Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:10][CH:9]([C:11]([OH:13])=O)[N:8]([CH3:14])[C:7]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:47][C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[CH2:55][NH2:56]>ClCCl>[CH:1]1([N:6]2[CH2:10][CH:9]([C:11]([NH:56][CH2:55][C:49]3[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:48]=3[Cl:47])=[O:13])[N:8]([CH3:14])[C:7]2=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)N(C2CCCC2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(C2CCCC2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
A mixture of 1-cyclopentyl-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (39 mg, 0.184 mmol), N-ethylmorpholine (0.094 ml, 0.735 mmol), 1-hydroxybenzotriazole hydrate (33.8 mg, 0.220 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42.3 mg, 0.220 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (32.3 mg, 0.184 mmol) in dichloromethane (1 ml) was added and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane (10 ml) and the mixture was washed with saturated sodium hydrogen carbonate solution (10 ml) and brine (10 ml), dried and evaporated. The residue was purified by mass-directed automated HPLC. The residue was triturated with ether and the resulting solid was collected and dried to give 1-cyclopentyl-N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (42 mg, 62%). LCMS [M+H]+=370, retention time=2.28 minutes.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](Br)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([C:4]2[O:3][C:2]([Br:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)c1cc(Br)oc1Br
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccnc(NC(C)=O)c2)oc1Br
Yield: 13.8 %

Procedure:
To a solution of ethyl 2,5-dibromo-3-furoate (0.21 g, 0.722 mmol) in 1,4-dioxane (2.2 mL) and water (0.50 mL) were added tetrakis(triphenylphosphine) palladium(0) (0.08 g, 0.07 mmol), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (0.19 g, 0.72 mmol) and cesium carbonate (0.71 g, 2.2 mmol). The reaction mixture was subjected to microwave irradiation at 95° C. for 15 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 5-[2-(acetylamino)pyridin-4-yl]-2-bromo-3-furoate (0.035 g, 14%) as a white solid. LCMS (FA): m/z=339.1 (M+H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([N:35]([CH2:43]OC)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:34])[CH3:33]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[C@@H:15]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:43][N:35]([CH:32]([CH3:34])[CH3:33])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(C(=O)OC(C)(C)C)C(C)C
Reactant: O=C(Cc1ccc(Cl)s1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
1.0M of titanium tetrachloride in DCM (30.9 mL, 30.9 mmol) was added dropwise to a solution of (R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43 g, 28.1 mmol) in DCM (170 mL) at −78° C., followed by N,N-diisopropylethylamine (9.78 mL, 56.2 mmol). The resulting dark blue mixture was stirred at −78° C. for 1 hour. tert-Butyl isopropyl(methoxymethyl)carbamate (11.4 g, 56.2 mmol) was then added. The mixture was stirred at −78° C. for 1 hour, and then allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hours, quenched with saturated NH4Cl (300 mL), and extracted with DCM (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc/hexane (0-20%) to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (10.2 g, 72%). MS (APCI+) [M+H]+ 507.2. 1H NMR (CDCl3, 400 MHz) δ 7.36-7.22 (m, 5H), 6.79 (d, J=4.0 Hz, 1H), 6.75 (d, J=4.0 Hz, 1H). 4.67-4.62 (m, 1H), 4.15-4.09 (m, 4H), 3.45-3.38 (m, 2H), 2.80-2.72 (m, 1H), 1.49 (s, 9H), 1.12 (d, J=6.0 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Sodium hydride (6.55 g) was added in small portions to a solution of 4-bromo-2-(trifluoromethyl)phenol (32.9 g) in THF (150 ml). After stirring at room temperature for 10 minutes, 1-(chloromethoxy)-2-methoxyethane (17 g) was then added by syringe. The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate (300 mL) and washed with water. Organics were dried over sodium sulphate and solvent evaporated under reduced pressure. The resulting residue was columned on silica gel using heptane as eluant to afford 4-bromo-1-((2-methoxy-ethoxy)methoxy)-2-(trifluoromethyl)benzene (78% yield).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C([C:10](=[CH2:14])[C:11]([NH2:13])=[O:12])CCC.[CH:15]([C:17]1C=CC=C[C:18]=1C=C)=[CH2:16].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:16]([NH:13][C:11](=[O:12])[CH:10]=[CH2:14])[CH2:15][CH2:17][CH3:18]
Reactant: C=C(CCCC)C(N)=O
Reactant: C=Cc1ccccc1C=C
Agent: C=CC(N)=O
Solvent: CCO
Solvent: O
Product: C=CC(=O)NCCCC

