Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@H:20]2[O:77][C@H:76]([CH2:78][O:79][C:80](=[O:82])[CH3:81])[C@@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C@H:53]4[O:70][C@H:69]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[C@@H:64]([O:65][C:66](=[O:68])[CH3:67])[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]4[O:55][C:56](=[O:58])[CH3:57])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[SH:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@H:20]2[O:77][C@H:76]([CH2:78][O:79][C:80](=[O:82])[CH3:81])[C@@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C@H:53]4[O:70][C@H:69]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[C@@H:64]([O:65][C:66](=[O:68])[CH3:67])[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]4[O:55][C:56](=[O:58])[CH3:57])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][S:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O[C@H]4[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]4COC(C)=O)O[C@@H]3COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)CCS
Solvent: CN(C)C=O
Product: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 79 %

Procedure:
Compound 93 (4.00 g, 3.0 mmol), methyl 3-mercaptopropionate (0.546 g, 0.49 ml, 4.5 mmol) cesium carbonate (1.17 g, 3.6 mmol) and N,N-dimethylformamide (25 ml), were stirred at room temperature until 93 had been consumed (7 h; TLC; SiO2, ethyl acetate:isooctane 4:1). The solvent was removed and the residue was chromatographed (SiO2, ethyl acetate:isooctane 3:1) to give 94 (3.22 g, 78%). [α]D25 +102° (c 1.0, chloroform). 1H-NMR (CDCl3, Me4Si) δ 5.36, 5.28, 5.19 (3d, each 1H, J=3.8, 4.1 and 3.7 Hz, H1', H1", H1"'), 4.57 (d, 1H, J=7.9 Hz, H1), 3.71 (s, 3H, MeO), 2.81, 2.71, 2.61 (3t, each 2H, J=6.7 Hz, CH2 --S--CH2 and CH2 --CO). 13C-NMR (CDCl3, Me4Si) δ 100.2 (Cl), 95.8, 95.6, 95.2 (Cl', Cl", Cl"'), 75.1, 73.7, 72.6, 72.0 71.9, 71.7, 70.7, 70.3, 70.0, 69.8, 69.6, 69.3, 69.2, 68.8, 68.4, 67.3, 65.2, 63.0, 62.9, 61.7, 60.3, 51.7, 34.6, 31.3, 27.2, 20.8-20.5.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH:24]([OH:28])[CH2:23][CH2:22]4)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc4c(c3)CCC4=O)cc3ccccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc4c(c3)CCC4O)cc3ccccc23)CC1
Yield: 59.7 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(1-indanon-5-yl)isoquinoline (0.20 g) obtained in the previous Example was dissolved in methanol (20 ml), followed by the addition of sodium borohydride (0.10 g) at room temperature, and the mixture was reacted for lSmin. The reaction solution was concentrated, and the resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.12 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1.[CH2:23]([NH2:26])[CH2:24][NH2:25]>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:25][CH2:24][CH2:23][NH2:26])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Reactant: NCCN
Solvent: O
Product: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1

Procedure:
Methanesulfonic acid 1-(6-methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl ester (1.96 g, 6.1 mmol) was heated to 100° C. in ethylene diamine (10 mL, 150 mmol) overnight. The reaction mixture was cooled, diluted with water and extracted 4× with a solution of 10% isopropanol in chloroform. The combined organic layers were washed with brine, dried over magnesium sulfate, and purified by column chromatography (silica, 10% MeOH in chloroform) to afford the title coompound as a white solid (1.3 g, quantitative yield as an adduct of two moles of water): LC/MS m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](F)=[CH:16][CH:15]=1>>[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][O:10][C:5]2=3)=[CH:16][CH:15]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2ccc(Br)c3ccccc23)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].B(O)O.[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:33]2[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=[C:31]([F:30])[CH:32]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: OBO
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3-fluoro,5-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[N:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ncn1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cccnc2)ncn1
Reaction time: 92 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[6-(3-pyridyl)pyrimidin-4-ylamino]aniline (Reference Example 20) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the reaction was conducted at room temperature for 92 hours and the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: C([N:8]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35](=[O:37])[NH2:36])[CH:29]=1)[CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C.FC(F)(F)C(O)=O>[C:35]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[OH:34])[O:27][CH2:26][CH2:25][NH:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:17][CH:18]=1)(=[O:37])[NH2:36]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nccs3)cc2)ccc1O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(-c3nccs3)cc2)ccc1O

