Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/C(/CCCCC(C1C=CC2C(=CC=CC=2)C=1)=O)=C/C(O)=O.C1(N[C:30](=[O:51])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=CC=2)=[O:38])C=CC=CC=1.[C:52]1([NH2:59])[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[NH2:58].NC1C=CC=CC=1>>[NH2:58][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[NH:59][C:30](=[O:51])/[CH:31]=[C:32](/[CH3:1])\[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[C:46]2[C:45](=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:43][CH:44]=1)=[O:38]
Reactant: C/C(=C/C(=O)O)CCCCC(=O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1N
Reactant: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccccc1
Solvent: Nc1ccccc1
Product: C/C(=C/C(=O)Nc1ccccc1N)CCCCC(=O)c1cccc2ccccc12
Yield: 99 %

Procedure:
Following a procedure described in Example 35, but substituting respectively acid 193 for acid 80 and 1,2-phenylenediamine for aniline, the compound 194 was obtained in 99% yield. 1H NMR: (300 MHz, CD3OD): 8.01 (d, 2H, J=8.0 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.65-7.54 (m, 3H), 7.09 (d, J=8.0 Hz, 1H), 6.68 (dd, J=7.7, 7.4 Hz, 1H), 5.97 (s, 1H), 3.22 (t, J=7.1 Hz, 2H), 2.82 (dd, J=7.4, 7.7 Hz, 2H), 1.91-1.80 (m, 2H), 1.77-1.63 (m, 2H). 13C NMR: (75 MHz, CH3OD): 25.1, 25.2, 28.7, 33.4, 39.1, 118.6, 119.6, 124.7, 125.4, 126.9, 127.8, 127.9, 128.7, 129.4, 129.5, 130.7, 131.1, 133.9, 135.5, 136.9, 140.8, 143.0, 157.6, 167.5, 202.6
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH3:21][NH:22][CH3:23].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C(O)C.CCOCC>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:22]([CH3:23])[CH3:21])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CNC
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Yield: 92.8 %

Procedure:
75 mg (0.18 mmol) 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole in 2.5 ml DMA were treated with 98 μl (0.54 mmol, 3 eq) 5.6 M N,N-dimethylamine in ethanol for 35 h at RT. The solution was diluted with ether and a saturated aqueous solution of NaHCO3. The inorganic phase was extracted with ether, the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 8:1 yielded 63 mg (92%) [2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-dimethyl-amine as colorless oil, MS: 377(MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]3[C:6]=2[CH2:7][CH:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:9]2[CH2:15][CH2:14][CH2:13][CH:10]23)=[CH:35][CH:34]=1
Reactant: COc1ccc(C2Cc3c(OS(=O)(=O)C(F)(F)F)cc(OC)cc3C3CCCC23)cc1
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C2Cc3c(-c4ccc(Cl)cc4)cc(OC)cc3C3CCCC23)cc1
Temperature: 90 °C
Yield: 310.3 %

Procedure:
Combine trifluoro-methanesulfonic acid 8-methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl ester (0.046 g, 0.1 mmol), 4-chlorophenyboronic acid (0.019 g, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (0.006 g, 5 mole %), sodium carbonate (0.12 ml 2N), and toluene/ethanol (4-1). Purge in vacuo briefly, and heat at 90° C. for 12 hours. Remove solvent, take in ethyl acetate and wash with water. Dry over anhydrous sodium sulfate and chromatograph the residue on silica gel with 5% ethyl acetate in hexanes to yield the titled compound (0.13 g, 31%). 1H NMR (CDCl3): 7.34 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2 H), 7.1 (d, J=8.87 Hz, 2H), 6.8 (d, J=8.8 Hz, 2H), 6.78 (s, 1H), 6.62 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.45 (m, 1H), 2.98 (m, 1H), 2.85(m, 1H), 2.57 (m, 1H), 2.3 (m, 1H), 2.21 (m, 1H), 1.65-1.2 (m, 5H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.CC(O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:20]1([CH2:1][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCCC2)CC1
Yield: 92.7 %

