Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:15][CH2:14][CH2:12][OH:13])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCCO
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Product: O=[N+]([O-])c1c(NCCO)cccc1NCCO
Temperature: 98 °C

Procedure:
0.25 mole (48 g) of 2,6-dichloronitrobenzene, prepared according to the method described by Alexander McKillop and Jonathan A. Tarbin in Tetrahedron Letters, Vol. 24 No. 14, page 1505 (1983), is added to 200 ml of ethanolamine. The mixture is heated to 98° C. for 8 hours. The reaction mixture is poured onto ice. After phase separation, the precipitate is taken up in the minimum quantity of ethanol, with stirring. After dilution with a mixture of ice and water, the expected product is filtered off, washed with water and then recrystallized from ethanol. It is identical with the product prepared in Example 1.
Reaction SMILES: [OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.Cl.C([N:26]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH2:26])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthoic acid (449 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (321 mg) and 1-hydroxy-1H-benzotriazole monohydrate (301 mg) were dissolved in DMF (7.6 ml), and diisopropylethylamine (216 mg) was added with stirring under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 18 h. Silica gel (3 g) was added to the reaction mixture and the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol containing aqueous ammonia (7%): 19/1) and the eluate was concentrated to dryness. The residue was recrystallized from ethanol to give the title compound (53 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[NH4+]>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:3]=[N:4][C:5]4[C:6]5[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=5[CH2:8][CH2:9][C:10]=4[CH:11]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Agent: Cl
Agent: [NH4+]
Product: c1ccc(N2CCN(c3cc4c(nn3)-c3ccccc3CC4)CC2)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
A mixture of comprising about 0.01 mol of 3-chloro-5,6-dihydrobenzo[h]cinnoline, about 0.05 mol of 1-phenylpiperazine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at 130° C. for 48 h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded bright yellow crystals, yield 88.1%; HPLC: 96.0% purity; HRMS calculated 342.1839, found 342.1831; 1H NMR (CDCl3): δ 8.474 (d, J=7.5, 1H), 7.222-7.400 (m, 4H), 7.012 (d, J=10, 2H), 6.925 (t, J=6.5, 3=7.5, 1H), 6.824 (S, 1H), 3.900 (s, 4H), 3.370 (d, J=4.5, 4H), 2.932 (s, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][C:18](O)=[O:19])[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14](O)=[O:15])[CH:8]=1>C1COCC1>[C:9]1([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=[C:7]([CH2:17][CH2:18][OH:19])[CH:8]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cccc(CCO)c1
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a two-liter, 3-necked round-bottomed flask equipped with a 500-ml constant pressure addition funnel, an overhead stirrer, thermocouple and nitrogen inlet was added 16 g (0.42 mol) of lithium aluminum hydride (95%) and 800 ml of anhydrous THF. The addition funnel was charged with a solution of 40 g (0.21 mol) of 1,3-phenylenediacetic acid in 500 ml of anhydrous THF. The diacid was added slowly over a period of 2 hours with cooling in an ice bath. Once addition was complete, the ice bath was removed and the suspension allowed to reach room temperature overnight after which time it was re-cooled and 100 ml of ethyl acetate was slowly added to decompose the remaining hydride. The addition funnel was recharged with 200 ml of 2M NaOH, which was then added slowly with vigorous stirring until the ensuing suspension became granular in appearance. The suspension was filtered and well washed with ethyl acetate. The combined filtrate and washings were then washed with brine, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator to yield 21 g (62%) of the title compound as a clear, colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(CCCN2CCCCC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCCN2CCCCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 32.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (110 mg, 0.24 mmol), 2-(methyloxy)-4-[3-(1-piperidinyl)propyl]aniline (57 mg, 0.21 mol), and p-toluenesulfonic acid (109 mg, 0.57 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (53 mg, 0.079 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.40 (d, J=6.23 Hz, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 8.25 (d, J=5.13 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.81 (d, J=7.69 Hz, 1H), 7.73 (dd, J=8.88, 0.82 Hz, 1H), 7.56-7.64 (m, 2H), 7.45 (dd, J=8.52, 7.23 Hz, 1H), 7.35-7.42 (m, 1H), 7.19 (t, J=8.15 Hz, 2H), 6.99 (t, J=6.87 Hz, 1H), 6.93 (s, 1H), 6.74 (d, J=8.06 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 3.81 (s, 3H), 2.56 (t, J=7.51 Hz, 2H), 2.20-2.31 (m, 6H), 1.68-1.77 (m, 2H), 1.41-1.50 (m, 4H), 1.30-1.40 (m, 2H). MS (ESI): 674 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=3)[CH:32]=[N:31][CH:30]=2)[CH2:24][C:23]1=[O:44])C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[H][H]>CO.CCOC(C)=O.[Pd]>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=3)[CH:32]=[N:31][CH:30]=2)[CH2:24][C:23]1=[O:44]
Reactant: [H][H]
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3ccccc3OCc3ccccc3)C(=O)C2)cc1F
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3ccccc3O)C(=O)C2)cc1F
Reaction time: 16 h

