Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>CO.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
The compound (5.06 g, 5.47 mmol) synthesized in Example 4 (4a) was dissolved in methanol (75 mL) and tetrahydrofuran (15 mL) and palladium chloride (II) (190 mg, 1.09 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. After the reaction mixture was subjected to celite filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1-3:1-2:1, V/V) to obtain the desired title compound (3.07 g, yield 63%) as pale yellow amorphous matter.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[NH:5][C:4]=2[N:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:23]([N:5]1[C:4]2[N:3]=[C:2]([Cl:1])[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(=O)[nH]c2nc(Cl)n(Cc3ccc(Cl)cc3)c2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.154 mmol, intermediate 10) in DMF (3 mL) was added (bromomethyl)benzene (50 mg, 0.29 mmol) followed by potassium carbonate (40 mg, 0.29 mmol). The mixture was stirred at 40° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with petroleum/ethyl acetate (5:1 to 3:1) to give 3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (60 mg, 93.6% yield) as white solid. LCMS retention time 1.893 min; LCMS MH+ 415.
Reaction SMILES: [OH-:1].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>CO>[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]([NH2:13])=[O:1])[CH:7]=3)[NH:3][CH:4]=2)[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: [OH-]
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(C(N)=O)cc23)CC1
Temperature: 2.5 °C
Yield: 11.3 %

Procedure:
A solution of KOH (1.0 g, 17.68 mmol) in methanol (20 mL) was added to 1H-indole-5-carbonitrile (1.0 g, 6.96 mmol). 1-methylpiperidin-4-one (1.0 g, 8.75 mmol) was then added dropwise with stirring, while cooling to 0-5° C. and the resulting solution was stirred for 1 hour at 50° C. The reaction mixture was then cooled to room temperature, concentrated, and the residue was purified by column chromatography using ethanol solvent system to give 200 mg of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:34])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step V (5.340 g) in 1,2-dichloroethane (60 mL) is added formaldehyde (1.94 mL of 37% aqueous solution, 23.88 mmol), followed by sodium triacetoxyborohydride (2.403 g, 11.34 mmol) in portions over 20 min. The mixture is stirred at room temperature overnight, then water is added to the mixture, and it is extracted with CH2Cl2. Organic fraction is washed with aqueous NaHCO3 and brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel eluting with 0-10% of MeOH in CH2Cl2 to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7].[CH3:10]O>>[Cl-:1].[OH:9][CH:4]([CH2:5][C:6]([O:8][CH3:10])=[O:7])[CH2:3][NH3+:2]
Reactant: NCC(O)CC(=O)O
Reactant: Cl
Reactant: CO
Product: COC(=O)CC(O)C[NH3+]
Product: [Cl-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Anhydrous hydrochloric acid gas was bubbled into a suspension of 4-amino-3-hydroxybutanoic acid (0.91 g, 7.61 mmol) in methanol (150 mL) until the solution was saturated and stirred at ambient temperature. After 18 h, the solution was concentrated to give the title compound (1.32 g). MS 134 (M+1).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.C([O:20][CH2:21][C:22](Cl)=[O:23])(=O)C.C1CCN2C(=NCCC2)CC1.Cl>CC#N.N1C=CC=CC=1>[CH3:15][C:2]1([CH3:16])[O:1][C:21](=[O:20])[C:22]([OH:23])=[C:3]1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (29.5 g, 122 mmol) in CH3CN (350 mL) were added pyridine (25 mL) and acetoxyacetyl chloride (25 g, 183 mmol). After a period of 7 h at r.t., DBU (31 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (35 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture was allowed to cool to r.t. The mixture was poured onto ice-water (2.5 L) containing 100 mL of concentrated HCl. The brown solid was collected and dissolved in hot acetonitrile and was filtered through a plug of silica. The solvent was evaporated and the resultant solid was swished in EtOAc to give the title compound (21.2 g, 62%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])#[N:14].Cl>CN(C=O)C>[CH2:26]([O:25][C:23]1[CH:22]=[C:17]([CH:16]=[C:15]([C:13]2[NH:14][N:3]=[N:2][N:1]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)cc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Sodium azide (1.5 g) and triethylamine hydrochloride (3.2 g) were added to a DMF (70 mL) solution of methyl 3-cyano-5-benzyloxybenzoate (2.07 g), and stirred at 100° C. for 6 hours and then overnight at room temperature. With cooling with ice, diluted hydrochloric acid was added to it, the precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Cl.[C:9]([Cl:12])(C)=O.CCOCC>CO>[NH2:1][C@@H:2]([C:5]([O:7][CH3:9])=[O:6])[CH2:3][SH:4].[ClH:12]
