Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-bromo-3-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-methyl-1H-pyrazole (88 mg, 022 mmol), 2-chlorophenylboronic acid (41 mg, 0.26 mmol), K2CO3 (91 mg, 0.66 mmol), Cl2Pd(dppf).DCM (18 mg, 10 mol %) and H2O (0.25 mL) in dioxane (2.5 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 4 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 40:60) to give the title compound (64 mg, 67%). Rf 0.14 (40% EtOAc/Hex); 1H NMR (CD2Cl2): δ 8.09 (1H, m), 7.85-7.76 m), 7.60-7.49 (2H, m), 7.45 (1H, s), 7.41-7.30 (3H, m), 7.21 (1H, d), 6.70 (1H, d), 3.97 (3H, s), 3.05 (3H, s); MS (ES): 429 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([NH:10]C(=O)OC(C)(C)C)[CH2:5]1.[ClH:18].O1CCOCC1>C1COCC1>[ClH:18].[NH2:10][N:6]1[CH2:5][C@H:4]([CH2:3][S:2][CH3:1])[O:8][C:7]1=[O:9]
Reactant: CSC[C@H]1CN(NC(=O)OC(C)(C)C)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CSC[C@H]1CN(N)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (R)-tert-butyl 5-(methylthiomethyl)-2-oxooxazolidin-3-ylcarbamate (429 mg, 1.63 mmol) in THF (3 mL), a solution of 4M HCl in dioxane (1.022 mL, 4.09 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. Conversion was complete. The title compound, precipitated as a white solid, was filtered, washed with diisopropyl ether and dried under vacuum, (260 mg, 1.31 mmol). Yield=80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]=1.[OH-:12].[Na+].OO>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=CCCc1cccc(Br)c1
Agent: OO
Agent: [Na+]
Product: OCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 1-bromo-3-(but-3-en-1-yl)benzene (CA46) (7.51 g, 35.6 mmol) in hexanes (80 mL) was added (1S,5S)-9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 74.7 mL, 37.4 mmol). The reaction was allowed to stir at room temperature overnight. To the resulting clear solution sodium hydroxide (6.0 M, 5.93 mL, 35.6 mmol) was added dropwise. The reaction was placed in an ice water bath and hydrogen peroxide (13.8 mL, 135 mmol) was added. The resulting mixture was then heated to an internal temperature of 50° C. for overnight. The reaction mixture was cooled to room temperature. The biphasic solution was partitioned, and the organic layer was washed with sodium bisulfite, and brine solution. The combined aqueous layers were made basic with saturated sodium carbonate, and extracted with diethyl ether (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The liquid was loaded on to silica and purified by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent providing the title compound as a clear liquid (7.50 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J=1.9 Hz, 1H), 7.37 (dt, J=7.6, 1.8 Hz, 1H), 7.28-7.17 (m, 2H), 4.39 (t, J=5.2 Hz, 1H), 3.40 (td, J=6.5, 5.2 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.65-1.51 (m, 2H), 1.49-1.35 (m, 2H); EIMS m/z 228 ([M]+).
Reaction SMILES: [OH:1][CH:2]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=3)[N:20]([CH3:30])[CH:19]=2)=[CH:5]1)[CH3:3].C(Cl)CCl.CN(C1C=CC=CN=1)C.[CH3:46][O:47][C:48]1[C:56]([O:57][CH3:58])=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](O)=[O:51]>C(Cl)Cl>[CH3:30][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:18]([C:17]2[C:16](=[O:31])[NH:15][C:14](=[O:32])[C:13]=2[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:2]([O:1][C:50](=[O:51])[C:49]3[CH:53]=[CH:54][CH:55]=[C:56]([O:57][CH3:58])[C:48]=3[O:47][CH3:46])[CH3:3])[CH:5]=2)=[CH:19]1
Reactant: CC(O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Reactant: COc1cccc(C(=O)O)c1OC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cccc(C(=O)OC(C)n2cc(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)c3ccccc32)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 3-[1-(1-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (165.3 mg, 0.678 mmol) (from step d) above), EDC.HCL (284.5 mg, 1.484 mmol), and dimethylaminopyridine (185.5 mg, 1.58 mmol) in 20 mL of CH2Cl2 was added 2,3-dimethoxybenzoic acid (287.4 mg, 0.668 mmol). The solution was stirred at room temperature for 0.5 hour, washed with saturated NaHCO3, brine, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 203 mg of 2,3-dimethoxy-benzoic acid 1-{3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-ethyl ester. (Yield 50%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[CH3:23][N:24]=[C:25]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:23]([NH:24][CH3:25])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Cl)cc2)c1=O
Yield: 57 %

Procedure:
A solution of 3-butyl-1-(4-chlorobenzyl)-6-hydrazinouracil (3.0 g, 9.3 mM) and methyl isothiocyanate (2.0 ml, 29 mM) in DMF (30 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave pale yellow crystals (1.91 g, 57%), m.p. 292°-294° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[OH-].[Li+]>C1COCC1.CCOCC>[CH3:33][C:18]1[C:17]([CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:7]=[CH:8]3)=[CH:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc2c(ccn2CC(=O)O)c1
Yield: 82.7 %

