Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: O=S1(=O)NCC(O)c2cc(Cl)sc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution 6-chloro-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-4-ol 1,1-dioxide (9.0 g, 37.6 mmol) in dimethylformamide (200 mL, anhydrous) and sodium hydride (60% in oil, 1.66 g, 41.5 mmol) was reacted with 1,4-dibromobutane at 0°. The reaction was stirred in an ice bath for 30 min and then it was allowed to warm to room temperature and stir for three days. The mixture was poured into ice water (400 mL) and extracted with diethyl ether (2×200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and then were dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel flash chromatography with hexane/ethyl acetate (7:3) to give 6-chloro-3,4-dihydro-2-(4-bromobutyl)-2H-thieno[3,2-e]-1,2-thiazine-4-ol 1,1-dioxide as a colorless oil (10.62 g, 75%); the 1H NMR was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19]O)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl>[CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][I:45])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of crude 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2Cl2 under N2 at 0° C. was added iodine over 15 min portionwise. The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred over 30 min. The reaction was quenched with 200 mL H2O, and the aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2×25 mL) and brine (25 mL), dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 5% -50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+=400.4.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH:9]1[CH3:12])=O)C.CO.[OH-].[Na+]>CCOCC>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:8]1([CH2:6][OH:5])[CH2:11][CH2:10][CH:9]1[CH3:12]
Reactant: CCOC(=O)C1(c2cccs2)CCC1C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC1CCC1(CO)c1cccs1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
Lithium borohydride (435 mg, 20 mmol) was added to a solution of ester 3 (2.3 g, 10 mmol) in Et2O (20 mL) at 0° C. After having stirred for 5 min, MeOH (640 mg, 20 mmol) was added dropwise and stirring continued at 0° C. until effervescence ceased. The mixture was warmed to 23° C. and was allowed to stir an additional hour, at which time the mixture was poured into 3N NaOH and stirred an additional 0.5 h. The organic layer was separated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude alcohol 4 was purified by FCC (silica gel, 1:1, hexane/CH2Cl2).
Reaction SMILES: COCCOCCOC.[CH2:10]([N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[S:19])[CH:11]=[CH2:12].N1CCOCC1.[CH:26](=O)[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:10]([N:13]1[C:17](=[O:18])[C:16](=[CH:26][CH2:27][CH2:28][CH3:29])[NH:15][C:14]1=[S:19])[CH:11]=[CH2:12]
Reactant: C=CCN1C(=O)CNC1=S
Reactant: CCCC=O
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: C=CCN1C(=O)C(=CCCC)NC1=S

Procedure:
A flask equipped with a reflux condenser, magnetic stirrer, and nitrogen atmosphere was charged with diglyme (10 mL), 3-allylthiohydantoin (1.0 g, 0.0064 mol), morpholine (0.56 g, 0.0064 mol), and freshly distilled butyraldehyde (0.94 g, 0.13 mol). The mixture was heated in a 70° oil bath for 250 min and, after cooling, was diluted with 20 mL of ethyl acetate. The resulting solution was washed with 2×10 mL 1.2 M HCl, 10 mL of water, and 10 mL of saturated aqueous NaCl. The solution was then filtered through 1 PS paper and concentrated to dryness at aspirator pressure and then high vacuum. The light orange crystalline residue weighed 1.26 g (97%). An HPLC trace at 215 nm indicated that the major product comprised 92% of the mixture. Another component (5%), with a nearly identical ultraviolet spectrum, eluted slightly more slowly. This possibly represents the other geometric isomer. NMR (CDCl3) δ 10 (bs, 1H), 5.2-6.3 (m, 4H), 4.6 (d, 2H), 2.3 (quart., 2H), 1.8 (sex., 2H), 1.0 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[NH:6]2.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[N:6]2[C:37]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2Cl)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(cc(C(=O)N4CCC(F)(F)CC4)n3-c3ccnc(Cl)c3)c2Cl)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [4-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 228), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (34%).
