Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[OH:24].[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[CH:22][C:23](=[O:24])[C:18]([Cl:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: Oc1ccncc1Cl
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 94.7 %

Procedure:
First, 267 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 171 mg of 3-chloro-4-hydroxypyridine, and 92 mg of powdered potassium hydroxide were added to 3 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 80 minutes in a nitrogen atmosphere. Ice water and 4N hydrochloric acid were then added to the reaction mixture so as to adjust its pH to about 2. The resultant yellow precipitate was filtered and washed with water. The precipitate was recrystallized with a mixture of dimethylformaldehyde and water to give 376 mg of yellowish white 6-nitro-7-(3-chloro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][N:4]([CH3:6])[CH3:5].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34]>>[CH2:7]([C@H:2]([NH:1][C:19]1[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]([CH3:34])=[C:15]([Cl:14])[N:20]=1)[CH2:3][N:4]([CH3:6])[CH3:5])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CN(C)C[C@@H](N)Cc1ccccc1
Product: Cc1c(Cl)nc(N[C@@H](Cc2ccccc2)CN(C)C)c(=O)n1CC(=O)OCc1ccccc1
Yield: 51.8 %

Procedure:
The title compound was prepared by a similar method to preparation 18 from N-[(2S)-2-amino-3-phenylpropyl]-N,N-dimethylamine (190 mg, 1.07 mmol; prepared as described in Chem. Pharm. Bull. 1970, 18, 1731-1736) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (361 mg, 1.10 mmol). The crude product was purified by chromatography (SiO2; gradient elution 100% hexane; 80:20 hexane:ethyl acetate; 60:40 hexane:ethyl acetate; 40:60 hexane:ethyl acetate; 20:80 hexane:ethyl acetate) to give the desired product (yellow solid, 260 mg, 50%). 1H NMR (CDCl3) δ 2.20 (m, 9H), 2.30 (m, 1H), 2.20 (m, 1H), 2.85 (m, 1H), 3.10 (m, 1H), 4.25 (m, 1H), 4.80 (s, 2H), 5.20 (s, 2H), 6.20 (m, 1H), 7.20 (m, 5H), 7.35 (m, 5H). LRMS m/z=469.2, 471.3 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH:22][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Br)ccc1Oc1ccccc1
Product: CCCc1ccc2c(Nc3cc(Br)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 124b (351 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (470 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.35 Hz, 3H) 1.72-1.93 (m, 2H) 2.91-3.02 (m, 2H) 6.70 (d, J=6.99 Hz, 1H) 6.97 (d, J=7.72 Hz, 2H) 7.10 (t, J=8.27 Hz, 2H) 7.27-7.36 (m, 2H) 7.68 (dd, J=8.82, 2.57 Hz, 1H) 7.78 (d, J=8.46 Hz, 1H) 7.82 (d, J=2.57 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 8.89 (d, J=8.82 Hz, 1H) 10.90 (s, 1H) 14.49 (s, 1H); MS (ESI+) m/z 436 (M+H−TFA)+.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]([OH:26])=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C1COCC1>[Pd].CO>[CH3:25][O:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:26])[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[CH:23]2
Reactant: COc1ccc2nc(O)c(C3=CCN(Cc4ccccc4)CC3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reaction time: 2 h

Procedure:
A mixture of 160 mg (0.462 mmol) 3-(1-benzyl-1.2.3.6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol and 20 mg palladium on charcoal (Pd/C 10%) in 30 mL MeOH was first of all hydrogenated for 17.5 h at 50° C. in a hydrogen atmosphere of 50 psi. Then 10 mL THF and 20 mg palladium on charcoal (Pd/C 10%) were added and hydrogenation continued for a further 2 h under the same conditions. Another 20 mg palladium on charcoal (Pd/C 10%) were added and the mixture was hydrogenated overnight at 50° C. in a hydrogen atmosphere of 60 psi. Then the reaction mixture was filtered, washed with DMF and the filtrate was evaporated down. The residue was added to EtOAc, triturated with PE and filtered. The precipitate was washed with DIPE and dried.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[C:6]1[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]1=[O:15]>CO.[Pd]>[OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[C:11](=[O:12])[O:10][C:9]([CH3:13])([CH3:14])[O:8][C:7]1=[O:15]
Reactant: COc1c(O)cccc1C=C1C(=O)OC(C)(C)OC1=O
Agent: [Pd]
Solvent: CO
Product: COc1c(O)cccc1CC1C(=O)OC(C)(C)OC1=O
Reaction time: 1.5 h

Procedure:
To a solution of 5-(3-hydroxy-2-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (entire amount) in methanol (100 mL) was added 10% palladium-activated carbon (62 mg), and the mixture was stirred for 1.5 hr under a hydrogen atmosphere.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[C:9]([Cl:17])=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(Br)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(O)c(O)c1Cl
Temperature: 55 °C
Reaction time: 60 h
Yield: 30.2 %

