Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C:10]([F:13])([F:12])[F:11])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27](O)=[CH:26][C:25]=1[CH3:32])(=[O:22])[CH3:21]>CC(=O)CC>[C:20]([O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:1][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[CH3:32])(=[O:22])[CH3:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)Oc1c(C)cc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1c(C)cc(OCC(F)(F)F)cc1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 74.9 %

Procedure:
2,2,2-Trifluoroethyl triflate (1.02 g, 4.40 mmol) and potassium carbonate (1.10 g, 1.01 mmol) were added to a solution of 4-hydroxy-2,6-dimethylphenyl acetate (673 mg, 3.73 mmol) in 2-butanone (15 mL). The mixture was stirred at 70° C. for 72 hours, then cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine and dried. The solvent was removed in vacuo and the residue purified on silica gel, eluting with 10% ethyl acetate in hexanes, to give 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl acetate (733 mg, 75%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CC#C.C(=O)=O.[CH2:12]([O:19][CH2:20][CH:21]([CH3:25])[CH2:22][CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:12]([O:19][CH2:20][CH:21]([CH3:25])[CH2:22][CH:23]([OH:24])[C:1]#[C:2][CH3:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CC=O)COCc1ccccc1
Reactant: [Li]CCCC
Agent: C#CC
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#CC(O)CC(C)COCc1ccccc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 72.8 ml. (0.146 mole) of 2 M n-butyllithium solution in hexaneand 420 ml. of anhydrous tetrahydrofuran was stirred and cooled to -50° C. while 112 ml. of liquified methylacetylene was added dropwise from a dry ice cooled addition funnel. After the addition was complete, the reaction mixture was allowed to warm to reflux temperature (8° C.) (dry ice condenser) and stirred at this temperature for 1 hour. The white slurry was then cooled to 0° C. and stirred while asolution of 14 g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. of anhydrous tetrahydrofuran was added dropwise. After stirring at 0° C. for 1 hour, the mixture was slowly warmed to 40° C. and stirred at this temperature for 1 hour whereupon the reaction mixture was treated with saturated aqueous ammonium chloride. The product was isolated by ether extraction and worked up as in Example 1. There was obtained 15.4 g. of crude material which was chromatographed on 400 g. ofsilica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane:ether afforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:14][N:15]2[C:22]([NH2:23])=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)(=O)C>[NH2:23][C:22]1[N:15]([CH2:14][C:13]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:11]([O:10][CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:12]=2)[C:16](=[O:17])[NH:18][C:19](=[O:20])[C:21]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=O)cc1OC1CCCC1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(N)c(N=O)c(=O)[nH]c2=O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
15.81 ml of 4N sodium nitrite solution was added dropwise at 65°-70° C. over 8 minutes to a solution of 20.53 g of 1-(3-cyclopentyloxy-4-methoxy-benzyl) 6-amino uracil in 300 ml of acetic acid. After 30 minutes the suspension was cooled to room temperature and the solid collected and washed with water to give the title compound (19.36 g) as pink crystals. The filtrate was evaporated to dryness, the residue suspended in 100 ml of water and the solid collected to give 1.98 g as a second crop.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([O-:19])=[O:18])[S:13][C:11]=2[N:12]=1.[OH-].[Na+].Cl>O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[S:13][C:11]=2[N:12]=1
Reactant: Cc1c(C(=O)[O-])sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0 h