Reaction SMILES: [CH2:1]([C:3]1([OH:36])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:35])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][C:26]([OH:28])=O)=[C:14]2[CH:31]=[CH:32][CH:33]=[CH:34][C:13]2=[N:12][C:11]3=1)[CH3:2].Cl.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.C(N(C(C)C)CC)(C)C>>[CH2:1]([C:3]1([OH:36])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:35])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][C:26]([N:39]([CH3:40])[CH3:38])=[O:28])=[C:14]2[CH:31]=[CH:32][CH:33]=[CH:34][C:13]2=[N:12][C:11]3=1)[CH3:2]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Compound 47 (1 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.099 mmol) and 1-hydroxybenzotriazole (catalytic amount). Dimethylamine (0.04 ml, M=2 in tetrahydrofuran) and diisopropylethylamine (0.1 ml) were added to the above solution at ice bath. The resulted solution was stirred at room temperature for 3 days. The reaction was quenched with 1 N HCl and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtrated through silica gel, and concentrated by rotary evaporation. Purification by radial preparative-layer chromatography (ethyl acetate/hexanes 50/50 to methanol/chloroform 2/98) provided 12 mg of Compound 48 as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:7][OH:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C.[Br:24][CH2:25][CH2:26]Br>CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:26][CH2:25][Br:24])[CH2:7][OH:8])[CH3:2]
Reactant: BrCCBr
Reactant: CCOc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCOc1cc(CO)ccc1OCCBr
Yield: 79.5 %

Procedure:
While stirring a mixture of 30 g of 3-ethoxy-4-hydroxybenzyl alcohol, 125 g of anhydrous potassium carbonate, and 600 ml of methyl ethyl ketone, 168 g of 1,2-dibromoethane was added to the mixture, and the resultant mixture was refluxed for 48 hours with stirring. After cooling, the reaction mixture was filtered under suction and the filtrate was distilled under reduced pressure to provide a pale-yellow oily matter. The product was dissolved in 300 ml of ether and the solution was washed twice each with 50 ml of an aqueous 5% sodium hydroxide solution and then with 50 ml of water, dried with anhydrous sodium sulfate, and distilled under reduced pressure to provide a yellow oily matter. To the product was added 100 ml of a mixture of ether and petroleum ether of 1:1 by volume ratio to form crystals, which were recovered by filtration under suction to provide 39 g of 3-ethoxy-4-(2-bromoethoxy)benzyl alcohol having a melting point of 51°-53° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-8-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), glycine (2.90 g, 38.6 mmol) and NaOMe solution (58 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 17 mg of the title compound MS: (+) m/z 458.17 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:24]([CH2:23][Cl:22])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Yield: 56.7 %

Procedure:
9.8 g (32.1 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxamidoxime were stirred with 7 g (41 mmol) of chloroacetic anhydride in 60 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 4 hours. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated, and the residue was chromatographed on silica gel while eluting with ethyl acetate. There were obtained 6.63 g (57%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 208°-210°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][O:7][CH2:8][C:9](N(OC)C)=[O:10].O1CCCC1.[O:29]1[CH2:34][CH2:33][CH2:32][O:31][CH:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[Mg]Br>>[O:29]1[CH2:34][CH2:33][CH2:32][O:31][CH:30]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=1[C:9](=[O:10])[CH2:8][O:7][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=1
Reactant: CON(C)C(=O)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Br[Mg]c1ccccc1C1OCCCO1
Solvent: C1CCOC1
