Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[CH:16]2[CH2:19][O:20][CH2:21][CH2:22][N:15]2[C:14]2[N:13]=[C:12](Cl)[N:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH:34]=[CH:35][NH:36]3)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:17](=[O:18])[CH:16]2[CH2:19][O:20][CH2:21][CH2:22][N:15]2[C:14]2[N:13]=[C:12]([C:32]3[CH:40]=[CH:39][CH:38]=[C:37]4[C:33]=3[CH:34]=[CH:35][NH:36]4)[N:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1Cc1ccccc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1C2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc2N1Cc1ccccc1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
5-Benzyl-2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x39, 200 mg, 0.605 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (294 mg, 1.209 mmol), and PdCl2(dppf) (22.12 mg, 0.030 mmol) was suspended in dioxane (3 mL) and aqueous saturated NaHCO3 (0.6 mL). The resulting brown suspension was heated to 100° C. for 18 hours, then diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×5 mL) and brine (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (80 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 3.06-3.19 (m, 1 H), 3.58-3.74 (m, 2 H), 4.01-4.12 (m, 1 H), 4.25-4.34 (m, 1 H), 4.49-4.63 (m, 2 H), 5.12-5.31 (m, 2 H), 7.11-7.18 (m, 1 H), 7.24-7.40 (m, 6 H), 7.40-7.44 (m, 1 H), 7.46-7.51 (m, 1 H), 7.99-8.03 (m, 1 H), 8.04-8.07 (m, 1 H), 11.20-11.26 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C24H21N5O2, 412.17; found 412.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(N(CC)CC)C.[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21]>C(#N)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:22][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: C#CCCO
Reactant: COC(=O)c1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C#CCCO)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A 50 mL round bottom flask, equipped with a magnetic stirrer and gas inlet, was charged with 0.8 mg (0.005 eq) of palladium chloride, 2.3 mg (0.01 eq) of triphenylphosphine, 1.6 mg of copper (1) iodide, 0.19 g of methyl 4-bromothien-2-ylcarboxylate (obtained by oxidation of 4-bromothien-2-ylaldehyde followed by esterification), 0.43 g of triethylamine, and 0.06 g of 3-but-yn-1-ol in 20 mL of acetonitrile under a nitrogen atmosphere. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 18 hours. After cooling to room temperature, volatiles were removed under reduced pressure and the residue was partitioned between chloroform and water. The organic extract was washed with water (2×), brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 2:1 hexane/ethyl acetate. Fractions homogeneous by thin layer chromatography for the major component were combined and concentrated under reduced pressure to give 0.12 g (66.7%) of methyl 4-(4-hydroxybut-yn-1-yl)thien-2-ylcarboxylate as a yellow oil; IR (KBr, cm-1): 3025 3021, 3015, 1713, 1446, 1293, 1261, 1231, 1228, 1225, 1222, 1214, 1192, 1080, 1053; UV (Ethanol):λmax =294 nm (epsilon=3680), 228 nm (epsilon=26,900); 1H NMR (CDCl3, 300 MHz) delta 7.72 (s, 1H), 7.53 (s, 1H), 3.87 (s, 3H), 3.79 (t, J=6.2 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.87 (bs, 1H); MASS: M+ =210 (EICEC).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(OCC)(=O)C.CCCCCC.C(O)C>[CH3:30][Si:29]([CH3:31])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To an anhydrous N,N-dimethylformamide (125 mL) solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (CAS registry number: 69222-61-3) (47.5 g) and imidazole (16.3 g) was added dropwise an anhydrous N,N-dimethylformamide (82.5 mL) solution of t-butyldimethylsilyl chloride (30.5 g) in a cold-water bath. The mixture was raised to room temperature and stirred for 2 hours, ethanol (1.25 mL) was then added to the reaction mixture, and the mixture was further stirred for 1 hour. The reaction mixture was poured into ice water (500 mL), hexane (200 mL) and ethyl acetate (100 mL) were added thereto, and the mixture was stirred. The two layers were separated, the organic layer was washed with 1 M hydrochloric acid (100 mL), water (100 mL×two times), a saturated aqueous sodium bicarbonate solution (100 mL) and a saturated saline (100 mL), dried with anhydrous sodium sulfate, and concentrated to obtain a titled compound (68.4 g) having the following physical property values.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2].[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:8]=[CH:9]1
