Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[C:4]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13](=O)[O:14]C(C)(C)C)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29]C(O)=O>>[Br:1][C:2]1[C:3]2[N:21]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)[C:9]([CH:10]([NH:12][C:13](=[O:14])[CH3:29])[CH3:11])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Br)c1Nc1cncc(F)c1
Reactant: CC(=O)O
Product: CC(=O)NC(C)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Reaction time: 120 h

Procedure:
A solution of (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate (2.4253 g, 5.35 mmol) in AcOH (17.83 mL) was heated at 100° C. with stirring. After 5 days, the mixture was removed from the heat and poured into a biphase of DCM (100 mL) and satd. sodium bicarbonate solution (100 mL). The mixture was basified with 10N NaOH (10 mL). The organic layer was washed with water (100 mL×3) and brine (100 mL X1), dried over MgSO4, filtered, and concentrated in vacuo to provide N-(1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide as a dark brown solid: LC-MS (ESI) m/z 376.9 [M+H (79Br)]+ and 379 [M+H (81Br)]+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1)[CH2:30][CH2:31][CH3:32]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.0 g, 3.78 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.08 ml of a 2M solution in tetrahydrofuran, 4.16 mmol). After stirring for 5 min tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reaction stirred for 10 min at −78° C. then allowed to warm to ambient temperature to give a solution of 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine in tetrahydrofuran (ca. 0.15M): m/z (ES+) 474, 476, 478 (M++H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:6]=1[CH:14](O)[CH2:15][CH3:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:14]([C:6]1[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:5]=1[OH:4])[CH2:15][CH3:16]
Reactant: CCCc1ccc(C(O)CC)c(OCOC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(CCC)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a solution of 1-[2-(methoxymethoxy)-4-propylphenyl]propan-1-ol (12.7 g, 53.3 mmol) and triethylsilane (21.3 mL, 133 mmol) in CH2Cl2 (120 mL) at 0° C. was added trifluoroacetic acid (16.4 mL, 213 mmol) slowly with an outlet needle attached to the round-bottom flask. The solution was stirred at 0° C. for 5 min and then at room temperature for 14 h. Water (40 mL) was added and the mixture was stirred at room temperature for 2 h. Extraction in CH2Cl2 (2×150 mL) with 50% saturated brine (5×100 mL) removed all of the trifluoroacetic acid. Flash chromatography with silica gel (gradient to 5% EtOAc/hexanes) furnished the title compound as a light green liquid (3.60 g, 38% yield): 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H, J=7.3 Hz), 0.97 (t, 3H, J=7.3 Hz), 1.62 (m, 4H), 2.52 (m, 4H), 4.58 (s, 1H), 6.60 (s, 1H), 6.69 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=7.6 Hz); MS m/e 179 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([S:8]([NH:11][C:12]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1.[C:25]([BH3-])#[N:26].[Na+].[CH2:29]=O.[OH-].[Na+]>C(#N)C.O.C(O)(=O)C>[CH3:29][N:26]([CH3:25])[C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([S:8]([NH:11][C:12]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2Cl)n1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cc(N(C)C)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an agitated solution of 3.7 g of 5-amino-2-chloro-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide and 0.88 g of sodium cyanoborohydride in 50 ml of acetonitrile is added 3 ml of formalin. To the reaction mixture is then added 1 ml of glacial acetic acid over a period of 10 minutes. The reaction is then stirred at room temperature for 2 hours, another ml of glacial acetic acid is added and stirring is continued for an additional 30 minutes. The reaction mixture is then poured into 50 ml of water, brought to pH 7 by the addition of aqueous sodium hydroxide and extracted several times with methylene chloride. The combined methylene chloride extracts are washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo yields the desired product, 5-dimethylamino-2-chloro-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)n3cccc3)s2)c1
Yield: 93 %

Procedure:
N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-methoxyphenylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:12]=1[OH:20]>>[NH2:17][C:16]1[C:11]([CH3:10])=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:20][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCCC1
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1c(N)cccc1OCCN1CCCC1