Procedure:
To a solution of the benzyl ether from Step F (402 mg, 0.647 mmol) in 5 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (200 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 16 hours, the solution was filtered through celite, and the filter pad was rinsed with 1:1 MeOH/EtOAc. Concentration in vacuo provided the titled product as a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.NC1N(C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)N=C(C#N)C=1SC(F)(F)F.OO.[NH2:35][C:36]1[N:40]([C:41]2[C:46]([Cl:47])=[CH:45][C:44]([C:48]([F:51])([F:50])[F:49])=[CH:43][C:42]=2[Cl:52])[N:39]=[C:38]([C:53]#[N:54])[C:37]=1[S:55]([C:58]([F:61])([F:60])[F:59])(=O)=[O:56].S(=O)=O>B(O)(O)O.ClC1C=CC=CC=1>[NH2:35][C:36]1[N:40]([C:41]2[C:42]([Cl:52])=[CH:43][C:44]([C:48]([F:49])([F:50])[F:51])=[CH:45][C:46]=2[Cl:47])[N:39]=[C:38]([C:53]#[N:54])[C:37]=1[S:55]([C:58]([F:59])([F:61])[F:60])=[O:56]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: O=S=O
Agent: OB(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 12 °C
Reaction time: 4.5 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (1660 g, 14.5 mol) was added to a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (436 g, 1.03 mol) and boric acid (5 g, 0.08 mol) in a glass reactor at 12° C. Hydrogen peroxide (131.5 g of 35% w/w, 1.35 mol) was added over 2 hours while maintaining the temperature at 12° C., and the mixture kept at this temperature for a further 4-5 hours. When the transformation had reached 97-98%, or the amount of unwanted 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole reached 2% (as judged by HPLC analysis), sulfur dioxide was added to quench any remaining hydrogen peroxide, and the mixture maintained at 10-18° C. for 0.5 hour. Chlorobenzene (370 g) was added and the mixture placed under reduced pressure (from 0.17 to 0.04 atmosphere) and heated to 47-50° C. with azeotropic distillation. A homogeneous fraction containing recovered trifluoroacetic acid was obtained. During the distillation additional chlorobenzene (1625 g) was added continuously in order to maintain a constant volume. At the end of the azeotropic distillation the reactor contents were maintained at 47-50° C. under reduced pressure (0.04 atmosphere), and a homogeneous fraction of chlorobenzene distilled. After release of the vacuum, the reactor was heated to 40° C., ethanol (207 g) and chlorobenzene (235 g) added, and the mixture heated to 80° C. with stirring to give a solution. On cooling to 40° C. the product crystallized. The reactor was placed under progressively reduced pressure (from 0.13 to 0.03 atmosphere) and the ethanol distilled at 40° C. The vacuum was released and the mixture cooled to 5° C. during 3.5 hours and left for a further 0.5 hour. The product was filtered off, washed with cold chlorobenzene, then with cold aqueous ethanol, then with water, and dried in vacuo at 135° C. to give the title compound (407.5 g), in a typical yield of 89% and purity of 95.5%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](OCC)(=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NNc1ccc(Cl)nn1
Solvent: CCO
Product: CCOC(=O)c1nnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.04 g of (6-chloro-3-pyridazinyl)hydrazine was dissolved in 70 ml of ethanol; 8.6 ml of diethyl oxalate was added, followed by stirring at room temperature for 16 hours and subsequent refluxing under heating for 1 day. After cooling, the precipitated crystal was washed with diethyl ether and dried to yield 7.32 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23].Br[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C(N(CC)CC)C.CCOCC.[Pd](Cl)Cl>[OH:24][CH2:20][CH2:21][C:22]#[C:23][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]
Reactant: C#CCCO
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=Cc1ccccc1C#CCCO
Temperature: 25 °C

