Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCBr)cccc21
Reaction time: 2 h
Yield: 281.4 %

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,5-dibromopentane (3.72 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. After 2 hours, water was added and the solution was repeatedly extracted with ether. The collected organic phases were washed with water, dried on Na2SO4 and evaporated under reduced pressure to give a solid (4.50 g), which was purified by chromatography on silica gel (Etp/Et2O 8:2) yielding 2.38 g of a white solid. Yield 68%.
Reaction SMILES: C[C:2]12[CH2:11][C:9]3([NH2:12])[CH2:10][CH:4]([CH2:5][C:6](C)([CH2:8]3)[CH2:7]1)[CH2:3]2.Cl.Cl>>[C:9]12([NH2:12])[CH2:10][CH:4]3[CH2:3][CH:2]([CH2:7][CH:6]([CH2:5]3)[CH2:8]1)[CH2:11]2
Reactant: CC12CC3CC(C)(C1)CC(N)(C3)C2
Agent: Cl
Product: NC12CC3CC(CC(C3)C1)C2
Yield: 5 %

Procedure:
In a manner similar to the preparation of the compound of formula DC in Example 13, the compound of formula SA was prepared except that the compound of formula EC was used in place of the compound of formula DB and memantine hydrochloride (i.e., the hydrochloride of 1-amine-3,5-dimethyl-adamantane, Sigma-Aldrich) was used in place of 1-adamantylamine (yield 5%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:19])[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:18])[CH:13]=1)[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1cc(C)cc(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and m-xylene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 3', 5'-dimethylbenzoin was obtained as a light-yellow oil (363.2 mg, 75.3% yield).
Reaction SMILES: [O:1]=[C:2]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][C:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:11]=2[O:10][C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:3]1.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][C:11]=2[O:10][C:4]2([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3]1
Reactant: O=C([O-])COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A mixture of ethyl (2-{(3,4-dihydro-4-oxospiro [2H-1-benzopyran-2,1'-cyclohexan]-6-yl)oxy}acetate (prepared in Preparation 27) (0.5 g, 1.57 mmol) and 1N sodium hydroxide (1.9 ml, 1.9 mmol), and ethanol (5 ml) is stirred at room temperature for one hour. The mixture is made acid with 1N HCl, filtered, and washed with small amount of water to separate crystalline precipitates. Recrystallization from a mixture of diethyl ether and hexane gives the title compound as a crystalline solid (0.39 g, 85.6%, m.p.=148°-149° C.).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20]C(O)=O>C1(C)C=CC=CC=1>[Cl:6][CH2:1][C:2](=[O:3])[CH2:20][C:14]1[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CCl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 ml of oxalyl chloride and 0.5 ml of dimethylformamide were added to a stirred suspension of 5.12 g of (2,6-dichlorophenyl)acetic acid in 120 ml of toluene. The mixture was stirred at room temperature for 2.5 hours and then evaporated to dryness. The residue was suspended in 40 ml of diethyl ether and the suspension was added gradually to 250 ml of a 0.25M solution of diazomethane in diethyl ether. The mixture was stirred at room temperature for 2 hours and then cooled to 0° C. Hydrogen chloride was then bubbled through the mixture for 10 minutes. 300 ml of water were added to the mixture and the phases were separated. The organic phase was washed with 200 ml of saturated sodium hydrogen carbonate solution and 300 ml of water, dried over anhydrous sodium sulphate and evaporated to give 6.04 g of 1-chloro-3-(2,6-dichlorophenyl)-2-propanone in form of a white solid. This solid was taken up in 21 ml of chloroform, 7.19 g of triphenylphosphine were added and the solution was stirred and heated under reflux for 6 hours. The mixture was cooled and poured into 200 ml of diethyl ether. The resulting precipitate was collected, washed with diethyl ether and dried to give 8.605 g of [3-(2,6-dichlorophenyl)-2-oxopropyl]triphenylphosphonium chloride in the form of a white solid. This solid was taken up in 1.5 l of warm water and the mixture was filtered. The filtrate was stirred while 12.5 ml of 5% sodium hydroxide solution were added. The mixture was extracted twice with 600 ml of diethyl ether each time and the combined extracts were washed with 1 l of water, dried over anhydrous sodium sulphate and evaporated. The residue was recrystallized from 150 ml of diethyl ether and yielded 4.286 g of [3-(2,6-dichlorophenyl)-2-oxopropylidene]triphenylphorphorane of melting point 98°-100° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].[CH3:21][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:21])[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c2nc(C(C)(C)C)sc2c1O
Yield: 89.2 %

Procedure:
A solution of 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (145 mg, 0.40 mmol), tetramethyl tin (220 μL, 1.6 mmol), dichlorobis(triphenylphosphine)-palladium II (30 mg, 0.04 mmol) in 2.5 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 10-50% ethyl acetate in hexanes) to give 105 mg of a white solid. MS (ESI−): m/z 293.4 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.[C:8](OC)(=[O:23])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].C[O-].[Na+].Cl>CO.C1C=CC=CC=1>[C:8]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)(=[O:23])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:10]
Reactant: OC1CCCNC1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(OC1CCCNC1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
30 ml of benzene, 0.4 g (4 mmol) of 3-piperidinol and 1.0 g (4 mmol) of methyl benzilate were put into a 50 ml 3-mouth flask equipped with a stirrer, a reflux condenser, and a molecular sieve 4A (15 g) tube and a soda lime tube for trapping methanol from out of the solvent that drips down through the reflux condensation, and the mixture was refluxed by heating while stirring. After all of the methyl benzilate had dissolved, 20 mg of sodium methoxide (made by Aldrich) was added to the solution and reaction was carried out for 3 hours. After the reaction had been completed, the reaction liquid was cooled to room temperature, and then 50 ml of 1N hydrochloric acid was added, and the organic solvent layer was removed. The aqueous solution layer obtained was washed twice with 50 ml of ether, and was then made basic using a 28% ammonium hydroxide aqueous solution. The aqueous solution was subjected to ether extraction, the ether layer obtained was washed twice with 50 ml of water, and then drying was carried out using anhydrous potassium carbonate. After removing the drying agent, the solvent was evaporated off under reduced pressure, thus obtaining an oily residue, and then this residue was recrystallized from ether-hexane, thus obtaining 0.5 g of (±)3-piperidyl benzilate ((±)3-PB) as crystals (yield 40%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[NH:6][C:7](=[O:20])[C:8]3[CH:18]=[C:17]([Br:19])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C1C=CN=CC=1.[FH:28].N([O-])=O.[Na+].[OH-].[Na+]>>[Br:19][C:17]1[CH:16]=[N:15][C:9]2[N:10]([CH2:13][CH3:14])[C:11]3[N:12]=[C:2]([F:28])[CH:3]=[C:4]([CH3:21])[C:5]=3[NH:6][C:7](=[O:20])[C:8]=2[CH:18]=1
Reactant: F
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(N)nc21
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(F)nc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A plastic bottle was charged with 2-amino-8-bromo-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (5.10 g, 14.6 mmol). HF-pyridine (100 g) was added and the resulting suspension was cooled to 0° C. Sodium nitrite (1.12 g, 16.1 mmol) was added in several portions over 30 min to produce a purple solution. The mixture was then stirred for 16 h at room temperature. The reaction mixture was poured onto ice and 6 N NaOH. The beige suspension was extracted with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated. The residue was triturated with Et2O/hexane to give the title compound (4.30 g, 84% yield).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:8][C:9]=2[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCc1oc(C2CCCCC2)nc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1oc(C2CCCCC2)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H32N4O3 (m/e) 400, obsd 401 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:11](Cl)([Cl:13])=[O:12]>C1C=CC=CC=1>[C:5]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:11]([Cl:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)N(C(=O)Cl)c1ccccc1

Procedure:
A solution of N-isopropylaniline (30 g) in dry benzene (150 ml) was cooled to 5°-10° C and phosgene passed therethrough slowly for 11/2 hours. The mixture was refluxed for 1 hour to remove excess phosgene, cooled and the amine hydrochloride was filtered off. The solvent was evaporated and the residue recrystallised from benzene-petroleum ether 1:1, giving 21.6 g, m.p. 89°-90° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[CH:6]=1.S(Cl)([Cl:16])(=O)=O>C(Cl)(Cl)Cl>[Cl:16][C:6]1[C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3][C:2]=1[CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc2cc(C#N)ccc2o1
Solvent: ClC(Cl)Cl
Product: Cc1oc2ccc(C#N)cc2c1Cl
Yield: 24.3 %

