Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:4]3[N:5]([C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COCn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccncc3)ccn2c1=O
Temperature: 20 °C
Yield: 80.2 %

Procedure:
To a degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (300 mg, 0.81 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (332 mg, 1.62 mmol) and K2CO3 (280 mg, 2.0 mmol) in 1,4-dioxane (10 mL) and H2O (3.0 mL) under argon at 20° C. was added Pd(PPh3)4 (47 mg, 0.043 mmol). The reaction mixture was refluxed for 15 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (20 mL), then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 0-60% gradient of EtOAc in hexanes to obtain the title compound as a yellow solid (241 mg, 0.65 mmol). MS: [M+H]+=367.2. 1H NMR (400 MHz, CDCl3) δ 3.45 (s, 3H), 5.32 (s, 2H), 6.59 (d, J=7.03 Hz, 1H), 7.04 (d, J=6.15 Hz, 2H), 7.18-7.23 (m, 2H), 7.26-7.30 (m, 2H), 7.85 (d, J=7.47 Hz, 1H), 8.53 (d, J=6.15 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[NH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:8]=1
Reactant: C=C(Cl)C(=O)OC
Reactant: FC(F)(F)CN=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A solution of N-(2,2,2-trifluoroethyl)-4-chlorobenzimidoyl chloride (10.2 g, 0.04 mol) and methyl 2-chloroacrylate (5.8 g, 0.048 mol) in N,N-dimethylformamide is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 19.5 g, 0.128 mol) over 30 minutes at such a rate that the temperature is kept at 40° C., stirred for two hours, and quenched with water and ethyl acetate. The organic layer is separated, washed sequentially with aqueous HCl and water, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 20% ethyl acetate in heptane solution and crystallization from heptane gives the title product as white crystals (4.2 g, 34.6% yield, mp 120.0-122.5° C.)
Reaction SMILES: C1(S([C:10]2[CH:25]=[CH:24][C:13]3[N:14]([C:18](=O)[CH2:19][CH2:20][NH:21][CH3:22])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=O)=O)C=CC=CC=1.B.Cl.Cl.[C:29]1([S:35](C2C=CC3N(CCCNC)CCOC=3C=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C1COCC1>[C:29]1([S:35]([C:25]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])[C:13]=3[CH:24]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCCCN1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CNCCC(=O)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCCCN1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C

Procedure:
To 1 mL of freshly distilled THF was added 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methylamino-propan-1-one (0.075 g, 0.210 mmol) and the resulting solution was cooled to 0° C. Borane:THF complex (0.315 mL of a 1 M solution, 0.315 mmol) was added dropwise over 2 minutes, during which offgassing was observed. The solution was warmed to reflux for 6 hours with stirring and then cooled to room temperature. Ethanolic hydrogen chloride (0.750 mL of a 2N solution, 1.5 mmol) was added dropwise accompanied by vigorous offgassing. The reaction mixture was refluxed for 2 hours at which time a white solid was observed in the solution. To the reaction mixture was added 2 mL diethyl ether and the solid was filtered and dried overnight under reduced pressure to give 0.045 g. of [3-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-methyl-amine hydrochloride as a fluffy white solid. MS: 347 (M+H)+, mp: 188.3-193.2° C. (as hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
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: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCNC5=O)n[nH]c3n2)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (18.0 mg, 0.0400 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (16.4 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 120° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=470.0/471.9. 1H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 8.16-7.97 (m, 3H), 7.07 (s, 1H), 4.00 (s, 6H), 3.49-3.40 (m, 2H), 3.07 (t, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][C@:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:29](=[O:31])[CH3:30])[CH2:19][O:18]1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][CH2:19][C@:17]([OH:18])([CH3:16])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29](=[O:31])[CH3:30])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccccc1OC[C@](C)(O)CNC1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 105.6 %

Procedure:
1-(4-chlorobenzyl)-4-piperidinamine (62 mg, 0.276 mmol) and N-(2-{[(2R)-2-methyloxiranyl]methoxy}phenyl)acetamide (61 mg, 0.276 mmol) in ethanol (1.5 ml) was stirred in a sealed vial at 80° C. for 4 hours. The reaction mixture was diluted with water and purified by reversed phase HPLC to give 130 mg (70%) of the title compound as a ditrifluoroacetate after lyophilisation. The optical purity was determined to 86% ee, by chiral HPLC on a Chiralpak AD-column.
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]3[CH:23]=2)=[CH:7][CH:6]=1)#[N:4]>C(Cl)Cl.CC(O)=O>[Br:1][C:23]1[N:14]2[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(Br)n12
Yield: 88 %