Procedure:
By the method of examples 2 and 3, 1-(2-chloroethyl)pyrrolidine hydrochloride and 2-methyl-3-nitrophenol were converted into the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:19].[I-].[Na+].C(N(C(C)C)C(C)C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]=[C:41]=[O:42]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:15]2[CH:16]=[CH:17][C:12]3[N:11]=[C:10]([NH:19][C:41]([NH:40][C:34]4[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:42])[S:9][C:13]=3[CH:14]=2)[CH:7]=1
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(C)cc1N=C=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1NC(=O)Nc1nc2ccc(Nc3cc(Cl)ncn3)cc2s1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A mixture of 4,6-dichloropyrimidine (180 mg, 1.21 mmol), benzothiazole-2,6-diamine (200 mg, 1.21 mmol), sodium iodide (216 mg, 1.45 mmol), ethyl diisopropylamine (0.25 mL, 1.45 mmol) and DMF (10 mL) was heated at 85° C. for 3 h. 2-Methoxy-5-methylphenyl isocyanate (0.20 mL, 1.33 mmol) was added and heating was continued at 85° C. for 3 h. The solvent was removed and the residue treated with CH2Cl2. The precipitate was separated (0.57 g, 85%). LC/ESI-MS: m/z=441 [M+H]+; m/z=439 [M−H]−; Rt=3.64 min.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([OH:37])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:41]1([O:47][C:48](Cl)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CO>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([O:37][C:48]([O:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[S:49])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1OC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
In an atmosphere of argon gas, 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (151 mg, 0.3 mmole) was dissolved into acetonitrile (5 ml), to which were then added 4-dimethylaminopyridine (75.1 mg, 0.62 mmole) and phenyloxythiocarbonyl chloride (57 μl, 0.33 mmole). After stirring the resulting mixture at room temperature for 24 hours. 0.1M aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water and then with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-(phenoxythiocarbonyloxy)cyclohexyl]-adenine (109 mg, Yield 56.8%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl[C:13]1[C:18](Cl)=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.[ClH:24]>C(COC)OC>[Cl:24][C:8]1[CH:7]=[C:6]([C:3](=[O:5])[CH3:4])[CH:11]=[C:10]([C:15]2[C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][CH:18]=[CH:13][N:14]=2)[CH:9]=1
Reactant: CC(=O)c1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1cc(Cl)cc(-c2ncccc2C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
To a suspension of 2.6 g (0.065 mol) of sodium hydride 60% in dimethoxyethane at room temperature is added 3.4 mL (0.029 mol) of acetophenone. After 45 min., 5.55 mL (0.038 mol) of 2,3-dichloro-5-(trifluoromethyl)pyridine is added. After 25 min., the reaction mixture is poured over 100 mL of hydrochloric acid 1N, extracted twice with 100 mL of ethyl acetate.
Reaction SMILES: [CH2:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)[CH2:2][CH3:3].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[C:16]=1[CH3:23]>CS(C)=O>[CH3:22][C:17]1[C:16]([CH3:23])=[C:15]([O:11][CH2:10][CH2:9][C:4]2([CH2:1][CH2:2][CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[CH:20]=[CH:19][N+:18]=1[O-:21]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCC1(CCO)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC1(CCOc2cc[n+]([O-])c(C)c2C)OCCO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a dimethylsulfoxide (22.5 ml) solution of the 2-(2-propyl-1,3-dioxolan-2-yl)ethanol (1.5 g, 9.35 mmol) obtained in the step (3b), sodium hydride, in oil (561 mg, 14 mmol as the content was regarded as 60%) and 4-chloro-2,3-dimethylpyridine1-oxide (1.33 g, 8.42 mmol) were added in a nitrogen stream and stirred at 60° C. for 2 hours. The mixture was allowed to stand at room temperature for 3 days and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran. NH silica gel was added to the resultant mixture, which was then concentrated to dryness and subjected to NH silica gel column chromatography (elution solvent: n-heptane/ethyl acetate/methanol=1/1/0→0/1/0→0/10/1) to obtain the title compound (1.53 g, yield: 58.2%) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][CH2:55]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:55][CH2:54][O:53][C:52]2[CH:58]=[CH:59][CH:60]=[CH:61][C:51]=2[O:50][CH3:49])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccccc1OCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Yield: 40 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (114 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-methoxyphenoxy)-1-propanol (69 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 35%).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10](Cl)[CH2:11][CH2:12][C:13](=[O:16])[O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.ClCCl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:10](=[O:9])[CH2:11][CH2:12][C:13]([O:14][CH3:15])=[O:16])=[CH:3][CH:2]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thioanisole (12.4 g) and 1,4-dioxo-4-methoxybutyl chloride (16.5 g) in dichloroethane (100 ml) were cooled to 0° C. and aluminum chloride (16 g) was added, followed by another equivalent (16 g) and the reaction mixture was stirred at 0° C. for 2 hours. Ice was added, followed by 1N HCl. Dichloromethane (100 ml) was then added and the organic layer was separated, washed with water and then brine and dried with Na2SO4. Removal of the solvents yielded the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-[3′-(4-fluorobenzoyl)-4′-methoxyphenoxy]benzoate (350 mg, 0.78 mmol) and TFA (2 mL) in CH2Cl2 (50 mL) at room temperature was added triethylsilane (0.5 mL, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with water (25 mL) and extracted with ether (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexanes, filtered and dried under reduced pressure to afford methyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzoate as a brown solid (0.31 g, 92%): mp 108-110° C.; 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 2 H), 7.06 (dd, J=6.0, 9.0 Hz, 2 H), 6.88 (t, J=8.7 Hz, 2 H), 6.70 (d, J=9.0 Hz, 1 H), 6.58 (d, J=3.0 Hz, 1 H), 6.48 (dd, J=3.3, 9.0 Hz, 1 H), 3.89 (s, 3 H), 3.83 (s, 2 H), 3.71 (s, 3 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:8); Rf=0.8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:18]=[C:19]([CH3:23])[C:20](=O)[CH3:21])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[C:29]1([C:35]2[N:36]([NH2:46])[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([N:18]=[C:19]([C:20](=[N:46][N:36]3[C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][CH:39]=[C:35]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:21])[CH3:23])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.6 %

