Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:42])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:55].Cl>>[ClH:55].[ClH:55].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:42])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C1CCNCC1)CC2
Yield: 100 %

Procedure:
tert-Butyl 4-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)piperidine-1-carboxylate (90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (85 mg, 100%) as an orange solid: 1H NMR (500 MHz, D2O) δ 7.56-7.53 (m, 2H), 7.48-7.40 (m, 6H), 7.02 (dd, J=8.4, 1.4 Hz, 1H), 6.33 (dd, J=7.5, 2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.16 (s, 2H), 4.63 (br s, 2H), 4.09-3.79 (br m, 2H), 3.69-3.53 (m, 6H), 3.26-3.23 (m, 2H), 3.14 (t, J=12.8 Hz, 2H), 2.49 (d, J=1.3 Hz, 2H), 2.16-2.04 (m, 2H); ESI MS m/z 469 [M+H]+; HPLC (Method B) 98.1% (AUC), tR=11.4 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@:8]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)([CH3:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(#N)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@:8]([CH2:26][OH:27])([CH3:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of {(R)-1-(tert-Butyl-dimethyl-silanyloxymethyl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-methyl-propyl}-carbamic acid tert-butyl ester (8.84 g, 16.8 mMol) in acetonitrile (150 ml) is added H2O (1.52 ml, 84.3 mMol) and Sc(OTf)3 (83 mg, 0.2 mMol). The reaction is stirred at RT for 3 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 0%→40% AcOEt in heptane gives {(R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-1-hydroxymethyl-1-methyl-propyl}-carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:24][N:25]([CH3:29])[C:26](=O)[CH3:27].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1.O.C1COCC1.ClCCl>[CH3:24][N:25]([CH2:26][CH2:27][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1)[CH3:29]
Reactant: CC(C)n1ncc2ccc(I)cc21
Reactant: CC(=O)N(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)n1ncc2ccc(CCN(C)C)cc21
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of 6-iodo-1-isopropyl-1H-indazole (49.6 mg, 0.17 mmol), tris-(dibenzylidenacetone)dipalladium(0) (8 mg, 8.7 μmol), S-BINAP (9 mg, 15 μmol), potassium bis(trimethylsilyl)amide (75 mg, 0.37 mmol) and N,N-dimethyl-acetamide (45 μL, 0.48 mmol) in 1,4-dioxane (2.5 mL) was heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (1 mL) and passed through an EXTUBE using dichloromethane to elute (10 mL). LiAlH4 (0.4 mL, 1M, 0.4 mmol) was added to a solution of the crude product in THF (2.5 mL) and the reaction mixture heated at reflux for 2 h. After cooling to room temperature, the mixture was quenched with Rochelle's salt (1 M, 1 mL) and silica gel (to absorb water) and passed through a frit using methanolic ammonia in dichloromethane (0-10%). The 5% fraction was further purified by flash chromatography (silica gel, 2-8% methanolic ammonia in dichloromethane) to give the product (5.9 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([F:38])=[C:28](B2OCC(C)(C)CO2)[CH:29]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:38])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:25]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CC1(C)COB(c2cc(Cl)ccc2F)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(Cl)ccc4F)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(5-chloro-2-fluorophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane were coupled in the same way as in Example 30 to give 2-[3-(5′-chloro-2,2′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (6 mg, 3%): m/z (ES+) 417 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:35][C:36]1[C:41](I)=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:41]5[C:36]([Br:35])=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Brc1ncccc1I
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-bromo-3-iodo-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.15 min; Mass spectrum (ESI+): m/z=498/500 (Br) [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[O:21].C1N2CCN(CC2)C1>>[OH:21][CH:20]([C:16]1[S:15][CH:19]=[CH:18][N:17]=1)[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1nccs1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCc1ccc(Cl)c(Cl)c1)C(O)c1nccs1
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 59 mg (0.26 mmol) of 3,4-dichlorophenylmethyl acrylate, 27 mg (0.24 mmol) of 2-thiazolecarboxaldehyde, and 31 mg (0.28 mmol) of DABCO was thoroughly shaken on a Vortex mixer, and then stored at 0° C. overnight. The product was purified by prep HPLC to give 34 mg (0.10 mmol; 42% yield) of the desired Baylis-Hillman adduct, 3,4-dichlorophenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate. 1H NMR (CDCl3): δ 5.12 (2H), 5.76 (1H), 6.07 (1H), 6.49 (1H), 7.12 (d of d, 1H), 7.71 ppm (d, 1H) MS m/z: 344.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=C(CS(=O)(=O)c1ccccc1Br)N1CCOCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CC(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-1-morpholinoethanone. MS (ESI): mass calcd. for C22H21FN4O4S, 456.5; m/z found, 457.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.7, 1.3, 1H), 7.83-7.72 (m, 1H), 7.72-7.63 (m, 1H), 7.58 (dd, J=8.5, 7.7, 1H), 7.45 (dd, J=7.2, 1.2, 1H), 7.42-7.31 (m, 2H), 3.67-3.55 (m, 4H), 3.48 (t, J=4.8, 2H), 3.39 (t, J=4.8, 2H).
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:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([CH2:21][N:11]([C@@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17](=[O:18])[NH2:19])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:23][CH:24]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 43 %

Procedure:
The titled compound (161 mg) was prepared in 43% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and methyl 4-(bromomethyl)benzoate according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.82 (d, 2 H, J=8.0 Hz), 7.75 (d, 2 H, J=8.0 Hz), 7.58 (d, 2 H, J=8.0 Hz), 7.33 (d, 2 H, J=8.0 Hz), 7.02 (s br, 1 H), 6.75 (s br, 1 H), 4.67 (AB2,2 H,Δv=20,Jab=24 Hz), 4.33 (m, 1 H), 3.84 (s, 3 H), 2.84 (m, 1 H), 1.73 (m, 4 H), 1.48 (m, 2 H); MS m/e 451.01 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cccc(Cl)c1F
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cccc(Cl)c1F)C2=O
Temperature: 100 °C

Procedure:
A degassed mixture of 2-bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate A) (0.392 mmol), 2-methoxyphenylboronic acid [5720-06-9] (0.549 mmol), (Ph3P)2PdCl2 (0.039 mmol) and K3PO4 (1.569 mmol) in DMF (4 mL) was heated at 100° C. for 8 h. After cooling to rt, the reaction mixture was concentrated. The residue was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3×). The combined organic phases were successively washed with water and brine, dried (Na2SO4) and concentrated. The residue was dissolved in MeOH and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional MeOH. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a light yellow solid. tR: 8.55 min (HPLC 2); ESI-MS: tR=1.43 min, [M+H]+523/525 (LC-MS 1); TLC: Rf=0.41 (98:2 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.56 (d, 0.5H), 7.50-7.56 (m, 1.5H), 7.45-7.49 (m, 1.5H), 7.30 (d, 1H), 7.27 (m, 1H), 7.19-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 6.92 (d, 0.5H), 6.51/6.67 (s, 1H), 6.25/6.27 (s, 1H), 3.93/3.97 (m, 1H), 3.77 (s, 3H), 1.87/2.36 (s, 3H), 1.27 (m, 3H), 0.48 (m, 3H).
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4cc(C)ccc43)CC2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4cc(C)ccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-5-methyl-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 5 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:24])[C:9]=1C(OCC)=O)([CH3:3])[CH3:2].[OH-].[K+]>CS(C)=O.O>[CH:30]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10](=[O:24])[CH:9]=1)([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1c(NCCN(C(C)C)C(C)C)c2ccccc2n(-c2ccccc2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(CCNc1cc(=O)n(-c2ccccc2)c2ccccc12)C(C)C
Temperature: 0 °C
Yield: 71.5 %

Procedure:
Dissolved in 50 ml of dimethylsulfoxide were 1.31 g (3 mmol) of ethyl 4-(2-diisopropylaminoethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate (Compound No. 7), followed by the addition of a solution of 0.68 g (10 mmol) of potassium hydroxide in 6 ml of water. They were reacted at 60° C. for 4 hours. The reaction mixture was poured into ice water, and the resulting precipitate was collected by filtration, washed with water and then dried. The resulting powder was dissolved in chloroform, purified by chromatography on a silica gel column, and then recrystallized from isopropyl ether, whereby 0.78 g of 4-(2-diisopropylaminoethylamino)-1-phenyl-1,2-dihydroquinolin-2-one (Compound No. 43) was obtained (yield: 71.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1.[CH2:31](B(O)O)[CH2:32][CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1COCC1.O>[CH2:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: Cc1nc2c(-c3ccc(Br)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Reactant: CCCCB(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCCCc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-bromophenyl)-2-(2-chlorophenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-9, 48.4 mg, 0.1 mmol), 1-butane boronic acid (12 mg, 0.12 mmol), K2CO3 (41 mg, 0.3 mmol), PdCl2dppf.CH2Cl2 (8 mg, 0.01 mmol) in THF (2 ml) was heated at 65° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined extracts were washed with 0.5 M citric acid, saturated aqueous NaCl, dried, and concentrated under vacuum. The crude residue was purified on a Chromatotron using 1 mm plates and 25% EtOAc/hexanes as a solvent to give 8A-1 (16 mg): MS (m/z) 475.5 (M+H)+; 1H NMR (400MHz, CDCl3): δ 7.53–7.49 (m, 1H), 7.47–7.36 (m, 3H), 7.31 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 4.98–4.78 (br m, 2H), 2.60 (s, 3H), 2.56 (t, J=7.5 Hz, 2H), 1.6–1.5 (m, 2H), 1.36–1.27 (m, 2H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)O)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 15 (2.90 g, 9.98 mmol) in THF/water, (3:1, 80 mL) was added lithium hydroxide monohydrate (838 mg, 20.0 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was extracted with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organic fractions were dried and evaporated to yield the title compound (2.62 g, 9.98 mmol, 100%) as white needles, which had spectral data in agreement with that reported.122 Mp 170-172° C. (lit. 200° C.)122 1H NMR (D6 acetone, 300 MHz): δ 7.09 (s, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.94 (m, 1H, H2″); 5.27 (dd J=1.3 Hz, 17.3 Hz, 1H, H3a″); 5.10 (dd J=1.3, 10.5 Hz, 1H, H3b″); 4.52 (m, 1H, H2); 4.41 (d J=5.5 Hz, 2H, H1″); 2.98 (dd, J=5.7, 14.1 Hz, 2H, H3a); 2.79 (dd, J=8.1, 14.1 Hz, 2H, H3b); 1.75 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH+]. HRMS calcd for C14H18NO4 264.1236, found 264.1246.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([NH2:31])=[C:26]([CH3:32])[CH:25]=1>>[F:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[C:26]([CH3:32])[CH:25]=1
Reactant: Cc1cc(F)c(F)cc1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1cc(F)c(F)cc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4,5-difluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.02 (s, 3H), 2.06 (s, 3H), 2.16 (s, 3H), 4.34 (bs, 2H), 6.81 (bs, 1H), 7.07-7.41 (m, 4H), 7.56 (bs, 1H), 7.63 (d, J=7.3 Hz, 1H), 8.42 (d, J=4.2 Hz, 1H); MS (ESI) m/z 356.6 (M+1)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.F[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH2:11].[C:21](Cl)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O>[C:21]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Sodium bicarbonate (17 g, 202 mmol) and 150 mL water were added to a solution of 3-fluoro-4-morpholinyl aniline (26 g, 133 mmol) of acetone (200 mL). The reaction mixture was cooled to −10˜0° C. Carbobenzoxy chloride (26 g. 152 mmol) was added dropwise within 1 hour. The mixture raised to room temperature (25° C.) naturally, and stirred at this temperature for 2 hours. Then the material liquid was poured into 500 mL ice water, filtered, and dried to provide 39 g of off-white solid in 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][OH:19])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH:18]=[O:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(CO)n1-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C=O)n1-c1ccc(F)cc1

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxylate (15) (210 mg, 0.80 mmol), and Dess-Martin Periodinane (DMP) (562 mg, 1.32 mmol) in dichloromethane (8 mL) was stirred at room temperature for 1 h. The reaction was added to a 1:1 mixture of Na2S2O3 (10% aq.) and NaHCO3 (sat.), then extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-formyl-1H-imidazole-5-carboxylate (16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][C:8](=O)[CH2:7][CH2:6]2.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of 6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (75 g of, 0.34 mol, 1 equiv) in THF (1L) was added BH3.DMS (10 M, 150 mL, 1.5 mol, 4.4equiv) dropwise at 25° C. After the addition, the mixture was stirred for 6 h at 60° C. The reaction was cooled and quenched with excess MeOH, concentration under reduced pressure and purified via chromatography on SiO2 t afford 6-(methyloxy)-7-nitro1,2,3,4-tetrahydroquinoline (51.5 g, 73% yield). 1H NMR (400 MHz, DMSO) δ 1.73-1.80 (m, 2 H), 2.71 (t, 2 H, J=6.4 Hz), 3.13-3.16 (m, 2 H), 3.75 (s, 3H), 5.83(br, 1 H), 6.88(s, 1 H), 6.95(s, 1 H).