Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN1CCCC1=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:5]=3)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: CC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Temperature: 150 °C
Reaction time: 7 h
Yield: 84.4 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and N-acetylpiperazine (166 mg, 1.3 mmol) and the resulting mixture was stirred at 150° C. for 7 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (105 mg, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(Br)C=C(F)C=1.[Mg].Cl[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[N:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][N:27]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCCCc1cnc(Cl)nc1
Reactant: Fc1cc(Cl)cc([Mg]Br)c1
Agent: Cl
Agent: Fc1cc(Cl)cc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCc1cnc(-c2cc(F)cc(Cl)c2)nc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A solution of 3-chloro-5-fluorophenylmagnesium bromide [prepared from 22.7 g (108.3 mmol) of 3-chloro-5-fluoro-bromobenzene and 2.7 g (111.0 mmol) of magnesium, and 100 ml of diethyl ether] in diethyl ether was added by drops to a mixture of 10 g (54.1 mmol) of 2-chloro-5-pentylpyrimidine, 0.4 g (0.5 mmol) of dichloro[1,1′-bis(diphenylphosphino) ferrrocene]palladium, and 300 ml of diethyl ether while being maintained at a temperature lower than −60° C., stirred at the same temperature for 1 hour, and then stirred at 10° C. for 10 hours. A diluted hydrochloric acid in an amount of 300 ml was added to the reaction mixture and extracted with 250 ml of heptane. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=1/1) to obtain 11.0 g of a crude 2-(3-chloro-5-fluorophenyl)-5-pentylpyrimidine. (Yield: 72.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][CH:29]3[CH3:32])=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)=[CH:23][CH:24]=4)[CH:29]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncccc1-c1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ncccc1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14]C)=[O:12].C[O-].[Na+]>CO>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]c2ccccc2c1N
Reaction time: 4 h
Yield: 41.9 %

Procedure:
To a solution of ethyl 3-aminoindole-2-carboxylate [Prepared according to P. Unangst. J. Het. Chem., 1983, 20, 495] (5.0 g) in methanol (50 ml) was added sodium methoxide (6.5 g). The resulting mixture was stirred for 4 hours and then quenched with saturated ammonium chloride solution. The resulting mixture was extracted with dichloromethane, dried (MgSO4) and evaporated to give a gum which was purified by column chromatography using iso-hexane:ethyl acetate (1:4) as eluent to give the desired product (1.95 g, 42%); NMR d (CD3SOCD3), 3.8 (s, 3H), 5.7 (s, 2H), 6.8-6.9 (m, 1H), 7.2 (m, 2H), 7.7 (d, 1H); M/z (+) 191.1 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:11][C:7]=1[C:8]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:30][CH:31]([CH3:32])[CH3:33])=[C:36]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:37]=1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccccc1OCC(C)C
Reactant: CC(C)COc1ccc(OCC(C)C)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)ccc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
In 50 ml of methylene chloride is dissolved 5.00 g of 2,5-diisobutoxybenzoic acid. After adding 2.0 ml of oxalyl chloride and subsequently 20 μl of N,N-dimethylformamide at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 7.51 g of aluminum chloride and subsequently 5.17 g of ethyl 3-(2-isobutoxyphenyl)-propanoate are added at −30° C., the mixture thus obtained is stirred at −10° C. for 10 minutes. The reaction mixture is added to a mixture of chloroform and ice water and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 9.21 g of ethyl 3-[5-(2,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoate as a yellow-colored oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[C:21][CH3:22]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:20]#[C:21][CH3:22]
Reactant: CC#CCBr
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(OC)c(OC)c1