Procedure:
After the addition of 0.69 g of palladium-on-carbon catalyst (10%), a solution of 3.0 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(thiazol-2-yl)-phenoxy]-2-propanol in a mixture of 30 ml of glacial acetic acid and 3 ml of trifluoroacetic acid is hydrogenated at 45° and normal pressure until the absorption of hydrogen has ceased. The suspension is filtered through a filter aid and the filtrate is freed of solvent; ice water is added to the residue, the pH is adjusted to approximately 9 with ammonia and extraction is carried out several times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated by evaporation and the residue is recrystallised from isopropanol, yielding 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(thiazol-2-yl)-phenoxy]-2-propanol having a melting point of 136°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of 1-(3-chlorophenyl)ethanone (16.79 mL, 129 mmol) and diethyl oxalate (18.05 mL, 136 mmol) in DMF (78.0 mL) was added, portionwise over 30 min., NaH (6.09 g, 155 mmol, 60% dispersion in mineral oil) and the resultant mixture was stirred at that temperature for 20 min. and then at room temperature for 16 h. The reaction mixture was diluted with water and acidified to pH=4-5 with 1N aq. HCl. The mixture was further diluted with copious amounts of water. The aq. layer was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude residue. It was purified by silica gel chromatography (220 g REDISEP® column, eluting with a 0 to 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A1C (27.1 g, 84%) as a solid. MS(ES): m/z=277.10 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (t, J=1.8 Hz, 1H), 7.95-7.86 (m, 1H), 7.60 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.06 (s, 1H), 4.43 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:2]1=2.C(O)(=O)C.C1C(=O)N([Br:24])C(=O)C1>ClCCl>[Br:24][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:2]=2[S:1][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1cccc2ccsc12
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1cccc2c(Br)csc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of benzo[b]thiophene-7-carboxylic acid amide (500 mg, 2.82 mmol) in dichloromethane (5 mL) is stirred at rt and acetic acid (5 mL) is added followed by NBS (750 mg, 4.23 mmol, 1.5 equiv.). The reaction is stirred at room temperature for 1 hour at which point LC-MS analysis shows full conversion of the starting material to the desired compound (79%) and dibrominated material (21%). The reaction is diluted with water (50 mL), neutralized with aqueous potassium disulfite, followed by sodium bicarbonate. The aqueous layer is then extracted with dichloromethane and the resulting organic layers are combined, washed with brine, dried over Na2SO4 and evaporated. The crude material is purified by LC using DCM as the eluent to afford the title compound as a white solid (300 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][OH:14])=[CH:5]2.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])(=O)C.[K+]>CC#N.O>[Cl:12][C:7]1[C:6]([CH2:13][OH:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:24])[CH:3]=2)[N:8]=1
Reactant: OCc1cc2cc(Br)ccc2nc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1ccc2nc(Cl)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-bromo-2-chloroquinolin-3-yl)methanol (19.8 g, 72.5 mmol, prepared as in example 2, step 2), o-tolylboronic acid (10.4 g, 76.1 mmol), potassium acetate (21.3 g, 217.4 mmol) and dichlorobis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)palladium (II) (0.51 g, 0.72 mmol) in CH3CN (300 ml) and water (100 ml) was heated in to reflux. After 2 h, the reaction was allowed to cool to RT and the aqueous phase was discarded. The organics were washed with 2×50% brine/water, and then 2× brine. The organics were concentrated to ˜100 mL, at which point the precipitate was filtered off to afford a pale yellow solid of (2-chloro-6-o-tolylquinolin-3-yl)methanol. Step 2: (2-chloro-6-o-tolylquinolin-3-yl)methanol (13.9 g, 49.0 mmol) was treated with DCM (100 ml) and thionyl chloride (106 ml, 1456 mmol) at ambient temperature. After 15 min, the solution was concentrated and azeotroped with 2×100 mL toluene, to afford a yellow solid of 2-chloro-3-(chloromethyl)-6-o-tolylquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11][CH:12]([CH3:14])[CH3:13])=[O:9])[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C=CC=CC=1>[CH3:36][O:35][C:33]([N:11]([CH:12]([CH3:13])[CH3:14])[NH:10][C:8]([C:6]1[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])=[O:34]
Reactant: COC(=O)Cl
Reactant: Cc1cc(Cl)nc(C(=O)NNC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: COC(=O)N(NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N′-isopropyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (12-a) (378 mg) was dissolved in pyridine (5 mL), methyl chloroformate (220 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 110 μL) was added. After 18 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=10:1, Rf=0.13) to afford 382 mg of the title compound (12) of the present invention of the formula
Reaction SMILES: C([O:8][C:9](=[O:38])/[CH:10]=[CH:11]/[CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:29][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)=[N:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[Cl:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]2[O:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH:16]4[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][C:9]([OH:38])=[O:8])[CH2:18][CH2:17]4)=[CH:20][CH:21]=3)=[CH:26][N:27]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(/C=C/CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Reaction time: 72 h
Yield: 86.1 %

