Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[NH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl>C(O)C>[CH3:1][S:2][C:3]1[C:4]2[NH:9][C:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1ccccc1NN
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Product: CSc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-(methylthio)phenyl hydrazine (5.32 g, 30.0 mmol) and 4-piperidone (4.07 g, 30.0 mmol) were partially dissolved in the ethanol (75 mL) and heated initially to reflux for 1 h. A heavy precipitate formed from the almost clear solution. The reaction was then treated with the conc hydrochloric acid (2.5 mL) and diluted with further ethanol (25 mL) to assist stirring and heating continued for a further 4 h. After cooling to RT overnight the solid was filtered washing isopropanol (25 mL). Obtained 7.70 g
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Fc1cccc(Cc2cc(Cl)ncn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2cccc(F)c2)ncn1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(3-fluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(3-fluorobenzyl)pyrimidine (the present compound (100)), m.p. 51.5° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.ClCCl.[Pd+2].C([O-])(=O)C.C([O-])(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:29]3[CH2:30][CH2:31][C:26]([O:25][CH3:24])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:27][CH2:28]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC1(c2ccccc2)CCNCC1
Reactant: CC(=O)N1CCN(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC1(c2ccccc2)CCN(c2ccc(N3CCN(C(C)=O)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 1-acetyl-4-(4-trifluoromethanesulfonyloxyphenyl)piperazine (3 g), 4-methoxy-4-phenylpiperidine (1.63 g), acetic acid palladium(II) salt (0.11 g), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.42 g) and cesium carbonate (3.88 g) in toluene (17 ml) was stirred for 30 minutes at ambient temperature. After being stirred for a further 17 hours at 100° C., the reaction mixture was diluted with dichloromethane. The suspension was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using ethyl acetate/methyl alcohol (30:1) as the elution to give 1-acetyl-4-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.65 g).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:16][CH3:15])=[O:9]
Reactant: CN
Reactant: O=C(O)c1ccccc1I
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (29.4 mL, 404 mmol) is added to a solution of (2-iodo-benzoic acid (50.0 g, 202 mmol) in dry toluene (600 mL). The mixture is heated to reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (600 mL) and cooled to 0° C. 40% methylamine (aq., 94.1 mL, 1.21 mol) is added dropwise at 0-5° C. during 30 minutes. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (300 mL) and extracted with ethyl acetate (3×300 mL) The combined organic fractions are washed successively with saturated sodium bicarbonate solution (250 mL) and brine (250 mL), dried (MgSO4) and concentrated in vacuo. This gives 50.8 g (96%) of crystalline 2-iodo-N-methyl-benzamide.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:20])[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:18]([O:17][C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:20])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]=2[N+:12]([O-:14])=[O:13])=[O:16])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)c([N+](=O)[O-])c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)c2ccc(OS(=O)(=O)c3ccc(C)cc3)c([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of ethyl 7-hydroxy-8-nitro-4-oxochromen-2-carboxylate [J.Chem. Soc. (c), 1970, 2609] ( (5.58 g, 0.02 mol) in anhydrous THF (100 mL) was added p-toluenesulfonyl chloride (7.63 g, 0.04 mol) and K2CO3 ( 5.52 g, 0.04 mol). The reaction mixture was allowed to stir for 12 hours at room temperature. The solution was filtered, and the filtrate was diluted with EtOAc (200 mL) and washed sequentially with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4, and filtered. The solvent evaporated to give a white solid which was recrystallized from EtOAc-hexane (1:1) to give 8.15 g (94%) of the title compound: mp 125° C.; 1H NMR (400 MHz, CDCl3): 1.39 (t, J=7 Hz, 3H), 2.48, (s, 3H), 4.42 (q, J=7.0 Hz, 2H), 7.14 (s, 1H), 7.38 (d, J=9 Hz, 1H), 7.67 (d, 1H), 7.80 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz); IR: 3450, 3080, 2980, 1740, 1670, 1610, 1540, 1490, 1230 cm−1; MS 451[M+NH4].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CC(C)(C)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C)c2)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