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(C#N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
7-Cyanoindole (1.0 g, 7.0 mmol) was stirred in DMF (10 mL) at 0° C. Sodium hydride (60%, 310 mg, 7.7 mmol) was added, and the reaction stirred 30 min at rt. SEM-chloride was added, and the reaction stirred 16 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/hexanes) to give 1.5 g (78%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, 1H, J=7.9, 0.9 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.17 (t, 1H, J=7.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 5.79 (s, 2H), 3.58 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). [M+H] calc'd for C15H20N2OSi, 273. found 273.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13](Cl)[N:12]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)O1>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.COCCOC>[CH:1]12[N:8]([C:9]3[CH:10]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[N:12]=[C:13]([C:34]4[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=4)[N:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
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: COCCOC
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(N)cc2)n1
Temperature: 120 °C
Yield: 75.7 %

Procedure:
A microwave vial was charged with 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.400 g, 1.42 mmol) and sodium carbonate (2M in water, 2.12 mL, 4.24 mmol). DME (7 mL) was then added to give a yellow biphasic solution. The solution was degassed with nitrogen for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (0.098 g, 0.085 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.372 g, 1.697 mmol) were added. The vial was sealed and heated to 120° C. for 40 minutes under microwave irradiation. LCMS indicated that the reaction had not gone to completion. Additional tetrakis(triphenylphosphine)palladium(0) (0.049 g, 0.043 mmol) was added and the reaction was heated to 120° C. for an additional 80 minutes under microwave irradiation. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was then concentrated under reduced pressure to provide a brown oil. The crude product was added to a silica gel column and was eluted with 0-10% methanol in methylene chloride to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)aniline (0.365 g, 76%) as a light orange solid. HRMS; [M+H]+ Obs'd=340.2133, [M+H]+ Calc'd=340.2131
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:12]([F:14])[C:5]2[N:6]([CH2:10][CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]([C@@H:19]1[O:21][CH2:20]1)=[O:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[CH2:10]([N:6]1[C:5]2[C:12]([F:14])=[CH:13][C:2]([NH:1][CH2:20][C@@H:19]([OH:21])[C:17]([O:16][CH3:15])=[O:18])=[CH:3][C:4]=2[O:8][C:7]1=[O:9])[CH3:11]
Reactant: CCn1c(=O)oc2cc(N)cc(F)c21
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCn1c(=O)oc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21

Procedure:
Prepared from 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2(3H)-one (Step 2, 0.90 g, 4.59 mmol), methyl (2R)-glycidate (0.469 g, 4.59 mmol) and lithium trifluoromethanesulfonate (0.716 g, 4.59 mmol) in acetonitrile (10 ml) according to the method of EXAMPLE 86, Step 8 (1.11 g, 81%); MS for C13H15FN2O5 m/z 299 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[N:26]=[C:25]([Br:27])[NH:24][N:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[Br:21][C:22]1[N:26]=[C:25]([Br:27])[N:24]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1n[nH]c(Br)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1nc(Br)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Trityl chloride (6.8 g, 24 mmol) was added to a solution of 3,5-dibromo-1H-1,2,4-triazole (5 g, 22 mmol) and triethylamine (3.4 mL, 24.2 mmol) in DMF (100 mL) and stirred 16 h. The mixture was poured into rapidly stirred water (300 mL). The white precipitate was collected, washed with hexanes and dried on high vacuum to yield 10.2 g of Intermediate 359.