Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.CC(C)([O-])C.[K+].[Br:24][C:25]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:26]=1[NH:27][C:28](=[O:31])[CH2:29]Cl>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[N:3]([CH2:29][C:28]([NH:27][C:26]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:25]=2[Br:24])=[O:31])[N:4]=1)[CH3:17]
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(CC(=O)Nc2cc(C(F)(F)F)ccc2Br)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxo-3H-phthalazin-1-ylacetate (3.36 g) and potassium t-butoxide (1.62 g) in dimethylformamide (15 ml) was slowly added a solution of 2'-bromo-5'-trifluoromethyl-2-chloroacetanilide (4.55 g) in dimethylformamide (15). After stirring the resulting solution overnight at room temperature, it was poured onto water (50 ml) and the resulting white precipitate was collected and air dried (yield 4.3 g; m.p. 160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C([O+](CC)CC)C.[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:36]([NH:38][NH2:39])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:36]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][N:30]=3)=[N:38][N:39]=[C:13]2[CH2:12]1)=[O:10]
Reactant: NNC(=O)c1cnccn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-[(2,4-dichlorophenyl)carbonyl]-2-piperazinone (I6) (0.273 g, 1 mmol) in dry Dichloromethane (DCM) (3 ml) was stirred at room temperature under argon. Triethyloxonium tetrafluoroborate (0.199 g, 1.050 mmol) was added and the reaction solution was stirred for 10 minutes. 2-pyrazinecarbohydrazide (0.166 g, 1.200 mmol, commercially available) was then added and the solution was stirred for a further 1 hour. The solvent was then concentrated before n-butanol (3.00 ml) was added and the solution was stirred, under reflux and argon, for 4 hours. LCMS confirmed product location, thus the solution was cooled to room temperature before the solvent was evaporated in vacuo. The remaining residue was then purified by flash chromatograpghy (Biotage SP4, 25M cartridge) with a gradient of 0 to 10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-directed automated HPLC. The solvent was then evaporated in vacuo, and the remaining solid was triturated with ether, and dried in a vacuum oven to yield the product in 0.137 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2ccccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A solution of 3-methylquinoline (275 mg), N-bromosuccinimide (343 mg) and 2,2′-azobis(isobutyronitrile) (31.6 mg) in carbon tetrachloride (8.0 g) was heated under reflux for 2 hours. The mixture was cooled to room temperature, and the insoluble materials were removed by filtration, and thereto was added toluene, and the mixture was concentrated under reduced pressure. To the residue was added toluene (5 mL) to give a solution of 3-bromomethylquinoline in toluene. To a 60% suspension of NaH (70 mg) in THF (2 mL) was added dropwise a solution of the compound (300 mg) obtained in Reference Example 3-2 in THF (3 mL). To the solution was added the solution of 3-bromo-methylquinoline in toluene as mentioned above, and the mixture was stirred at 35° C. for one hour. Water was added to the reaction solution, and the organic layer was separated, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (460 mg, 74%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:16][OH:17])[O:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1-O-Benzyl-3-t-butyldimethylsilyl-2-O-carboxymethylglycerol (5 g) was dissolved in methanol (50 ml), and a solution of 85% potassium hydroxide (7 g) in water (50 ml) was added thereto. The mixture was stirred at room temperature for 60 hours to complete the reaction.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:32])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH:18]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[OH:31])=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:22][C:20]1([F:23])[CH2:19][CH:18]2[N:17]([C:14]3[CH:15]=[CH:16][N:11]4[C:12]([N:13]=3)=[C:8]([C:6](=[O:7])[NH:5][CH2:4][C@H:3]([OH:32])[CH2:2][O:31][C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=32)[CH:9]=[N:10]4)[CH2:21]1
Reactant: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NC[C@H](O)COc2ccc(F)cc2C2CC(F)(F)CN2c2ccn3ncc1c3n2
Temperature: 85 °C
Yield: 20 %

Procedure:
A mixture of N-((S)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.060 g, 0.128 mmol) and Cs2CO3 (0.208 g, 0.639 mmol) in DMF (6.4 mL) was heated at 85° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material which was purified by silica gel flash column chromatography (CH2Cl2 to NH4OH:MeOH:CH2Cl2=0.5:5:95) to afford a mixture of the diastereomers. The isolated diastereomers were further purified by chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Fractions having a retention time of about 17.1 minutes were isolated to afford the title compound designated as Diastereomer 1 (11 mg, 20% yield; MS (APCI) m/z=434.2 (M+H). Fractions having a retention time of about 21.0 minutes were isolated to provide the title compound designated as Diastereomer 2 (13 mg; 24% yield); MS (APCI) m/z=434.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:10](O)=[O:11])[CH3:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: CCOC(=O)CCCCC(CCc1ccc(C#N)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(CO)CCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