285 mg (1.53 mmol) of 3-bromo-4-methylaniline, 300 mg (1.68 mmol) of 3-tert-butylbenzoic acid and 698 mg (1.83 mmol) of HATU were dissolved in 3 ml of DMF, 0.32 ml (1.83 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at RT for 16 h. The reaction was then stirred into 20 ml of 0.1 M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 490 mg (88% of theory) of the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[OH-].[NH4+:17]>C(#N)C>[NH2:17][C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1cnc(N)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (2.15 g, 9.34 mmol) was dissolved in acetonitrile (11.7 ml), and, with stirring at room temperature, aqueous 32% ammonium hydroxide (11.36 ml, 93 mmol) was added drop wise. A white suspension was obtained after few seconds. Acetonitrile was evaporated and the aqueous suspension was filtered on a buckner funnel. The obtained solid was washed with water (20 ml) and dried affording ethyl 2-aminopyrimidine-5-carboxylate as a white solid (1.192 g, 7.13 mmol, 76% yield, MS/ESI+ 168.1 [MH]+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=12.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+].[CH:60]1([C:63]([NH2:65])=[O:64])[CH2:62][CH2:61]1>C1(C)C=CC=CC=1.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:11][C:9]1[NH:8][C:7]2=[C:2]([NH:65][C:63]([CH:60]3[CH2:62][CH2:61]3)=[O:64])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1
Reactant: NC(=O)C1CC1
Reactant: Cc1cc2ccnc(Cl)c2[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Temperature: 110 °C
Reaction time: 4 h
Yield: 31.7 %

Procedure:
To a solution of 7-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.1 g, 06 mmol) in toluene were added tris (dibenzylidene acetone) dipalladium (302 mg, 0.3 mmol), Xantphos (0.286 g, 0.49 mmol), cesium carbonate (4.3 g, 13.2 mmol), and cyclopropanecarboxamide (0.842 g, 9 mmol). The resulting reaction mixture was heated to 110° C. and stirred for about 4 hours. The reaction mixture cooled to room temperature diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography to afford N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (0.45 g, 40% yield).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)COS(C)(=O)=O)[CH2:6]2.O.[CH2:27](O)[CH3:28]>>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:20]=[CH:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:28][CH:27]=1)[CH2:6]2
Reactant: Cc1ccc2c(c1)CN(C(COS(C)(=O)=O)c1ccccc1)C2=O
Reactant: CCO
Agent: [Na]
Solvent: O
Product: Cc1ccc2c(c1)CN(CC=Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under argon sodium metal (0.58 g, 24.37 mmol) was slowly added to anhydrous ethanol. After all the sodium was reacted methanesulfonic acid 2-(5-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl ester (5.61 g, 16.25 mmol) dissolved in ethanol was added to the reaction mixture and the solution was stirred for 6 h at room temp. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was used in the next step without further purification. Yield 3.64 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[C:8](=[N:9][C:10]([CH3:23])=[CH:11][CH:12]=2)[C:7]=1[C:24]1[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCCC1>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:13]2[C:8](=[N:9][C:10]([CH3:23])=[CH:11][CH:12]=2)[C:7]([C:24]2[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2cccnc2OC)c2nc(C)ccc2n1Cc1ccccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncccc1-c1c(C(=O)O)n(Cc2ccccc2F)c2ccc(C)nc12
Temperature: 70 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
Compound B4 was diluted with tetrahydrofuran (3 mL) and to the resulting solution was added 1M aqueous lithium hydroxide (2 mL, excess). The reaction was heated to 70° C. and allowed to stir at this temperature for 14 hours. The reaction was then acidified using 1M HCl, and extracted several times with ethyl acetate. The organic layer was collected and concentrated in vacuo to provide 1-(2-Fluoro-benzyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid B5 (0.2 g, 80% yield). MS: 392.16 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:44](=[O:45])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc([C@H]2C[C@H]3COC(=O)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A solution of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (20 mg, 0.041 mmol) (Example 7) and DIEA (72 μL, 0.412 mmol) in acetonitrile (0.5 mL) was treated with carbonyldiimidazole (8.0 mg, 0.049 mmol). After 1 h, the starting material was completely consumed. The reaction mixture was quenched with 1.0 N aqueous NaOH solution (1.0 mL) and the mixture was stirred vigorously for 5 min, then, diluted with DCM (10 mL). The organics were washed with brine (2 mL) and dried over Na2SO4 and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-oxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (2.0 mg, 7% yield). LCMS (m/z): 511.3, 513.3 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92-7.84 (m, 2H), 7.46 (s, 1H), 7.44-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.34-7.28 (m, 1H), 5.19 (t, J=5.87 Hz, 1H), 4.61-4.56 (m, 1H), 4.34 (dd, J=3.52, 9.00 Hz, 1H), 4.24-4.15 (m, 1H), 3.92-3.80 (m, 1H), 3.74-3.62 (m, 1H), 2.41 (td, J=5.72, 11.64 Hz, 1H), 1.84-1.71 (m, 1H).