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 6H) 7.28-7.35 (m, 9H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH:47]1([CH2:53][CH2:54][OH:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH2:53][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCCC1CCCCC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cyclohexylethanol, the title compound was obtained as a colorless solid (0.09 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.17 (t, J=6.6 Hz, 2H), 2.87 (s, 6H), 1.76-1.60 (m, 7H), 1.54-1.42 (m, 1H), 1.28-1.11 (m, 3H), 1.02-0.90 (m, 2H); MS (ES−) m/z 405.1, 407.1 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH:10](Br)[CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15](C(OC(C)(C)C)=O)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>ClCCl>[N:15]1[N:14]2[CH:10]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:26])[CH2:11][CH2:12][C:13]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1ccc(CCC(Br)C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCc2ccnn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 16.9 g (40.0 mmol) of tert-butyl 3-[4-(benzyloxy)-3-bromo-4-oxobutyl]-1H-pyrazole-1-carboxylate from step E above in 50 mL of dichloromethane was added 50 mL of TFA. The resulting mixture was stirred for 2 h at ambient temperature then all volatiles were evaporated in vacuo. The residue was then diluted with 50 mL of toluene and evaporated again in vacuo to remove all residual TFA. The crude material was then dissolved in 125 mL of anhydrous acetone and 14.0 g (100 mmol) of solid potassium carbonate was slowly added over 15 min followed by 1.2 g (8.0 mmol) of sodium iodide. The resulting mixture was then heated at reflux for 16 h, cooled to room temperature and evaporated to dryness in vacuo. The residue was diluted with 100 mL of a saturated, aqueous ammonium chloride solution and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 10-80% ethyl acetate in hexanes gradient to afford the title compound as a clear gum 6.2 g (64% yield). LC-MS: m/z (ES) 243 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][CH:8]([CH2:14][NH2:15])[CH2:7]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>CN1CCCC1=O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:15][CH2:14][CH:8]2[O:9][CH2:10][C:11]([CH3:13])([CH3:12])[N:6]([CH2:5][C:4]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC1(C)COC(CN)CN1Cc1ccc(Cl)c(Cl)c1
Solvent: CN1CCCC1=O
Product: CC1(C)COC(CNC(=O)Cc2ccc(Cl)cc2)CN1Cc1ccc(Cl)c(Cl)c1
Yield: 39.9 %

Procedure:
A mixture of Intermediate 3 (0.030 g) and 4-chlorophenylacetic acid (0.020 g) were treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W microwave oven, at full power, for 4 min. The crude mixture was purified by chromatography on silica gel (Varian Bond-Elut cartridge, 1 g) eluting with cyclohexane/ethyl acetate (19:1 followed by 1:1) to give a brown solid which was triturated with ether to give thetitle compound as an off-white solid (0.018 g).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:3]3[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc3[nH]ncc3c2)[nH]c1=O
Temperature: 80 °C
Yield: 88 %

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (358 mg, 1.671 mmol) and 1H-indazol-5-amine (222 mg, 1.671 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (HGN-0042) (441 mg, 88% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([CH3:25])[CH2:7][N:8]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:24].C(N(CC)CC)C.C1C=CC=CC=1>O>[Cl:3][CH:6]([CH3:25])[CH2:7][N:8]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:24]
Reactant: CC(O)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cl)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Reaction time: 1 h
Yield: 85.1 %

Procedure:
18 g of thionyl chloride was added dropwise to a mixture of 27.9 g of 2-(2-hydroxypropyl)-4-phenyl-1(2H)-isoquinolone prepared as described above, 11.1 g of triethylamine and 200 ml of benzene and then the resulting mixture was stirred at 50° to 60° C. for 1 hour. After allowing the mixture to cool, water was added to the mixture which was then thoroughly shaked. The benzene layer was separated and dried over sodium sulfate. The solvent was distilled off, and the resulting crystals were recrystallized from a mixture of chloroform and petroleum ether to obtain 25.3 g (85% yield) of 2-(2-chloropropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 141° C. as colorless needles.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](=[C:18]1[CH:23]=[CH:22][C:21]([NH:24]C(=O)C(F)(F)F)=[CH:20][CH2:19]1)[P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[OH-].[Na+]>[CH2:13]([O:12][P:10]([C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH2:23]1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: CCOP(=O)(OCC)C(=C1C=CC(NC(=O)C(F)(F)F)=CC1)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(OCC)C(=C1C=CC(N)=CC1)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 88.9 %

