Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>N1C=CC=CC=1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[C:3](/[CH:1]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:4]1
Reactant: O=Cc1c[nH]c2ccccc2c1=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1c[nH]c2ccccc2c1=O

Procedure:
A solution of 3-formyl-4(1H)-quinolone (6 g) from Example 33 and malonic acid (18 g) in pyridine (300 ml) was heated on a steam bath for four hours. The reaction mixture was then evaporated down and the residue washed thoroughly with water. Recrystallisation from DMF/H2O gave the title compound, m.p. 242°-244° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2ccccn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
10-bromo-2-hydroxy-5-(2-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (190 mg) obtained in Example 85 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (130 mg) was added. After stirring the mixture at room temperature for 30 minutes, t-butyl bromoacetate (110 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to obtain the title compound (88 mg, 36%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][S:8]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>C(#N)C>[CH3:20][N:21]([CH3:26])[S:22]([N:13]1[CH:14]=[N:15][C:11]([S:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:4][CH:5]=2)(=[O:10])=[O:9])=[N:12]1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2ccc(C(F)(F)F)cc2)n1
Yield: 86.4 %

Procedure:
1.0 g of 3-(4-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 3 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate anhydride was added, and 0.59 g of dimethylsulfamoyl chloride was gradually added at room temperature while stirring the solution. The solution was then refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.18 g of the titled compound was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)COCc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2coc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 42.9 %

Procedure:
To a solution of 2-Benzyloxy-acetamide (1.40 g, 8.56 mmol) in 4 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (2.0 g, 8.56 mmol) and the reaction mixture was heated at 130° C. for 6 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (1.1 g, 44%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1CSc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To 10 mL of a chloroform solution containing 183 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 114 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 36 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 228 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 135 mg of 7-fluoro-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1.O>O1CCCC1>[C:26]1([C:18]2[N:17]=[C:16]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])[C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1nc(-c2ccccc2)cc2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Sodium hydride (6.5 g, 80% strength in oil) is placed with tetrahydrofuran (160 cc) under nitrogen, and a solution of diethyl malonate (34.9 g) in anhydrous tetrahydrofuran (200 cc) is added dropwise. After 1 hour's stirring at room temperature (approximately 20° C.), a solution of 1-bromomethyl-3-phenylisoquinoline (16.2 g) in anhydrous tetrahydrofuran (200 cc) is added. After 20 hours' stirring at 20° C., water (200 cc) is added and the aqueous phase extracted with ethyl acetate. The organic phase is dried and evaporated to dryness under reduced pressure. The residual product is chromatographed on silica gel with a cyclohexane/ethyl acetate (8:2 by volume) mixture as eluant. The product (11.5 g) is recovered, taken up in concentrated hydrochloric acid (115 cc) and brought to boiling for 20 hours. Water (200 cc) is added, and the precipitate is filtered off and washed with water and acetone. 3-Phenyl-1-isoquinolinepropanoic acid (6.7 g) m.p. 160° C., is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
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: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyl ester (50 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H30N4O4, 499.23. found 499.4.
Reaction SMILES: CS([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([Br:24])=[C:13]2[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1)(=O)=O.CC(C)([O-])C.[K+].Cl>CS(C)=O.O>[Br:24][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([OH:5])=[CH:7][CH:8]=2)[C:13]=1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(OS(C)(=O)=O)cc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-1-(tert-butoxycarbonylamino)naphth-7-yl methanesulfonate, as described above in Step E, (5.87 g, 14.09 mmol) in DMSO (70 mL) was added potassium tert-butoxide (5.17 g, 42.27 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 1 hour, then neutralized with aqueous HCl, diluted with water and extracted with Et2O (2×). The combined organic extracts were washed with water (3×), dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (50 mg, 0.1 mmol) in EtOH (2 mL) was added triethylamine (0.1 mL, 0.6 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (27 mg, 0.11 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was pjurified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg). MS found: (M+H)+=556.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:11][C:10]1([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]1=[CH2:1]
Reactant: COc1ccc(CBr)cc1
Reactant: CC1=Nc2ccccc2C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C1N(Cc2ccc(OC)cc2)c2ccccc2C1(C)C
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a solution of 4.0 g of 2,3,3-trimethylindolenine in 25 ml of chloroform was added 5.6 g of p-methoxybenzyl bromide and the mixture was heated in an autoclave at 80° C. for 21 hours. The resulting precipitate was recovered by filtration to give 8.5 g of 1-(4-methoxybenzyl)-2,3,3-trimethylindolenium as white crystals. To these crystals was added 85 ml of 10N aqueous potassium hydroxide solution in a nitrogen atmosphere and the mixture was heated at 50° C. for 3 hours. The reaction mixture was then extracted with ether and the extract was dried over magnesium sulfate and concentrated under reduced pressure to give 5.7 g of 3,3-dimethyl-1-(4-methoxybenzyl)-2-methyleneindoline (Yield 80.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34].C(O)COCCO.O.NN.[OH-].[K+]>>[CH3:36][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:28])[CH3:29])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34]
Reactant: COc1ccc(OC)c(P2C(C)(C)CC(=O)CC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(OC)c(P2C(C)(C)CCCC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 210 °C
Reaction time: 7 h
Yield: 26.5 %

Procedure:
A round bottom flask was charged with 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphinan-4-one (1.03 g, 2.02 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (10.6 mL, 111 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The flask was charged with hydrazine hydrate (0.892 mL, 10.1 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (918 mg, 10.1 mmol, 5 equiv). The mixture was immersed in an oil bath at 170° C. The temperature of the bath was gradually increased to 210° C. over 1 hour and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen. Reaction material that had condensed on the Claisen adapter was washed down into the reaction flask with ethyl acetate (5 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (2×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. Purification of the crude material by silica gel column chromatography on an Isco CombiFlash system (40-g column; gradient: 2 column volumes heptane, ramp up to 85:15 heptane:ethyl acetate over 8 column volumes, hold at 85:15 for 4 column volumes) afforded the title compound as a white solid (266 mg, >99 area % by HPLC, 27% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.95 (s, 2H), 6.85 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.56 (s, 3H), 2.95 (hept, J=6.9 Hz, 1H), 2.49 (hept, J=6.7 Hz, 2H), 2.10-1.89 (m, 2H), 1.71-1.51 (m, 2H), 1.45-1.26 (m, 8H), 1.21 (d, J=6.8 Hz, 6H), 1.14 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 6H), 0.80 (d, J=8.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 154.3, 151.9 (d, J=11 Hz), 146.3, 145.5 (d, J=2 Hz), 140.1 (d, J=42 Hz), 132.5 (d, J=9 Hz), 127.7 (d, J=46 Hz), 119.7, 110.6, 107.1, 54.3 (d, J=62 Hz), 40.8 (d, J=4 Hz), 34.0 (d, J=5 Hz), 33.4, 30.7, 30.3 (d, J=24 Hz), 30.1 (d, J=3 Hz), 25.5, 24.2 (d, J=13 Hz), 20.8. 31P NMR (CDCl3, 202 MHz) δ ppm −6.0 (br s). HRMS (TOF-ESI+) calcd for [M, C32H49O2P]+ 496.3470. Found 496.3465.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].[F:35][CH:36]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][NH2:44])[CH2:37]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:44][CH2:43][CH2:42][N:38]2[CH2:39][CH2:40][CH2:41][CH:36]([F:35])[CH2:37]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCCN1CCCC(F)C1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCCC(F)C1

Procedure:
{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid was coupled with 2-(3-fluoro-piperidin-1-yl)-ethylamine to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:20]1[CH2:19][CH2:18][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:4]3[N:3]=[C:2]([OH:1])[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4nccn4c(O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1nc(-c2ccc(C3CCNCC3)cc2)cc2nccn12
Yield: 78.8 %

Procedure:
To a flask charged with tert-butyl 4-(4-(5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)phenyl)piperidine-1-carboxylate (1.75 g, 4.44 mmol) in 40 mL of dichloromethane was added 2,2,2-trifluoroacetic acid (15 mL, 195 mmol) at ambient temperature for 3 hours. The solvent was concentrated under reduced pressure and the resulting crude was taken up in methanol (10 mL) and to it was added aqueous saturated sodium bicarbonate slowly. The resulting solid was collected by means of vacuum filtration and was dried overnight on high vacuum. This solid was triturated with water (50 mL) and solids were collected by means of vacuum filtration and dried on high vacuum to afford 7-(4-(piperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-ol (1.03 g, 3.50 mmol, 78.9% yield). MS (apci) m/z=295.1 (M+H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.P(Cl)(Cl)(Cl)=O>>[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCCN1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)Cc1ccccc1N2C1=NCCCC1

Procedure:
Reaction of acridan, 2-piperidone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(3,4,5,6-TETRAHYDRO-2-PYRIDYL)ACRIDAN as a distillablle oil, b.p. 145°-150°C. at 0.15 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(3,4,5,5-TETRAHYDRO-2-PYRIDYL)ACRIDAN HYDROCHLORIDE as the hemihydrate, m.p. 190.5°-192.5°C. (corr.) by trituration with hot benzene in a 19% overall yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:5]([C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8])[C:4]1[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)[C@H](CC[C@H](CC1CCCCC1)C(=O)O)Cc1cccc(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CC[C@H](CC1CCCCC1)C(=O)O)Cc1ccccc1
Yield: 30 %

Procedure:
To a solution of (2R,5R)-2-(3-chlorobenzyl)-5-(cyclohexylmethyl)hexanedioic acid (37 mg, 0.10 mmol) in MeOH (2 mL) and EtOAc (2 mL) was bubbled through Argon for 5 min. Then 5% Pd/C (40 mg) was added to the solution. The reaction was stirred at 1 atm of hydrogen (balloon) for 2 hr. The reaction was filtered through CELITE® and washed with MeOH. The combined filtrate and MeOH wash was concentrated. The resulting residue was purified using RP prep-HPLC (Method B). The desired fraction was concentrated in vacuum and lyophilized with CH3CN to give (2R,5R)-2-benzyl-5-(cyclohexylmethyl)hexanedioic acid (10 mg, 0.030 mmol, 30% yield) as a white solid.
Reaction SMILES: Br[C:2]1[N:15]([CH2:16][C:17](OCC)=[O:18])[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH2:42])O1.O.C(=O)([O-])O.[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([C:3]2[C:4]3[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=3[N:15]3[C:2]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:17](=[O:18])[CH2:16]3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CCOC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CC(=O)Nc1ccccc1-3
Temperature: 110 °C
Yield: 26.2 %

Procedure:
To a suspension of ethyl 2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (457 mg, 1.05 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (275 mg, 1.25 mmol) obtained in the same manner as in the method described in Example 1-1, Step 1 in 1,2-dimethoxyethane (7.5 ml) and water (3.5 ml) were added sodium hydrogen carbonate (260 mg, 3.14 mmol) and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) and the mixture was stirred with heating at 110° C. for 3.5 hr. The mixture was allowed to cool to room temperature and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give ethyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (111 mg, yield 26%).
Reaction SMILES: S(O[CH2:12][CH:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:26].[Na+]>CC(C)=O>[CH:20]1([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][I:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCC(c2ccccc2)C2CCCCC2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICC(c1ccccc1)C1CCCCC1

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 13.9 g (39.4 mmol) 2-(cyclohexyl)-2-phenylethanol tosylate, 80 mL acetone and 6.49 g (43.3 mmol) sodium iodide. The reaction was refluxed 36 hr, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and aqueous sodium bisulfite solution, dried over sodium sulfate, and evaporated to an oil, 12.11 g (98%), which was used directly in the next step.