Procedure:
Br2 (1.0 eq.) was added, dropwise, to a solution of (A2) in DCM/AcOH=1:1 (0.05 M) at RT and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica using a gradient of EtOAc/Petroleum ether from 30:70 to 50:50 to yield (88%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.24 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.6 Hz), 7.93 (1H, d, J=8.6 Hz), 7.55-7.45 (2H, m), 4.02 (3H, s). MS (ES+) C16H10BrN3O2 requires: 355/357, found: 356/358 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of benzenesulfonyl chloride (0.155 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. MeOH (ca. 0.5 mL) was added to the residue which resulted in the precipitation of a solid. The solid was filtered, washed with MeOH (2 mL) and dried, to afford the title compound (88 mg). LCMS (A) m/z: 425 [M+1]+, Rt 1.40 min (basic).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:46])([F:45])[S+]1C2C=CC=CC=2C2C=CC(S([O-])(=O)=O)=CC1=2>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[C:24]([C:27]([F:46])([F:45])[F:26])[C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])c1ccc2c3ccccc3[s+](C(F)(F)F)c2c1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3c(C(F)(F)F)c(N)ccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
To a stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-amino-benzimidazol-1-yl]pyrimidine (330 mg, 1 mmol, 1 eq) in DMF (2 mL) was added S-(trifluoromethyl)-dibenzothiophenium-3-sulfonate (166 mg, 0.5 mmol, 0.5 eq) and the mixture was heated to 80° C. for 7 hours. The reaction was cooled and the DMF was removed under reduced pressure. The residue was diluted with water and extracted wth CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography (eluted with 3.5% MeOH/CH2Cl2) followed by preparative thin layer chromatography (eluted 2× with 3.5% MeOH/CH2Cl2) to give 46 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.63 (3H, d, J=7 Hz), 4.32 (3H, s), 5.13 (1H, br s), 5.80 (1H, br s), 6.62 (1H, br), 6.70 (1H, d, J=5.5 Hz), 7.29 (1H, m), 7.39 (2H, t, J=7.5 Hz), 7.43 (2H, d, J=7 Hz), 7.62 (1H, br), 8.38 (1H, d, J=5.5 Hz), 8.40 (1H, br). Mass spectrum (ESI) 398.14 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]1([N:7]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Reactant: COc1cc(CBr)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03 g (65%).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12].CC(C)=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:19](=[O:20])[NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 74.1 %

Procedure:
A suspension of 6-methylisocytosine (0.98 g, 7.8 mmol), and 2-isocyanatoethyl methacrylate (2.20 g, 14.1 mmol) in dry pyridine (35 mL) was heated under reflux for 2 h, giving a clear solution. Cooling induced the formation of crystals. Acetone was added (20 mL), and the resulting microcrystalline powder was filtered. Recrystallization from ethanol/CHCl3 (1:1, v/v) gave analytically pure product (1.62 g, yield is 74%) 1H NMR (400 MHz, CDCl3) 13.00 (s, 1H, intramol H-bonding), 11.97 (s, 1H, CH2—NH—CO), 10.53 (s, 1H, CH2—NH—CO—NH), 6.20 (s, 1H, CHH.═.C), 5.80 (s, CCH3CH—CO), 5.56 (s, 1H, CHH═C), 4.31-4.28 (t, J=5.6, 2H, OCH2CH2N), 3.62-3.58 (q, J=5.6 Hz, 2H, OCH2CH2N), 2.26 (s, 3H, CH3—C—NH), 1.96 (s, 3H, CH3—C═CH2), IR (neat) 3250-2800, 1726, 1699, 1664, 1641, 1583, 1521, 1253, 1172, 939 cm-1; Melting point Tm=206.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].Cl.[CH3:15][NH:16][CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([N:16]([CH3:17])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(c1cccnc1)N(C)C
Yield: 53 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol) was reacted in a sealed tube, at rt., in CH2Cl2, overnight with N,N-dimethylamine hydrochloride (3.34 g; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. The desired product was isolated as a yellow oil (1.12 g; 53% yield). MS(ES) calc'd: [M+H]+=208.1 m/z. Found: 208.1 m/z.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C@@H:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20]([CH3:29])([CH3:28])[O:19][C:18]4=[O:30])=[CH:13][CH:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39][CH:38]=1>O1CCOCC1>[CH3:28][C:20]1([CH3:29])[O:19][C:18](=[O:30])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:41]5[CH:42]=[N:37][CH:38]=[N:39][CH:40]=5)=[CH:3][C:4]4=[N:10][N:9]=3)=[CH:12][CH:13]=2)[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(I)ccn34)cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(-c5cncnc5)ccn34)cc2)[C@H]1c1ccccc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-(7-Iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (70 mg, 0.137 mmol), sodium carbonate (2 M, 137 μL, 0.274 mmol), 5-pyrimidinylboronic acid (17.00 mg, 0.137 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (11.20 mg, 0.014 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (457 μL) and stirred at 130° C. for 1 hour. LC-MS indicated that there was complete conversion to the desired product. The final reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-5,5-dimethyl-4-phenyl-3-(4-(7-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)oxazolidin-2-one (15 mg, 0.032 mmol, 23.64% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 2H), 9.27 (s, 1H), 8.66-8.66 (m, 1H), 8.68 (dd, J=0.88, 6.36 Hz, 1H), 8.45 (dd, J=1.17, 1.86 Hz, 1H), 7.86-7.96 (m, 2H), 7.71-7.81 (m, 2H), 7.51 (dd, J=2.15, 7.43 Hz, 1H), 7.37-7.46 (m, 2H), 7.28-7.37 (m, 3H), 5.57 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 463.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:3]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: Fc1cc(I)ccc1Br
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Yield: 100 %