Product: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,5-bis(trifluoromethyl)benzyloxy)-N-methoxy-N-methylacetamide (5.0 g, 14 mmol) in tetrahydrofuran (20 mL, 247 mmol) at −78° C. was added (2-(1,3-dioxan-2-yl)phenyl)magnesium bromide (0.25M in tetrahydrofuran) (64 mL). The ice bath was replaced with a 0° C. bath and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The mixture was diluted with pentane and the layers separated. The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated. Flash chromatography (12% EtOAc/Hex) gave 3.20 g (49%) as a white crystalline solid. 1H-NMR (CDCl3, 300 MHz) δ 7.80 (s, 2H), 7.78 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 5.87 (s, 1H), 4.70 (s, 2H), 4.61 (s, 2H), 4.16 (dd, J=11.3, 4.9 Hz, 2H), 3.92 (m, 2H), 2.11 (m, 1H), 1.38 (d, J=13.7 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 202.2, 140.7, 136.9, 136.1, 131.7 (q, J=33.6 Hz), 130.9, 128.4, 127.7, 126.7, 123.4 (q, J=273 Hz), 121.7, 98.7, 75.2, 71.6, 67.4, 25.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2.[CH3:23][O:24][C:25]([CH2:27][CH2:28][C:29](Cl)=[O:30])=[O:26].C(=O)([O-])O.[Na+]>O.C(N(CC)CC)C.ClCCl>[Cl:22][C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:25]([O:24][CH3:23])=[O:26])=[CH:20][CH:19]=[C:18]([Cl:21])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2
Reactant: COC(=O)CCC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline (1.67 g), triethylamine (0.9 ml) and anhydrous dichloromethane (84 ml) was added 3-methoxycarbonylpropionyl chloride (0.7 ml). After stirring at ambient temperature for 9 hours, triethylamine (1.8 ml) and 3-methoxycarbonylpropionyl chloride (1.4 ml) were added thereto and the mixture was stirred for additional 30 minutes. The reaction mixture was washedwith water and saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with chloroform to give 8-[2,6-dichloro-3-(3-methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoline (2.04 g) as a pale yellow oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>O>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:11][N:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCC(c2nn(-c3ccccc3)c3cc(Cl)ccc23)CC1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3CCNCC3)nn(-c3ccccc3)c2c1
Yield: 79.5 %

Procedure:
A mixture of 1-acetyl-4-(6-chloro-1-phenyl-1H-indazol-3-yl)piperidine (8.2 g; 0.023 mol) of Example 95(b) was stirred and refluxed with 6N HCl (75 ml) for 5 hours. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate was evaporated and filtered. The aqueous solution was chilled, stirred and 50% NaOH was added dropwise. The resultant basic mixture was extracted with ethyl acetate and the organic extract was washed and dried and then concentrated to yield an oil which solidified on standing to yield 5.7 g of 6-chloro-1-phenyl-3-(4-piperidinyl)-1H-indazole.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:21]=3Br)=[O:19])=[CH:15][C:10]=2[O:9][CH2:8]1>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:21]4[C:20](=[CH:25][C:24]([O:26][CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[C:18](=[O:19])[CH:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCCOc1ccc(Br)c(C(=O)C=Cc2ccc3c(c2)OCO3)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A 1 L three-necked flask equipped with mechanical stirrer was charged with DMF (1.5 L), PPh3 (3.6 g, 13.7 mmol), K2CO3 (67.5 g, 0.489 mol), PdCl2 (0.855 g, 4.82 mmol) and 3-(1,3-Benzodioxol-5-yl)-1-(2-bromo-5-propoxyphenyl)-2-propen-1-one (75 g, 0.193 mol). Upon purging the solution with nitrogen, heat the mixture at 110° C. for 0.5 h, cool to 40° C., concentrate to 1/2 volume (57° C., 40 mm Hg), and add H2O (750 ml) and stir the reaction mixture at room temperature for 1 h. Filter the precipitate and wash with H2O (500 mL). Transfer the wet solid (62 g) to a 1 L 3-necked flask, add EtOAc (500 ml) and 20% KSCN solution (250 mL) and heat the biphasic mixture to 65° C. for 1 h. Remove the aqueous layer, wash the organic layer with brine (2×250 mL), dry over MgSO4 and concentrate in vacuo. Slurry the crude solid in iPrOAc/iPrOH (200 ml, 1:1) and stir for 1.5 h at 5° C. Filter the product, wash with cold iPrOH (50 ml, 0° C.) and air dry to afford 3-(1,3-Benzodioxol-5-yl)-6-propoxy-1H-inden-1-one as an orange solid (43 g, 73% yield): mp 99.0-101.0° C.; 1H NMR δ 7.3-7.2 (m, 3 H), 7.1 (m, 2 H), 6.9 (d, J=8.1 Hz, 1 H), 6.75 (dd, J=2.5, 8.2 Hz, 1 H), 6.05 (s, 1 H), 5.8 (s, 1 H), 3.95 (t, J=6.6 Hz, 2 H), 1.8 (quintet, J=7.8 Hz, 2 H), 1.05 (t, J=7.4 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]2.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]3)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2cc(Br)ccc2nc1C
