Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:17]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:17])[NH2:2]
Reactant: S
Reactant: CCOC(=O)c1cc2cc(C#N)cnc2o1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(C(N)=S)cnc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 5-cyanofuro[2,3-b]pyridine-2-carboxylate (773 mg, 4.14 mmol) was dissolved in a mixed solvent of pyridine (40 ml) and triethylamine (8 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 14 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give ethyl 5-thiocarbamoylfuro[2,3-b]pyridine-2-carboxylate as a yellow solid. Acetone (80 ml) and methyl iodide (8.0 ml) were added and the mixture was refluxed under heating for one hour. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 5-[(1-methylthio)-iminomethyl]furo[2,3-b]pyridine-2-carboxylate. Methanol (80 ml) and ammonium acetate (694 mg, 9.00 mmol) were added and the mixture was refluxed under heating for 3.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=97/3-4/1) to give 2.05 g of ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride as a yellow solid (69% in 3 steps).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[F:23][C:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH:34]=O)[CH:25]=1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:26]5[CH:25]=[C:24]([F:23])[C:29]6[O:30][CH2:31][CH2:32][O:33][C:28]=6[CH:27]=5)[CH2:3][CH2:4]4)[C:13]=1[C:12]=23
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Reactant: O=Cc1cc(F)c2c(c1)OCCO2
Product: Cl
Product: O=c1ccc2ncc(Cl)c3c2n1CC3CN1CCC(NCc2cc(F)c3c(c2)OCCO3)CC1
Yield: 56 %

Procedure:
The free base of the title compound was prepared from 4-[(4-amino-1-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (32 mg) and 8-fluoro-2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde (18.2 mg) according to the general method of Example 2(h) in 56% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:23]3[CH:24]=[CH:25][N:26]=[CH:21][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2ccncn2)CC1

Procedure:
EXAMPLE 93 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,4-dichloro-pyrimidine followed by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=361.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ncccc2F)CC1
Yield: 6.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-fluoropyridine (100 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (9 mg), a yellow solid, in 7% yield.
Reaction SMILES: C([Mg]Br)(C)C.I[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1>C1COCC1>[OH:25][C:22]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:23][CH2:24][C:19]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:20][CH2:21]1
Reactant: N#Cc1cccc(I)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: N#Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of iso-propyl-magnesium bromide (Aldrich, 2.0 M in THF, 8 mL, 16 mmol) was slowly dropped into a solution of 3-iodo-benzonitrile (Aldrich, 3.25 g, 14.2 mmol) in THF (20 mL) at 0° C. After addition, the reaction was stirred for another 30 min. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.22 g, 14.2 mmol) in THF (5 mL) was added to the reaction mixture at 0° C. The reaction was then stirred for additional 2 hours. The reaction was quenched with diluted NH4Cl solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of mesylate 105 (26.38 g, 63.57 mmol) in anhydrous N,N-dimethylformamide (DMF, 120 mL) was treated with solid potassium phthalimide (12.95 g, 70.0 mmol, 1.1 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (400 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (3×100 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 106 (27.85 g, 94%) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H12FIN2O4, LCMS (EI) m/e 467 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Br)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cc(Cl)cc(Br)c1F
Yield: 102.3 %