Procedure:
Following the same procedure as in Example 2, 15.4 g (0.1 mole) of 1-hydroxy-3,4-dimethoxybenzene, 13.8 g (0.1mole) of anhydrous potassium carbonate in ml 50 of acetone and 13.3 g (0.1 mole) of 1-bromo-2-butyne were reacted. After work up and evaporation of the mixture u.v. (20° C./21 mbar), a residue was obtained, that after purification on silica gel column (eluant n-hexane:ethyl acetate 5:1 v/v) gave a thick oil that after some time solidified with low melting point (28-30° C.), whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH3:12][O:13][CH2:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCCOc1cc(F)c(CO)c(Cl)c1
Yield: 90 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 179 to give the product as a yellowish oil (382 mg, 90%); MS (EI): 248.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[O:9][C:10]([C:12]1([NH:15]C(OCC2C=CC=CC=2)=O)[CH2:14][CH2:13]1)=[O:11].[H][H].C1CC=CCC=1>[Pd]>[CH3:7][C:4]1([CH3:8])[CH2:5][CH2:6][C:2]([CH3:1])([CH3:26])[CH:3]1[O:9][C:10]([C:12]1([NH2:15])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC1(C)CCC(C)(C)C1OC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CC1(C)CCC(C)(C)C1OC(=O)C1(N)CC1
Reaction time: 0.13 h

Procedure:
N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester is dissolved in absolute alcohol at 0° C. in an ultrasound bath. Palladium on carbon (10%) is added. The hydrogen source, 1,4-cyclohexadiene, is added, and ultrasound is commenced for eight minutes. The slurry is then filtered through a bed of Celite with ethyl alcohol. The solvent is removed by rotary evaporation to yield 1-aminocyclopropylcarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: C(C1NC(=O)C1)C=C.C([Li])CCC.CC(C)=O.[CH2:18]([C@@H:21]1[NH:24][C:23](=[O:25])[C@H:22]1[C:26]([OH:29])([CH3:28])[CH3:27])[CH:19]=[CH2:20]>O1CCCC1.CCCCCC.C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH2:18]([CH:21]1[NH:24][C:23](=[O:25])[CH:22]1[C:26]([OH:29])([CH3:28])[CH3:27])[CH:19]=[CH2:20]
Reactant: C=CC[C@@H]1NC(=O)[C@H]1C(C)(C)O
Agent: C=CCC1CC(=O)N1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCC1NC(=O)C1C(C)(C)O
Reaction time: 0.17 h

Procedure:
A solution of 4-allylazetidin-2-one (0.25 g) in dry tetrahydrofuran (25 ml) was stirred at -5° C. under argon and treated with a 2.5 M solution of n-butyl-lithium in hexane (3.0 ml). A period of 1 hour was allowed for the dianion to form and dry acetone (1.0 ml) was then added. After a further 10 mins. water (5 ml) was added to the reaction mixture, which was then concentrated to about 10 ml in volume. This was extracted with methylene chloride (20 ml), and the organic phase was then dried over sodium sulphate and concentrated. The residue was chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 1:1 grading to ethyl acetate to give the cis and trans aldol products. The least polar isomer was cis-4-allyl-3-(2-hydroxy-2-propylazetidin)2-one (0.029 g); m.p. 144° (ethyl acetate/60°-80° petroleum ether). ν max (CHCl3) 3400, 2980, 2930, 1745 and 1640 cm-1 ; δ(CDCl3) 1.35 (3H, s), 1.51 (3H, s), 2.18 (1H, br), 2.5-2.9 (2H, m), 3.28 (1H, d, J 5 Hz), 3.85 (1H, td J 9 and 5 Hz), 4.9-6.1 (3H, m), and 7.20 (1H, br) (Found: C, 64.2; H, 9.0; N, 8.2%. C9H15NO2 requires C, 63.9; H, 8.9 and N, 8.3%). The more polar isomer was trans-4-allyl-3-(2-hydroxy-2-propyl)azetidin-2-one (0.042 g); νmax (CHCl3) 3400, 2980, 2930, 1750 and 1640 cm-1, δ(CDCl3) 1.29 (3H, s), 1.39 (3H, s), 2.41 (3H, br t J 6 Hz), 2.88 (1H, d, J 2 Hz), 3.69 (1, 6d J 6 and 2 Hz), 4.9-5.4 (2H, m), 5.89 (1H, ddt J 18, 9 and 6 Hz), and 6.50 (1H, br).
Reaction SMILES: C(OCCO)C.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1I)(=[O:9])[CH3:8].C([O-])(=O)C.[K+].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:26]=[CH:25][C:24]([O:28][CH3:29])=[O:27])(=[O:9])[CH3:8]
Reactant: C=CC(=O)OC
Reactant: CC(=O)Nc1ccc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Product: COC(=O)C=Cc1cc(Cl)ccc1NC(C)=O
Temperature: 50 °C
Yield: 74.1 %

