Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:25][P:26]([CH2:29]Cl)([CH3:28])=[O:27].O>CN(C)C=O>[CH3:25][P:26]([CH2:29][N:14]1[CH2:15][CH2:16][CH:11]([O:10][C:9]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:8]=2[F:7])[CH2:12][CH2:13]1)([CH3:28])=[O:27]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CP(C)(=O)CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 30 h
Yield: 22.2 %

Procedure:
To a stirring mixture of 9.0 g of potassium carbonate in 100 ml of dimethylformamide was added 8.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 9.5 g of dimethylphosphinylmethyl chloride. After stirring at 80° C. for 30 hours, the reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The desired fractions were evaporated to yield a solid which was sublimed to afford 2.37 g (22.1%) of 1-[(dimethylphosphinyl)methyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 120°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4]Br.CC[N:14](CC)CC>N.CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4][NH2:14]
Reactant: CCN(CC)CC
Reactant: Fc1cc(Br)c(CBr)cc1Br
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCc1cc(Br)c(F)cc1Br

Procedure:
A solution of 2,5-dibromo-4-fluorobenzyl bromide (0.350 g, 1 mmol) in 7M NH3/MeOH was heated in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled and concentrated to give a white solid which was dissolved in CH2Cl2 and treated with Et3N (1 mL) then concentrated. The resulting residue was triturated with ethyl acetate (25 mL), filtered and concentrated to give the title compound (0.291 g) as a pale yellow oil. HRMS (M+H) calcd for C7H7Br2FN: 283.94; found: 283.93.
Reaction SMILES: [C@H]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:42].Cl.Cl.NC1CCN([CH2:52][C@@H:53]([N:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]2)C)CC1>>[ClH:42].[ClH:42].[OH:61][CH:58]1[CH2:59][CH2:60][N:55]([C@@H:53]([CH3:52])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][CH2:57]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(F)cc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113, see example 60) and amine 50 analogously to the method described in example 1.
Reaction SMILES: C(O[CH:5]([C:28]1[N:40]=[C:31]2[N:32]=[C:33]([CH3:39])[C:34]3[CH2:38][CH2:37][CH2:36][C:35]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[CH3:39][C:33]1[C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:40]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg, 0.31 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phosphate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 13%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 378. 1H NMR (DMSO-d6) δ 6.80 (s, 1H), 6.76 (s, 1H), 6.25 (s, 1H), 3.24 (m, 2H), 2.96 (m, 2H), 2.49 (s, 3H), 2.25 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:34]([CH3:33])(=[O:36])=[O:35])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and methanesulfonyl chloride in N,N-dimethylformamide, to give the desired product as a colorless foam (54%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH:31]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:38][S:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: NS(=O)(=O)C1CCC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Temperature: 40 °C

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutanesulfonamide (Example 271G, 256 mg, 1.894 mmol) using the general procedure described in Step A of Example 272, albeit with an oil bath heated at 40° C. The crude product was purified by silica gel chromatography eluting with a gradient of EtOAc in hexanes. The product was obtained as a white powder (220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:30]4[O:29][C:28]([C:31]([NH2:33])=O)=[CH:27][C:26](=[O:34])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:30]4[O:29][C:28]([C:31]#[N:33])=[CH:27][C:26](=[O:34])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Yield: 95 %

Procedure:
Following the process described in example 2 (point D), reacting 8-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide with phosphorous oxychloride in DMF for 0.5 h at 0° C., the title compound was prepared (95% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: CC(=O)C1CC(c2ccccc2)CCC1=O
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccccc1)CC2

Procedure:
2-Acetyl-4-phenylcyclohexanone, 1.68 g, 0.73 g of cyanoacetamide and a small quantity of piperidine were mixed with 10 ml of ethanol followed by heating to reflux for 2 hours. After cooling, the precipitated crystals were taken out by filtration and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-phenylisoquinoline.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])[CH:2]=[CH2:3].[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](Br)=[CH:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:12]([O:11][C:10]([NH:9][C@@H:6]([CH2:7][CH3:8])[C:5]([NH:4][CH2:1]/[CH:2]=[CH:3]/[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:26]=1)=[O:17])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Reactant: C=CCNC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 90 °C

