Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Li]C1C=CC=CC=1.[Li]C(CC)C.CN([CH:38]=[O:39])C>C1COCC1>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:38]=[O:39])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(-c2ccc3c(I)n[nH]c3c2)cc1OC
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 71 %

Procedure:
In a 100-mL round-bottom flask, 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (921 mg, 2.245 mmol, 1.00 equiv) was dissolved in THF (36 mL) and cooled to −78° C. (allow 8 min at this scale). A solution of PhLi (2.5 mL, 1.8 M, 4.49 mmol, 2.00 equiv) was added and the mixture was allowed to stir for 30 min. A solution of s-BuLi (3.63 mL, 4.71 mmol, 2.1 equiv) was added and the reaction mixture was allowed to stir for 1 h at −78° C. Neat DMF (1.4 mL, 18 mmol, 8.0 equiv) was added. The cold bath was removed and the reaction was allowed to slowly warm to 0° C. in the air. As the ice melted saturated sodium bicarbonate (20 mL) was added. The product was extracted into ethyl acetate (200 mL) from saturated sodium bicarbonate (75 mL more), dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica, 4:6 ethyl acetate/hexane) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (498 mg, 71%)): Rf sm 0.30, p 0.14 (ethyl acetate-hexane 4:6); 1H NMR (CDCl3) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.67 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.7 Hz), 7.19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][C:43]([CH3:45])=[CH2:44])=[O:41].CCCCCC>CCOC(C)=O>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:40](=[O:41])[O:42][C:43]([CH3:45])=[CH2:44])=[C:25]([F:29])[CH:24]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A bi-phasic mixture of Example A4 (1.00 g, 2.142 mmol) in EtOAc (25 mL) and satd. NaHCO3 (25 mL) was treated with isopropenyl chloroformate (516 mg, 4.28 mmol) and stirred vigorously at RT for 3 h. Hexane (10 mL) was added and the resulting solid collected via filtration and dried. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and combined with the above-isolated solid to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (1.168 g, 98% yield). MS (ESI) m/z: 551.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCc2c(Cl)cccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4-chloro-1-indanylidene) acetic acid (5.5 g, 0.03 mol) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 mL) was treated with oxalyl chloride (6.6 g, 0.05 mol) and allowed to stir at room temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1>O1CCCC1.[Cl-].[Na+].O>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Benzoyl isothiocyanate (15 mL, 112 mmol) is added to a 0° C. solution of benzyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (34.7 g, 106 mmol) in tetrahydrofuran (347 mL). The mixture is warmed to room temperature and stirred for 1 hour. Brine (300 mL) is added, the aqueous layer is separated, the organic layer is dried over magnesium sulfate, and concentrated to give the title compound (51 g, 98%). ES/MS (m/e): 390 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:18][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoic acid dissolved in 100 ml THF were treated with 9.6 ml of a 2M lithium diisopropylamide solution, at −23° C. The mixture was kept at that temperature for 15 min. then, 1.19 ml of methyl iodide were added dropwise. The reaction mixture was kept at 0° C. for 4 hours then allowed to warm at room temperature for several days. The mixture was quenched with 100 ml of 1N hydrochloric acid solution. The mixture was extracted with three portions of 100 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of a saturated aqueous sodium chloride solution. The organic phase was dried with MgSO4, and the solvent was evaporated. The yellow oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes). 1H NMR (CDCl3): 7.31 (d, J=2.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 1.67 (s, 4H), 1.58 (s, 6H), 1.27 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].O>C(O)(=O)C>[F:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)cc1F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.3 ml, 13.8 mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0 g, 7.9 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h and water (2 ml) was added and the stirring was continued for 30 minutes at room temperature. The mixture was evaporated to dryness in vacuo. The yield of the crude product was 1.3 g (100%) and it was used without further purification.
Reaction SMILES: Cl.C([C@@H]1C(OC)=[N:9][C@@H:8]([CH2:13][C@@H:14]([CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]([O:29]C)=N1)(C)C.[C:31]([O-])(O)=[O:32].[Na+]>C(#N)C>[CH3:31][O:32][C:7](=[O:29])[C@@H:8]([NH2:9])[CH2:13][C@@H:14]([CH:26]([CH3:27])[CH3:28])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:20][CH:21]=1
Reactant: O=C([O-])O
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Temperature: 25 °C