Procedure:
175 mg (0.37 mmol) {5-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester and 0.75 ml 1N lithium hydroxide solution were stirred in 2 ml THF at RT for 2 h. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in ether/heptane 1:19 and the resulting crystals were filtered off to give 135 mg of pure {5-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[C:31]2[N:30]=[CH:29][N:28](C(OC(C)(C)C)=O)[C:27]=2[CH:26]=[CH:25][CH:24]=1.[ClH:39]>>[ClH:39].[ClH:39].[N:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][O:14][C:13]3[C:8]([NH:7][C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)=[N:9][CH:10]=[CH:11][CH:12]=3)[C:31]=2[NH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc3nc[nH]c23)n1
Yield: 14.1 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 70 mg, 0.338 mmol), potassium carbonate (117 mg, 0.844 mmol) and tert-butyl 4-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate (105 mg, 0.338 mmol) [Moon, M., J. Med. Chem. (1992), 35(6), 1076] were reacted according to the method of Example 3, Steps B and C, to provide 3-((3H-benzo[d]imidazol-4-yl)methoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine dihydrochloride (19.6 mg, 14.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.72 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.61 (t, 1H), 7.09 (dd, 1H), 6.79 (s, 1H), 5.70 (s, 2H), 2.29 (s, 3H). Mass spectrum (apci) m/z=338.1 (M+H-2HCl).
Reaction SMILES: F[C:2]1C=C(N)C=C[C:7]=1OC1C2C(=CC(OC)=CC=2)N=CC=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:36]=1)[C:28](=[O:35])[C:29]([C:32]([OH:34])=[O:33])=[CH:30][N:31]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C([O-])(O)=O.[Na+]>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:36]=1)[C:28](=[O:35])[C:29]([C:32]([O:34][CH2:2][CH3:7])=[O:33])=[CH:30][N:31]=2
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(C)cn2c1=O
Reaction time: 16 h
Yield: 45.9 %

Procedure:
Steps 2 and 3: N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide. To a suspension of ethyl 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (0.11 g, 0.47 mmol) in ethanol was added 1 N NaOH solution (3 mL, 3 mmol) at RT. The reaction mixture was stirred for 16 at RT. The resultant was concentrated, and the residue was diluted with water. The aqueous solution was washed with diethyl ether and then acidified with 2N HCl solution and extracted with dichloromethane. The organic solution was dried over magnesium sulfate and concentrated to give a yellow solid (0.090 g, 93%): MS (ESI pos. ion) m/z: 205 (MH+). Calc'd exact mass for C10H8N2O3: 204. A mixture of 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (0.08 g, 0.3 mmol), 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (0.08 g, 0.4 mmol), HATU (0.4 g, 0.8 mmol) in dichlormethane was stirred for 16 h. Then, the mixture was diluted with dichloromethane and aq. NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by ISCO (0-5% MeOH in EtOAc) to give the title compound as a yellow solid (0.032 g, 24%): MS (ESI pos. ion) m/z: 471 (MH+), Calc'd exact mass for C26H19FN4O4: 470; 1HNMR (400 MHz, CDCl3): 11.4 (s, 1H), 9.4 (s, 1H), 9.1 (s, 1H), 8.6 (d, J=6 Hz, 1H), 8.3 (d, J=9 Hz, 1H), 8.0 (dd, J=3, 12 Hz, 1H), 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (d, J=3 Hz, 1H), 7.0-7.3 (m, 2H), 6.4 (d, J=3 Hz, 1H), 3.98 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](I)=[CH:13][C:12]=1[CH3:19]>>[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][C:12]=1[CH3:19]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: OB(O)c1cccnc1
Product: Cc1cc(-c2cccnc2)cc(C)c1Br

Procedure:
The title compound is prepared from pyridine-3-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.99 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15])[CH2:6][CH2:5]1.[Mg].BrC1C=CC([C:24]2[C:25]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH2:10]([Si@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[CH:29]=[CH:24][C:25]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)=[CH:26][CH:27]=3)=[CH:28][CH:29]=2)[CH2:5][CH2:6]1)[CH2:11][CH:12]=[CH:13][CH2:14][CH3:15]
Reactant: Fc1ccc(-c2ccccc2-c2ccc(Br)cc2)cc1F
Reactant: CCC=CCC[Si@H]1CC[C@H](CCCl)CC1
Agent: [Pd]
Agent: [Mg]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC=CCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)c(F)c4)cc3)cc2)CC1

Procedure:
24.5 g (100 mmol) of trans-1-(2-chloroethyl)-4-(3-hexenyl)-4-silacyclohexane was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 34.5 g of 4-bromo-3",4"-difluoroterphenyl and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). After a conventional after treatment, the reaction mixture thus obtained was purified by means of chromatography to obtain 39.6 g (yield 87%) of the target product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCCc1nc(-c2ccccc2)co1
Yield: 92.2 %