Procedure:
A 50 mL sealed tube was charged with (S)-tert-butyl 1-(allylamino)-1-oxobutan-2-ylcarbamate (500 mg, 2.07 mmol), 3-bromo-indole-1-carboxylic acid tert-butyl ester (620 mg, 2.09 mmol), palladium (II) acetate (59 mg, 0.263 mmol), tri-o-tolylphosphine (180 mg, 0.591), acetonitrile (10 mL), and triethylamine (0.6 mL, 4.30 mmol). The tube was flushed with argon and sealed, then stirred and heated to 90° C. for 24 h. The resulting mixture was concentrated in vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF65-150 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield (S,E)-tert-butyl 3-(3-(2-(tert-butoxycarbonylamino)butanamido)prop-1-enyl)-1H-indole-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.23-7.36 (m, 4H), 6.60-6.66 (m, 1H), 6.20-6.51 (m, 1H), 4.05-4.11 (m, 1H), 3.86-3.91 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.72 (m, 1H), 1.44 (s, 18H), and 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Under nitrogen atmosphere, to a solution of 9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (0.10 g, 0.28 mmol) in tetrahydrofuran (0.84 mL) was added cyclopropyl magnesium bromide (1M solution in tetrahydrofuran, 0.84 mL, 0.84 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a pale yellow powder (82.4 mg, 0.21 mmol, 74%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][CH2:4][C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[CH:6][O:7]C.O1CCCC1.Cl.[OH-].[Na+]>C(OCC)C>[F:26][C:2]([F:1])([F:25])[CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH:6]=[O:7]
Reactant: COC=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 91.7 %

Procedure:
A solution of 5-(4,4,4-trifluoro-1-methoxymethylene-butyl)-2-(4-trifluoromethyl-phenyl)-pyridine (4.1 g, 10.9 mmol) and tetrahydrofuran (50 mL) is treated with concentrated hydrochloric acid (5 mL) and heated to reflux under nitrogen. The reaction is monitored by HPLC and allowed to cool upon completion. The solution is neutralized with 20% NaOH solution and diluted with diethyl ether. The two phases are separated and the organic layer washed with brine and water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Chromatography gives purified 5,5,5-trifluoro-2-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentanal (3.6 g, 10 mmol) 79% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](OC)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[Li+].[OH-].Cl.C[O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([NH:49][CH2:48][CH2:47][C:46]([OH:50])=[O:45])=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=1)=[O:18]
Reactant: COC(=O)c1cc2c(cc1Br)C(N(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1)CCO2
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCOc3cc(C(=O)NCCC(=O)O)c(Br)cc32)CC1

