Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:13][C:11]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCOC(=O)c1cnc2ccccc2c1O
Temperature: 200 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Diethyl ethoxymethylenemalonate (115 g) was dropwise added to aniline (50 g), and the mixture was refluxed for 1 hr. The resulting ethanol was evaporated under atmospheric pressure, and the residue was heated at 200° C. and poured into diphenyl ether (750 mL). The mixture was stirred at 220-250° C. for 2 hr with heating. The resulting ethanol was again evaporated under atmospheric pressure, and the reaction mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with hexane to give ethyl 4-hydroxyquinoline-3-carboxylate (51.0 g) as a white powder.
Reaction SMILES: [OH:1][C:2]1([C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>CO.[Pd]>[OH:1][C:2]1([C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:3][NH:4][CH2:5]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Yield: 105.7 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate (1.07 g, 3.5 mmol) in methanol was added wet 10% palladium on carbon (50% by mass, 250 mg). The resulting suspension was subjected to 1 atmosphere of hydrogen for 7 h, and an additional 250 mg of catalyst was added over the course of the reaction. The catalyst was then removed by filtration through celite. The filtrate was then concentrated in vacuo to provide 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate as a colorless syrup (800 mg, quantitative yield). MS (EI) for C10H20N2O3: 161 (M-tert-butyl+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[F:13][C:14]([F:19])([F:18])[CH:15]1[O:17][CH2:16]1>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:16][CH:15]([OH:17])[C:14]([F:19])([F:18])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)C1CO1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: OC(CNc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 88.5 %

Procedure:
EX-321A) 3-Trifluoromethoxyaniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated to 80° C. for 24 h. The excess aniline was removed by distillation (70° C. at 16.2 Torr) to give 8.6 g (88%) of the desired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. 1H NMR (CDCl3) δ 3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). 19F NMR (CDCl3) δ −79.36 (s, 3F), −58.44 (s, 3F).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1COCC1>[C:17]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)C(=O)NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNC(=O)C(=O)O
Reaction time: 6 h

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]23[CH2:17][CH:16]([CH2:18]2)[C:15](=[O:19])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]3=[O:20])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.96 g of n-pentyl iodide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation, the product is obtained having a melting point of 75°-79°.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[O:9])[O:3]1
Reactant: NCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Product: O=C(NCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1c[nH]c(=O)o1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21 step 1) and 3,5-dichlorobenzyl 4-(2-aminoethyl)piperazine-1-carboxylate (step 2) analogously to Example 15 step 3;
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[O:17])=[CH:3]1.[Br:18]Br>CC(O)=O>[Br:18][C:3]1[C:2](=[O:1])[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]=1[CH:16]=[O:17]
Reactant: BrBr
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Solvent: CC(=O)O
Product: O=Cc1[nH]cc(OCc2ccccc2)c(=O)c1Br
Temperature: 25 °C
Yield: 74.1 %