Procedure:
To 1,1-dimethylethyl 4-formyl-1-piperidinecarboxylate (1.02 g, 4.78 mmol) in 1,2-dichloroethane (50 mL) was added sequentially, HOAc (6.00 mL, 1M in DCM, 6.00 mmol), piperidine (1.0 mL, 10.1 mmol) and sodium triacetoxyborohydride (1.60 g, 7.55 mmol). The reaction was stirred at rt for 2 hours at which time HOAc (1.00 mL, 1M in DCM, 1.00 mmol) and sodium triacetoxyborohydride was added. When complete by TLC the reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The combined organic layer was washed with H2O, dried (MgSO4) and concentrated to provide the title compound (1.25 g, 4.43 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-0.91 (m, 2H), 1.29-1.35 (m, 11H), 1.38-1.46 (m, 4H), 1.59 (d, J=10.6 Hz, 3H), 2.00 (d, J=6.8 Hz, 2H), 2.21 (br. s., 4H), 2.62 (br. s., 2H), 3.85 (d, J=12.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([Br:13])[C:4]=2[N:3]=1.C([O-])(=O)C.[NH4+:18]>O>[CH3:1][C:2]1[N:18]=[C:6]([OH:7])[C:5]2[C:4](=[C:12]([Br:13])[CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1nc2c(Br)cccc2c(=O)o1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1nc(O)c2cccc(Br)c2n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Part B: A mixture of 17.0 g (71 mmol) of 2-methyl-8-bromo-3,1-benzoxazin4-one and 84.8 g (1.1 mol) of ammonium acetate was heated to 140° C. while stirring for 2 hours. After cooling to room temperature 250 ml of water was added under intensive stirring to the mixture. The resulting precipitate was collected by filtration and washed three times with 50 ml of water. The product was dried in vacuo, suspended in 150 ml of diisopropylether, stirred for 30 minutes and collected by filtration. The product was washed three times with diisopropylether and dried in vacuo resulting in a total of 14.2 g of 2-methyl-4-hydroxy-8-bromo-quinazoline (84% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29](O)[CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:30]=1)[CH3:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(CCCOC)c(O)c1
Solvent: CCN(CC)CC
Product: CCc1ccc(CCCOC)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) followed by triethylamine (0.42 mL, 3 mmol) was added to a cooled 0° C. solution of 5-ethyl-2-(3-methoxy-propyl)-phenol (0.45 g, 2.3 mmol). The reaction was stirred for 1 hour and then warmed to room temperature. The reaction was partitioned between 1 N HCl and EtOAc. The organic extracts were washed with bring, dried over Na2SO4 and concentrated to a black oil. 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J=7.6 Hz, 3H), 1.89 (m, 2H), 2.65 (d, J=7.6 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 3.35 (s, 3H), 3.40 (t, J=7.6 Hz, 2H), 7.07 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:11]([N:14]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COCCOCN(c1c(I)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOCN(c1c(-c2ccccc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2-[(5-{{[4-(tert-Butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-4-iodo-1-methyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 14) (1.95 g), benzeneboronic acid (0.78 g) and cesium carbonate (5.26 g) were suspended in 1,4-dioxane (50 ml) and water (5 ml). The mixture was degassed (vacuum and nitrogen atmosphere×5) and then tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and the mixture degassed again. The mixture was heated at reflux for 2 hours and cooled to room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 ml×3). The combined organics were washed with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica eluting with a gradient elution of ethyl acetate:hexane (1:2 to 2:1) yielded the desired product as an off white solid (1.112 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O-:17].[Na+]>CO>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([O:17][CH3:16])=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2ccc(OC)nc2c1N

Procedure:
A solution of methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared according to the procedure in Example 10A (5 g, 21 mmol) and sodium methoxide (4.5 g, 82 mmol) in methanol (150 mL) was refluxed for 18 hours, concentrated and partitioned between ethyl acetate and saturated aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4) and concentrated, and the residue was chromatographed on silica gel with 5:1 hexanes/ethyl acetate to provide the title compound. MS (DCI/NH3) m/e 239 (M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:24])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([Cl:24])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Yield: 100 %

