Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[C@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[CH3:43])[C:37](O)=[O:38].[NH2:63][C@@H:64]([CH2:71][CH:72]1[CH2:76][CH2:75][CH2:74][CH2:73]1)[C:65]([C@@:67]1([CH3:70])[CH2:69][O:68]1)=[O:66]>CN(C=O)C>[CH:72]1([CH2:71][C@H:64]([NH:63][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH3:43])[C@H:35]([OH:34])[C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[C:65]([C@@:67]2([CH3:70])[CH2:69][O:68]2)=[O:66])[CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2CCCC2)CO1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sequentially HATU (1.84 g, 4.80 mmol) and DIEA (0.63 mL, 20 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (1.65 g, 4.00 mmol) and (S)-2-amino-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.2 g, 4.0 mmol) in DMF (30 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1 to EtOAc) to afford (2S,3R)-N-((S)-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (1.45 g, 61% yield) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ 7.40 (d, J=5.7 Hz, 1H), 7.32-7.22 (m, 2H), 7.06-6.99 (m, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.26-5.21 (m, 1H), 4.68-4.60 (m, 2H), 4.58-4.39 (m, 2H), 4.01-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25 (d, J=4.8 Hz, 1H), 2.99-2.85 (m, 2H), 2.53-2.39 (m, 4H), 1.74-1.61 (m, 8H), 1.53 (s, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.28-1.20 (m, 3H). MS(EI) for C30H44N4O8, found 589.3 (MH)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCO[CH2:37][CH2:36]1>>[CH:31]([N:28]1[CH2:27][CH2:26][N:25]([C:23]([C:19]2[CH:20]=[C:21]3[C:22](=[CH:17][CH:18]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:6][CH2:36][CH3:37])[CH2:9][CH2:10]2)[CH:15]=[CH:16]3)=[O:24])[CH2:30][CH2:29]1)([CH3:33])[CH3:32]
Reactant: C1COCCO1
Reactant: CC(C)N1CCN(C(=O)c2ccc3c(ccn3C3CCN(C(=O)OC(C)(C)C)CC3)c2)CC1
Agent: Cl
Product: CCCN1CCC(n2ccc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)CC1
Temperature: 60 °C

Procedure:
4-[5-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (example 26) was treated with 4N HCl in dioxane and evaporated to dryness. The residue was used in the consecutive step without further purification. The residue was dissolved in THF and treated with KOtBu. Propyliodide was added and heated to 60° C. After evaporation to dryness the residue was dissolved in methanol/DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to the title compound. MS (m/e): 397.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:17](Br)([CH3:19])[CH3:18].Cl>>[CH:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-propylbromide: m.p. 220° C. (HCl); MS m/z (rel. intensity, 70 eV) 281 (M+, 4), 266 (bp), 187 (5),129 (5), 115 (5)
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20]3)=[O:17])[C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[C:18]=2[CH2:19]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 1, 2, 3, 4 Tetrahydroisoquinoline (25 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 7.9 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(O)[O-].[Na+].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:24]([CH:9]([OH:10])[C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)CC1CCCCC1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Example 1B (19.7 g, 77.1 mmol) and sodium bisulfite (8.0 g, 77.1 mmol) in water (500 mL) at 5° C. was stirred for 24 hours, warmed to room temperature, treated with a solution of potassium cyanide (5.1 g, 78.8 mmol) in ethyl acetate (350 mL), and stirred for 5 hours. The aqueous phase was separated and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide tert-butyl (1R)-2-cyano-1-(cyclohexylmethyl)-2-hydroxyethylcarbamate.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=[O:6].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:3][CH:4]([CH2:10][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1nc(-c2ccccc2)cc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Sodium hydride (2.1 g, 60% strength in oil) and anhydrous tetrahydrofuran (50 cc) are placed under nitrogen. A solution of diethyl methylmalonate (9.1 g) in anhydrous tetrahydrofuran (50 cc) is added dropwise. Stirring is continued for 1 hour at room temperature (approximately 20° C.) and a solution of 1-bromomethyl-3-phenylisoquinoline (10.4 g) in anhydrous tetrahydrofuran (100 cc) is added. After 20 hours of contact, water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×50 cc). After removal of the solvents under reduced pressure, the product (19 g) recovered is brought to boiling for 20 hours in concentrated hydrochloric acid (70 cc) and acetic acid (70 cc). After being cooled, the mixture is poured into water (1000 cc) and alkalinised to pH 10 with sodium hydroxide solution, and the aqueous phase is washed with ethyl acetate (100 cc) acidified with hydrochloric acid and extracted with chloroform (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. α-Methyl-3-phenyl-1isoquinolinepropanoic acid (7.4 g), m.p. 184° C., is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[C:24]([CH3:39])=[C:25]([CH3:38])[C:26]2[O:31][C:30]([CH3:35])([CH2:32][CH2:33]O)[CH2:29][CH2:28][C:27]=2[C:36]=1[CH3:37]>ClCCl>[Br:20][CH2:33][CH2:32][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]2[C:36]([CH3:37])=[C:23]([OH:22])[C:24]([CH3:39])=[C:25]([CH3:38])[C:26]=2[O:31]1