Reactant: CC(=O)Cl
Reactant: N[C@H](CS)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](N)CS
Yield: 80.7 %

Procedure:
To a cooled (0° C.) solution of H-D-Cys-OH.HCl (2.0 g, 0.013 mol) in 89.0 mL of MeOH was added 4.5 mL (0.063 mol) of AcCl. The resulting colorless solution was heated at reflux for 5 h, cooled, concentrated on a rotary evaporator, and then stripped down with Et2O until a white solid resulted. Additional Et2O (~100 mL) was added, the solid filtered, washed with Et2O, and excess solvent removed in vacuo to provide H-D-Cys-OMe.HCl as a white solid (1.80 g). The synthesized compound was identical (1H NMR) to commercially available H-Cys-OMe.HCl (Sigma).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](Cl)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[CH:20][CH:21]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 82 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methylpiperazine-1-carboxylate (2.00 g, 9.99 mmol, 1.00 equiv), 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene (5.46 g, 20.1 mmol, 2.01 equiv), potassium carbonate (6.90 g, 49.9 mmol, 5.00 equiv), acetonitrile (30 mL). The resulting solution was stirred overnight at 82° C. in an oil bath. The resulting solution was diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 1.70 g (53% yield) of tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate as a light yellow solid. LCMS: (ESI, m/z): 435 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(4-bromophenyl)propanoic acid (14.5 g, 63.60 mmol, 1.00 equiv) in thionyl chloride (80 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum to give 15.5 g (99%) of 3-(4-bromophenyl)propanoyl chloride as a light yellow oil.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[OH-].[Na+].[C:14]12([C:24]([CH2:26]Br)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1>[C:14]12([C:24]([CH2:26][CH:2]([C:3]([O:5][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To tert-butyl malonate was added, in THF, an equimolar amount of sodium hydroxide. To this mixture was added bromomethyl adamantyl ketone, and the mixture was stirred for 3 hours. The salt precipitated was filtered off, and the filtrate was concentrated to obtain di-tert-butyl 2-((1-adamantyl)carbonyl-methyl)malonate (ADTB).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][C:10]2[N:11](C(OC(C)(C)C)=O)[C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[NH:14][C@H:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(CC(O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(/C=C/C2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a cold (0° C.) solution of 2-[2-(4-fluorophenyl)-2-hydroxyethyl]-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acid, tert-butyl ester (256) (690 mg, 1.5 mmol) in dichloromethane (2 mL) is added TFA (2 mL). The reaction mixture is stirred at RT overnight. Reaction mixture is rotary evaporated and the residue purified by chromatography on silica gel; elution with dichloromethane:MeOH (9:1) gives 110 mg of the product 259. 1H NMR (CDCl3) δ 8.10 (d, 1 H), 7.60-7.35 (m, 2 H), 7.15-6.85 (m, 9 H), 6.85-6.60 (m, 4 H), 5.20 (s, 2 H); MS: m/z 343 (M++1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=1)=O.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:14]>>[CH3:12][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:17]3[CH:16]=[C:15]([CH2:13][CH3:14])[CH:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: CCc1ccnc(N)c1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Product: CCc1ccn2cc(-c3ccc(C)c(C)c3)nc2c1

Procedure:
The title compound, MS: m/e=250.8 (M+H+), was prepared in accordance with the general method of example 8 from 2-Bromo-1-(3,4-dimethyl-phenyl)-ethanone and 4-Ethyl-pyridin-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[F:38]C1C=CC=CC=1S>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:38])=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: Fc1ccccc1S
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2F)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromommethyl-2-methoxybenzoate (Intermediate 89) and 2-fluorothiophenol.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.C([Li])CCC.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.CC[O:26]CC>>[OH:26][C:15]1([CH:18]=[CH:19][CH:20]=[CH:21][CH:14]1[C:13]([F:23])([F:22])[F:12])[CH2:16][C:2]1[S:6][CH:5]=[N:4][CH:3]=1
Reactant: CCOCC
Reactant: Brc1cncs1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Li]CCCC