Procedure:
2.62 g of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridine carboxaldehyde and 0.83 g NaAc were dissolved in 50 ml AcOH and 2 g Br2 were dropped in while stirring at room temperature. After 2 hours the solvent was distilled off and the residue stirred with 50 ml ice water. A precipitate of crude title compound was obtained. Isolation by filtration, washing with water and recrystallization from diozane yielded 2.61 g title compound.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(N)=O)cc2)cc1
Yield: 8.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (4.00 g, 11.7 mmol) in 100 mL of dichloromethane and 4-aminobenzamide (3.20 g, 23.5 mmol) in 26 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, recrystallized from ethanol-water-DMF, triturated with a hot mixture of methanol and DMF, and filtered to yield 0.563 g of the title compound, mp >270° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C@H:33]4[CH2:38][CH2:37][C@H:36]([O:39][P:40]([O:47]C(C)(C)C)([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]4)=[C:29]4[C:25]=3[C:26](=[O:53])[N:27]([CH3:52])[CH2:28]4)[C:20]([C:54]([F:57])([F:56])[F:55])=[CH:19][N:18]=2)=[C:12]([O:58][CH3:59])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C@H:33]4[CH2:34][CH2:35][C@H:36]([O:39][P:40]([OH:42])([OH:47])=[O:41])[CH2:37][CH2:38]4)=[C:29]4[C:25]=3[C:26](=[O:53])[N:27]([CH3:52])[CH2:28]4)[C:20]([C:54]([F:57])([F:55])[F:56])=[CH:19][N:18]=2)=[C:12]([O:58][CH3:59])[CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(OC(C)(C)C)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl[4-({4-[(7-{trans-4-[(di-tert-butoxyphosphoryl)oxy]cyclohexyl}-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate (Compound 228A, 38.5 mg, 0.044 mmol) in THF (2 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. Solvents were then removed in vacuo and the residue was purified by MDP (formic acid conditions) to obtain 31.9 mg of the desired product (yield: 95%). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.6 Hz, 6H), 1.41-1.46 (m, 2H), 1.66-1.76 (m, 4H), 2.12-2.15 (m, 2H), 2.49 (m, 1H), 3.04 (s, 3H), 3.29 (d, J=21.20 Hz, 2H), 3.73 (s, 3H), 3.96-4.03 (m, 4H), 4.12 (m, 1H), 4.47 (s, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.43 (s, br, 1H), 8.36 (d, J=0.8 Hz, 1H), 8.98 (s, 1H), 10.54 (s, 1H). MS (ES+): m/z 758.21 [MH+]. HPLC: tR=1.27 min (UPLC TOF, polar—3 min).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15](N)=[CH:16][C:4]=2[S:3]1.Cl.N([O-])=O.[Na+].[C:24]([O-])(=O)[CH3:25].[Na+]>O.C1C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15]([C:25]3[CH:24]=[CH:13][CH:5]=[CH:4][CH:16]=3)=[CH:16][C:4]=2[S:3]1
Reactant: CCOC(=O)Cn1c(=O)sc2cc(N)c(Cl)cc21
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)Cn1c(=O)sc2cc(-c3ccccc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-oxo-5-chloro-6-amino-3-benzothiazolineacetate (347.8 g) and conc.hydrochloric acid (1040 ml) was stirred for 30 minutes at ambient temperature. After the resultant mixture was cooled to 2° C., a solution of sodium nitrite (88.3 g) in water (120 ml) was added dropwise thereto below 5° C. in the course of 40 minutes. The mixture was stirred for 20 minutes at 0° C. To the resultant mixture was added benzene (5.2 l) in the course of 30 minutes. After the reaction mixture was stirred for an hour and 40 minutes under ice-cooling, a solution of sodium acetate.3H2O (1.56 kg) in water (3.6 l) was added dropwise thereto under ice-cooling in the course of an hour. The mixture was stirred overnight at ambient temperature. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a residue, which was recrystallized from ethanol to give ethyl 2-oxo-5-chloro-6-phenyl-3-benzothiazolineacetate (311.5 g).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH2:27][C@H:28]([CH3:31])[CH2:29][OH:30].FC(F)(F)C(O)=O>C(O)CCC>[OH:30][CH2:29][C@H:28]([N:27]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:31]
Reactant: C[C@@H](N)CO
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2cccnc2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: C[C@H](CO)n1cnnc1-c1cccc(NC(=O)c2cc(-c3cccnc3)ccn2)c1
Temperature: 150 °C
Yield: 23 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (210 mg, 0.61 mmol), (R)-2-amino-1-propanol (0.3 mL), and trifluoroacetic acid (0.05 mL) in n-butanol was heated in a microwave to 150° C. for 1 hour. The solvent was removed under reduced ressure and the residue was purified by reverse-phase HPLC to give (R)—N-(3-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (55 mg, 0.138 mmol, 23% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[CH:15]([NH:16][C:17](=[O:27])[CH2:18][S:19]([CH2:22][C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:20])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:29]([S:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[CH2:30][CH2:31][NH:32][C:33]([NH2:35])=[O:34])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(#N)C>[F:25][C:23]([F:24])([F:26])[CH2:22][S:19]([CH2:18][C:17]([NH:16][CH:15]1[C:14](=[O:28])[N:13]2[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH:29]([S:36][C:37]3[NH:41][N:40]=[N:39][N:38]=3)[CH2:30][CH2:31][NH:32][C:33]([NH2:35])=[O:34])[CH2:10][S:11][C@H:12]12)=[O:27])(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 3 h

Procedure:
The ester is dissolved in acetonitrile and trifluoroacetic acid is added. The solution is stirred for 3 hours, then evaporated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN([C@H]2CCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 20 %