Procedure:
A solution of 2-methylbenzofuran-5-carbonitrile (J. Het. Chem., 4, 441, 1967) (1.52 g) and sulphuryl chloride (1.49 g) in chloroform (25 ml) was heated under reflux for 9 hours and then cooled. The solution was washed successively with water, dilute sodium hydroxide solution, water and then dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised twice from methanol to give 3-chloro-2-methylbenzofuran-5-carbonitrile (0.45 g), m.p. 131.5°-133.5°.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C:20]([C:22]1[CH:23]=[N:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH3:42])=[CH:29][CH:28]=2)[CH:26]=1)=[O:21])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([C:20]([C:22]1[CH:23]=[N:24][N:25]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH3:42])=[CH:31][CH:32]=2)[CH:26]=1)=[O:21])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CC(=O)OC(C)(C)C)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CC(=O)OC(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution of tert-butyl N-{2-(tert-butyldimethylsilyloxy)ethyl}-N-{[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]carbonyl}glycinate prepared in Example 67-(2) (0.220 g) in tetrahydrofuran (2.0 ml), a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.37 ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=18:1) to give the titled compound (0.180 g) as a colorless oil.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:20]1[CH:21]=[CH:22][C:18]([CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:19]1
Reactant: [N-]=[N+]=NCCc1ccsc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 40.8 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.485 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.089 g, 0.581 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.067 g, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.12 (d, 1H), δ 6.83 (s, 1H), δ 6.70 (d, 1H), δ 6.29 (s, 1H), δ 4.41 (t, 2H), δ 3.04 (t, 2H), δ 2.50 (t, 2H), δ 2.29 (t, 2H), δ 1.72 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.8, 146.8, 137.7, 127.8, 127.6, 125.7, 122.6, 121.9, 109.0, 50.7, 30.7, 27.9, 23.7 ppm; HRMS (ESI) calcd for C14H18N6S (M+) 302.1313. Found 302.1317.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reaction time: 1.5 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (200 mg) was dissolved in trifluoroacetic acid (4 ml) and stirred for 1.5 hours. The solvent was evaporated, and the residue was subjected to azeotropic distillations twice with methanol (10 ml) and twice with ethanol (10 ml) and washed with ether to obtain trifluoroacetic acid salt of Gly-Gly-Phe-Gly-OH (225 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:18][CH3:19])=[C:9]2[C:14](=O)[C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]>C(Cl)Cl.C(OCC)C.[Zn+2].[I-].[I-]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:18][CH3:19])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:17])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C)(C)C2=O
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1sc(SC)c2c1CCC(C)(C)C2

Procedure:
To a suspension of anhydrous ZnI2 (647 mg, 2.03 mmol) and Na(BH3CN) (117 mg, 1.86 mmol) in DCM (5 mL), a solution of 5,5-dimethyl-3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (539 mg, 1.81 mmol) in DCM (5 mL) is added. The yellow suspension is refluxed over night before another portion of ZnI2 (100 mg, 0.314 mmol) and Na(BH3CN) (26 mg, 0.419 mmol) is added. The reaction mixture is refluxed for further 24 h. The mixture is diluted with diethyl ether and washed with sat. aq. NaHCO3 solution and brine. The organic layer is separated, dried over Na2SO4 and the solvent is removed under reduced pressure to give 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester as a beige resin; LC-MS: tR=1.15 min, [M+1]=285.2; 1H NMR (CDCl3): δ 4.30 (q, J=7.0 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.54 (t, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Cc1ccnc(Br)c1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4cc(C)ccn4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromo-4-methylpyridine
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Temperature: 130 °C

Procedure:
A mixture of ethyl 4-fluorobenzoate (4.47 g), dimethylpyrrolidin-3-ylamine (3.04 g), potassium carbonate (3.68 g) and dimethyl sulfoxide (20 ml) was heated at 130° C. for 7 hours. After cooling, the mixture was diluted with water and extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 262.35 (C15H22N2O2) was obtained in this way; MS (ESI): 263 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O)=[O:19])[CH3:13].N1CCCCC1>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (126 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:19][CH:20]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl) butoxy)benzamido)propanoate (70 mg, 0.14 mmol) was dissolved in methanol (2 mL) and 1M lithium hydroxide (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The methanol was removed under reduced pressure and the residue was diluted with water (2 mL). Upon stirring a precipitate forms. The solution was further diluted with water (15 mL) and 1M NaOH (3 mL). The solution was extracted with ether (20 mL). The organics were washed with water (10 mL) and the aqueous layers were combined. The aqueous solution was acidified with 1M HCl to give a cloudy solution. The solution was extracted with ethyl acetate (2×15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give (+/−)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoic acid (53.1 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3, δ): 7.89 (s, 1H), 7.66-7.60 (m, 2H), 7.58 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 6.97-6.92 (m, 2H), 6.77 (t, J=6 Hz, 1H), 5.29 (dd, J=9, 4.4 Hz, 1H), 3.73-3.63 (m, 2H), 2.66-2.64 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.83 (m, 1H), 1.62 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H). MS (M+1): 490.2.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]COC)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl>C(O)C>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2OCOC)cc1
Agent: Cl
Solvent: CCO
Product: C=CCOc1ccc(C(=O)c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 4-allyloxy-2′-(methoxymethyloxy)-benzophenone (1.1 g) in ethanol (15 mL) was concentrated hydrochloric acid (0.96 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1) to give 4-allyloxy-2′-hydroxy-benzophenone (0.87 g).