Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.O1CC[C@H](N)C1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:33][C@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCOC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (38.2 μL, 0.348 mmol), (S)-tetrahydrofuran-3-amine-HCl (15.47 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((S)-tetrahydrofuran-3-yl)acetamide (12.9 mg, 0.026 mmol, 37.1% yield): LCMS=501.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.24 (4 H, m), 7.48-7.79 (14 H, m), 5.00-5.21 (2 H, m), 4.35-4.47 (2 H, m), 3.91-3.99 (2 H, m), 3.74-3.91 (4 H, m), 3.57-3.70 (2 H, m), 2.13-2.33 (2 H, m), 1.80-1.98 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.4 min (mixture of diastereomers).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[O:23][C:22]1[CH:30]=[CH:31][C:19]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(N2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Yield: 35.9 %

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)-piperazine (4.4 g, 17.8 mmol), 2-(4-bromophenoxy)-tetrahydropyran (4.6 g, 17.8 mmol), palladium acetate (159 mg, 0.71 mmol), BINAP (666 mg, 1.07 mmol) and sodium tert-butoxide (2.2 g, 23.1 mmol) in toluene (40 ml) was refluxed under a nitrogen atmosphere for 5 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenyl)piperazine (2.7 g, yield 35%) as a white powder.
Reaction SMILES: [H-].[Na+].[I-].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1.[CH2:37]1[O:47][C:40]2([CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[O:39][CH2:38]1.OS([O-])(=O)=O.[Na+]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[C:38]2[CH2:37][O:47][C:40]3([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[O:39]2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: Clc1ccc(-c2ccccc2C=C2COC3(CCCCC3)O2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 51.3 %

Procedure:
A suspension of sodium hydride (60% in mineral oil, 77 mg, 1.92 mmol) in DMSO (5.8 mL) was heated for 1 hour at 80° C. and then cooled to rt. ((4′-Chlorobiphenyl-2-yl)methyl)triphenylphosphonium iodide (1.04 g, 1.76 mmol) was added to the suspension and then, after stirring 10 minutes at room temperature, 1,4-cyclohexanedione monoethylene acetal (0.25 g, 1.60 mmol) was added. The reaction mixture was heated at 80° C. for 3 hours. After standing at rt overnight, the reaction mixture was poured into a saturated solution of NaHSO4 and extracted with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (silica gel, 0% to 30% EtOAc in heptane) to give ((4′-Chlorobiphenyl-2-yl)methylene)-1,4dioxaspiro[4.5]decane (0.28 g, 52%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.12-7.33 (m, 8 H), 5.98 (s, 1 H), 3.92 (s, 4 H), 2.30-2.36 (m, 2 H), 2.22-2.29 (m, 2 H), 1.62-1.71 (m, 2 H), 1.52-1.58 (m, 2 H).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1C)[CH3:16]>>[CH2:18]([N:17]([CH2:15][CH3:16])[C:25]1[CH:20]=[CH:21][C:22]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:23][CH:24]=1)[CH3:19]
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCn1c(C)cc2ccccc21
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
The keto-glutaric anhydride (I) is reacted mol-for-mol with a compound such as 1-ethyl-2-methylindole (T) in the presence of a catalyst, as previously disclosed, to yield keto-acid (II).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)CCCC>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][NH:8]2
Reactant: Nc1ccccc1OCCCCl
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCCO
Product: ClCCCOc1ccccc1Nc1nc(Cl)nc2[nH]cnc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2,6-Dichloropurine (10 mmol) and 2-(3-Chloro-propoxy)-phenylamine (˜20 mmol) are dissolved in 1-pentanol and heated up to 70° C. and the mixture is stirred at this temperature for 5 hours. While cooling down to R the product precipitated. The solid material was filtered off and washed with 1-pentanol and diethyl ether. A solid powder with mp. 205° C., Rf=0.42 (CH2Cl2/MeOH=10:1) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2Br)=[O:19])[CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:18]2[O:19][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)[CH:5]=[C:6]([C:7]2[O:8][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:17]=1
Reactant: O=C(Nc1ccccc1Br)c1cc(Br)cc(C(=O)Nc2ccccc2Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Brc1cc(-c2nc3ccccc3o2)cc(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Yield: 88.5 %