Procedure:
To a solution of (E)-4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoic acid benzyl ester (139 mg, 0.283 mmol) in EtOAc/EtOH (5:1 v/v, 6 mL) is added Pd(OH)2 (100 mg) the mixture is stirred in an hydrogenated at 1 atm for 72 h. The catalyst is filtered and washed with EtOAc. The filtrated is then concentrated and dried under high vacuum to give the title compound (107 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.09 (m, 2 H) 1.18-1.25 (m, 2H) 1.39-1.48 (m, 2H) 1.49-1.57 (m, 2 H) 1.82 (d, J=10.11 Hz, 4 H) 1.74-1.85 (m, 1 H) 2.18 (t, J=7.33 Hz, 2 H) 6.99 (ddd, J=7.96, 2.02, 0.88 Hz, 1 H) 7.28-7.33 (m, 3 H) 7.40 (s, 1 H) 7.47-7.52 (m, 3 H) 7.85 (t, J=2.02 Hz, 1 H); (M+H)+=439.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[CH:5]=[C:4]([CH3:38])[N:3]=1.[OH-].[Na+]>C(O)C>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:38])=[CH:5][C:6]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc(-c2c(OCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)cc(C)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(-c2ccc(C(=O)O)cc2)c(C)n1

Procedure:
2,6-Dimethyl-3-(4-ethoxycarbonylphenyl)-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (50 mg) was added to a mixture of 1M sodium hydroxide solution (0.2 ml) and ethanol (2 ml), and the mixture was heated at reflux for 1 hour. Additional 1M sodium hydroxide solution (0.1 ml) was added and the mixture was heated at reflux for a further 30 minutes. Volatile material was removed by evaporation. The residue was dissolved in water (10 ml) and the mixture was extracted with dichloromethane. The aqueous phase was separated and adjusted to pH 5 with 1M citric acid solution. The resultant precipitate was collected by filtration to give 3-(4-carboxyphenyl)-2,6-dimethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine as a solid, m.p. 207°-210° C. (decomposition); NMR (d6 -DMSO): 2.1(s, 3H), 2.44(s, 3H), 5.13(s, 2H), 6.94(s, 1H), 7.03(d, 2H), 7.15(d, 2H), 7.38(d, 2H), 7.55(m, 4H), 9.8(d, 2H); mass spectrum (+ve FAB, methanol/nitrobenzyl alcohol): 478(M+H)+ ; microanalysis, found: C, 66.6, H, 5.0; N, 13.9%; C28H23N5O3.1.5H2O requires: C, 66.7; H, 5.1; N, 13.9%.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]([O:15][CH2:16]C)=[O:14])[N:6]([CH3:18])[N:5]=2)[CH2:3][CH2:2]1.IC1C(C2C=C[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=NN(C)C=1C(OC)=O>>[CH3:18][N:6]1[C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:9]([F:10])([F:11])[F:12])[C:4]([C:1]2[CH:3]=[CH:2][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:5]1
Reactant: COC(=O)c1c(I)c(-c2ccc(C(F)(F)F)cc2)nn1C
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C2CC2)nn1C
Product: COC(=O)c1c(C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
This compound is prepared analogously to the preparation of ethyl 3-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate from methyl 4-iodo-1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)Nc3cccnc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
3-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (333 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (445 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.33 (s, 3H) 2.44 (td, J=5.81, 1.29 Hz, 2H) 2.57 (td, J=5.92, 1.22 Hz, 2H) 3.50-3.57 (m, 2H) 3.61-3.68 (m, 2H) 6.44 (s, 1H) 6.83-6.94 (m, 2H) 7.00-7.09 (m, 2H) 7.28-7.41 (m, 2H) 7.64-7.74 (m, J=7.28, 2.03, 1.07, 1.07 Hz, 1H) 7.87-7.96 (m, 2H) 8.16 (dd, J=4.80, 1.44 Hz, 1H) 8.58 (dd, J=2.60, 0.72 Hz, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23[O:20][CH2:19][CH2:18][O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccc(C3CCCCC3)cc2C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(C3CCCCC3)cc2C12OCCO2

Procedure:
5-Cyclohexyl-1H-indole-2,3-dione (1 equivalent), ethane-1,2-diol (5 equivalents) and p-toluenesulphonic acid (0.02 equivalents) in dry toluene were heated under reflux overnight with azeotropic removal of water. The reaction mixture was cooled, washed with saturated sodium bicarbonate solution, and then worked up in the usual manner to afford the title compound.