Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[S:19][C:9]2=[N:10][C:11]3[N:17]([CH3:18])[N:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]2[CH2:7]1)=[O:5])C.[OH-].[Li+]>O1CCOCC1.O>[C:4]([CH:6]1[S:19][C:9]2=[N:10][C:11]3[N:17]([CH3:18])[N:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]2[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cn2c(nc3c(cnn3C)c2=O)S1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc2c(=O)n3c(nc21)SC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
In a mixture of 50 ml of dioxane and 14 ml of water was dissolved 1.30 g (6.24 mmol) of Compound 42 prepared in Example 33, and 0.52 g (12.5 mmol) of lithium hydroxide was added to the solution, followed by stirring at room temperature for 30 minutes. After evaporation of the solvent, the residue was dissolved in water, and then hydrochloric acid was added. The precipitated crystals were collected by filtration, and washed with water, followed by recrystallization from dimethylformamide/water to give 1.09 g (69%) of Compound 43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:28])([O:16]C3C=CC(C4NN=NN=4)=CC=3)[CH3:15])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:45]#[N:46].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:15])([CH3:28])[O:16][C:49]3[C:48]([F:51])=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=3[F:41])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1c(F)cc(C#N)cc1F)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 18 h

Procedure:
A solution of 0.10 g (0.24 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol (Example 88, intermediate b) and 38 mg (0.24 mmol) 3,4,5-trifluorobenzonitrile in 2 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 0.53 ml (0.26 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and stirring was continued for 18 h. The reaction mixture was poured onto aqueous saturated ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane for 5 min., then with a gradient of dichloromethane:ethyl acetate (100:0 to 95:5). Light brown foam (45%). MS (Turbo Spray): m/z=556.2 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:20])[C:11](=[C:17]([CH3:19])[CH3:18])[O:12]2.[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>CC(=O)CC>[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[O:20])[C:11](=[C:17]([CH3:18])[CH3:19])[O:12]3)=[CH:25][CH:24]=1
Reactant: CC(C)=C1Oc2cccc(O)c2C1=O
Reactant: ClCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=C1Oc2cccc(OCc3ccc(CCl)cc3)c2C1=O
Yield: 19.8 %

Procedure:
2.8 g Potassium carbonate is added over 3 hours to a mixture of 3.8 g 4-hydroxy-2-isopropylidenecoumaran-3-one, 3.5 g 1,4-bis-(chloromethyl)benzene and 150 ml butanone at 70-75° C. The mixture is refluxed for 16 hours, then filtered, the filtrate evaporated and the residue purified by silica gel chromatography (eluent isohexane/ethyl acetate 3:1) to give 1.3 g of the desired intermediate.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
3 ml of trifluoroacetic acid are added to a solution of 3.18 g of 2-methylpropan-2-yl 4-(acetyloxy)piperidine-1-carboxylate in 40 ml of dichloromethane, cooled to 0° C. The reaction medium is stirred for 1 hour at 0° C. and then 1 hour at ambient temperature. 5 ml of trifluoroacetic acid are added and the reaction medium is stirred for 30 minutes at ambient temperature. The reaction medium is evaporated to dryness under reduced pressure, and the resulting product is taken up with dichloromethane and an aqueous 1% NH4OH solution. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated, so as to give 175 mg of piperidin-4-yl acetate in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:18]=[CH2:19])=[CH:13][C:12]=3[Cl:20])[N:10]=[C:6]2[C:5]([F:21])=[CH:4][N:3]=1.[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=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+]>O1CCOCC1.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]>[Cl:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH2:19])[CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:29][C:25]3[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=3)=[N:3][CH:4]=[C:5]([F:21])[C:6]2=[N:10]1
Reactant: Cc1cc(N)ncn1
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(Cl)c1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
A mixture of 4-bromo-2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (295 mg, 0.76 mmol), 6-methylpyrimidin-4-ylamine (99 mg, 0.91 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (44 mg, 0.076 mmol) and cesium carbonate (495 mg, 1.52 mmol) in dioxane (8.0 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 80° C. in a sealed vial overnight. The resultant mixture was allowed to cool to room temperature, before being partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-80% ethyl acetate in cyclohexane) to afford the title compound as a beige solid (197 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.24 (d, J=2.6 Hz, 1H), 8.67 (d, J=1.2 Hz, 1H), 8.36 (s, 1H), 7.98-7.93 (m, 3H), 6.88-6.78 (m, 1H), 6.22 (d, J=17.6 Hz, 1H), 5.58 (d, J=11.0 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=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+]>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>[Cl:23][C:21]1[CH:22]=[C:17]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][N:13]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
5-((4-Methylpiperazin-1-yl)methyl)pyridin-2-amine (3.2 g, 15.5 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (3.64 g, 16.3 mmol, Eq: 1.05), xantphos (1.35 g, 2.33 mmol, Eq: 0.15) tris(dibenzylideneacetone)dipalladium (0) (1.07 g, 1.16 mmol, Eq: 0.075) and cesium carbonate (15.2 g, 46.5 mmol, Eq: 3.00) were added to a sealed tube under nitrogen. Dioxane (103 ml) was added and the solution was degassed with nitrogen. The tube was capped and heated at 110° C. overnight. The reaction mixture was filtered through celite and the cake was washed with DCM. 1M HCl was added to and the layers were separated. The aqueous layer was basified with 2M NaOH and extracted several times with DCM. Most of the solvent was evaporated and the residue was triturated with ether. The solid that formed was filtered and dried to give 2.75 g (50.8%) of product which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C@@H:28]([NH:38]C(=O)OC(C)(C)C)[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)=[N:13][CH:14]=[C:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2].[ClH:46].O1CCOCC1>CO>[ClH:46].[NH2:38][C@H:28]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([CH:5]=2)[C:1]([NH2:2])=[O:3])=[CH:16][C:15]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])=[CH:14][N:13]=1)[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1-c1ccc(F)c(C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-tert-butyl 1-(3-(3-carbamoyl-4-fluorophenyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (30G, 29 mg, 0.047 mmol) was dissolved in 0.5 mL of methanol and cooled to 0° C. To it was added 4N HCl/1,4-dioxane (0.05 ml). The reaction mixture was stirred at room temperature for 10 minutes and concentrated to afford the title product. MS (m/z) 516.96 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH2:3]1.F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]2[C:17]3[C:18]([N+:27]([O-:28])=[C:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]2=[N:4][CH2:3]1)=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3
Reactant: CC1(C)CN=C(Cc2ccccc2)NC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CN=C2C(c3ccccc3)=[N+]([O-])c3cc(C(F)(F)F)ccc3N2C1
Temperature: 40 °C
Yield: 26.8 %