Procedure:
A mixture of Compound 10 (20.3 g, 36.7 mmol), CuI (0.700 g, 3.67 mmol), Cs2CO3 (23.9 g, 73.5 mmol), 1,10-phenanthroline (1.32 g, 7.35 mmol) and 1,4-dioxane (300 mL) was degassed with Ar and then maintained at about 120° C. overnight. Upon confirming consumption of the starting material by TLC (SiO2, 4:1 hexanes-ethyl acetate), the reaction was cooled to RT and diluted with EtOAc (ca. 300 mL) and H2O (ca. 400 mL). The resulting suspension was then filtered and the filtrant washed copiously with H2O and CH3OH to provide Compound 11 (12.7 g, 88%) as an off-white solid: confirmed by LCMS (APCI): calculated for C20H11BrN2O2 (M+): 391; Found: 391.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:8]2[C@@H:12]([O:13][CH2:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[CH2:11][CH2:10][N:9]2[C:23](OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:8]2[C@@H:12]([O:13][CH2:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH3:23])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CC[C@H](OCc2cc(C)cc(C)c2)[C@@H]1C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(CO[C@H]2CCN(C)[C@H]2C(c2ccccc2)c2ccccc2)c1

Procedure:
To a solution of cis-2-(diphenylmethyl)-3-(3,5-dimethylbenzyloxy)-1-ethoxycarbonylpyrrolidine (Example 1e, 0.500 g, 1.1 mmol) in tetrahydrofuran (5.0 ml) was added 1.0M lithium aluminium hydride (5.0 ml, 5.0 mmol) and then the solution heated at reflux for 1 h. To the cooled solution was carefully added water (2 ml), 4M sodium hydroxide (2 ml) and water (4 ml) followed by ethyl acetate. The suspension was filtered through Celite and the filtrate was washed with saturated brine and dried (MgSO4). Removal of the solvent in vacuo gave cis-2-(diphenylmethyl)-3-(3,5-dimethylbenzyloxy)-1-methylpyrrolidine, as an oil. 1H NMR (360 MHz, CDCl3) δ7.05-7.43 (10H, m), 6.85 (1H, s), 6.68 (2H, s), 4.30 (1H, d, J=15.0 Hz), 4.01 (1H, d, J=16.0 Hz), 3.77 (1H, m), 3.63 (1 H, d, J=16.0 Hz), 3.24 (2H, m), 2.30 (1H, m), 2.26 (6H, s), 1.91 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:29])[C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:15]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:29][C:18]1[CH:17]=[C:14]([C:15]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)[CH:13]=[C:12]([CH3:11])[C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)[nH]2)cc(C)c1OCCN1CCOCC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 2-amino benzamide (136 mg, 1.0 mmol) in N,N-dimethyl acetamide (5 mL) were added 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (263 mg, 1.0 mmol), sodium hydrogen sulphite (58.5%) (196 mg, 1.1 mmol) and p-toluenesulfonic acid (19 mg, 0.1 mmol). The reaction mixture was stirred at 150° C. overnight. Water (40 mL) was added. The formed solid was filtered off, washed with water and a small amount of methanol and dried under vacuum to give the title compound (190 mg, 50%) as an off-white solid. To a solution of the above compound (174 mg, 0.458 mmol) in 2:1 anhydrous CH2Cl2-methanol (15 mL) was added 1.0 M solution of hydrogen chloride in ether (1.5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was triturated with 10% methanol in anhydrous ether to give the hydrochloride of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one (187 mg, 98%), as an off-white solid. Selected data: MS (ES) m/z: 380.10; MP 300-302° C. (hydrochloride).
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.O1CCCC1.[OH-].[Na+]>O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(Sc2ccccc2)n1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 6-phenylthio-2-pyridylcarboxylic acid (0.75 g, 3.25 mmol) in 10 ml of tetrahydrofuran in an ice bath is added dropwise a borane-tetrahydrofuran solution (6.7 ml total, 6.70 mmol) over a period of 20 minutes. The reaction mixture is stirred at RT overnight. 3 N aqueous sodium hydroxide (4 ml) is added slowly and stirring is continued for another 8 hours. The solution is diluted with water, saturated with solid potassium carbonate and extracted with water. The extract is washed with water, saturated NaHCO3 and brine and dried to yield (6-phenylthio-2-pyridyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][OH:25]>[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([O:25][CH3:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: CO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (60 mg, 0.18 mmol) obtained in Step 1 was dissolved in methanol (10 mL), silver nitrate (37.20 mg, 0.22 mmol) was added thereto, stirred for 3 hrs at RT, and filtered. The organic layer was separated, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 14 mg of the titled compound (yield: 24%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[Na+].[Na+].[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=1B(O)O)=[O:46])([CH3:43])([CH3:42])[CH3:41]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(F)cc3CNC(=O)OC(C)(C)C)[nH]c2c1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International patent application WO2004/087714, from commercially available methyl indole-6-carboxylate) in dioxane (0.07 M) was added 0.2 eq of bis(triphenylphosphine)palladium(II) dichloride at RT under a nitrogen atmosphere. Then aqueous Na2CO3 (2 M solution, 2 eq.) and [2-(N-tert-butoxycarbonyl-amino-methyl)-4-fluorophenyl]-boronic acid (2 eq.) were added and the reaction flask immersed in a preheated oil bath at 100° C. for 2 h. The reaction mixture was allowed to cool and filtered. The filtrate was diluted with DCM and the organic phase washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography (1:9 EtOAc/PE) to afford the title compound as a solid (87%); MS (ES+) m/z 481 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=2[F:24])[O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) produced in Example 16(vi) was dissolved in pyridine (3.0 ml), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (145 mg, 0.65 mmol) was added, and the mixture was stirred at 70° C. for 12 hr. 1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (70 mg, 0.32 mmol) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and tetrahydrofuran (1 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (5 mL), and the suspension was stirred at room temperature for 10 min. The solid was collected by filtration, and washed successively with ethyl acetate and n-hexane to give the title compound (170 mg, 70%) as a colorless powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[SH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8](=[O:16])[N:7]=1
Reactant: N#Cc1nccs1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2nccs2)sc2ccccc12
Yield: 71.4 %