Procedure:
A mixture of 9.6 g (40 mmol) of methyl 3-bromo-4,5-dihydroxybenzoate, 8.4 g (62 mmol) of sulphuryl chloride and 400 ml of glacial acetic acid is stirred at 55° C. for 60 hours and subsequently concentrated at 40° C. in a vacuum. The residue is dissolved in 200 ml of methanol and saturated with hydrogen chloride. After standing at room temperature for 5 hours the solvent is distilled off in a vacuum. The residual material is treated with about 100 ml of dichloromethane/ethyl acetate/petroleum ether (1:1:1 v/v) and filtered. The filtrate is concentrated and the residue is crystallized and recrystallized from diethyl ether/petroleum ether. There are obtained 3.4 g of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate as white crystals of melting point 103° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:29]=[C:30]([C:36]2([C:54]([F:57])([F:56])[F:55])[CH2:40][C:39]([C:41]3[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:42]=3)=[N:38][CH2:37]2)[CH:31]=[C:32]([Cl:35])[C:33]=1[Cl:34]>CN(C)C=O.C(OC)(C)(C)C>[Cl:27][C:28]1[CH:29]=[C:30]([C:36]2([C:54]([F:55])([F:57])[F:56])[CH2:40][C:39]([C:41]3[CH:49]=[CH:48][C:44]([C:45]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:46])=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=3)=[N:38][CH2:37]2)[CH:31]=[C:32]([Cl:35])[C:33]=1[Cl:34]
Reactant: COC(=O)CN
Reactant: O=C(O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)CNC(=O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of methyl glycinate hydrochloride (0.36 g, 2.89 mmol) in N,N-dimethylformamide was added triethylamine (0.59 g, 5.78 mmol) at 0° C. Then 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.40 g, 1.73 mmol), 4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzoic acid (0.73 g, 1.44 mmol) was added to the solution. Reaction mixture was stirred for overnight at room temperature. The reaction mixture was diluted with t-BuOMe, washed with H2O, and dried over MgSO4. After evaporation, the residue was purified by column chromatography (0.13 g, 16%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1>CO.[Pd].[H][H]>[F:33][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 50 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 56 in 3 ml of methanol, 10 mg of palladium-on-carbon catalyst was added, followed by 6 hours' stirring at ambient temperature and pressure in hydrogen atmosphere. The reaction liquid was filtered with Celite, and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4, and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]-propyl]-4-piperidinyl]-1,2-benzisoxzole as a beige solid, m.p.=156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].CC(O)=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCC(=N)Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 72 h
Yield: 24.6 %