Procedure:
A mixture of 1,4,5,6-tetrahydro-5,5-dimethyl-2-phenylmethylpyrimidine (1.69, 8 mmol), 1-fluoro-2-nitro-4-trifluoromethylbenzene (1.679, 8 mmol) and potassium carbonate (550 mg, 4 mmol) in acetonitrile (25 ml) was heated overnight at 40° C. The solvent was removed in vacuo and the resulting yellow solid recrystallised from ethyl acetate to yield 2,3-dihydro-2,2-dimethyl-5-phenyl-8-trifluoromethyl-1H-pyrimido[1,2-a]quinoxaline 6-oxide (800 mg) as a yellow crystalline solid, m.p. 225°-227° C. (Found: C, 64.42, H, 4.95, N, 11.23%; C20H18F3N3O requires C, 64.34, H, 4.86, N, 11.25%) and represented by the structural formula: ##STR6##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-])=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1.C[Mg]Br>C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:8]([CH:13]=1)[C:9]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NCC1CCN(c2ccncc2)CC1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: Nc1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 3 h

Procedure:
A solution of methyl 5-nitro-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzoate (400 mg, 1.08 mmol) was treated with the magnesium salt of 2-amino-5-chloropyridine [freshly prepared by the addition of methyl magnesium bromide (2.16 mmol) to a solution of 2-amino-5-chloropyridine (2.16 mmol) in THF (11 mL)] and the mixture was heated at reflux. After 3 h, the mixture was cooled, sonicated, and the resulting solid (645 mg) collected by filtration. Using a similar procedure to that described in Example 2-B, the crude material was reduced to yield 370 mg of the titled compound; which was used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>O1CCCC1>[F:31][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:3]=12
Reactant: O=C1NCCn2c3c(c(Br)c21)CCCC3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1NCCn2c3c(c(F)c21)CCCC3
Temperature: -78 °C
Yield: 16.3 %