Procedure:
To 100 ml of ethylene glycol monoethyl ether were added 10 g of 2-acetylamino-5-chloroiodobenzene, 3.96 g of anhydrous potassium acetate, 2.84 g of methyl acrylate, 5.8 mg of palladium acetate and 17.4 mg of triphenylphosphine. The resulting mixture was allowed to react at 130° C. for 8 hours under the stream of a nitrogen gas. The reaction solution was cooled to 50° C. and poured into 300 ml of water, and then a large amount of white crystal precipitated. This crystal was filtered off, washed with water and vacuum-dried to obtain 6.2 g of methyl 2-acetylamino-5-chlorocinnamate. The yield was 72.5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CCOCC>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:22])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)nc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1(c2ccc(Cl)nc2)CCNCC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
HCl (4M in dioxan, 4.22 mL, 16.88 mmol) was added in one portion to a stirred suspension of tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (1.32 g, 4.22 mmol) in ethyl acetate (20 mL) at ambient temperature. The resulting mixture was stirred at 50° C. for 90 minutes then cooled to room temperature, diluted with ether (20 mL) and filtered. The filtered solid was washed with ether and dried then taken up in methanol, applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Product-containing fractions were combined and evaporated then purified by flash silica chromatography, elution gradient 10 to 20% 2M ammonia in methanol in DCM. Pure fractions were evaporated to dryness to afford 4-(6-chloropyridin-3-yl)piperidin-4-ol (0.43 g, 48%) as a pale orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:32][C:33](=[O:43])[C@@H:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:42][C@@H:34]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]([OH:32])=[O:43])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 89.6 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-phenyl propionic acid methyl ester (24.4 mg, 0.13 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 59.2 mg of the title compound as a white solid.
Reaction SMILES: Cl.Cl.C[C@H]1CCCN1[C@@H]1CCNC1.[C:14]([C@:21]1(C)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(OC(C)(C)C)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH3:14][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CCCCN1C1CCNCC1
Agent: C[C@H]1CCCN1[C@@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: C[C@H]1CCCCN1C1CCNCC1
Yield: 94 %

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2S,3′R)-2-Methyl-[1,3′]bipyrrolidinyl dihydrochloride by acid hydrolysis of BOC-(S)-2-Methyl-[1,4′]bipiperidinyl which was synthesized by condensation of corresponding tosylate with (S)-(−)-2-methylpiperindine to get 1.37 g (94% yield) of the title product as a clear oil.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([O:15][C:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:23])=[O:8])=[O:17]
Reactant: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)O

Procedure:
A total of 55.5 g. of benzyl-(R)-2-(2-furoyloxy)-isocaproate were hydrogenated in 400 ml. of alcohol after the addition of 5 g. of palladium-on-charcoal (5 percent) until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off by suction and the filtrate evaporated under reduced pressure at 40°. The oil thus obtained was dissolved in 250 ml. of 8 percent sodium bicarbonate solution and the resulting solution washed twice with 80 ml. portions of ether. The pH of the bicarbonate solution was adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with 100 ml. portions of ethyl acetate. The ethyl acetate solutions were washed twice with 50 ml. portions of water, dried with magnesium sulphate and evaporated under reduced pressure at 45°. The residual oil was dried for 2 hours at 0.4 Torr and 40° to give (R)-2-(2-furoyloxy)-isocaproic acid; [α]D25 = + 7.0 (c = 4.0 in alcohol).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Mg].II.[C:12]([O:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][C:22](=[O:27])N(OC)C)[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCOC(C1N=C(C2N3C(=NC(C4C=CC=CC=4)=N3)SC=2)SC=1)=O>O1CCCC1>[C:12]([O:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][C:22](=[O:27])[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: BrCC1CCCCC1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Agent: CCOC(=O)c1csc(-c2csc3nc(-c4ccccc4)nn23)n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(CCC(=O)CC1CCCCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Add dropwise bromomethylcyclohexane (16.96 mL, 0.121 mol) to a stirred warm solution of magnesium (granulae, 3.02 g, 0.124 mol), a crystal of iodine and tetrahydrofuran (130 mL). Heat the mixture to reflux for one hour. Add the Grignard reagent (30 mL) to a stirred mixture of [2-(methoxy-methyl-carbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (3.0 g, 12.0 mmol, prepared according to Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron 2002, 1719-1737) and tetrahydrofuran (120 mL) kept at 0° C. under N2. Stir the mixture for one h at 0°C. and for 2 h at room temperature. Add more of the Grignard reagent (40 mL) and stir for another hour at room temperature. Add saturated aqueous ammonium chloride and separated the layers. Extract the water layer with diethyl ether (×3). Dry the combined organic layers, filter and concentrate. Purify the crude residue by flash column chromatography, eluting with ethyl acetate/hexane (1:9) to yield 1.0 g of the title compound. 1HNMR (CDCl3) δ 3.46-3.40 (m, 2H), 2.85 (s, 3H), 2.68-2.60 (m, 2H), 2.29 (d, 2H), 1.87-1.60 (m, 6H), 1.46 (s, 9H), 1.33-1.07 (m, 3H), 0.99-0.86 (m, 2H).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+:6].[Na+].[CH3:8][C:9]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[C:18]([OH:20])=[O:19])=[O:10]>O>[C:9]([O:11][C:12]1[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]([O-:20])=[O:19])(=[O:10])[CH3:8].[Na+:6]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]