Product: OC1(Cc2cncs2)C=CC=CC1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromothiazole in 12 ml of ether at -78° C., 2.1 ml of 2.5M n-butyl lithium were added dropwise over 30 minutes. The resulting brown suspension was stirred at -78° C. for 2 hours and then a solution of 2-(trifluoromethyl)benzaldehyde in 2 ml of diethyl ether was added dropwise. The reaction was quenched 1 hour later with 10 ml of water saturated with ammonium chloride. The reaction mixture was extracted twice with 2 ml of diethyl ether. The organic phases were combined, dried (MgSO4) and concentrated in vacuo to yield 1.16 g of a brown oil. This oil was heated to 50° C. at 0.01 mm Hg to remove volatiles leaving 1.16 g of brown oil which was then chromatographed on silica gel using hexane-ethyl acetate (75-25) as the eluant. The last fraction to come off the column contained 297 mg of the desired product, 5-(1-hydroxy-2'-trifluoromethylbenzyl)-thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:35]1[CH:36]=[CH:37][S:33][CH:34]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(-c3ccsc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 86.1 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), 3-thiopheneboronic acid (120 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), toluene (6 ml), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml) was heated under reflux under a nitrogen atmosphere for 6 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (260 mg).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[F:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[C:17](=[O:19])[CH3:18]>BrC(Br)C.C(OCC)C>[CH:1]1([C:17]([C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[F:6])([OH:19])[CH3:18])[CH2:3][CH2:2]1
Reactant: BrC1CC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(Br)Br
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(c1ccc(C(F)(F)F)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A few drops of dibromoethane and then 6.30 g (52.1 mmol) of cyclopropyl bromide, dissolved in 20 ml of diethyl ether, were added under argon to 1.33 g (54.7 mmol) of magnesium in 90 ml of dry diethyl ether. The mixture was heated under reflux for 2 h. After cooling, 21 ml (9.94 mmol) of the supernatant reaction solution were added dropwise under argon to a solution of 850 mg (4.12 mmol) of 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone in 17 ml of diethyl ether, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient with addition of 0.1% triethylamine) to result in 157 mg (15% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH:18]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])([CH3:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(C)C
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-4,6-dinitro-o-cymene (4.0 g, 0.0155 mole) and isopropylamine (3.2 g, 0.054 mole) in toluene is heated in a bomb at 100° C. for 4 hours. The cooled mixture is washed with aqueous bicarbonate solution, dried over magnesium sulfate, and concentrated to leave the crude product which is purified by dry column chromatography to yield 3.2 g of product with mp 54°-55° C. By using one of the aforementioned procedures for the dinitration of the appropriate N-alkyl-4-alkyl-m-toluidines or by reacting the appropriate amine with the desired 3-chloro-2,4-dinitro-6-alkyltoluene the following compounds are prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH2:18])[CH:14]=[C:13]([C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH2:28])[CH:12]=2)=[CH2:10])=[CH:5][CH:4]=1.C1COCC1.[H][H]>[Pd].CCO>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH:27]([C:13]2[CH:14]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH3:18])[CH:16]=[C:11]([CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:10])[CH:12]=2)[CH3:28])=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: C=C(c1ccc(OC)cc1)c1cc(C(=C)c2ccc(OC)cc2)cc(C(=C)c2ccc(OC)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(C)c2cc(C(C)c3ccc(OC)cc3)cc(C(C)c3ccc(OC)cc3)c2)cc1

Procedure:
A mixture of 1,3,5-tris(1-(4-methoxyphenyl)vinyl)benzene (4) (19.61 g, 41 mmol), 5% Pd/C (500 mg), THF (50 mL) and EtOH (50 mL) was hydrogenated (50 torr) on a Parr® apparatus for 5 h. After this time the uptake of hydrogen ceased. The mixture was filtered through diatomaceous earth to remove the catalyst and rotary evaporated leaving the title compound as a colorless, viscous oil. Yield: 19.6 g (100%). 1H NMR (300 MHz, CDCl3, δ, ppm): 7.06 (d, J=8.7 Hz, 6H), 6.88-6.84 (m, 3H), 6.79 (d, J=8.9 Hz, 6H), 4.0 (q, J=7.5 Hz, 3H), 3.78 (s, 9H), 1.52 (d, J=7.3 Hz, 9H). 13C NMR (75 MHz, CDCl3, δ, ppm): 157.16, 145.83, 145.78, 145.74, 138.03, 137.99, 137.97, 127.55, 123.54, 123.46, 123.41, 113.36, 54.61, 42.94, 42.92, 21.29. Anal. calcd for C33H36O3: C, 82.46; H, 7.55. Found: C, 82.23; H, 7.40.