Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1.[C:34]([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:37][C@@H:38]([CH3:42])[C:39]([NH:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([C:21](=[O:22])[NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:10]2)[CH2:5][O:4]1)=[O:40])(=[O:36])[CH3:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CN)CO4)C3)nc(C)n2)ccc1F
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(=O)[C@H](C)OC(C)=O)CO4)C3)nc(C)n2)ccc1F
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 6-((S)-5-((2R,5R)-5-(aminomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.15 g, 0.326 mmol, Preparation #J.1) in DCM (3 mL) at 0° C., was added TEA (0.100 mL, 0.718 mmol) followed by (S)-(−)-2-acetoxypropionylchloride (0.045 mL, 0.359 mmol, Spectrochem). The reaction mixture was stirred for 30 min. at the same temperature and was quenched with water (10 mL). The product was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified using silica gel column chromatography by eluting with 70% EtOAc in hexane. The relevant fractions containing compound were combined and concentrated to afford (S)-1-(((2R,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methylamino)-1-oxopropan-2-yl acetate 0.11 g (58%); 1H NMR (400 MHz, DMSO): δ 9.48 (t, J=6.4 Hz, 1H), 8.13 (s, 1H), 7.17-7.11 (m, 2H), 6.89-6.86 (m, 1H), 4.87-4.85 (m, 1H), 4.79-4.78 (m, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.88-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.63 (m, 2H), 3.49-3.37 (m, 4H), 3.26-3.21 (m, 2H), 3.09-3.07 (m, 2H), 2.75 (s, 3H), 2.04 (s, 3H), 1.30 (d, J=6.8 Hz, 3H); LC/MS) (Table 1, method c) Rt=3.12 min; MS: m/z 574 (m+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1ccncc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg, 0.06 mmol) in 50% aqueous of MeOH (10 mL) was treated with 5-10 drops of conc. HCl and heated at 80° C. for 3 days. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and neutralized with aqueous NaHCO3 to pH 7. It was then extracted with EtOAc to provide crude 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide which was purified by preparative HPLC. 1H NMR (400 MHz, CDCl3) δ 8.34 (br, 2H), 8.29 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.6 Hz, 2H), 5.98 (s, 1H); MS m/z: 478.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[I-].C[N+]1C=CN([C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)nc(OC(=O)N(C)c2ccccc2)n1
Yield: 59.6 %

Procedure:
A solution of 4,6-dimethyl-2-hydroxypyrimidine (0.37 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.46 g, 60% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:46][C@H:45]([C:44]([OH:43])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Valine methyl ester hydrochloride (34 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.28-12.62 (br.s, 1 H), 8.94 (s, 1 H), 7.92 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.15 (dd, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.54 (t, 2 H), 2.39 (s, 3 H), 2.19 (td, 2 H), 2.02 (m, 1 H), 1.78 (m, 2 H), 0.88 (s, 3 H), 0.87 (s, 3 H); MS (APCI+) m/z 658 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>C(Cl)Cl>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][O:6][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Dissolve 4,4,5,5,5-pentafluoropentanol (8.27 g, 46.42 mmol) in CH2Cl2 (100 mL) and cooled the solution to 0° C. Add triethylamine (20.00 mL, 143.49 mmol), followed by the drop wise addition of methanesulfonyl chloride (4.40 mL, 56.84 mmol). Stir the solution for 45 minutes, then pour into HCl (0.5 N, 100 mL). Wash the organic layer with HCl (0.5 N, 2×100 mL). Dry the organic layer (Na2SO4), filter, and concentrate in vacuo. Recovered 11.48 g (96%) of the desired methanesulfonic acid 4,4,5,5,5-pentafluoro-pentylester as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.31 (t, J=6.0 Hz, 2H), 3.03 (s, 3H), 2.2 (m, 2H), 2.08 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[O:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:22][C:23]1[O:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Cl)o1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)o4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloro-2-furyl)methanol (94 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (3.8 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[N:35][C:30]([Br:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(Br)nc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Br)nc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-bromopyridine-3-carbaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 548.
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[S:21]([O:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1(C(C)O)COCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a mixture of ethyl 5-(1-hydroxyethyl)-1,3-dioxane-5-carboxylate (16.8 g, 83 mmol) in dry pyridine (40 mL) at 0° C. was added 4-toluenesulfonyl chloride (19.1 g, 99 mmol). The mixture was stirred at rt for 16 h. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×400 mL). The organic layer was washed with brine (3×). After concentrated in vacuo, the crude product was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate 25:1 to 5:1 to provide the title compound (22.7 g, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (m, 3H), 1.34 (d, J=6.8 Hz, 3H), 2.45 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.87 (d, J=11.6 Hz, 1H), 4.02 (d, J=11.6 Hz, 1H), 4.08 (d, J=12.0 Hz, 1H), 4.20-4.17 (m, 2H), 5.03-4.98 (m, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1c2ccccc2cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 53.7 %

Procedure:
40% Methanolic Triton B (0.378 mL, 0.832 mM) was added to a solution of 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.235 g, 0.64 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.125 mL, 0.202 g, 1.28 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.105 g, 0.32 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 1 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue-was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.151 g (53%) of the title compound (5-benzyl-1-carbamoyl-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a brown foam (MP 120–125° C., MW 438.49).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:38]1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: F[C@H]1CCNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC[C@H](F)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and (S)-(+)-3-fluoropyrrolidine hydrochloride (Oakwood, Cat. No. 013157). LCMS (M+H)+: m/z=531.2.
Reaction SMILES: P(Cl)(Cl)[Cl:2].O[CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28]#[N:29])[CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[Cl:2][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28]#[N:29])[CH:10]=[CH:11][CH:12]=1
Reactant: ClP(Cl)Cl
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(CCl)c3)c2cc1OC
Temperature: 27.5 °C
Yield: 81.3 %