Reactant: BrBr
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To 11.0 g (0.042 mol) of triphenylphosphine in 200 ml of dichloromethane is added dropwise a solution of 6.71 g (0.042 mol) of bromine in 50 ml of dichloromethane. The solution is stirred for 30 min at room temperature, then 10.0 g (0.04 mol) of 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ethanol (CAS 79907-48-5) is added. The resulting solution is refluxed for 4 hours, allowed to cool overnight, washed with a solution of 15 g of sodium carbonate in 200 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil is crystallized from methanol to give 9.22 g of 3,4-dihydro-2-(2-bromoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[C:15]=1[CH3:16])=[O:10])[CH3:7].C([N-]C(C)C)(C)C.[Li+].C(I)C>C(OCC)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=2[C:15]=1[CH2:16][CH2:2][CH3:3])=[O:10])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry tetrahydrofuran (3 ml) solution of 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (50 mg) was added lithium diisopropylamide (1.2 ml, 0.5N in THF) at −78° C. After 30 minutes ethyl iodide (160 μl) was added at the same temperature. Then reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and dried over anhydrous sodium sulfate then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-propyl-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (5.1 mg). FAB-MS: m/z 462 (MH+); 1H-NMR (CDCl3): δ 1.12-1.54 (21H, m), 2.09 (2H, m), 2.75 (3H, s), 3.52 (2H, dd, J=7.6 Hz, 9.9 Hz), 4.09 (2H, t, J=5.9 Hz), 4.43 (2H, q, J=7.3 Hz), 6.61 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=8.6 Hz, 7.9 Hz).
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](O)(=[O:20])[CH:13]([CH:15]([C:17](O)=[O:18])[OH:16])[OH:14]>C1(C)C=CC=CC=1>[CH2:1]([N:11]1[C:17](=[O:18])[CH:15]([OH:16])[CH:13]([OH:14])[C:12]1=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCCCCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCN1C(=O)C(O)C(O)C1=O
Temperature: 100 °C

Procedure:
N-Decyl DL-tartarimide was prepared by the reaction of n-decyl amine with DL-tartaric acid. DL-Tartaric acid (10.143 g, 67.579 mmole) and toluene (17.332 g) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Claisen adapter was placed in the center neck, a Dean-Stark trap was placed on top of the Claisen adapter, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing n-decyl amine (10.630 g, 67.578 mmole) and toluene (6.257 g, added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>C(#N)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:9][C:8]1[CH:10]=[CH:11][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Methylparaben (8.85 g, 58.19 mmol) and K2CO3 (16.1 g, 116.38 mmol) were stirred in acetonitrile (100 mL) for 5 minutes and then 2-fluorobenzyl bromide (10 g, 52.9 mmol) was added. The suspension was heated to 50-55° C. and held for 2 hours. The mixture was then cooled to 20-25° C., filtered, and the filtrate solution concentrated to a thick residue. The residue was then dissolved in CH2Cl2, washed with a 1 M Na2CO3 solution, dried over Na2SO4, and concentrated to a solid. The solid was then stirred vigorously for 1 hour in just enough hexanes to allow for agitation (˜40 mL) and then cooled to 0-5° C. After 15 minutes, the product was isolated by filtration and washed with ˜25 mL of hexanes. After drying under vacuum, 1 was isolated as a white solid (13.1 g, 87% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4](Cl)[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=2)[C:18]([NH2:20])=[O:19])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxy)-acetic acid (100 mg, 0.37 mmol), 2-amino isonicotinamide (77.89 mg, 0.56 mmol) and DMAP (92.58 mg, 0.75 mmol) in DMF 5 ml was added PyBOP (394.3 mg, 0.75 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.076 g, 52% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]Br)=[CH:5][CH:4]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][SH:15])=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCS)cc1
Reaction time: 2 h

Procedure:
A mixture of 3-(p-methoxyphenyl)-1-propylbromide (14 g; 61 mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours. Evaporation of the solvent provided a clear glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide. After stirring the resulting mixture for two hours, the product was extracted into ether (3×), and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated. Chromatographic purification of the crude thiol on a silica gel column eluting with 2% either in hexane delivered 10.2 g of 3-(p-methoxyphenyl)-1-propylmercaptan as a clear liquid 1H NMR (300 MHz, CDCl3):δ 1.34 (t, 1H); 1.88-1.92 (m,2H); 2.49-2.53 (m,2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 (m,2H); 7.06-7.24 (m,2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:24]>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[N:7]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1)[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCOc2cc(C#N)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (7-cyano-chroman-4-yl)-carbamic acid tert-butyl ester (769 mg, 2.81 mmol, 1.0 eq), NaH (Aldrich, 449 mg (60% by weight), 11.2 mmol, 4.0 eq) in DMF (15 mL) was stirred at RT for 3 h. Iodomethane (Aldrich, 1.99 g, 14.1 mmol, 5.0 eq) was added slowly. The resulting mixture was stirred at RT for 21 h. The reaction was quenched with saturated NH4Cl (40 mL) DMF was removed with a rotary evaporator at 70° C. The crude was diluted with H2O (100 mL), extracted with EtOAc (80 mL×4). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-15% EtOAc-Hexane) afforded the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 289 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(OCC)(=O)[CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].Cl>O.C(O)(C)(C)C>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=CCC(=O)O)c2ccc(C)cc2)cc1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 29.7 grams (141 mmol) 4,4'-dimethylbenzophenone and 141 mL t-butanol forming a solution, followed by 17.4 grams (155 mmol) potassium t-butoxide and 29.5 grams (170 mmol) diethyl succinate. The reaction was refluxed for 18 hours, cooled, and acidified with 6N hydrochloric acid, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated, and the residue taken up in 200 mL glacial acetic acid. It was then treated with 70 mL 48% hydrobromic acid and refluxed for 36 hours. The reaction was cooled, partitioned between water and ethyl acetate, and the combined organic layers washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford the product as low melting solid, 25.0 grams (66%), Rf =0.25 in 5% methanol/methylene chloride on silica gel. This material was used directly in the next step.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:34]=1
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Yield: 65.8 %

Procedure:
A mixture of 0.58 g of 1-(6-iodohexyl)-2,3-bis(phenyl-methoxy)benzene, 0.18 g of 3-hydroxybenzoic acid methyl ester and 0.25 g of potassium carbonate in 15 mL of acetone was stirred at reflux for 18 hours. Workup as in Example 16 and purification by HPLC using toluene gave 0.40 g (66% yield) of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[Cl:14]/[CH:15]=[CH:16]/[CH2:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:18]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:19])[C:8]=2[S:9][CH:10]=1
Reactant: Clc1csc2c(CBr)cccc12
Reactant: CNC/C=C/Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 2.62 g-(10 mmol) of 7-bromomethyl-3-chlorobezo(b]thiophene in 10 ml of dimethyl sulfoxide were added 1.7 g (12 mmol) of (E)-N-(3-chloro-2-propenyl)methylamine hydrochloride and 2.07 g (15 mmol) of ground potassium carbonate. The mixture was stirred for 16 hours at room temperature, and poured into 150 ml of dichloromethane. The organic layer was washed with 100 ml×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-heptane). The desired fractions were put together and concentrated under reduced pressure to obtain 2.12 g (yield: 74%) of the above identified compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])=[CH2:13].[H-].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[C:3]([CH2:2][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])[C:21](=[O:23])[CH3:22])=[CH:8][C:7]([F:9])=[C:6]([Cl:10])[N:5]=1
Reactant: C=Cc1ccccc1NC(C)=O
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred mixture of 1B (0.5 g, 1.93 mmol) and N-(2-vinyl-phenyl)-acetamide bb (0.314 g, 1.95 mmol) in DMF (5 mL) was added NaH (47 mg, 1.95 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at room temperature, then poured into H2O (50 mL) and extracted with Et2O (20 mL). The Et2O layer was washed with H2O (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1C (0.63 g, 96%). HPLC Rt=3.212 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).