Procedure:
Enantiomer A of methyl 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]chromane-7-carboxylate (25 mg) was saponified with aqueous LiOH and then coupled to β-alanine methyl ester HCl salt following the procedure described (Example 3/4) to give N-({6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-3,4-dihydro-2H-chromen-7-yl}carbonyl)-β-alanine. HPLC/MS: m/z=684.2 (M+1), Rt=2.50 min. 1H NMR (DMSO-d6): δ 12.20 (1H, br s), 8.56 (1H, s), 8.38 (1H, t, J=5.5 Hz), 7.46 (2H, d, J=9.0 Hz), 7.21 (2H, d, J=9.0 Hz), 6.72 (1H, s), 4.68 (1H, m), 4.36 (1H, dt, J=2.0 Hz, 11.5 Hz), 4.20 (1H, t, J=11.5 Hz), 3.90 (1H, m), 3.37 (2H, m), 2.73 (1H, m), 2.48 (2H, t, J=7.0 Hz), 1.98-1.72 (7H, m), 1.28-1.04 (4H, m), 0.88 (9H, s).
Reaction SMILES: O.O.[C@@H:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:23]([C@@:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=c1[nH]c(=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(=O)[nH]c32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL flask was added xanthosine dihydrate (1.0 g, 3.52 mmol) and N,N-dimethyl-4-aminopyridine (0.0086 g, 0.07 mmol). N,N-dimethylformamide (16 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (8 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (1.6 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[ClH:16]>>[Cl:16][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Reactant: Cl
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 2.19 g (0.0104 mole) of methyl 2-(4-hydroxymethylphenoxy)propionate and 3.00 g (0.0823 mole) of 36% hydrochloric acid was stirred for fifteen minutes at room temperature. The reaction mixture was then poured into ice-water, and the resulting mixture was extracted with diethyl ether. The extracts were combined and washed in succession with water and a saturated aqueous solution of sodium bicarbonate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a colorless liquid. This liquid was placed on a column of silica gel and eluted with methylene chloride. After the product-containing fractions were combined and the solvent evaporated under reduced pressure, 1.6 g of methyl 2-(4-chloromethylphenoxy)propionate was isolated as a colorless liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=O)=[O:3].CC(OC1C=CC=CC=1C(O)=O)=O.[O:27]=[CH:28][C@@H:29]([C@H:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])[OH:32])[OH:30]>O>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([C@@:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])([OH:32])[C@@H:29]([OH:30])[CH:28]=[O:27])=[O:13])(=[O:3])[CH3:1]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[C@](O)([C@H](O)[C@H](O)CO)[C@@H](O)C=O

Procedure:
Elemental analysis: C15H18O9, Calculated: C, 52.63; H, 5.30 Found: C, 52.51; H, 5.42. Mass: M+1, m/z 343.0999 (M+H calculated formula: C15H19O9. Solubility of glucose-3-aspirin in water: 2.32 g/100 mL, Aspirin solubility: 0.33 g/100 mL (1 g in 300 mL water at 25° C.) (Merck Index, pp. 134, vol. 11, 1989). Thus, the aspirin-glucose conjugate was 700 times more soluble than aspirin.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.Cl>CCOCC>[C:10]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])(=[O:15])[CH3:9]
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Cyclohexylmagnesium bromide (240 ml of a 2M solution in ether) in ether (200 ml) was added dropwise to a solution of 2-methyl-4H-3,1-benzoxazin-4-one (100 g) in ether (1100 ml) at -10° C. over 2 h. The mixture was stirred at this temperature for 2 h, then at ambient temperature for 30 min. After cooling to -10° C. the suspension was treated with 2M HCl (600 ml), keeping the temperature below 0° C. After stirring for 15 min the layers were separated, and the ethereal layer washed sequentially with water (500 ml), 5% sodium hydroxide solution (2×500 ml) and finally water (2×500 ml). The organic layer was separated, dried (MgSO4), evaporated in vacuo and chromatographed on silica gel using petrol:ethyl acetate (2:1) to give (2-acetamidophenyl) cyclohexyl methanone (28 g). Mp 66° C. 1H NMR (CDCl3, 360 MHz) δ 1.25-1.89 (10H, m), 2.23 (3H, s), 3.33 (1H, m), 7.13 (1H, d of t, J=6 and 1 Hz), 7.53 (1H, d of t, J=6 and 1 Hz), 7.92 (1H, d, J=6 Hz), 8.76 (1H, d, J=6 Hz), 11.73 (1H, brs).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:27]>C(#N)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(CC(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 11.7 g. (50 mmole) ethyl 4-(piperazin-1-yl)-benzoate, 13.8 g. (0.1 mole) powdered anhydrous potassium carbonate, 125 ml. acetonitrile and 11.7 g. (50 mmole) 2-bromo-4'-chloroacetophenone (p-chlorophenacyl bromide) is stirred for 20 hours at 20° C. The reaction mixture is then suction filtered and the filter cake is washed with acetone. The combined organic phases are evaporated to dryness in a vacuum to give 15.4 g. (80% of theory) of crude product. After recrystallisation from ethyl acetate, there are obtained 9.8 g. (51% of theory) of pure product; m.p. 152°-153° C. and from the mother liquor a further 1.4 g. (7% of theory) (m.p. 150°-152° C.) of product are obtained.