Procedure:
To 14 ml of DMF was added phosphorous trichloride (0.70 ml, 8.0 mmol) with stirring at 25-30° C. After 60 m, the mixture was cooled to 0° C., and a suspension of 4-[3-(hydroxymethyl)phenylamino]-6,7-dimethoxy-3-quinolinecarbonitrile (1.34 g, 4.0 mmol) in 6 ml of DMF was added. The mixture was warmed to 25° C., stirred 15 m, recooled in ice bath, and partitioned with methylene chloride-aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated to give 1.15 g of an amber solid; NMR (CDCl3) δ 4.79(s, CH2Cl).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[O:4][CH:5]=1
Reactant: O=c1cc(CBr)occ1O
Reactant: C1COCCN1
Solvent: CC#N
Product: O=c1cc(CN2CCOCC2)occ1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one 21 (5.0 g, 24.4 mmol), morpholine (4.3 mL, 48.8 mmol) and acetonitrile (120 mL) were charged in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 3 h at 80° C. Acetonitrile was evaporated and the residu was extracted with EtOAc (400 mL). The organic layer was washed with water (20 mL), brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. Diethyl ether (25 mL) was added and the product was precipitated and filtered to give after drying 5-hydroxy-2-(morpholinomethyl)-4H-pyran-4-one 22 (4.8 g, 72% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH3:23]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:22]([CH3:23])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Solvent: CO
Product: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A solution of 2 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of 2M dimethylamine in methanol was stirred at room temperature for 1 hour. Concentration and purification by chromatography (SiO2; ethyl acetate/cyclohexane 1:1) yields the title compound as a colorless solid. MS (m/e): 309.1 (MH+, 100%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([OH:31])([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](C)[N:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[CH3:33][N:34](C1C=CC=C(Br)N=1)[CH3:35]>>[CH3:33][N:34]([CH3:35])[C:26]1[N:25]=[C:24]([C:17]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:32])[CH:8]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(C(O)(c2ccccn2)c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)n1
Reactant: CN(C)c1cccc(Br)n1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2cccc(N(C)C)n2)c2[nH]c(=O)[nH]c2c1

Procedure:
A procedure similar to that used for 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one, using 6-bromo-2-N,N-dimethylaminopyridine as the starting material was used to produce the intermediate (C32H36N6O5, 585.2 (M+1)), which was taken directly to the deprotection step to yield the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:23]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>>[CH2:23]([N:30]([S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 164°-166° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (300 mg, 1.04 mmol) in CH2Cl2 (5 mL) was cooled using an ice water batch. To this stirring solution was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (312 mg, 1.56 mmol), followed by triethylamine (210 mg, 291 μL, 2.08 mmol). After letting the reaction warn to room temperature, it was stirred overnight. The mixture was partitioned between water and CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a viscous yellow oil. Purification via silica gel chromatography using 0-30% EtOAc in CH2Cl2/hexanes (2:1) gave (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a bright yellow foam/solid. (413 mg, 88%). LC/MS: m/z 453.1 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.01 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.02-3.65 (m, 8H), 2.52 (s, 3H), 1.82-1.73 (m, 1H), 1.47-1.34 (m, 2H), 0.91 (dd, J=6.5, 4.1 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([C:8]2[S:24][C:11]3[N:12]=[C:13]([CH3:23])[N:14]=[C:15]([CH2:16][NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:32][CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Na+].[Na+]>O>[CH:18]1([N:17]([CH2:16][C:15]2[C:10]3[CH:9]=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4]4)[S:24][C:11]=3[N:12]=[C:13]([CH3:23])[N:14]=2)[CH2:32][CH2:33][CH2:34][OH:35])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OCCCBr
Reactant: Cc1nc(CNC2CCCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN(CCCO)C2CCCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}cyclopentaneamine (128 mg) and DMF (3 mL) were added 3-bromopropan-1-ol (100 μL) and Na2CO3 (110 mg), followed by stirring at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and then water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 3-(cyclopentyl{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}amino)propan-1-ol (88 mg).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=1[N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1>O>[F:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=1[N:39]1[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]1
Reactant: COc1cc(F)c(N2CCC(=O)CC2)cc1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCN(c2cc(F)c(OC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
A reaction vessel was charged with methoxymethyltriphenyl-phosphonium chloride (1.114 g), the atomosphere indide the vessel was substituted with nitrogen, and anhydrous tetrahydrofuran (2 mL) was added, followed by further dropwise addition of 1.57 M n-butyl lithium-in-hexane solution (2 mL) at room temperature and thereafter 10 minutes' stirring at room temperature. To the reaction mixture a mixture of 1-(2,5-difluoro-4-methoxyphenyl)piperidin-4-one (676 mg) and anhydrous tetrahydrofuran (0.5 mL) was added dropwise, followed by 30 minutes' stirring at room temperature. To the reaction mixture water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Distilling the solvent off, the crude product as obtained was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=10:1) to provide 1-(2,5-difluoro-4-methoxyphenyl)-4-methoxymethylenepiperidine (257 mg).