Procedure:
To a solution of N-(4-chlorophenyl)butyrimidamide (compound 3, 3.5 g, 17.80 mmol), NaHCO3 (3.14 g, 37.38 mmol) in i-PrOH was added ethyl bromopyruvate (compound 4, 4.7 mL, 37.38 mmol) under N2. The reaction mixture was stirred at 85° C. for 72 hrs, then added AcOH (15 mL). After 4 hrs, the mixture was concentrated under reduced pressure. The residue was diluted with H2O, and extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and 1N-HCl solution, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera™ FLASH Purification System was used for normal phase column chromatography with EtOAc and hexane) to provide the title compound (1.28 g, 25%) as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:17])[O:5][N:4]=1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:17])[O:5][N:4]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1noc(C)c1-c1cc2ccccc2[nH]1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In the alternate procedure, 41.8 grams (0.163 moles) of silver trifluoromethanesulfonate is added portionwise to a solution of 33.5 grams (0.148 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in 450 milliliters of methylene chloride. The resulting suspension is then treated by dropwise addition with 12.8 grams (0.163 moles) of acetyl chloride in 50 milliliters of methylene chloride. The temperature rises to 35° C. during the addition. After the addition is complete the mixture is stirred at room temperature for 4 hours and then filtered. The filtrate is washed with 150 milliliters of of 2N sodium hydroxide, water and 2N sodium hydroxide, then dried over anhydrous magnesium sulfate and finally evaporated in vacuo to yield an oil. The oil is crystallized from ether to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-acetyl indole, m.p. 170°-173° C.
Reaction SMILES: [SH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>O1CCCC1>[C:9]([O:8][C:7]1[C:2]([SH:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccnc1S
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1cccnc1S
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Mercapto-3-pyridinol (25) (1.27 g) was dissolved in tetrahydrofuran (50 ml) and treated with acetic anhydride (2 ml) and pyridine (1 ml). The reaction was stirred at room temperature for 48 hours, the solvent evaporated and the residue chromatographed on silica H [Merck Kieselgel 60 (>230 mesh)] to yield 3-acetoxy-2-mercaptopyridine (26) as a yellow crystalline solid from ethyl acetate (0.9 g) m.p. 178°-80°; νmax (CHCl3) 3400, 1760, 1605, 1590, 1460, 1180 cm-1 ; δ (CDCl3 +DMSO-d6) 2.36 (3H, s, COCH3) 6.80 (1H, dd, J18, 20 Hz, CS-H), 7.18 (1H, d) and 7.60 (1H, d,) C4 and C6 H's (Found: C, 49.77; H, 4.16; N, 8.36. C7H7NO2S requires C, 49.70; H, 4.14; N, 8.28%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4o3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
A mixture of 6.06 g (34 mmol) of 1-(4-hydroxyphenyl)piperazine and 5.36 g (32 mmol) of 2-chloromethylbenzoxazole in 100 ml of absolute DMF was warmed to 80° C., and 737 mg of powdered K2CO3 were added with stirring (under a nitrogen atmosphere) in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total additio of 2.21 g (16 mmol) of K2CO3). The mixture was stirred for a further 3 hours at 80° C., the DMF was substantially removed by distillation in vacuo, and the residue was taken up in 200 ml of ether and 100 ml of water. After separating the phases, the aqueous phase was extracted a further twice with ether. The combined ether extracts were dried, filtered and evaporated in vacuo. The residue was taken up in diisopropyl ether, whereafter crystallization occurred. The crystalline substance was filtered off under suction. 7.10 g (71.7% of theory) of 1-(4-hydroxyphenyl)-4-(benzoxazol-2-ylmethyl)piperazine, melting point 155°-56° C., were obtained,
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]I.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>S([O-])([O-])(=O)=O.[Ag+].[Ag+].C(O)C>[I:12][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CCO
Product: Nc1ncc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a mixture of 5-(trifluoromethyl)pyridin-2-amine (12.0 g), silver(I) sulfate (23.1 g) and ethanol (400 mL) was added iodine (37.6 g) in several parts at room temperature, and the reaction mixture was stirred overnight at room temperature. To the reaction solution was added saturated aqueous sodium thiosulfate solution, and the mixture was stirred for 30 min, and neutralize with 1N aqueous sodium hydroxide solution. The insoluble substance was removed by filtration, the filtrate was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.3 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C=O)C.C(Cl)(Cl)Cl>[F:32][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:2]([NH2:1])[NH:3][C:4]=3[CH:10]=2)=[CH:17][CH:16]=1)=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1c2ccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)cc2NC1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a mixture of 2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to similar procedures as described for Intermediates 4, 5, and 6 and Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl3 (3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol). After stirring for 3 h at rt, the reaction mixture was washed with water and extracted with CHCl3. The organic layer was dried over MgSO4 and evaporated. The crude material was purified with silica gel column chromatography (AcOEt) to give the product of Example 23 (11.0 mg, 11%) and the title compound (34 mg, 25%): 1H NMR (DMSO-d6) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.51 (d, 1H), 7.47 (d, 1H), 7.46 (d, 2H), 7.38 (m, 1H), 7.02 (brs, 2H), 6.97 (d, 2H), 6.82 (d, 1H), 6.70 (dd, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][F:30].[H-].[Na+]>C(OCC)(=O)C>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:28][CH2:29][F:30])[CH2:15][CH2:14]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: FCCBr
Reactant: O=C1NCCc2cccc(N(Cc3ccccc3)Cc3ccccc3)c21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2c(cccc2N(Cc2ccccc2)Cc2ccccc2)CCN1CCF

Procedure:
1.06 g (3.095 mmol) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one are combined with 1.5 ml (12 mmol) 1-bromo-2-fluoro-ethane and at ambient temperature 780 mg (19.50 mmol) sodium hydride are added batchwise over a period of 30 h. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:15].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:17]1[CH:18]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:14]3[N:13]=[CH:12][NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[Cl:15])[CH:16]=1)[C:20]#[N:21]
Reactant: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]cnc23)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]cnc23)c1
Temperature: 90 °C

Procedure:
To a solution of 4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-benzimidazole 430 mg, 1.201 mmol) in DMF (5 mL) was added palladium tetrakistriphenylphosphine (416 mg, 0.360 mmol) and zinc cyanide (141 mg, 1.201 mmol) and the mixture heated to 90° C. for 1 hour. This mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic extract was washed with water (10 mL), dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified on silica gel eluting with 0-20% ethyl acetate/methylene chloride to give the title compound. LRMS (M+1)=303.8.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[C:13]([F:16])[CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1>[C:20]([O:19][C:18]([NH:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][N:7]2[CH:6]([C:5]1[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:32]([OH:34])=[O:33])=[O:24])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)cc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To the mixture of tert-butyl 1-(4-chlorobenzyl)-6-fluoro-1H-indol-4-ylcarbamate (8 g, 0.021 mol) in THF (300 mL) was added dropwise BuLi (2.5 M, 34 mL, 0.084 mol) at −78° C. and the mixture was stirred for another 30 min at −78° C. An excess of dry ice was added and the solution was warmed slowly to room temperature. The resulting mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound (8 g, yield 89%). LC/MS m/z=363.1 [M-tBu+H]+.