Procedure:
Polystyrenesulfonate (22.5 mmoles, 3.918 g), acrylamide (3.45 mmoles, 0.245 g), n-butylacrylamide (3.45 mmoles, 0.439 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 15 mL ethanol and 5 mL water in a 40 mL vial fitted with a septa cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A clear, light yellow gel formed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[C:37]=3[CH:47]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[K+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[C:37]=3[CH:47]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCc4ccccc4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OCc4ccccc4)cc3)cc21
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
0.090 g of benzyl 4-(4-benzyloxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate is dissolved in 3 ml of dioxane. 3 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 3.5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 10 ml of water and extracted with tert-butyl methyl ether (3×30 ml). The combined organic phases are washed with 10 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:26][C:24]1([CH3:27])[CH2:25][CH:20]([NH:19][C:15]2[N:14]=[C:13]([C:3]3[C:4]4[C:9](=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH:18]=[CH:17][N:16]=2)[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23]1
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(C#N)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 1H-indole-7-carbonitrile and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 10 mg (6%).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([Cl:11])=[C:5]2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=3[C:22]([F:23])([F:25])[F:24])=[CH:3][S:4][C:5]=12
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Reactant: Clc1ccnc2c(Br)csc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(-c2csc3c(Cl)ccnc23)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 91.4 %

Procedure:
A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (123 mg, 0.495 mmol), 4-fluoro-2-(trifluoromethyl) phenylboronic acid (123 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (20.21 mg, 0.0.025 mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K3PO4 (0.74 mL, 1.485 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 40%-60% CH2Cl2/hexanes at 30 mL/min. Concentration of appropriate fractions provided the title compound (150 mg, 91% yield) as a white solid. LC/MS: Example 101A @ 3.94 min (RT) (Condition G). MS (ES): m/z=331.94, [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:8][C@H:4]([CH2:5][CH:6]1[OH:7])[CH2:3][NH:2]2.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[OH:7][CH:6]1[C@H:1]2[CH2:8][C@H:4]([CH2:3][N:2]2[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: OC1C[C@@H]2CN[C@H]1C2
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C[C@@H]3CC(O)[C@H]2C3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 47.2 %

Procedure:
To a round bottom flask was added (1S,4R)-2-azabicyclo[2.2.1]heptan-6-ol (0.5 gm, 3.34 mmol), 4-fluorobenzonitrile (0.405 gm, 3.34 mmol), DMF (6 ml) and K2CO3 (1.386 gm, 10.03 mmol). The reaction was stirred at 80° C. for 5 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (4×) and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give product 4-((1R,4S)-6-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (338 mg, 1.578 mmol, 47.2% yield) as a white solid. Anal. Calcd. for C13H14N2O m/z 214.2, found: 215.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:8][C@H:9]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ncoc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ncoc1[C@@H](N)Cc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-5-[1-(tert-butoxycarbonylamino)2-phenylethyl]oxazole-4-carboxylate, (Tett. Lett., 1982, 23, 235; 417 mg) was dissolved in trifluoroacetic acid (3 ml) and stood at ambient temperature for 1 hour and concentrated to give an oil. Trituration with diethyl ether gave the title compound as a white solid. (281 mg).
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=3)[N:21]=2)=[CH:18][CH:19]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.1 %

Procedure:
A solution of methylene chloride (10.4 mL) was cooled to −78° C. To this was added dimethyl sulfoxide (416 uL) and oxalyl chloride (340 uL) and the solution was stirred for 5 minutes. {4-[5-(4-Isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (574 mg, 1.86 mmol) and diisopropyl ethyl amine (2.7 mL) were added to the reaction mixture and stirred at −78° C. for 30 minutes. The reaction mixture was warmed to room temperature, concentrated in vacuo and diluted with ethyl acetate. The mixture was washed with 1N HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to provide a crude residue. This residue was slurried in hexanes (10 mL) and heated to reflux. The solution was allowed to cool to ambient temperature and the resulting slurry was stirred for 1 hour and filtered. The solid was washed with minimal cold hexanes and dried in vacuo to give the title compound (183 mg, 32% yield) as a solid.
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.II.O.O.I(O)(=O)(=O)=O.S(=O)(=O)(O)O.[I:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][CH2:30][CH2:31]2.IC1C=C2C(=CC=1)CCCC2>C(O)(=O)C.O>[I:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: Ic1cccc2c1CCCC2
Agent: II
Agent: Ic1ccc2c(c1)CCCC2
Agent: O=S(=O)(O)O
Solvent: c1ccc2c(c1)CCCC2
Solvent: CC(=O)O
Solvent: O
Product: IC1CCCc2ccccc21
Temperature: 70 °C
Yield: 83.4 %