Procedure:
To a solution of ethyl 4-phenyl-2-oxazolepropionate (1.4 g) in THF (20 ml) was added sodium borohydride (0.86 g). Methanol (4 ml) was dropwise added to the mixture over a period of 10 minutes under reflux. The reaction mixture was refluxed for further 30 minutes, concentrated, made acidic and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4, and distilled to obtain crystals of 3-(4-phenyl-2-oxazolyl)propanol (1.07 g, 92%). Recrystallization from ether-hexane gave colorless prism crystals of mp 55°-56° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH2:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.C(=O)([O-])[O-].[Na+].[Na+].[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1.O>[CH3:3][C:4]1([CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a suspension of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (1.3 g) in tetrahydrofuran (10 mL) was added a solution of sodium carbonate (0.95 g) in water (5 mL) with ice-cooling and the mixture was stirred for 5 minutes. Then, 0.26 mL of acetyl chloride was added dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to provide 1.1 g of the title compound. Yield 90%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([OH:26])=O)=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:24]([N:48]2[CH2:49][CH2:50][CH:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]2)=[O:26])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
0.05 g (0.1 mmol) of 5-methyl-3-pyrimidin-5-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid (intermediate 11) in 1.0 ml of oxalyl chloride (11.7 mmol) was treated at RT while stirring with one drop of DMF; after 30 min, the excess of oxalyl chloride was removed by evaporation in a high vacuum at RT. The residue was dissolved in 2.0 ml of CH2Cl2 and cooled down to 0° C.; then, 0.08 ml=0.056 g (0.6 mmol) of Et3N was added while stirring, followed by 0.022 g (0.1 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After two hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.049 g (71%) of the title compound as yellow solid. MS: 495.3 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([S:29]([C:4]2([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccc(F)c(F)c4)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 3,4-difluorobenzenesulfonyl chloride (79 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.88 (m, 1H), 7.73 (m, 1H), 7.65 (m, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.11 (br s, 2H), 6.75 (dd, J=8.0, 0.4 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.97 (d, J=6.0 Hz, 2H), 3.69 (br d, J=11.6 Hz, 2H), 2.34 (m, 2H), 1.87 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 450 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:15]1[C:16]([I:42])=[C:17]([CH2:37][O:38]C(=O)C)[C:18]([I:36])=[C:19]([C:34]=1[I:35])[C:20]([NH:22][CH2:23][CH:24]([O:30]C(=O)C)[CH2:25][O:26]C(=O)C)=[O:21])[C:8](=[O:14])[CH2:9][O:10]C(=O)C)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][CH2:6][N:7]([C:15]1[C:16]([I:42])=[C:17]([CH2:37][OH:38])[C:18]([I:36])=[C:19]([C:34]=1[I:35])[C:20]([NH:22][CH2:23][CH:24]([OH:30])[CH2:25][OH:26])=[O:21])[C:8](=[O:14])[CH2:9][OH:10]
Reactant: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(N(CCO)C(=O)CO)c1I
Reaction time: 0.5 h

Procedure:
5-[N′-(2-acetoxyethyl)-acetoxyacetamido]-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (2.76 g, 2.96 mmol) was dissolved in methanol (4 ml) at room temperature. An aqueous solution of sodium hydroxide (2M, 11.1 ml) was slowly added with efficient stirring. After 30 minutes, the pH of the solution was adjusted to 6 by the addition of a strongly acidic ion exchange resin (Amberlyst 15). The resin was filtered off and the solution was evaporated to a crystalline residue. The product was purified by preparative HPLC. Yield: 1.80 g (84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 86 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 86%. Melting point: 161-163° C. (Ethyl acetate-hexane)
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1N=CN[CH:5]=1.[N:12]1C(N)=C2C(N=CN2)=N[CH:13]=1>>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:13][NH2:12]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
An ADE2 fragment and a LYS2 fragment were also prepared under similar reaction conditions using A451 genomic DNA as a template and ADE-1 (5′ ATG GAT TCT AGA ACA GTT GGT 3′ (SEQ ID NO: 127)) and ADE-2 (5′ TTA CTT GTT TTC TAG ATA AGC 3′ (SEQ ID NO: 128)) or LYS-1 (5′ ATG ACT AAC GAA AAG GTC TGG 3′ (SEQ ID NO: 129)) and LYS-2 (5′ TTA AGC TGC TGC GGA GCT TCC 3′ (SEQ ID NO: 130)) as primer DNAs. The resultant HIS3 fragment and ADE2 fragment were introduced into pRS435GGF/YH1 successively to thereby obtain pRS435GGF/YH1-AH that exhibited non-histidine requirement and non-adenine requirement as phenotypes. On the other hand, the LYS2 fragment and URA3 fragment were introduced into YPH500 successively to thereby obtain YPH500-KU that exhibited non-lysine requirement and non-uracil requirement as phenotypes.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:41]4[CH2:42][CH2:43][CH:38]([O:37][CH2:36][CH2:35][OH:34])[CH2:39][CH2:40]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: OCCOC1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(OCCO)CC4)c3)n2)n1
Yield: 49.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 4-(2-hydroxyethoxy)piperidine [CAS-no. 40256-14-2] (0.297 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.120 g, 49%) as a white foam. MS (ISP) 598.3 [(M+H)+].