Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:21])[C:14]([O:22]C)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].Br.O>C(O)(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:21])[C:14](=[O:22])[NH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: COc1ncc(-c2ccc(CN(C)C)cc2)c2c(O)cccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN(C)Cc1ccc(-c2c[nH]c(=O)c3cccc(O)c23)cc1
Yield: 67.9 %

Procedure:
Process 2: To a solution of 4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-methoxyisoquinoline (102 mg, 331 μmol) in acetic acid (15 mL) were added 47% hydrobromic acid (1.5 mL) and water (1.5 mL), and the mixture was refluxed for 1 hour. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, which was made basic with saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals were collected by filtration, washed with water, and then air-dried, thereby affording 66.2 mg of the title compound as brown powder. Yield 68%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=CC(S(Cl)(=O)=O)=C[CH:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])O.[Na+]>C(O)(C)(C)C>[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([O:23][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:22]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
P-toluenesulfonyl chloride (53.5 g) was added to a pyridine (100 ml)/tert-butanol (300 ml) solution of 2,6-dichloro-5-fluoronicotinic acid (24.5 g), and stirred overnight at room temperature. The reaction liquid was poured into aqueous 10% sodium hydrogencarbonate solution, stirred at room temperature for 2 hours, and then extracted with ethyl acetate. The extract was washed with saturated saline water, dried with anhydrous magnesium sulfate, the solvent was evaporated off, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (29.5 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:29][C:26]([C:23]3[CH:22]=[N:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)([OH:27])[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C2(C)CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.5 mmol) was dissolved in 5 mL DMF and stirred for 10 min at RT. Sodium hydride (300 mg, 7.5 mmol) was added portionwise at 0° C. and the reaction mixture was stirred for 10 min. 2-Methoxy-5-(2-methyl-oxiranyl)-pyridine (566 mg, 3.75 mmol) was diluted in DMF (2 mL) and added dropwise at the same temperature and stirred for 12 h. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (7×30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel (eluent: 15% MeOH in DCM) and further crystallized in ether-hexane to obtain 190 mg of 1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(6-methoxy-pyridin-3-yl)-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.22 (s, 1H), 7.5 (d, 1H), 7.1 (s, 1H), 7.0 (d, 1H), 6.83 (d, 1H), 6.5 (d, 1H), 4.1 (m, 2H), 3.91 (s, 3H), 3.5 (m, 2H), 2.63-2.81 (m, 4H), 2.41 (s, 3H), 2.39 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provides enantiomers 64a and 64b.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[C:20](OC(=O)C)(=O)C.C(O)=O>O1CCCC1>[CH3:20][NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A portion (100 mg) of the compound obtained in Example 81 was suspended in tetrahydrofuran (THF; 3 ml) and to the suspension was added a solution (1M; 0.5 ml) of an acid anhydride prepared from acetic anhydride and formic acid in THF at -20° C. The mixture was stirred for 20 minutes. The solid obtained by concentrating the reaction mixture was suspended in THF (3 ml) and to the suspension was added a solution of borane-methyl sulfide complex in THF (10M; 100 μl). The mixture was heated to reflux for 1 hour and allowed to cool. 3N solution (10 ml) of hydrochloric acid in methanol was added to the reaction mixture, followed by stirring for 1 hour at room temperature. The reaction mixture was made basic with 3N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 90 mg (85%) of the titled compound.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: OCCOC1c2ccccc2COc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]oxepin-11-yloxy)-ethanol (256 mg, 1.0 mmol), tributylphosphine (223 mg, 1.1 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (278 mg, 1.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 175 mg (37%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.93 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 3.65-3.75 (m, 1H),3.78-3.88 (m,1 H), 3.95 (t, IH), 4.10 (t, 2H), 4.15 (q, 2H), 4.85 (d, 1H), 5.25 (s, 1H), 6.15 (d, 1H), 6.75 (d,2H), 6.85-6.95 (m, 2H), 7.10 (d, 2H), 7.15-7.40 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added 5-bromo-2-nitropyridine 111-1 (2.3 g, 11.4 mmol), 1-(piperazin-1-yl)ethanone 111-2 (1.6 g, 12.8 mmol), triethylamine (4.8 mL, 34.2 mmol) and DMSO (5 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone 111-3 as a light yellow solid. MS m/z 251.1 (M+1).
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>CO>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)N1CCN(C)CC1
Yield: 14.3 %