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C:22]3[CH:23]=[CH:24][C:25]4[O:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=4[N:31]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>C1COCC1.[Ni]>[C:1]1([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=4[N:31]=3)[CH2:15][CH2:16]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COc2ccc(C=CCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C1COc2ccc(CCCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1

Procedure:
6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.098 g, 0.226 mmol) was hydrogenated using Ra—Ni in THF for 16 hours. The reaction was filtered and concentrated to give an oil. Purification by chromatography on silica gel (0–5% MeOH/EtOAc) afforded the title compound as a film (0.059 g, 61%). This was dissolved in Et2O and 1M HCl in Et2O (1 equivalent) was added. The resulting precipitate was filtered and dried to give a white solid. MS: APCI: M+1: 435.5 (Exact Mass: 434.27).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[N:19]=[C:18]([N:20]2[C:28]3[C:23](=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([N:20]2[C:28]3[C:23](=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:17]=[CH:16][N:15]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A suspension of 3-chloroperoxybenzoic acid (77%, 3.11 g) in CHCl3 (40 mL) was slowly added at 0° C. under N2 to a mixture of 1-(2-methylsulfanylpyrimidin-4-yl)-4-nitro-1H-indole (3.93 g, 14.0 mmol) in CHCl3 (50 mL). The resulting mixture was allowed to warm up to RT, and stirred overnight. The reaction mixture was then diluted with DCM (200 mL) and washed with aqueous NaHCO3 (saturated). The resulting yellow precipitate was collected by filtration and dried under reduced pressure to give 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-nitro-1H-indole (2.36 g). The mother liquors were dried over Na2SO4, filtered and evaporated under reduced pressure to give a second aliquot (690 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:32])[CH:30]=[CH2:31])[CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a mixture of above crude 2-(4,5-dichloro-2-ethylphenylamino)-1-(piperazin-1-yl)ethanone hydrochloride (82 mg) and Et3N (69 mg, 0.686 mmol) in DCM (3 mL) 0° C., a solution of acryloyl chloride (23 mg, 0.251 mmol) in DCM (1 mL) was added. The resulting mixture was stirred at room temperature for 1 h and then was quenched withed saturated NaHCO3 solution. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (20 mg, 18.76% yield, 2 steps) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.11 (s, 1H), 6.58 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.36 (dd, J=1.6, 16.4 Hz, 1H), 5.79 (dd, J=1.6, 10.4 Hz, 1H), 5.08 (bs., 1H), 3.89-3.52 (m, 10H), 2.52 (q, J=7.2 Hz, 2H), 1.29-1.26 (t, J=7.6 Hz, 3H). ESI-MS m/z: 370.2[M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[C:4](=[O:21])[CH:3]=1.[CH:22]1([CH2:28][CH2:29][CH2:30]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Li+].[OH-]>C(OCC)(=O)C.O.C1COCC1>[CH:22]1([CH2:28][CH2:29][CH2:30][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:11]([OH:13])=[O:12])[C:4](=[O:21])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OCCCC1CCCCC1
Reactant: CCOC(=O)C(C)(CCn1ccc(O)cc1=O)S(C)(=O)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
Ethyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (285 mg, 0.898 mmol) was weighed into a 20 ml septa cap vial with THF (10 ml) added. To this was added 3-cyclohexyl-1-propanol (0.191 ml, 1.26 mmol), followed by triphenylphosphine (330 mg, 1.21 mmol). The reaction mixture was stirred at RT for 20 minutes and then DIAD (0.248 ml, 1.26 mmol) was added. The reaction mixture was stirred for 72 hours at RT, was then diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate (50 ml). The product was re-extracted with ethyl acetate (100 ml). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dioxane (6 ml) and ethanol (6 ml). To this was added a 2.0M aqueous solution of LiOH (2.6 ml, 5.3 mmol). The reaction mixture was stirred at RT overnight, then was diluted with 30 ml of water and washed with ethyl acetate (2×50 ml) to remove any TPPO. The aqueous phase was adjusted to pH-2 with 1N HCl (10 ml) and the product was extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid (190 mg, 51%). MS (LC/MS) m/z 414.1 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.81-1.08 (m, 2H) 1.16-1.44 (m, 6H) 1.72 (s, 9H) 2.01 (s, 1H) 2.29-2.47 (m, 1H) 2.48-2.68 (m, 1H) 3.18 (s, 3H) 4.04 (s, 2H) 4.07-4.17 (m, 1H) 4.22-4.37 (m, 1H) 5.97-6.12 (m, 1H) 6.25-6.36 (m, 1H) 7.57-7.73 (m, 1H)
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[C:28]([Si:32]([CH3:47])([CH3:46])[O:33][CH2:34][C:35](B1OC(C)(C)C(C)(C)O1)=[CH2:36])([CH3:31])([CH3:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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]>[Si:32]([O:33][CH2:34][C:35]([C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1)=[CH2:36])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:46])[CH3:47]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1; 3.0 g, 6.93 mmol) in 1,4-dioxane (60 mL), tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (3.09 g 10.39 mmol), potassium phosphate (2.94 g, 13.86 mmol), and water (6 mL) were added, and the mixture was degassed with argon for 15 minutes. PdCl2(dppf) (0.85 g, 1.04 mmol), was added, and the mixture was degassed with argon again for 5 minutes. The reaction was then heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using 15% ethyl acetate/petroleum ether as eluent to yield 2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calcd. for C29H38ClN5OSi [M+H]+ 536. found 536.