Procedure:
With stirring at room temperature, 36 ml of 1N hydrochloric acid are added to a solution of 3.55 g of 2(R)-isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butylphenyl)-propyl]-2,5-dihydro-3,6-dimethoxy-pyrazine in 36 ml of acetonitrile and the mixture is then stirred for a further 3 hours. The reaction solution is then poured onto a mixture of 45 ml of saturated NaHCO3 solution and ice and the suspension is extracted with dichloromethane. The extracts are concentrated by evaporation and purified by FC (700 g of silica gel, eluant: dichloromethane/methanol/NH3 =200:10:1), yielding the title compound: Rf (dichloromethane/methanol/conc. ammonia=200:10:1)=0.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH3:15])[CH:6]=[CH:7][CH:8]=O.[O:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:32]2[O:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH3:15]
Reactant: COc1cc(C=CC=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-2,4-oxazolidinedione.
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: O=C(Cc1ccc(Cl)s1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(C(=O)OC(C)(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
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: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([O:16]C(C)(C)C)=[O:15])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc2c(ccn2CC2CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2c(ccn2CC2CC2)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2A, 1.1 g, 4.0 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 50° C. for 15 h. The mixture was concentrated in vacuo to give 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (2B, 0.9 g, 4.0 mmol) as a brown oil. The material was used for next reaction without further purifications. ESI-MS: m/z 217.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]1[NH:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:7]=1[CH2:6]2
Reactant: NNc1ccccc1
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5-methoxy-4,6-dimethyl-1-indanone (3.0 g, 16 mmol) and phenylhydrazine hydrochloride (2.3 g, 16 mmol) was heated to reflux in ethanol (20 cm3) containing concentrated hydrochloric acid (2 cm3). The reaction mixture was heated at reflux for 6 hours, and cooled to room temperature. Water was added, and the resulting precipitate filtered off. This product was dried in a vacuum oven, and purified by column chromatography to yield the title compound as a colourless solid. Yield: 2.8 g, (67%). M.p. 177° C. from ethyl acetate petrol (60°-80° C.). 1H NMR (CDCl3)δ: 2.36 (6H, s,), 3.56 (2H, s,), 3.76 (3H, s,), 7.1-7.6 (5H, m,), 8.2 (1H,br,).
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5][C:4]2[C:9]([CH2:12][CH2:13][CH2:14][CH2:15]N3CCN(C4C=CC5OC(C(N)=O)=CC=5C=4)CC3)=[CH:10][NH:11][C:3]=2[CH:2]=1.ClCCCC(C1C2C(=CC=C(C#N)C=2)NC=1)=[O:39].[BH4-].[Na+].Cl>C(O)(C)C>[OH:39][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[C:4]2[C:3](=[CH:2][CH:1]=[C:6]([C:7]#[N:8])[CH:5]=2)[NH:11][CH:10]=1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1ccc2[nH]cc(CCCCO)c2c1

Procedure:
As per the process described in CN'932 publication, vilazodone is prepared by reacting 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile with sodium borohydride in isopropanol at reflux temperature, followed by treating the reaction mass with dilute hydrochloric acid and subsequent workup and then subjecting to column chromatography purifications to produce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile. The hydroxylbutyl intermediate obtained is then subjected to sulfonylation using a sulfonylating agent selected from p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride to produce corresponding sulfonylated intermediate, which is then condensed with 5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile to produce vilazodone.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH3:9])=[N:5][C:4]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])=[O:2].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O.CC(O)C>CC(C)=O.S(=O)(=O)(O)O.O>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([C:4]2[N:5]=[C:6]([NH:8][CH3:9])[S:7][C:3]=2[C:1]([OH:27])=[O:2])[CH3:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C=O)s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C(=O)O)s1
Reaction time: 1 h
Yield: 20 %

Procedure:
5-Formyl-4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (1.00 g, 2.9 mmoles) was dissolved in acetone (20 ml). Jones reagent (chromic acid (VI) dissolved in a mixture of concentrated sulfuric acid and water) (2 ml) was added dropwise thereinto while cooling the system with ice, after which it was stirred for one hour. Then, an additional 2 ml of Jones reagent was added dropwise and the resulting mixture was stirred for one hour. A small quantity of 2-propyl alcohol was added to the reaction mixture, it was extracted with ether, and the ether layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the desired 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylic acid (205 mg, 0.58 mmole, yield 20%) as a white crystalline product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 2-bromo-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-yl boronic acid (70 mg, 0.542 mmol) and Pd(PPh3)4 (57 mg, 0.0493 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74 (br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H23NO2S, 306.1 (M+H), found 306.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37]C)=[N:35][CH:36]=1>CN(C=O)C>[OH:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(O)nc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a solution of N-(4-(4-hydroxy-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (5-3, 1.92 g, 5.91 mmol) in DMF (15 mL) were added cesium carbonate (2.41 g, 7.39 mmol) and Cu (116 mg, 1.78 mmol, 0.30 equiv). The mixture was stirred at 80-90° C. for 60 min. 5-Bromo-2-methoxy-pyridine (9-1, 1.67 g, 8.87 mmol) was added to the solution and the reaction mixture was stirred at 100° C. for additional 24 hr. The solution was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 5 (0.97 g) in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.89 (d, J=5.0 Hz, 2H), 8.23 (d, J=5.0 Hz, 2 H), 8.02 (s, 1 H), 7.37 (d, J=3.0 Hz, 1 H), 6.89 (s, 1 H), 6.80 (d, J=9.0 Hz, 1 H), 6.69 (s, 2 H), 3.94 (s, 3H), 2.17 (s, 6 H), ESI-MS=m/z 433.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[CH:17](O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[CH:17][N:8]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1NCC1CCOCC1
Reactant: O=CO
Product: Brc1ccc2ncn(CC3CCOCC3)c2c1

Procedure:
A solution of the crude product of Example 5B (8.41 g, 29.5 mmol) in formic acid (10 mL, 261 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was concentrated and dissolved in ethyl acetate. The mixture was washed with 10% aqueous potassium carbonate and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 50-100% ethyl acetate/hexane then 10% 2:1 methanol/water in ethyl acetate, followed by recrystallization from ethyl acetate/hexane, afforded the title compound. MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][OH:28])=[CH:22][C:21]=1[F:29]>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][O:28][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:22][C:21]=1[F:29]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cc(F)cc(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cc(F)cc(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and (4-(3,5-difluorophenoxy)-3,5-difluorophenyl)methanol (88 mg, 0.323 mmol) in DMF (2 mL)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH2:16])=[O:9].[C:31]1([O:37][CH2:38][CH:39]2[O:41][CH2:40]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][CH2:40][CH:39]([OH:41])[CH2:38][O:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCNCC(O)COc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
In 20 ml of ethanol were dissolved 1.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.64 g of glycidyl phenyl ether, and the solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95.5 v/v), and 0.87 g of 2-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was treated with an ethanol solution of hydrochloric acid to provide 0.8 g of hydrochloric acid salt as amorphous powder.