Procedure:
Ethyl 2-bromo-3-phenylpropionate (1.95 g) was treated with 3.05 g N-methylpiperazine as described in Example 95 to afford 0.30 g pure product after chromatography (9:1 CH2Cl2 :MeOH). NMR (300 MHz, CDCl3) delta 1.10 (d, J=7 Hz, 3H), 2.26 (s, 3H), 3.37 (m, 1H), 4.00 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: C=CCc1c(O)ccc(C(=O)NC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-N-methyl-3-(2-propenyl)benzamide (770 mg, 3.7 mmol), the compound of Example 23 (650 mg, 1.55 mmol), and potassium carbonate (321 mg, 2.32 mmol) were added to about 20 ml of DMF, and the reaction mixture was stirred overnight at room temperature in a 100 ml pear-shaped flask. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated under vacuum and chromatographed on silica gel using 40% ethyl acetate/hexane as eluant to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2.C([O:20]O)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([OH:20])([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2
Reactant: CC(C)(C)OO
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: [Zr+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 30 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (also known as methyl 5-chloro-1-oxo-2,3-dihydroindene-2-carboxylate) (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) and zirconium(IV) isopropoxide (0.0086 g, 0.022 mmol) in toluene (1.34 g, 1.56 mL) at 30° C. was added an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol). The reaction mixture was stirred for 24 hours at 30° C. and then diluted with acetonitrile (about 6 mL). Quantitative HPLC analysis showed 92% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming racemic methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 89% yield (97% chemoselectivity).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:20](=[CH:21][CH:22]=1)[N:19]1[C:10](=[N:11][C:12]3[C:17]([C:18]1=[O:23])=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:24])([O:3]CC)=[O:2].Cl>C[Si](I)(C)C.CCOCC.[OH-].[Na+]>[C:1]([C:6]1[CH:7]=[C:8]2[C:20](=[CH:21][CH:22]=1)[N:19]1[C:10](=[N:11][C:12]3[C:17]([C:18]1=[O:23])=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:24])([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Agent: C[Si](C)(C)I
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)c1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Temperature: 25 °C

Procedure:
A solution of 8-carboethoxyindolo[2,1-b]quinazoline-6,12-dione (2 mmol, from Example 42) in 3 mL of trimethylsilyl iodide (TMSI) is heated to 100° C. for 4 h. The reaction mixture is cooled to room temperature, diluted with ether, and 3 mL of 0.5N NaOH solution is added. The reaction mixture is acidified with 6N HCl and extracted with chloroform. The chloroform extracts are dried, filtered, and concentrated to give 8-carboxyindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27](=O)[NH2:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Yield: 69.6 %

Procedure:
1-(2,4-Difluorophenyl)-1-(4-(4-carbamoylthiazol-2-yl)-thiophen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (1.2 g) was dissolved in pyridine (7.1 ml). The solution was cooled on an ice bath, and phosphorus oxychloride (0.29 ml) was added thereto. The resultant mixture was stirred for 30 minutes. After the reaction, the reaction mixture was added with saline and extracted with ethyl acetate. An organic layer was washed once with 6N hydrochloric acid (20 ml) and then each once with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. After the thus-washed organic layer was dried over magnesium sulfate, the solvent was distilled out, and the residue was purified by chromatography on silica gel. Recrystallization from a solution of dichloromethane in ether was further conducted to obtain a solid (800 mg). Melting point: 172°-173° C.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH3:10][CH2:11]O>O=S(Cl)Cl>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1csc(Br)c1