Procedure:
To a suspension of palladium chloride (11.0 mg, 0.618 mmol) and cuprous iodide (Aldrich gold label, 43.5 mg, 0.229 mmol) in triethylamine (distilled from calcium hydride, 53 mL) was added, sequentially, triphenylphosphine (439 mg, 1.67 mmol), 3-butyn-1-ol (8.0 mL, 106 mmol), and 2-bromobenzaldehyde (10.6 mL, 88.3 mmol). The mixture was refluxed for 7 hours. The mixture was cooled to room temperature, diluted with ether (300 mL) and filtered. The pad was washed with ether (3×50 mL) and the combined filtrates were concentrated in vacuo to an oil: 16.1 g; 1H NMR (270 MHz, deuteriochloroform) δ 10.4 (1H, s), 7.85 (d, J=7 Hz), 7.35-7.50 (m, 3H), 3.0-4.0 (br s, 1H), 3.85 (t, J=6 Hz, 2H), 2.74 (t, J=6 Hz, 2H);
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].CO>>[ClH:25].[CH:20]1[C:21]2[C:16](=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: c1cc(OC2CCNCC2)c2ccncc2c1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 45 (164 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (128 mg) as white powdery solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1.CN([CH:18]=[O:19])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH:18]=[O:19])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 82.5 °C
Reaction time: 4.5 h
Yield: 85 %

Procedure:
Phosphorous oxychloride (255.58 g, 1.666 mol) was slowly added to a solution of DMF (355.0 ml) and 2,3-dihydrobenzofuran (100 g, 0.833 mol) maintaining the temperature 80-85° C. The reaction mixture was stirred for 4-5 hr and the reaction progress monitored by HPLC. The reaction mixture was then poured into ice water and extracted with toluene (2000 ml). The organic layer was washed with 5% sodium bicarbonate solution (500 ml) and then 10% brine solution (500 ml). The organic layer was distilled off under vacuum at 50-60° C. A liquid product was isolated. Yield: 85-90%, Purity: 90-92%
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH3:6])[NH:12][CH:11]=1)=[O:24]
Reactant: COc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2[nH]cc(C=O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add phosphorus oxychloride (1.1 eq.) with vigorous stirring to DMF (cooled in an ice bath). After the addition is complete, allow to stir in the ice bath for ˜10 minutes, then add a solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF with vigorous stirring. Allow to stir at 0° C. After 1 hour, warm to room temperature. After 16 hours, carefully add 4 eq. of 2N NaOH with vigorous stirring. Heat to about 80° C. and then cool. Pour the reaction mixture into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry in a vacuum oven at room temperature to give the title compound. Acidify the filtrate and extract with EtOAc. Combine the organic layers and wash with 50% brine. Collect the organic layer, dry (MgSO4) filter, and remove the solvent to give the title compound as a light purple solid. Total yield of the title compound is 5.44 g: MS (ES+): m/z 175 (M+H)+, 160 (M−CH3)+; (ES−): m/z 174 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:30][C:31]1([CH3:42])[O:36][CH2:35][CH2:34][NH+:33]([CH2:37][B-](F)(F)F)[CH2:32]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:37][N:33]5[CH2:34][CH2:35][O:36][C:31]([CH3:42])([CH3:30])[CH2:32]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC1(C)C[NH+](C[B-](F)(F)F)CCO1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOC(C)(C)C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (2,2-dimethyl-morpholinium-4-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 3): tR=1.27 min; Mass spectrum (ESI+): m/z=520 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(C)c1
Product: Cc1cc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)ccc1Cl