Procedure:
1,3-Thiazole-2-carbonitrile (0.32 g, 2.9 mmol) and methyl thiosalicylate (0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 2 hrs. After cooling, the precipitates were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.51 g, 70%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:12])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(=O)Nc1ncc(Br)cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)cnc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a degassed solution of N-(5-bromo-3-methyl-pyridin-2-yl)-acetamide (4.92 g, 21.48 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.16 g, 25.77 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (6.03 g, 53.69 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.21 g, 0.43 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.78 g, 1.72 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of ethyl acetate/triethylamine (10:0→4:1) and then recrystallized from ethyl acetate/heptane to provide 2.96 g (45%) of the title compound in 70% purity according to 1H NMR. 1H NMR (250 MHz, DMSO): δ 1.03-1.28 (m, 2H), 1.39 (s, 9H), 1.82 (dd, J=12.3 Hz, J=3.9 Hz, 2H), 1.98 (s, 3H), 2.72-2.98 (m, 2H), 3.11-3.29 (m, 1H), 3.84 (d, J=13.4 Hz, 2H), 4.52 (d, J=8.7 Hz, 1H), 5.60 (br s, 2H), 6.73 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H). MS (ESI): 307.2 [M+H]+.
Reaction SMILES: Cl.COC[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]3)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1>CO>[OH:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]3)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1
Reactant: COCOC1CCN(CCN(CCCCOc2ccc3[nH]c(=O)ccc3c2)Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: O=c1ccc2cc(OCCCCN(CCN3CCC(O)CC3)Cc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
10 ml of 10% hydrochloric acid was added to a solution of 1.07 g of 6-[4-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-benzylamino}butoxy]carbostyril in 10 ml of methanol. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with chloroform and then made alkaline with a 10% aqueous potassium hydroxide solution, followed by extraction with chloroform. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 5% methanol/chloroform), followed by recrystallization from ethyl acetate-diethyl ether, to obtain 330 mg of 6-[4-{N-[2-(4-hydroxy-1-piperidinyl)ethyl]-N-benzylamino}butoxy]-carbostyril.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 15), 401 (M+H+, 100).