Procedure:
The above 1-(Bis-diethylphosphonomethylene-4-(N-trifluoroacetylamino)benzene (1.2 g, 2.52 mmols) in NaOH solution (0.1 N, 10 mL) was heated to 60_C for 5 h. The reaction mixture was cooled to rt, and extracted with methylene chloride. Combined organic layers were dried over sodium sulfate and concentrated to afford the product (0.85 g, 97%). MS: 412 (M+23).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1.O>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)CCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 70 °C
Yield: 85.5 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-(2,3-dihydrobenzofuran-5-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (126 mg, 0.242 mmol) in MeOH/THF/water=2/2/1 (10 mL) was treated with LiOH (110 mg, 4.59 mmol) and the mixture was heated at 70° C. until the reaction was judged complete. The mixture was concentrated, water was added and then adjusted to pH 2 with 1N HCl. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford (S)-2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-(2,3-dihydrobenzofuran-5-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (105 mg, 0.207 mmol, 86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62-7.47 (m, 1 H), 7.39-7.27 (m, 1 H), 7.16-7.05 (m, 2 H), 7.05-6.96 (m, 2 H), 6.92 (dd, J=4.7, 8.2 Hz, 1 H), 6.30-6.16 (m, 1 H), 5.64-5.54 (m, 1 H), 5.51-5.43 (m, 1 H), 5.43-5.33 (m, 1 H), 4.67 (td, J=4.2, 8.7 Hz, 2 H), 3.41-3.20 (m, 2 H), 2.70 (s, 3H), 0.99-0.89 (s, 9 H); LC/MS ES+=507.35 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Br[C@H:19]([CH3:41])[C:20]([N:22]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:21]>C(#N)C>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:19]([CH3:41])[C:20]([N:22]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:21])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Reactant: CCC[C@H](N)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
Introduce 123 g of ethyl (2S)-2-aminopentanoate, 160 ml of triethylamine and 160 ml of acetonitrile into a reactor, and then bring the mixture to 60° C., slowly add the solution obtained in Step A and reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield benzyl (2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]-propionyl}octahydro-1H-indole-2-carboxylate.
Reaction SMILES: NC1N=C(C)C2C(=O)CC(C3C=C([F:20])C=CC=3C3C=CC=CC=3)CC=2N=1.[NH2:27][C:28]1[N:37]=[C:36]([CH3:38])[C:35]2[C:34](=[N:39][OH:40])[CH2:33][CH:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:31][C:30]=2[N:29]=1>>[NH2:27][C:28]1[N:37]=[C:36]([CH3:38])[C:35]2[C:34](=[N:39][OH:40])[CH2:33][CH:32]([C:41]3[CH:46]=[CH:45][C:44]([F:20])=[CH:43][C:42]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:31][C:30]=2[N:29]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1cc(F)ccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (16 mg, 0.046 mmol) from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH2:33](O)[CH3:34]>>[CH2:33]([O:29][C:28](=[O:30])[C:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=2)[CH:22]=1)([F:31])[F:32])[CH3:34]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C(=O)O)c2)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(F)(F)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 52 μL, 2.1 mmol) is added to a solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid [65 mg, 0.14 mmol, Example 81(a)] in ethyl alcohol (6 mL) and the reaction mixture is stirred overnight at 65° C. The reaction is cooled to room temperature, quenched with water, extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid ethyl ester [18 mg, Example 81(c)]. LCMS: RT=3.19 minutes; MS: 496, 498 (M+H); 1H NMR [300 MHz, CDCl3]: □8.18 (2H, d, J=3.5 Hz), 7.7 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.4 (1H, s), 7.42 (1H, s), 7.18 (2H, s), 6.45 (1H, s), 5.08 (1H, b), 4.3 (2H, q, J=4 Hz), 4.05 (3H, s), 3.72 (2H, b), 3.08 (2H, t, J=3.5 Hz), 1.3 (3H, t, J=4 Hz).