.8 g) and 3-mercaptopropionic acid (2.54 g) in pyridine (50 cc) are heated under reflux for 11 hours. After a treatment similar to that described in Example 54 for 2-[(2-phenyl-4-quinolyl)thio]acetic acid, 3-[(2-phenyl-4-quinolyl)thio]propionic acid (3.4 g) is isolated, the proton NMR spectrum of which, in deuterated chloroform, has the following characteristics:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21]C2CCCCO2)[CH:16]=1)[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Mg]Br>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:28])[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Agent: C[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(OCCCO)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-tert-Butyl-N-methoxy-N-methyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzamide (O3.059; 5.49 g) was dissolved in THF (100 ml), cooled to 0° C. and admixed with lithium bis(trimethylsilyl)amide (14.47 ml, 1 M in MTB ether). After stirring at 0° C. for 30 min, methylmagnesium bromide (9.65 ml, 3 M in ether) was added dropwise. The cooling bath was removed and, after stirring at RT for 2 h, the mixture was diluted with water and extracted by shaking with EA. The EA phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using silica gel (200 g, n-heptane/EA 4:1). 3.4 g of the title compound were obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH:24]=[O:25])[CH:7]=1.[OH-:26].[K+]>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[C:24]([C:8]1[CH:7]=[C:6]([C:2]2[O:1][CH2:5][CH2:4][N:3]=2)[CH:23]=[CH:22][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1)([OH:26])=[O:25]
Reactant: [OH-]
Reactant: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=O)on1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C(=O)O)on1
Reaction time: 0.03 h
Yield: 38.2 %

Procedure:
A solution of 4.7 g of silver nitrate in 6 ml of distilled water was added to a stirred suspension of 4.0 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-formylphenoxy]pentyl}-3-methylisoxazole (Example 70) in 60 ml of ethanol. The mixture was stirred for about two minutes, and then a solution of 8.4 g of potassium hydroxide in 140 ml of water was slowly added. The latter mixture was stirred for two hours, then filtered and the filtrate acidified. The solid product was collected, washed with dilute hydrochloric acid, dried and recrystallized from methanol to give 1.6 g of 5-{5-[2-carboxy-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, m.p. 170°-171° C.