Procedure:
In a round bottom flask, there are introduced 200 ml of thionyl chloride and there are then added, in small fractions, 35 g (122 mmoles) of the acid obtained in stage (a), above. The reaction mixture is heated to reflux until the emission of gases ceases. The reaction mixture is evaporated to dryness, taken up in 100 ml of anhydrous benzene and again evaporated to dryness, yielding 37 g of the expected product (100% yield) having a melting point of 153°-154° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](Cl)=[O:43])=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][N:31]([C:42](=[O:43])[CH2:41][O:40][C:39]2[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCNCc1cc(-c2ccc3ncccc3c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2CN(CC)C(=O)COc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-quinolin-6-yl-biphenyl-3-yl)-acetic acid ethyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH:17]([NH2:20])[CH:18]=[O:19].[CH:21]1C=CC=CC=1>>[CH3:21][N:20]([CH2:17][CH:18]=[O:19])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: CC(N)C=O
Reactant: c1ccccc1
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methyl-aminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-ureido] acetaldehyde.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[C:3]=1C=NO.[C:19](OCC)(=[O:21])C>C(O)C.C(O)(=O)C.[Ni]>[F:15][C:4]1[CH:3]=[C:2]([CH:19]=[O:21])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(C=NO)c1F
Reactant: CCOC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Reaction time: 1 h
Yield: 56 %

Procedure:
tert-Butyl 4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO 2011/016469) (3.90 g, 17.6 mmol) was dissolved in ethanol (40 mL) and acetic acid (40 mL). Raney nickel (ca. 10 g) was added to the mixture at room temperature, and the resulting mixture was stirred for 1 hour under hydrogen flow. After the insoluble material was removed by filtration through Celite, water was added to the filtrate, and the resulting mixture was extracted three times with ethyl acetate, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then water and a saturated aqueous solution of sodium hydrogen carbonate were added to the mixture. The resulting mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→2:1, v/v) to give the title compound (2.21 g, yield: 56%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[CH2:21][CH2:20]2)=[N:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]=[CH:9][N:8]([C:5]3[N:4]=[C:3]4[C:2]([NH:1][C:35](=[O:36])[N:18]4[C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22](=[O:29])[CH2:21][CH2:20]4)=[CH:7][N:6]=3)[C:12]=2[CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C1CC[C@@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)c2ccccc21
Yield: 26.4 %

Procedure:
A solution of (4R)-4-(5-amino-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)pyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (32 mg) and CDI (100 mg) in THF (6 mL) was stirred at room temperature overnight and refluxed for 2.5 h. Volatiles were removed in vacuo and the residue was purified by preparative HPLC to afford 9 mg of the title compound as the TFA salt. 1H NMR (CD3OD) δ 9.20 (s, 1H), 8.36 (s, 1H), 8.20 (m, 1H), 7.68 (m, 1H), 7.58-7.47 (m, 3H), 7.20-7.14 (m, 2H), 6.10 (m, 1H), 3.09-2.93 (m, 3H), 2.49 (m, 1H); MS (MH+) 415.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CCOC(=N)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=NC(C)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 41 g (22.3 mmol) of ethyl o-chlorobenzimidate and 25 g (25 mmol) of triethylamine in 500 ml of methylene chloride is treated dropwise with 19.5 g (24.8 mmol) of acetyl chloride, the temperature being held at 40° C. by the use of cooling. The reaction mixture is stirred at room temperature for a further 30 minutes, and the mixture is then washed in sequence with water, 5% sodium bicarbonate solution and semi-saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After distillation of the crude product at 110° C./0.16 mmHg (21.33 Pa) there is obtained ethyl N-acetyl-o-chlorobenzimidate as a colourless liquid.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.Cl[Si](C)(C)C.CCN(C(C)C)C(C)C.Cl[CH:23]([O:25][C:26](Cl)=[O:27])[CH3:24].[C:29]([OH:39])(=[O:38])/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[C:32]1(/[CH:31]=[CH:30]/[C:29]([O:39][CH2:24][CH2:23][O:25][C:26]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:27])=[O:38])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Reactant: NC1(C(=O)O)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(/C=C/c1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 16.1 %