Procedure:
The titled compound (68 mg) was prepared in 20% yield from cis-2-(4-Chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and 4-bromomethyl-benzonitrile according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.70 (d, 2 H, J=8.0 Hz), 7.71 (d, 2 H, J=12.0 Hz), 7.60 (d, 2 H, J=8.0 Hz), 7.42 (d, 2 H, J=8.0 Hz), 7.07 (s br, 1 H), 6.73 (s br, 1 H), 4.65 (AB2,2 H,ΔV=20,Jab=24 Hz), 4.33 (m, 1 H), 2.84 (m, 1 H), 1.72 (m, 4 H), 1.47 (m, 2 H); MS m/e 418.00 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.[BH4-].[Na+]>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOCCl
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COCCOCOc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled suspension (0° C.) of 60% NaH (660 mg, 16.5 mmol) in THF (35 mL) is added dropwise a solution of 3-hydroxybenzaldehyde (1.89 g, 15 mmol) in THF (15 mL) and the resulting mixture stirred for 20 min. To the mixture is added 2-methoxyethoxymethyl chloride (1.88 mL, 16.5 mmol) and DMPU (5 mL), the cold bath removed and stirred for 1 hr. The reaction mixture is cooled to 0° C. then slowly added 2M NaBH4 (in triglyme) (3.75 mL, 7.5 mmol) and let stir for 1 hr. Slowly quenched with 2N HCl soln (3.9 mL) and diluted reaction mixture with ether. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 60% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (EI) 212 (M)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[CH:8][C:9]=2[F:16])=[O:13])[CH2:30][CH2:31]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 82.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (272 mg) described in Preparation Example 23 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (371 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)nc([C@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)nc([C@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(5-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 14 (100 mg, 0.398 mmol), 6-chloro-9H-purine (74 mg, 0.478 mmol) and DIPEA (0.347 mL, 1.99 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 20 h at 120° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then triturated with acetonitrile affording 117 as an off-white solid (54 mg, 37%). LCMS: RT 3.11 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 12.90 (1H, bs), 8.20-8.00 (2H, m), 7.84 (1H, s), 7.69-7.39 (6H, m), 7.07-6.89 (2H, m), 5.49 (1H, bs), 2.39 (3H, s), 1.53 (3H, d, J=6.79 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)OB([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]2[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccccc2)c2c(Cl)ncnc21
Temperature: 70 °C
Yield: 47.9 %

Procedure:
A stirred suspension of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (3.31 g, 11.3 mmol), tetramethyl-2-phenyl-1,3,2-dioxaborolane (2.76 g, 13.53 mmol) and sodium carbonate (3.59 g, 33.8 mmol) in 1,4-dioxane (90 ml) and water (18.0 ml) was degassed by bubbling N2 through it for 10 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.921 g, 1.13 mmol) was then added and the reaction mixture degassed with N2 again for 10 min before heating at 70° C. for 2 h. The solvent was removed in vacuo and the residue partitioned between saturated sodium hydrogen carbonate (90 ml) and dichloromethane (90 ml). The layers were separated and the aqueous phase extracted with dichloromethane (3×45 ml). The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (1.32 g, 48%). LCMS RT=1.26 min, [M(35Cl)+H]+=244.1, [M(37Cl)+H]+=246.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:19]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Reaction time: 12 h
Yield: 97 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.1 g, 9.8 mmol, 1 eq) and K2CO3 (2.4 g, 17.4 mmol, 1.8 eq) in 15 mL of DMF was added 1.3 mL of bromo-acetic acid ethyl ester (11.7 mmol, 1.2 eq) under nitrogen. After 12 h, the mixture was worked up and crude compound recrystallized to give (2-acetyl-4-bromo-phenoxy)-acetic acid ethyl ester in 97% yield (2.87 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 4.7 (s, 2 H) 6.7 (d, J=8.8 Hz, 1 H) 7.5 (dd, J=8.8, 2.8 Hz, 1 H) 7.9 (d, J=2.8 Hz, 1 H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:6]1
Reactant: C1CCNC1
Reactant: CC1(C)OB(/C=C/CCl)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(/C=C/CN2CCCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (E)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 4.94 mmol) in acetonitrile (10 mL) was treated with potassium carbonate (1.366 g, 9.88 mmol) and pyrrolidine (0.531 mL, 6.42 mmol). The suspension was stirred at ambient temperature for 20 hours. The reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator to provide the title compound. MS ESI(+) m/z 238.2 [M+H]+.