Procedure:
132.2 g (1.00 mol) of tetralin was dissolved in 600 ml of 80% acetic acid, and 101.5 g (0.40 mol) of iodine, 45.5 g (0.20 mol) of periodic acid dihydrate and 15 ml of concentrated sulfuric acid were added thereto. The mixture was heated to 70° C. with stirring. The mixture was further stirred for 3 hours at the same temperature whereupon disappearance of tetralin was confirmed to terminate the reaction. The reaction mixture was added to 1000 ml of water, and the separated oily substance was extracted with 1000 ml of toluene. The toluene layer was washed with water and concentrated and then subjected to distillation under reduced pressure (bp: 120° C./3 mmHg) to obtain 215.3 g of the main fraction (yield: 83.4%). This product was a mixture of 5-iodotetralin and 6-iodotetralin in a blend ratio of 1:2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32].ClC1SC(COC2C=CC(CCC(OCC)=O)=C(C)C=2C)=C(C2C=CC(Cl)=CC=2)C=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2cc(Cl)sc2CO)cc1
Agent: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(C)c1C
Product: CCc1ccc(-c2cc(Cl)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 197 by coupling of [5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.32 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.02 (s, 2H), 6.91 (d, J=8.1 Hz, 2H), 6.61 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.64-2.71 (m, 2H), 2.49 (t, J=8.4 Hz, 2H), 2.28 (s, 3H), 2.16 (s, 3H), 1.28 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H25ClO3S, 427.1[M−H]. found 427.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][C@@H:15]([CH3:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][C@H:15]([CH3:18])[CH2:14][Br:13])[CH:6]=1
Reactant: C[C@@H](CO)CBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OC[C@H](C)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560 mole) was added In a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][C:18]([CH3:22])=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>[Ni].CO.C1COCC1>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][C:18]([CH3:22])=[CH:17]2)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C)cnc23)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C)cnc23)c(N)c1
Yield: 21.8 %

Procedure:
In a similar fashion using route 6 general procedure 14, 4-methyl-N-(3-methylquinolin-8-yl)-2-nitrobenzenesulfonamide (Intermediate 157) (100 mg, 0.28 mmol), Raney nickel (20 mg, 20% wt), hydrazine hydrate (42 mg, 0.84 mmol) and MeOH/THF (4:1, 5 ml) gave the title compound (20 mg, 22%) after purification by column chromatography with n-hexane/EtOAc (1:0-4:1) gradient elution.
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH2:13][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncoc1Cc1ccccc1
Product: ClCc1ncoc1Cc1ccccc1

Procedure:
5-Benzyl-4-oxazolecarboxylic acid is converted to 5-benzyl-4-hydroxymethyl xazole by the procedure of Example 135. Treating this hydroxylmethyl compound with thionyl chloride gives 5-benzyl-4-chloromethyloxazole.
Reaction SMILES: [CH2:1]([C:16]([OH:18])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].O[CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C1(C)C=CC=CC=1>[CH2:1]([C:16]([O:18][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[CH3:28])[CH3:23])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)CC=C(C)CCC=C(C)CCC=C(C)C
Yield: 78.7 %

Procedure:
A mixture of farnesyl carboxylic acid (5.0 g), farnesol (4.44 g) and triethylamine (4.85 g) was added dropwise at room temperature to a stirred solution of 2-chloro-1-methylpyridinium iodide (5.61 g) in 40 ml of toluene. After complete addition, the reaction mixture was heated on boiled water bath for three hours. After cooling, the mixture was washed with water and dried (Na2SO4). The solvent was removed in vacuo and gave a pale yellow oil. This material was purified by silica gel chromatography by using n-hexane and gave 7.15 g of the titled compound.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.CC(C)C=CC([Cl:21])=O.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1/[CH:38]=[CH:39]/[C:40]1[CH:45]=CC=C[CH:41]=1.Cl>CO>[ClH:21].[CH3:41][CH:40]([CH3:45])/[CH:39]=[CH:38]/[C:30]1[N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: CC(C)C=CC(=O)Cl
Agent: Cl
Agent: Nc1ccccc1Nc1ccccn1
Solvent: CO
Product: CC(C)/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 4-methyl-2-pentenoyl chloride (Yamada, T.; Takashima, K.; Miyazawa, T.; Kuwata, S.; Watanabe, H. Bull. Chem. Soc. Jpn. 1978, 51, 878) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to give the titled compound. MW: 299.81; mp: 140.0-141.0° C.; 1H-NMR (DMSO) δ: 8.81-8.79 (1H, m), 8.25 (1H, td, J=8.1, 1.8 Hz), 7.85-7.79 (2H, m), 7.77-7.71 (1H, m), 7.56-7.45 (3H, m), 7.31 (1H, dd, J=16.1, 7.0 Hz), 6.47-6.40 (1H, m), 2.75-2.55 (1H, m), 1.05 (6H, d, J=7.0 Hz).