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (2.45 g, 8.1 mmol) in toluene (28 mL) was treated with DMF (14 mL), 2,5-diphenyl-pyrrol-1-ylamine (1.99 g, 8.5 mmol) and p-toluene sulfonic acid (73 mg). The resulting suspension was fitted with a Dean Stark trap and heated to reflux in an oil bath for 21 h, then cooled to rt and allowed to stand under Ar for 4 days. The desired compound did not crystallize, therefore the solution was concentrated in vacuo. Approximately half of the residue was purified by flash chromatography (SiO2, 5-100% EtOAc/heptane) to afford some pure desired 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (780 mg) and some desired contaminated with starting 2,5-diphenyl-pyrrol-1-ylamine. The remaining crude residue was flash chromatographed (SiO2, 33-50% CH2Cl2/heptane) in an attempt to remove excess amino pyrrole. No separation was achieved, therefore all of the fractions were combined, together with the impure material from the first column and concentrated in vacuo. This mixture was suspended in toluene (15 mL) and treated with DMF (5 mL), 2,3-butanedione (0.81 mL, 9.24 mmol) and p-toluene sulfonic acid (7 mg). The resulting suspension was heated to 70° C. in an oil bath, and stirred under Ar for 3 h, then cooled to rt and concentrated in vacuo. The resulting solid was washed with water, heptane and toluene (to remove 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one and 2,3-butanedione) and dried in vacuo to afford 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (1.42 g) as a yellow solid. Overall, 2.2 g (52% based on 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one) of 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane was isolated as a yellow solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.71 (s, 6H), 6.44 (s, 4H), 7.22-7.36 (m, 20H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[C:33]([Cl:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[Cl:36])=[CH:20][CH:19]=2)[C:15]#[N:16])=[C:10]([CH3:37])[CH:9]=1.[BH4-].[Na+]>CO.C1COCC1.[OH-].[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[C:29]([Cl:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[Cl:34])=[CH:22][CH:23]=2)[CH2:15][NH2:16])=[C:10]([CH3:37])[CH:9]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(-c4ccccc4Cl)cc3C)cc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)c3ccc(-c4ccccc4Cl)cc3C)cc2)c(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2-(2′-chloro-3-methylbiphenyl-4-yl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile from step 4 (1 eq.) in MeOH/THF (4:1; 0.08M) at room temperature was added cobaltous chloride hexahydrate (CoCl2.6H2O; 2 eq.) and then portionwise sodium borohydride (10 eq.). The final black mixture was stiffed for 12 h at room temperature, poured in aqueous NaOH (1N) and diluted with EtOAc. The precipitate was filtered-off on celite and the organic extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3 2M) 4%, afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.52-7.48 (m, 1H); 7.40-7.25 (m, 6H); 7.11 (s, 2H); 6.98 (d, 2 H); 6.80 (d, 2H); 4.39-4.32 (m, 4H); 3.35 (m, 1H); 3.10 (m, 2H); 3.0-2.75 (m, 4H); 2.30 (s, 3 H); 2.20 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].Br[C:12]1[O:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:12]1[O:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1coc(Br)c1
Reactant: CC(C)c1ccccc1S
Product: CC(C)c1ccccc1Sc1cc(C(=O)O)co1

Procedure:
Following the procedure of Example 9, o-isopropylthiophenol [4.77 g., 31.4 mmoles; Hansch and Blondon, J. Am. Chem. Soc. 70, 1561 (1948)] was reacted with 5-bromofuran-3-carboxylic acid. Rather than recover the initial crude product by filtration, the mixture was reextracted with ethyl acetate, the ethyl acetate back-washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated to yield crude product. Recrystallization from hexane produced purified 5-(2-isopropylphenylthio)furan (785 mg., m.p. 117°-120° C., m/e 262).