Procedure:
Following the general procedure for the one pot synthesis, ACPC (0.4 g, 3.9 mmol) was reacted with chlorotrimethylsilane (0.99 mL, 7.88 mmol) in anhydrous chloroform (10 mL) in the presence of DIEA (1.45 mL, 7.8 mmol). Subsequent reaction of the intermediate with 1-chloroethylchloroformate (0.83 mL, 5.85 mmol) followed by a mixture of DIEA (1.45 mL, 7.8 mmol) and trans-cinnamic acid (1.16 g, 7.88 mmol) provided 0.200 g (16.6% yield) of the title compound (16) as a buff-colored solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 169.3-172.2° C. 1H NMR (CDCl3, 400 MHz): δ=7.71-7.67 (d, 1H, J=15.6), 7.50 (d, 2H), 7.38 (m, 3H), 6.95 (q, 1H), 6.40 (d, 1H, J=16), 5.58 (s, 0.3H), 5.34 (s, 0.7H), 1.60-1.54 (m, 5H), 1.27-1.24 (m, 2H). MS (ESI) m/z 342.00 (M+Na)+; 318.02 (M−H)−.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10](S(C)(=O)=O)[C:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C1N=C(N2CCCC2)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1)(=O)=O.C([Li])CCC.[OH:66][C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>>[N:1]1([C:6]2[N:11]=[C:10]([O:66][C:67]3[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=3)[C:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(N2CCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(N3CCCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-(N-pyrrolidinyl)-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product from Example 36, Step A (50 mg, 0.10 mmol) was reacted with 2 equivalents each of n-butyl lithium and 3-hydroxypyridine by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=497 (M++1); Rt=3.84 min. 1H-NMR 400 MHz (CDCl3): δ 1.91-2.00 (m, 4H), 3.23-3.35 (s, 2H), 3.55-3.62 (s, 2H), 7.08-7.21 (m, 6H), 7.35-7.39 (m, 2H), 7.56-7.58 (m, 1H), 8.48 (d, J=6 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: [C:1](Cl)(C(Cl)=O)=[O:2].[Cl:7][C:8]1[CH:9]=[C:10]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:31]=[C:30]4[C:26]([CH:27]=[CH:28][NH:29]4)=[CH:25][CH:24]=3)[N:19]=2)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].Cl.[OH-].[Na+]>C(Cl)Cl.O.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:31]=[C:30]4[C:26]([C:27]([CH:1]=[O:2])=[CH:28][NH:29]4)=[CH:25][CH:24]=3)[N:19]=2)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4cc[nH]c4c3)no2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(C=O)c[nH]c4c3)no2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DMF (0.28 mL) was added dropwise to a solution of (COCl)2 (0.31 mL) in DCM (9 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. Then a solution of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D101) (1.06 g) in DCM (30 mL) was added. The reaction mixture was warmed to RT and stirred overnight. Then water and 2 M HCl was added. After stirred for 2 hours, the mixture was neutralized with 2 M aqueous NaOH solution until pH was between 8 and 9. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D102) (620 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.46 (6H, d), 5.51 (1H, m), 7.99 (1H, d), 8.14 (1H, d), 8.30 (1H, s), 8.42 (1H, d), 8.46 (1H, d), 8.90 (1H, d), 8.98 (1H, br s), 10.12 (1H, d).
Reaction SMILES: C(N(CC)CC)C.C1C[O:11][CH2:10]C1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([NH:28][NH2:29])=[O:27])=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]>O>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[O:27][C:10](=[O:11])[NH:29][N:28]=3)=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]
Reactant: C1CCOC1
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(Cl)cc2)CC1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(Cl)cc2)CC1C
Reaction time: 72 h
Yield: 89 %

Procedure:
Triethylamine (744 μL, 534 μmol) was added to a THF (10 mL) solution of compound 115 (100 mg, 267 μmol) at room temperature, and 1,1′-carbodiimidazole (64.9 mg, 400 μmol) was further added thereto. The resulting mixture was stirred for 3 days at the same temperature. Water was added to the reaction liquid, and the mixture was extracted with chloroform. Subsequently, the organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1-÷ 1:2), and thus 94.8 mg (89%) of the title compound was obtained as a pale yellow amorphous substance (cis:trans=3:1).