Procedure:
A solution of 5-bromo-thiophene-3-carboxylic acid (14.5 g, 70 mmol) was dissolved in SOCl2 and the mixture was refluxed for 2 hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was was dissolved in EtOH and the mixture was refluxed for 1 hour, then concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as an oil (16.46 g, quantitative).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(F)c(C#N)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 82% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: C(O)(=O)C.C([O:12][C:13]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])C1C=CC=CC=1.CO>[C].[Pd].C(Cl)(Cl)Cl>[OH:12][C:13]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1O
Temperature: 75 °C
Reaction time: 7 h
Yield: 55.1 %

Procedure:
To an acetic acid (20 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-phenylbenzoate (0.77 g), 10% palladium-carbon (0.35 g) was added, followed by stirring under hydrogen pressure (5 kg/cm2) at 70 to 80° C. for 7 hours. The reaction mixture was cooled to room temperature, and acetic acid, methanol, and chloroform were added thereto. The insoluble substance was removed by filtration. The solvent was removed under reduced pressure, and then chloroform and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.36 g of tert-butyl 2-(2-hydroxy-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:23]([O:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([C:10]2[O:9][N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:11]=2)[CH2:17][CH2:16]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: OCC1CCC(c2nc(-c3ccncc3)no2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCOC[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1

Procedure:
A solution of 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexylmethanol (Preparation 6) in THF was treated with sodium hydride, 1-bromobutane and tetrabutylammonium iodide, as described for Example 104, to afford the title compound: RT=4.16 min, m/z (ES+)=316.3
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:33][C:29]2[CH:28]=[C:27]3[C:32]([C:24]([C:22]([NH:21][CH3:20])=[O:23])=[C:25]([CH3:35])[N:26]3[CH3:34])=[CH:31][CH:30]=2)[CH:8]=1)=[O:12]
Reactant: CN(C)CCN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCN(C)C)sc34)ccc12
Yield: 14.9 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 29a (0.167 g, 0.56 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.123 g, 0.56 mmole) and Cs2CO3 (0.182 g, 0.56 mmole) in a manner as previously described for example 1 to give a yellow solid (0.040 g, 13%). 1H NMR (400 MHz, CD3OD) δ8.71 (1H, d, J=6.8 Hz), 8.06 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0 Hz), 7.09 (1H, d, J=6.8 Hz), 7.05 (1H, dd, J=2.0, 8.6 Hz), 3.90 (2H, t, J=5.8 Hz), 3.64 (3H, s), 3.42 (2H, t, J=5.8 Hz), 3.23 (6H, s), 2.93 (3H, s), 2.88 (3H, s), 2.58 (3H, s). HRMS (MH+): Calcd: 480.2090; Found: 480.2069.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[NH:26]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[C@H:25]([CH3:24])[CH2:29][CH2:28][S:27]4(=[O:31])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3)CC2)c(C)c1

Procedure:
To a mixture of [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (848 mg) described in Preparation Example 113, (R)-3-methylisothiazolidine 1,1-dioxide (272 mg) described in Preparation Example 2, potassium carbonate (555 mg) and copper(I) iodide (192 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (0.20 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give (R)-[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone. The obtained (R)-[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (453 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.26 mL) was added, and the precipitate was collected by filtration to give the title compound (372 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:20][CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of [4′-(trifluoromethyl)-3-biphenylyl]methanol (177 mg, 0.70 mmol) in dry DCM (10 mL) was cooled to 0° C. (ice/water bath) under nitrogen and treated with CBr4 (256 mg, 0.77 mmol) in one portion. PPh3 (202 mg, 0.77 mmol) was then added portion-wise and the resulting mixture stirred for 1 hour at this temperature and was then allowed to warm to rt. The resulting mixture was then reduced and the residue purified directly by SPE (silica, 10 g cartridge) eluting with cyclohexane:DCM afforded the title compound as a colourless oil (220 mg).