Reactant: Cc1ccc(OB([O-])[O-])cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc2cc(-c3ccc(C)cc3)ccc2nc1C
Temperature: 25 °C
Yield: 100.6 %

Procedure:
Under argon atmosphere, a solution of methyl 6-bromo-2-methylquinoline-3-carboxylate (1.22 g), 4-methylphenyl borate (0.65 g) and potassium carbonate (1.18 g) in toluene-ethanol-water (40-4-4 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakis-triphenylphosphinepalladium (0.15 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:1) to give methyl 6-(4-methylphenyl)-2-methylquinoline-3-carboxylate (1.27 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2)[CH3:3]>[Rh]>[CH3:3][N:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([CH3:14])[CH2:8][CH2:7]2)[CH3:1]
Reactant: Cc1ccc2cc(N(C)C)ccc2n1
Agent: [Rh]
Product: CC1CCc2cc(N(C)C)ccc2N1

Procedure:
6-(N,N-Dimethylamino)quinaldine was reduced with rhodium on carbon to give 6-(N,N-dimethylamino)-2-methyltetrahydroquinoline.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][N:2]1[C:18](OC(C)(C)C)=O.C(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O.C1COCC1.CO>[CH2:18]([N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:12]=3[C:13]=2[CH2:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C(=O)OC(C)(C)C)CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A solution of 2-tert-butyl 8-methyl 3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (0.5 g, 1.5 mmol) in dichloromethane/trifluoroacetic acid (1:1, 10 mL) was stirred at room temperature for 1 h. The reaction mixture was then concentrated, diluted with acetic acid (5 mL) and concentrated again to give an oily residue. The residue was dissolved in THF/MeOH (4:1, 10 mL) followed by the addition of benzaldehyde (170 μL, 180 mg, 1.7 mmol), sodium triacetoxyborohydride (485 mg, 2.3 mmol) and acetic acid (175 μL, 185 mg, 3.1 mmol). Additional amounts of benzaldehyde (4×170 μL) and sodium triacetoxyborohydride (4×485 mg) were added over the course of the ensuing 8 h. The resulting reaction mixture was stirred at room temperature overnight then poured over saturated sodium bicarbonate solution (30 mL). The aqueous layer was then extracted with dichloromethane (3×30 mL) and the combined organic layer was washed with water (2×30 mL), dried over MgSO4, filtered and concentrated. Column chromatography (neat dichloromethane→3% MeOH/CH2Cl2) provided methyl 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate as a white crystalline solid (320 mg, 66%). 1H NMR (CD3OD): δ 8.17 (1H, d, J=1.1 Hz); 7.73 (1H, dd, J=8.7, 1.8 Hz); 7.44-7.27 (6H, m); 3.88 (3H, s); 3.83 (2H, br s); 3.73 (2H, br s) 2.95-2.88 (4H, m). MS (M+H)+=321.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccn1
Yield: 80 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.568 g (5 mmol) of 2-chloropyridine, 0.748 g (5.5 mmol) of ortho-tolylboronic acid, 0.011 g (0.05 mmol) of palladium (II) acetate, 0.959 g (17 mmol) of potassium fluoride and 10 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.029 g (0.05 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 24 hours. After the completion of the reaction, 10 ml of 10% aqueous sodium hydroxide solution was added, followed by separation. The organic phase was purified by column chromatography to afford 0.677 g of 2-ortho-tolylpyridine (yield: 80 mol % based on 2-chloropyridine). The identification of the product was made by mass spectroscopy.