Procedure:
The title compound was prepared from rac-[(4-chloro-3-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 2) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 484.1 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2)([O:3]C)=[O:2].C[O-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.Cl>CO.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([OH:3])=[O:2])[CH:14]=[CH:13][C:12]=1[C:10]([OH:9])=[O:11]
Reactant: COC(=O)c1ccc2c(c1)COC2=O
Reactant: O=Cc1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(CCc2ccccc2F)c1

Procedure:
8.5 G. of 5-carbomethoxyphthalide and 2.43 g. of sodium methoxide were refluxed for 15 minutes in 250 ml of methanol, and then 5.55 g. of o-fluorobenzaldehyde was added. The mixture was refluxed for 20 hours and then poured into water and acidified with dilute hydrochloric acid. The solution was extracted with ethyl acetate and the extract washed, dried and evaporated. The residue was refluxed for 48 hours in 75 ml of acetic acid and 45 ml of 57% aqueous hydriodic acid containing 7.5 g. of red phosphorus. The mixture was poured into water and filtered. The residue was dissolved in ethanol and the solution filtered and evaporated to afford 2-(o-fluorophenethyl)benzene-1,4-dicarboxylic acid which was cyclized according to the method described in Example I, A to obtain 2-carboxy-9-fluoro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 248.5° to 249.5° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][C:16](=[O:18])[CH3:17])=[C:7]([Cl:19])[C:6]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][C:16](=[O:18])[CH3:17])=[C:7]([Cl:19])[C:6]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(OC(C)=O)c2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)Oc1c(Cl)c(Oc2ccc(N)cc2)c(OC(C)=O)c2ccccc12
Yield: 105.2 %

Procedure:
Following a procedure similar to that described in Preparation 1(c), 8.5 g of the 1,4-diacetoxy-3-chloro-2-(4-nitrophenoxy) naphthalene [prepared as described in step (b) above] were hydrogenated under an atmosphere of hydrogen and in the presence of 1.7 g of 10% palladium-on-charcoal in 200 ml of tetrahydrofuran at room temperature for 5 hours, to give 8.3 g of 1,4-diacetoxy-2-(4-aminophenoxy)-3-chloronaphthalene as an oily substance.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([O:19]C)=[O:18])=[CH:6][CH:5]=1.Cl>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:21])[CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([OH:19])=[O:18])=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Cn1cccc1C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Lithium hydroxide (116.73 mg, 2.15 mmol) was added to a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (515 mg, 1.85 mmol) in THF (9 mL) water (1 mL) and stirred at room temperature overnight. The mixture was acidified to pH 2 with aqueous HCl (1 M) and extracted with EtOAc (3×10 mL). The organic layers were combined and dried (MgSO4), filtered, concentrated in vacuo to give a cream white solid. The solid was triturated with cold CH2Cl2 to give 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a white solid (310 mg, 64%). 1H NMR (400 MHz, d6-DMSO): δ 5.86 (s, 2H), 6.16 (dd, 1H, J 3.9, 2.6 hz), 6.86 (dd, 1H, J 3.9, 1.8 Hz), 7.08 (t, 1H, J 2.1 Hz), 7.65-7.70 (m, 2H), 8.02-8.08 (m, 2H), 12.07 (br s, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: N#Cc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 73 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (265 mg, 0.69 mmol, prepared in Synthetic Example 25) in DMF (7 ml) was added hydrazine monohydrate (80%, 82 μl, 2.05 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (190 mg, 73%).