Procedure:
A cold solution (10° C.) of sodium acetylsalicylate was prepared by adding 34.6 gms. of sodium carbonate hydrate and 100 gms. of aspirin to 600 ml. of distilled water stirring until all solids had dissolved and using an additional 320 ml. of distilled water to wash down the walls of the container. Twenty-five gms. of instant tea was added with stirring until the tea dissolved. To 750. ml. of cold distilled water (5° C.) was added 250 ml. of the aspirin-tea solution and 20 ml. of glacial acetic acid. After a period of one hour the remaining aspirin-tea solution was added in 50 ml. portions with glacial acetic acid being added after each addition, the first amount being 4.0 ml. and increasing each addition by 1.0 ml.; a stirring period of 10 minutes occurred between each addition. The coprecipitate was allowed to settle, the supernatant was decanted, the coprecipitate was washed with glycine buffer solution and collected by filtration. After air drying, the product weighted 79.2 gms. Analysis of the coprecipitate showed it contained 95.3% aspirin, 4.17% tea constituent, 0.03% salicylic acid and 0.50% water.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][F:30])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C>FC(F)(F)C(O)=O>[F:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@H:9]([C:31]([OH:33])=[O:32])[NH2:8])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C[C@@H](Cc1ccc(OCCCF)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.11 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[4-(3-fluoropropoxy)-benzyl]-D-glutamate were taken up in 3 mL of trifluoro acetic acid and stirred overnight at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and then evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](O)=[O:36])[C:29]=2[O:28][CH2:27][C:26]1=[O:38]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[C:29]3[O:28][CH2:27][C:26](=[O:38])[N:25]([CH3:24])[C:30]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:10])[N:12]=1
Reactant: CN1C(=O)COc2c(C(=O)O)cccc21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC(=O)N3C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=517.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([F:30])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:31])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]3[C@@H:17]([N:9]([CH2:8][C:7]4[CH:32]=[CH:33][CH:34]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=4)[C:10](=[O:31])[O:11]3)[CH2:16][S:15](=[O:18])(=[O:19])[CH2:14]2)=[CH:22][C:23]=1[F:30]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc([N+](=O)[O-])c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
A solution of (3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-7-(3-fluoro-4-nitro-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (4.0 g, 8.1 mmol) in THF (150 mL) was hydrogenated over 10% Pd/C (300 mg) at 45° C. and 1 bar. After 16 h the catalyst was filtered off over Celite and the filtrate was evaporated. The residue was recrystallized from THF-hexane to yield the title compound as beige crystals: TLC (hexane-EtOAc 1:1) Rf=0.29; HPLC RtA=1.94 min; ESIMS [M+NH4]+=478; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H), 7.30 (d, 1H), 7.27 (s, 1H), 7.09 (d, 1H), 6.76 (dd, 1H), 6.7 (m, 2H), 4.52 (d, 1H), 4.31 (d, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.05 (m, 3H), 2.80 (dd, 1H), 2.5-2.8 (m, 3H), 1.31 (s, 9H).