Procedure:
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 119a (40 g, 148.62 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), followed by the addition of n-BuLi (2.4 M) (218 mL, 3.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred at −40° C. for 3 h. To this was added a solution of N-fluorobenzenesulfonimide (98.7 g, 313.33 mmol, 2.10 equiv) in tetrahydrofuran (200 mL) dropwise with stirring at −78° C. The resulting solution was stirred at room temperature for 3 h, quenched by the addition of 200 mL of water and extracted with 3×500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (30 g) was purified by Prep-HPLC with the following conditions (mobile phase, A: 0.05% trifluoroacetic acid/water; B: CH3CN; gradient: 10% B-25% B) to afford 5.05 g (16%) of 119b as a white solid. MS: [M+H]+ 209. 1H NMR (300 MHz, CDCl3) δ 6.16 (br, 1H), 3.90-3.86 (m, 2H), 3.65-3.62 (m, 2H), 2.53-2.47 (m, 4H), 1.88-1.80 (m, 2H), 1.77-1.72 (m, 2H).
Reaction SMILES: O[C@H:2]([CH3:40])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[O:26])=[CH:21]N=3)[CH:15]=[C:14]([O:34][C@@H:35]([CH3:39])[CH2:36][O:37][CH3:38])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+:54]>O1CCCC1>[CH3:38][O:37][CH2:36][C@H:35]([CH3:39])[O:34][C:14]1[CH:15]=[C:16]([CH:17]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH3:40])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:13]=1)[O:18][C:19]1[CH:24]=[N:23][C:22]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[CH:21][N:54]=1
Reactant: [NH4+]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
N-[(2R)-2-Hydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrole-2-carboxamide (447 mg, 0.81 mmol) synthesized in Example (131c) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (282 mg, 1.62 mmol) and triethylamine (0.34 mL, 2.43 mmol) were added, followed by stirring at 50° C. for 4 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out twice with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (279 mg, yield 65%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]>CN(C=O)C.[Cu](I)I>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12]
Reactant: COc1ccccc1Br
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Methoxyisatin (2 g, 0.0113 mol) in anhydrous DMF (15 mL) was cooled in an ice-bath under a nitrogen atmosphere and treated with sodium hydride (0.54 g, 1.2 equivalents, 60% dispersion in mineral oil). The reaction was stirred at 0° C. for 0.5 hour and then 2-bromoanisole (1.4 mL, 1 equivalent) was added along with copper iodide (4.3 g, 2 equivalents). The reaction was heated in an oil-bath at 140° C. for 16 hours. The reaction was then cooled to room temperature and filtered. The filtrate was evaporated to dryness. The dark brown oily solid was used directly for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 56 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoroethylamine instead of morpholine, to the title compound (18 mg, 56%) which was obtained as an off white solid. MS: m/e=395.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:15]=[O:16])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH3:14])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1
Reactant: CN(C)c1ccc2c(Cl)cc(C=O)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc2c(Cl)cc(CO)nc2c1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Referring to FIG. 21, compound 14b (50 mg, 0.213 mmol) was dissolved in absolute ethanol (2 mL). NaBH4 (8 mg, 0.213 mmol) was added to the solution and the mixture was stirred for 30 min. The solvent was evaporated and the residue dissolved in methanol and filtered. The filtrate was adsorbed onto silica gel and purified by column chromatography (7:3 EtOAc/hexane) to obtain 15b (30 mg, 0.126 mmol, 60%). 1H NMR (CDCl3) δ 8.02 (1H, d, J=8.8 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.11 (1H, d, J=2.8 Hz), 7.07 (1H, s), 4.81 (2H, s), 3.14, (6H, s); 13C NMR (CDCl3) δ 159.4, 152.1, 149.6, 143.1, 125.1, 117.9, 116.5, 114.3, 106.3, 64.2, 40.6; FTIR (neat) 2918, 1622, 1535, 1508, 1394, 1284, 1207, 1174, 1134; MS (ESI) m/z calculated for (C12H13ClN2O+H)+ 237, found 237; HRMS (ESI) m/z calculated for (C12H13ClN2O+H)+ 237.0838, found 237.0832.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][CH:31]1[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:33]5[CH2:34][CH:31]([F:30])[CH2:32]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1CN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.079 g, 0.20 mmol), 3-fluoro-[1,3′]biazetidinyl (0.029 g, 0.22 mmol) in DCE (3 mL), trimethoxymethane (0.22 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.065 g, 0.30 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 16:84) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 5:95) to give 345 as an off-white solid (0.054 g, 53%). LCMS (Method G): RT=5.78 min, [M+H]+ 506.2. 1H NMR (CDCl3, 400 MHz) δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.28-7.24 (m, 2 H); 5.15 (dt, J=57.3, 5.4 Hz, 1 H); 4.38-4.33 (m, 4 H); 3.90-3.85 (m, 6 H); 3.83 (s, 2 H); 3.72-3.62 (m, 3 H); 3.48-3.39 (m, 3 H); 3.35 (q, J=7.5 Hz, 2 H); 3.35-3.19 (m, 2 H); 3.17-3.15 (m, 2 H); 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[N:4][C:3]=1[CH2:2][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole was allowed to react with p-hydroxybenzaldehyde to give 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde. Recrystallization from chloroform-ether gave colorless prisms, m.p.163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10](OCC)(=O)[CH:11]=[O:12].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:7]2[N:8]=[CH:10][C:11](=[O:12])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1ccnc(Cl)c1N
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2c(Cl)nccc2[nH]1
Temperature: -20 °C

Procedure:
A suspension 2-chloropyridine-3,4-diamine (2.5 g, 17.41 mmol) and a 50% solution of ethyl glyoxalate in toluene (3.45 mL, 17.41 mmol) in ethanol (34.8 mL) was stirred at reflux for 24 hours. The solution was cooled to −20° C. for 16 hours, and the resulting precipitate was collected by vacuum filtration and rinsed with ethanol. The crude product was purified via reverse-phase HPLC, eluting with 5-50% acetonitrile/0.1% trifluoroacetic acid in water/0.1% trifluoroacetic acid, to afford the title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H).