Procedure:
To a solution of 3-bromo-5-chloro-2-fluoroaniline (SM-5, step 3, 0.52 g, 2.3 mmol) in pyridine (2.5 mL) cooled in an ice water bath was added propane-1-sulfonyl chloride (0.3 mL, 2.8 mmol). After 4 hours the solution was concentrated and partitioned between EtOAc (75 mL) and aqueous 0.1 M HCl solution (30 mL). The layers were separated and the organic phase was then washed with brine, dried (Na2SO4) and concentrated to give 778 mg of N-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide as a yellow solid which was carried forward without further purification: LCMS(m/z) not observed, tR=0.95 minute.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([O:50][CH2:51][CH2:52][CH2:53][CH2:54]O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.CCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:54][CH2:53][CH2:52][CH2:51][O:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:18][CH:17]=1
Reactant: OCCCCOCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 14.36 g (82.5 mmol) of diethyl-azo-dicarboxylate in 50 ml of tetrahydrofuran was added within 30 minutes to a solution of 11.4 g (75.0 mmol) 4-hydroxy-benzoic acid methyl ester, 20.65 g (78.8 mmol) of triphenylphosphin and 13.5 g (75.0 mmol) of 4-benzyloxy-1-butanol dissolved in 100 ml of tetrahydrofuran. The reaction mixture was then stirred for 1 hour at room temperature, 1 g of triphenylphosphin was added and stirring continued for 1 hour at room temperature and for 30 minutes at reflux. The reaction mixture was then diluted with 200 ml of hexane and filtered. The filtrate was poured into 200 ml of a saturated potassium carbonate solution and extracted 3 times with 200 ml of ethylacetate. The combined ethylacetate phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 98:2 v/v mixture of dichloromethane and ether as the eluent giving 21.8 g (92.4%) 4-(4-benzyloxy-butoxy)-benzoic acid methyl ester as colorless viscous oil, MS: 314 (M+).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:21]=[CH:20][C:5]([CH2:6][C:7]3[NH:8][CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)c[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.8 g, 10 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (3.6 g, 20 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazole, which was treated as described in general procedure R using 1,4-diiodobenzene (13.2 g, 40 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:31]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C/C=C\[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C/C=C\[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A solution of benzyl (1S,2S,4R)-4-hydroxy-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g, 20.7 mmol) in methylene chloride (60 mL) was treated with imidazole (2.1 g) and cooled to 0° C. The resultant solution was charged with tert-butylchlorodimethylsilane (3.4 g, 22.8 mmol) and then stirred for 18 h at 30° C. before being quenched with water. The organic phase was separated, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g). MS found: (M+H)+=404.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@:4]1([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)proline methyl ester (1.30 g) in THF (20 mL) at −78° C. was added a solution of KHMDS (1.25 g) in THF (20 mL). After 45 minutes, a solution of 4-bromobenzyl bromide (1.59 g) in THF (20 mL) was added at −78° C. The reaction mixture was warmed to room temperature over 3 hours and stirred for an additional 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel; EtOAc/hexane 1:2) afforded N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline methyl ester (0.474 g). MS (m/z) 398 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([CH3:19])[CH:12]=1.[Na].C([O:23][C:24](=O)[C:25](=[O:32])[CH2:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])C>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([N:5]2[CH:15]([C:14]3[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=3[CH3:19])[C:26]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[C:25]([OH:32])[C:24]2=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Reactant: Nc1cccc(Cl)c1F
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1cccc(Cl)c1F
Yield: 21 %