Procedure:
To a solution of 33 mmol of 3-fluoro-4-bromo iodobenzene, 0.6 mmol of copper iodide and 1.1 mmol of dichlorobistriphenylphosphine palladium in 100 ml of diethylamine were added dropwise 33 mmol of 4-propyl phenylacetylene under an argon stream while stirring. After completion of the addition, the solution was stirred at room temperature for a further 2 hours and placed into water. The solution was extracted with heptane, washed with water and concentrated under reduced pressure to afford a brown oily product. The product was isolated and purified by a silica gel column chromatography to afford 33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene as a pale yellow oily product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].S(O[CH:22](OS(C1C=CC(C)=CC=1)(=O)=O)[C:23]([CH3:26])([CH3:25])[CH3:24])(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[CH3:22][C:23]1([CH3:26])[CH2:25][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OC(OS(=O)(=O)c2ccc(C)cc2)C(C)(C)C)cc1
Reactant: Sc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CSc2ccccc2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
15 g of dimercaptobenzene were slowly added dropwise while cooling to 5.55 g of sodium hydride (50% in mineral oil) in 150 ml of dimethyl sulfoxide, whereby the internal temperature was held between 15° and 23° C. Subsequently, the reaction mixture was stirred at room temperature for 1 hour and cooled with ice/methanol. Thereafter, 50 g of 2,2-dimethylpropanediol ditosylate in solid form were added in one portion and the reaction mixture was heated to 80° C. for 3 hours. Thereafter, the reaction mixture was cooled, poured on to ice, extracted with ether, the extract was washed with water and dried. After evaporation of the solvent, there was obtained a yellow oil which was chromatographed on silica gel (petroleum ether/ethyl acetate 99:1). There were obtained 14 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][C:11]([Br:19])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate (1.81 g, 6.70 mmol) obtained in Example 47(b) was dissolved in dimethylformamide (20 ml), and N-bromosuccinimide (1.27 g, 7.11 mmol) was added thereto in an ice bath followed by stirring under a nitrogen atmosphere for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:2) to afford the title compound (2.32 g, 99% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[C:6]([S:33][CH3:32])=[N:7][CH:2]=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: C[S-]
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1ncccc1Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2c1C=CCN2C
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.11 mmol) in 2 mL of DMSO was added sodium thiomethoxide (0.024 g, 0.34 mol). The mixture was heated in a sealed tube at 100° C. for 15 h, cooled to room temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, and again via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 448.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.05 (br s, 1H), 8.86 (br s, 1H), 8.41 (br s, 1H), 8.02 (s, 1H), 7.86 (br s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 4.22 (br s, 1H), 3.13 (s, 3H), 2.61 (s, 3H), 2.11 (br s, 1H), 1.87-1.72 (m, 5H), 1.48-1.39 (m, 3H).