54.19 ml of a 1 M borane-THF complex solution (54.19 mmol) are added dropwise to a solution of 8.6 g (27.1 mmol) of 2-[2-(4-cyanophenyl)ethyl]heptanedioic acid 7-ethyl ester from Example 84A in 200 ml of THF at −10° C. After warming to 0° C., the mixture is stirred at this temperature for 2 hours. After reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:10→1:4). 5.1 g (97% purity, 60% yield) of a colorless solid are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH2:17][CH2:18]O)[C:11]=1[OH:20])([CH3:9])[CH3:8])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:23])([F:22])[F:24])[CH2:6][C:7]([C:10]1[C:11]2[O:20][CH2:18][CH2:17][C:12]=2[CH:13]=[C:14]([F:16])[CH:15]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)cc(CCO)c1O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)cc2c1OCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.1 %

Procedure:
4-(5-Fluoro-2-hydroxy-3-(2-hydroxyethyl)phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (3.90 g, 10.2 mmol) is dissolved with triphenylphosphine (3.14 g, 12 mmol) and triethylamine (2.1 ml, 15 mmol) in acetonitrile (150 ml), mixed with carbon tetrachloride (2 ml) and stirred for 3 days in a nitrogen atmosphere at room temperature. The solvent is distilled off in a rotary evaporator, and the residue is taken up in ethyl acetate (150 ml) and water (75 ml). The ethyl acetate phase is separated, washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 3.31 g of the product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([NH2:18])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O[CH:24](OCC)[N:25]([CH3:27])[CH3:26])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([N:18]=[CH:24][N:25]([CH3:27])[CH3:26])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 0 °C

Procedure:
A mixture of 0.48 g (1.4 mmol) of 3-(4-acetylamino-benzylamino)-5-amino-4-cyano-pyrazole containing 21.06% THF, 0.245 ml (1.43 mmol) of N,N-dimethylformamide diethyl acetal and 4 ml of toluene is heated under reflux for 4.5 hours. The reaction mixture is then cooled to approx. 0° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 206-211° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([CH3:28])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][N:30]=2)(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCC[C@@H]1c1ccnn1C
Yield: 77.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (356 mg, 0.632 mmol) prepared in Example 52b, triethylsilane (0.20 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (202 mg, 68%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[C:21]([NH2:22])=[N:27][C:28]([NH2:30])=[N:29]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2C#N)CC1
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3nc(N)nc(N)c23)CC1
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
In a reaction vessel, 4-(2-cyano-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (613.7 mg; 2 mmol) and guanidine carbonate (360.6 mg; 2 mmol) were suspended in 2 mL DMA. The reaction mixture was heated to 145° C. for 22 hours. The mixture was cooled to room temperature and 4 mL of water was added and stirred for 15 minutes. The solid was collected by vacuum filtration and washed with water and ethyl acetate and dried under vacuum to yield 278.4 mg (40% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)=[CH:19][N:20]=2)[N:17]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:7][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
NaH (34 mg, 0.85 mmol) was suspended in NMP (1.5 mL) under argon. 3-Chloroaniline (108 μL, 1.017 mmol) was added and the RM was heated to 85° C. After 10 min, 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 100 mg, 0.339 mmol) was added and the RM was stirred at 85° C. for 1 h. The mixture was then heated to 160° C. for 10 min. The mixture was diluted with EtOAc and washed with water (3×). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and crystallized in Et2O to afford the title compound as a yellow solid (tR 4.99 min (conditions 4), MH+=386.1, 1H-NMR in DMSO-d6: 9.57 (s, 1H); 8.82 (m, 1H); 7.93 (m, 3H); 7.86 (m, 1H); 7.71 (m, 1H); 7.56 (s, 1H); 7.47 (dd, 1H); 7.43 (m, 1H); 7.25 (t, 1H); 6.99 (m, 1H); 6.85 (d, 1H); 4.50 (s, 2H)).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncc(Br)c(Cl)n1
Temperature: 120 °C

Procedure:
5-Bromo-2-methylpyrimidin-4-ol (MM1) (30 g, 159 mmol) was suspended in phosphorous oxychloride (150 mL). The reaction mixture was heated at 120° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and azeotroped twice with toluene. The crude residue was diluted with EtOAc (600 mL) and cooled to 0° C. Aqueous sodium bicarbonate (150 mL) was slowly added with stirring. The organic layer was washed once more with sodium bicarbonate (150 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a dark oil, which was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 207.0 found, 207.4 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.ClCCl.CO.C(OCC)(=O)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(OC)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.94 g, 1.90 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.52 g, 1.80 mmol), and N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) in acetonitrile (30 mL). Heat to reflux. After 18 hours, cool and dilute the reaction mixture ethyl acetate (300 mL). Extract three times with an aqueous 1% sodium bicarbonate solution, and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 25% methanol/ethyl acetate containing concentrated ammonium hydroxide (20 mL/3 L). Evaporate the product containing fractions in vacuo to give a residue. Dissolve the residue in dichloromethane, filter, and evaporate in vacuo to give a the title compound: Rf=0.20 (silica gel, 20% methanol/ethyl acetate).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[C:13](Cl)(=O)[CH3:14]>O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:4]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:13]=2[CH3:14])=[CH2:12])=[C:4]1[CH3:12])[CH3:2]
Reactant: CCn1c(C)cc2ccccc21
Reactant: CC(=O)Cl
Solvent: O
Product: C=C(c1c(C)n(CC)c2ccccc12)c1c(C)n(CC)c2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-ethyl-2-methylindole (15.9 g, 0.1 mole) and acetyl chloride (9.4 g, 0.12 mole) was stirred at room temperature for 20 hours. Then, water (100 ml) was added to the reaction mixture and the resulting grains were filtered and dried. The dried product was recrystallized from toluene/methanol. Yield: 13.0 g (77.0%). M.P.: 183°-185° C. IR (KBr) spectrum was identical to that of the product in Example 1.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[N:22]1[NH:23][N:24]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)[CH:26]=1.O.Cl.Cl.[CH2:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH:38]1[NH:46][C:47]1[N:48]=[CH:49][C:50]2[CH2:55][NH:54][CH2:53][C:51]=2[N:52]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:37][CH:38]1[NH:46][C:47]1[N:48]=[CH:49][C:50]2[CH2:55][N:54]([C:31](=[O:33])[CH2:30][CH2:29][CH2:28][O:27][C:25]3[NH:24][N:23]=[N:22][CH:26]=3)[CH2:53][C:51]=2[N:52]=1
Reactant: O=C(O)CCCOc1cn[nH]n1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CCCOc1cnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Yield: 44.2 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.168 g; 1.5 equiv; 0.88 mmoles) and diisopropylethylamine (0.41 mL; 4 equiv; 2.34 mmoles) to a solution of 4-(2H-triazol-4-yloxy)butanoic acid (0.1 g; 1.0 equiv; 0.58 mmoles) and N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (0.201 g; 1.0 equiv; 0.58 mmoles), and N,N-dimethyl-4-pyridinamine, (0.014 g; 0.2 equiv; 0.12 mmoles) in dichloromethane (5.8 mL). Stir the reaction for 2 hours then load the reaction mixture directly onto a silica gel column. Purify by column chromatography (10% (2 N ammonia in methanol)/ethyl acetate) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-4-(1H-1,2,3-triazol-5-yloxy)butan-1-one (0.104 g; 44%) as a white solid: MS (m/z): 406(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)CCC(=O)c1ccc(NC(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a stirred, partial solution of 4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-butyric acid, methyl ester (0.5748 g, 0.00177 mol) in THF (11 mL) was added 1.0 M NaOH (3.7 mL, 0.0037 mol), and the mixture was stirred overnight. The resulting suspension was filtered, and the filtercake was washed with THF. The solids were partitioned between EtOAc-THF and 0.2 M HCl, and left for 8 days. The solids were filtered, washed with water, and dried in vacuo to give 0.2133 g of 4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 257-258° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:19])[CH2:18][NH:17][CH2:16]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:14][C:15]1([F:19])[CH2:18][N:17]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: FC1(F)CNC1
Reactant: COC(=O)Cc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(N2CC(F)(F)C2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a sealed microwave reaction vessel containing methyl 2-(6-chloropyridin-3-yl)acetate (200 mg, 1.08 mmol), 3,3-difluoroazetidine hydrochloride (154 mg, 1.19 mmol), Xantphos (93 mg, 0.162 mmol), Cs2CO3 (1.054 g, 3.23 mmol), and Pd2(dba)3 (99.0 mg, 0.11 mmol) was added 3.0 ml of dioxane. The reaction mixture was microwave radiated at 90 C for 60.0 min. It was cooled to room temperature and diluted with CH2Cl2 (20.0 ml). The suspension was filtered, washed with CH2Cl2 (3×10.0 ml), and the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered. The filtrate was concentrated. The residue was purified by a standard method to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:17][C:18]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1cccc(F)c1)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Intermediate 65 (1.50 g, 6.51 mmoles) was taken in a RB flask and to this acetic anhydride (15 ml) and sodium acetate (3.74 g, 45.60 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as colourless solid (1.1 g, 68% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05 (dd, J=7.9, 1.6 Hz, 1H), 7.83 (m, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.50 (m, 2H), 7.24-7.13 (m, 3H), 2.29 (s, 3H).