Procedure:
A mixture of 3-chloro-2-fluoro-aniline (0.70 g, 4.8 mmol), 4-chloro-2-methyl-benzaldehyde (0.74 g, 4.8 mmol) and the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (1.0 g, 4.8 mmol) in acetic acid (6 mL) was refluxed for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→9:1), followed by crystallization from EtOAc/hexane, to provide 426 mg of the title compound. tR: 5.47 min (HPLC 1); ESI-MS: 422 [M+H]+ (LC-MS 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:39][Cl:40]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:39][Cl:40])=[O:14])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2)cc1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(=O)OCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-methoxybenzyloxy) benzoic acid (5.16 g, 20 mmole) in 100 ml 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide (14.27 g, 22 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (35.3 g 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl acetate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 4.48 g=73%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]CC)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:41]([CH3:43])[CH3:42])[O:15][N:14]=1)(=[O:11])=[O:10].O1CCCC1.CO.[OH-].[Na+]>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)=[C:16]([CH:41]([CH3:43])[CH3:42])[O:15][N:14]=1)(=[O:10])=[O:11]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1onc(CS(=O)(=O)c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 75 °C
Yield: 27.3 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfonyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (4 mg, 0.006 mmol) in 1:1 tetrahydrofuran:methanol (0.5 mL) was added 1 N sodium hydroxide (0.020 mL, 0.020 mmol). The solution was heated in a microwave reactor at 75° C. for approximately 10 minutes. Then the mixture was diluted with dichloromethane and 1 N hydrochloric (0.020 mL, 0.020 mmol) was added. The solution was washed with water, dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)sulfonyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (1 mg, 25%). 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=8 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.10-8.07 (m, 2H), 7.71 (d, J=8 Hz, 2H), 7.47-7.38 (m, 3H), 7.12 (d, J=8 Hz, 2H), 5.16 (s, 2H), 4.86 (s, 2H), 3.25 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). LRMS m/z 609 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][C:9](=[S:19])[N:8]=1.[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]2[C:9]([S:19][CH2:23][CH2:24]2)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:10]3[C:9]([S:19][CH2:23][CH2:24]3)=[N:8][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(C2=NC(=S)N=C2c2ccccn2)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccccn3)nc3n2CCS3)cc1
Product: Fc1ccc(-c2nc3n(c2-c2ccccn2)CCS3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.76 g (0.036 mol) of 4-(2-pyridinyl)-5-(4-fluorophenyl)-imidazole-2-thione, prepared as described in part d, in 250 ml of dry N,N-dimethylformamide was treated with 3.52 g (0.073 mol) of a 50% oil dispersion of sodium hydride. The solution was stirred for 30 minutes, followed by the addition of 13.95 g (0.074 mol) of 1,2-dibromoethane. The reaction mixture was stirred for 3 hours, and then poured into ice/water. The aqueous suspension was extracted several times with methylene chloride. The combined organic layers were washed with water, dried (MgSO4), and concentrated. The products were separated by chromatography on silica gel with 10% acetonitrile in methylene chloride and 25% acetonitrile in methylene chloride as eluants. Each product was recrystallized from acetonitrile-hexane to give the title Formula (I) compounds 5-(2-pyridinyl)-6-(4-fluoro-phenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 152°-154° C., and 5-(4-fluorophenyl)-6-(2-pyridinyl)-2,3-dihydroimidazo[ 2,1-b]thiazole, m.p. 164°-166° C.
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[C@@H]([C@H](C(O)=O)O)O.[C:13]1([C:19](=[O:23])[C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[OH:23][C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([O:22][CH3:3])=[O:21]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 70 °C
Reaction time: 67 h
Yield: 93.9 %

Procedure:
To a dispersion of 1.0 g (26.3 mmol) of sodium borohydride in THF (80 ml), there was added 3.95 g (26.3 mmol) of L-(+)-tartaric acid, and the mixture was heated under reflux for four hours in an oil bath at 70° C. with stirring. The resulting mixture was cooled in a cryostat at -20° C., a solution of 1.0 g (6.6 mmol) of phenylglyoxylic acid in THF (5 ml) was added dropwise with stirring over a period of ten minutes, and stirring was continued for 67 hours. The reaction mixture was cooled in an ice bath, 30 ml of 1N HCl was added, and stirring was further continued for 30 minutes. After distilling off the solvent under reduced pressure, the residue was extracted twice with 20 ml ether, and the combined extract was washed with 50 ml of a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The dried solution was concentrated to about 30 ml, and an ethereal solution of diazomethane was added to the concentrate to esterify the reaction product. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography, giving 1.03 g of methyl (R)-(-)-2-hydroxy-2-phenylacetate as a fraction in ethyl acetate:n-hexane (1:5). Its specific rotation [α]D21 was -100.0° (cl. 09, MeOH). The synthesis yield was 93% and the optical yield was 65% e.e. (see Reference 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH2:23])=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(F)cc1C(F)(F)F
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid (1.22 g, 5.2 mmol) in THF (10 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (0.99 g, 7.80 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.53 g (40%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylamide.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:30][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CNC1CCCCC1

Procedure:
2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 20 ml of ethanol was refluxed for 2 hours with 1.86 ml of cyclohexylamine and the solvent was eliminated under reduced pressure. The residue was chromatographed over silica (eluent: chloroform-methanol 9-1) to obtain 1.97 g of 2-[3-(cyclohexylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide