Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][N:7]1C(=O)C2[C:9](=CC=CC=2)[C:8]1=O)[CH2:4][OH:5].O.NN.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH2:31][C:32]3[N:36]4[N:37]=[C:38](C(=O)C)[CH:39]=[CH:40][C:35]4=[N:34][N:33]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH:3]([O:6]/[N:7]=[C:8](/[C:35]1[CH:40]=[CH:39][C:38]2[N:33]([C:32]([CH2:31][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:21]=[CH:22][CH:23]=[CH:24]4)=[N:36][N:37]=2)[N:34]=1)\[CH3:9])[CH2:4][OH:5]
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: O=C1c2ccccc2C(=O)N1OC(CO)CO
Agent: NN
Solvent: O
Product: C/C(=N\OC(CO)CO)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 27.8 %

Procedure:
The title compound (12 mg, 28.6%) was synthesized from 2-(1,3-dihydroxypropan-2-yloxy)isoindoline-1,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.11 mmol) using the same procedure as described in the synthesis of example 44. After purification by HPLC (acidic with 0.05% TFA, then neutralized to basic), the title compound was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (d, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.86 (s, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.42 (m, 1H), 4.77 (s, 2H), 4.49 (m, 1H), 4.00 (dd, 4H), 2.33 (s, 3H). LC-MS (method B): [MH]+=393.2, tR=1.708 min.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.Cl>O1CCCC1.O>[CH:14]1([CH2:13][C@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=2)=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 60 °C
Yield: 4.4 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 45, 188 mg, 0.45 mmol) in tetrahydrofuran (3 mL) was treated with a 3N aqueous hydrochloric acid solution (3 mL). The resulting reaction mixture was heated under reflux at 60° C. for 4 h. After such time, the reaction was cooled to 25° C, diluted with water (5 mL), and then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate with 1% acetic acid) afforded 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (8 mg, 4%) as a white solid: [α]23589=−41.4° (c=0.099, chloroform); FAB-HRMS m/e calcd for C20H20Cl2N2O3 (M+H)+407.0930, found 407.0928.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C:7]([CH3:28])([CH3:27])[C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([C:16]([CH3:26])([CH3:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:12]=1)=[O:9].C(OCC)C>CN(C=O)C>[CH3:26][C:16]([C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:7]([S:3][C:1](=[O:4])[CH3:2])([CH3:28])[CH3:27])=[O:9])[O:15][N:14]=1)([CH3:25])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Potassium thioacetate (6.6 g, 58.0 mmol) is added at 0° C. to a solution of 2-bromo-N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-propionamide (15.0 g, 38.6 mmol) in DMF (150 mL). After stirring the reaction mixture at room temperature for 12 h, ice water and diethyl ether are added. The two phases are separated, the organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 8.7 g of thioacetic acid S-(1-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylcarbamoyl}-1-methyl-ethyl) ester as a pale yellow solid. Yield: 58%; m/z 383 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.35 (6H, d, J=8.07 Hz), 1.45-1.88 (12H, m), 2.37 (3H, s), 3.30-3.58 (2H, m), 3.69-3.87 (2H, m), 4.58 (1H, t), 6.35 (1H, s), 9.44 (1H, br. s.).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[Na]>C(OCC)(=O)C.C(O)C>[C:9]1([CH:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)C(Br)c1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A solution of 25.4 g (0.1 mole) of 1-bromo-1-phenyl-3,3-dimethyl-butan-2-one in 50 ml of ethyl acetate was added dropwise, at the boil, to a solution of 12.85 g (0.1 mole) of 4-chlorophenol and 2.3 g (0.1 mole) of sodium in 100 ml of ethanol. After boiling for 12 hours under reflux, the sodium bromide which had separated out was filtered off hot. The filtrate was distilled in vacuo and the solid residue which remained was recrystallized from ligroin. 20.2 g (67% of theory) of 1-phenyl-1-(4'-chlorophenoxy)-3,3-dimethyl-butan-2-one of melting point 103° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[C:33][C:34]([O:36][CH3:37])=[O:35])[N:27]=3)=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]2C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][C:26]3[N:27]=[C:28]([C:32]#[C:33][C:34]([O:36][CH3:37])=[O:35])[CH:29]=[CH:30][CH:31]=3)=[C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)n(C(=O)OC(C)(C)C)c3cc(OC)ccc23)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 6-methoxy-3-(6-methoxycarbonylethynylpyridin-2-ylmethyl)-2-phenylindole-1-carboxylate (100 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added dichloromethane and an aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (75.1 mg). 1H-NMR (CDCl3) δ ppm: 3.84-3.89 (6H, m), 4.45 (2H, s), 6.75 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.04-7.10 (1H, m), 7.31-7.55 (7H, m), 8.09 (1H, br s). ESI-MS (m/z): 397 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH2:19])[CH2:11][CH2:10]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl>[CH3:20][N:21]([CH3:25])[C:22]([NH:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[CH2:10][CH2:11]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: NC1CCC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
In 25 ml of dichloromethane containing 2.8 ml of triethyl amine, 2,32 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine are added followed by 2.16 g of dimethylcarbamoyl chloride. The mixture is heated at reflux for 3 hours, cooled to room temperature, washed successively with 50 ml of H2O, 50 ml of 3N NaOH, 50 ml of 3N HCl and 50 ml of H2O. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from toluene to give the title compound, melting point 157° C to 162° C.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:3][CH:2]=1.[F:29][C:30]([F:41])([F:40])C1C=CC=C(N=C=O)C=1>>[F:29][C:30]([F:41])([F:40])[C:6]1[CH:5]=[C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:3]=[CH:2][CH:1]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Product: O=C(Nc1ccc(Oc2cc(C(F)(F)F)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 2.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 2.5 h. The title compound is obtained as a white solid: ES-MS: 442.9 [M+H]+; single peak at tR=9.83 min (System 2).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)n(C(C)(C)C)n1

Procedure:
164 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2,4-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13].N1CCCCC1>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:26]\[C:23]1[NH:22][C:21]([CH3:28])=[C:20]([C:18]([NH:17][CH2:16][CH2:15][N:14]([CH2:29][CH3:30])[CH2:12][CH3:13])=[O:19])[C:24]=1[CH3:25]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To the solution of 5-bromoindolin-2-one (262 mg, 1.24 mmol) in EtOH (5 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (298 mg, 1.12 mmol) and piperidine (112 μL, 1.13 mmol). The mixture was stirred at 80° C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (368 mg) as orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1.Br[C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[S:17](=[O:20])(=[O:19])[CH:18]=1>O1CCCC1.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH:14]2[CH2:18][S:17](=[O:20])(=[O:19])[CH:16]([CH2:21][OH:22])[CH2:15]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=S1(=O)C=C(Br)C=C1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CSC2CC(CO)S(=O)(=O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. slurry, under argon, of 0.502 g of sodium hydride (60% oil dispersion) in 9 ml of dry tetrahydrofuran is added, dropwise over 5 minutes, 1.69 mi of p-methoxy-α-toluenethiol in 9 ml of dry tetrahydrofuran. The reaction is warmed to room temperature for 30 minutes, recooled to 0° C. and a solution of 2.31 g of product from Example 176 in 10 ml of dry tetrahydrofuran is added. The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is diluted with 100 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 0-90% ethyl acetate/hexane) to give 3.0 g of the desired product (1:1 mixture of isomers).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[NH2:12][OH:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.7 %

Procedure:
3,4-Dichlorobenzaldehyde (5.25 g) and 2.1 g of hydroxylamine hydrochloride were dissolved in 75 mL of pyridine. The mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was taken up in 100 mL of 1N HCl and extracted 3× with 75 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a solid. The crude material was triturated in hexane and collected by filtration to yield 5.8 g of the title compound of Step A as a white solid melting at 118-119° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11](Cl)(=[O:13])=[O:12])([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12])([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
2-Nitro-α-toluenesulfonyl chloride (0.943 g, 4.0 mmole) was dissolved in dry dioxane (7 ml) and treated with a solution of dimethylamine (4 ml 2M solution in THF, 8.0 mmole), and stirred at room temperature for a total of 6 h. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the pure 2-nitrobenzyl-N,N-dimethylsulfonamide, 0.829 g (85% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)(=[O:41])[CH3:40]
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To the solution of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and acetyl chloride (3.9 μL, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 131 as off-white solid. MS m/z 430.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.50 (s, 1H), 8.45 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.71 (d, 2H), 7.57 (s, 1H), 7.49 (d, 1H), 7.42 (d, 2H), 7.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 2.48 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]([CH3:24])[CH3:23])=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH:25]([C:10]1[CH:11]=[C:12]([CH:22]([CH3:24])[CH3:23])[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]=1[OH:8])([CH3:26])[CH3:27]
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(OCc2ccccc2)c(C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(O)c(C(C)C)c1
Yield: 92.9 %

Procedure:
4 g of 10% Pd on carbon are added to a solution of 49.3 g (0.136 mol) of the benzyl ether from step 4 in 1 l of ethyl acetate and 100 ml of glacial acetic acid and the mixture is shaken in a hydrogen atmosphere (vigorous absorption of H2) for 20 minutes. The catalyst is filtered off, the filtrate is concentrated, the residue is taken up several times in toluene and the solution is in each case concentrated in vacuo. 34.4 g of the title compound are obtained as a colorless oil, b.p. 115° C./0.1 torr.
Reaction SMILES: [CH3:1][C:2]([OH:30])([CH3:29])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1.Br[C:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].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.O>[CH3:29][C:2]([OH:30])([CH3:1])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Reactant: CC(C)n1nc(Br)c2ncccc21
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(Oc3nc4ccccc4n3CC(C)(C)O)cc2)c2ncccc21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol (237 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (139 mg), Cs2CO3 (378 mg), Pd(PPh3)4 (20.1 mg), DME (5 mL), and water (1 mL) was stirred at 140° C. for 30 min under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (175 mg).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH2:38][CH3:39])[CH2:28][CH2:27][C:26]([C:40]([OH:42])=O)=[CH:25][C:24]=3[CH:43]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH2:38][CH3:39])[CH2:28][CH2:27][C:26]([C:40]([NH:29][C:23]4[CH:24]=[CH:43][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:42])=[CH:25][C:24]=3[CH:43]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OCC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OCC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (138 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (103 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 63) (161 mg) as yellow crystals.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[CH2:15]([C:9]1[CH:10]=[CH:11][C:12]([C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCCCCc1ccc(C(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glutaric anhydride (77.6 g) is added in one portion to a stirred mixture of 1-phenylheptane (400 ml) and anhydrous aluminum chloride (200 g). The mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and carefully treated with a mixture of water (300 ml) and conc. HCl (100 ml). After the addition is complete, the mixture is allowed to return to room temperature and then extracted with ether (3×500 ml). The combined ether extracts are dried over MgSO4, filtered and concentrated on a rotary evaporator. The solid precipitate is separated from the phenyl heptane solution, and then mixed with water (600 ml) and heated under reflux for 15 min. After cooling to room temperature the product is extracted with methylene chloride (2×300 ml). The extract is dried over MgSO4, filtered and concentrated. The residue is recrystallized from heptane to provide 4-(4-n-heptylbenzoyl)butanoic acid (34.86 g) as a white crystalline solid, m.p. 101°-103.5°0 C.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.Cl>ClC1C=CC=CC=1>[Cl:1][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
Aluminum trichloride (11.75 g.; 0.088 mole) was added portionwise to a stirred mixture of the p-chlorophenylacetyl chloride and chlorobenzene (30 ml.). Following addition, the mixture was allowed to stand for 24 hours. The resulting dark brown paste was scooped out and stirred into a slurry of ice and conc. hydrochloric acid which was then extracted with methylene chloride. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride; dried over sodium sulfate and concentrated in vacuo. Recrystallization from methanol afforded 16.47 g. (71% yield), m.p. 111.5°-114° C.