Procedure:
A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.502 g), 1 mol/L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was dissolved by stirring with heating. The reaction mixture was allowed to cool under room temperature, neutralized with 1 mol/L hydrochloric acid (12.8 mL), and water (8.3 mL) was added. The mixture was stirred at about 75° C. for 1.5 hr, water (50 mL) was added (solvent amount was set to 100 mL), and the mixture was cooled to about 21° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 4 minutes 14 seconds. The height of the solid at that time was 2.3 cm (bulk 16.2 cm3). Then, an operation of washing the obtained solid with water (25 mL), followed by reduced pressure filtration at 50 hpa was repeated 3 times to confirm that the filtrate had pH 7. At this point, the total filtration time necessary for increasing the pressure was 10 minutes 2 seconds and the height of the final solid was 1.5 cm (bulk 10.6 cm3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14].CC(C)([O-])C.[K+].O1CCCC1.[ClH:26].C(O)(C)C>CC1CCCO1>[ClH:26].[NH2:11][CH2:12][CH2:13][O:14][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: NCCO
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Solvent: CC(C)O
Product: N#Cc1ccc(Br)cc1OCCN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, reaction of 11 with 2-aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with trimethylaluminum gave 33 (Scheme 14). A solution of 11 (10 g, 50 mmol) and 2-aminoethanol (3.1 mL, 50.8 mmol) in 2-methyltetrahydrofuran (80 mL) was cooled to 0° C. and a solution of 1M potassium tert-butoxide in tetrahydrofuran (55 mL, 55 mmol) was slowly added while maintaining the solution temperature below 5° C. The reaction was stirred at 0° C. for 30 min until judged complete by HPLC at which point it was warmed to 25° C. A solution of 0.5M HCl in isopropanol (100 mL, 50 mmol) was added and the desired HCl salt 3 crystallized directly from the solution. The solid was collected by filtration and dried under vacuum with a nitrogen bleed to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37 as a white solid. (12.1 g, 87% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[CH3:7].[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:7][C:6]1[O:5][C:4]([C:8]([NH:15][C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([O:12][CH3:11])=[O:20])=[O:10])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)O)oc1C
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc(C)c(C)o1
Yield: 27 %

Procedure:
Prepared in a similar manner to example 4 using 4,5-dimethyl-furan-2-carboxylic acid and D-leucine methyl ester. Yield: 27%. 1H NMR (500 MHz, CDCl3): ÿ 0.96 (t, 6H), 1.66 (m, 3H), 1.96 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 4.78 (m, 1H), 6.51 (d, 1H), 6.89 (s, 1H). MS (M+H, 268).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>C1COCC1.C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=2[F:21])[O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[CH:7]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Yield: 76.4 %

Procedure:
Dissolve N-[6-(3-amino-4-fluoro-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (400 mg, 1.4 mmol) in THF (4 mL) and DCM (10 mL), add 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol). Stir the reaction at room temperature overnight. Filter and collect the solid to get the title compound (545 mg, 77%). MS: (M+1): 510.2.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:25][CH2:24][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCCCC1
Yield: 57 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclooctylamine (0.113 ml, 0.81 mmol), and acetic acid (0.1 ml) were used to give 82.9 mg (0.24 mmol, 57% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH:17]=O)[C:8]2=[O:19])=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH:17]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])[C:8]2=[O:19])=[CH:20][CH:21]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc2ccccc2n(Cc2ccc(Cl)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc3ccccc3n(Cc3ccc(Cl)cc3)c2=O)S1
Yield: 68 %

Procedure:
1.50 g of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-3-carboxaldehyde and 0.826 g of 2,4-thiazolidinedione were suspended in 30 ml of toluene, and five drops of piperidine and five drops of acetic acid were added, followed by heating and refluxing for 6 hours. The resultant was allowed to cool to precipitate a solid. The precipitated solid was collected by filtration and dried, giving 1.36 g of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-3-ylmethylidene]thiazolidine-2,4-dione as a yellow powder (68% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:25]1[N:30]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[N:28]=[C:27]([O:41][CH2:42][CH2:43][CH2:44][OH:45])[CH:26]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][S:31][C:29]1[N:30]=[C:25]([NH:17][S:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH:26]=[C:27]([O:41][CH2:42][CH2:43][CH2:44][OH:45])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Reactant: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-(aminosulfonyl)-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from example 15, step i), 0.4 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-diphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and 3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)propan-1-ol (the product from step i), 0.4 g) in 1,4-dioxane (40 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 3 h. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.83 g
Reaction SMILES: [O:1]=[C:2]1[C:7]([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)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]1)=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.31 g, 1 mmol), tert-butyl piperidin-4-ylcarbamate (CAS 73874-95-0, 0.2 g, 1 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.38 g, 1 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.7 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with sequentially with 20 mL of 1 N HCl, water, 20 ml, of 1 N NaOH, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (m, 8H), 7.21 (m, 2H), 4.45 (m, 2H), 4.03 (m, 1H), 3.77 (m, 1H), 3.49 (m, 2H), 3.11 (m, 1H), 2.79 (m, 1H), 2.63 (m, 2H), 1.97 (m, 2H), 1.83 (m, 2H), 1.45 (m, 9H), 1.32 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([O:23]CC4C=CC=CC=4)=[CH:18][C:17]=3[O:31]CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])C=CC=C[CH:2]=1.CO>C(OCC)(=O)C.[Pd]>[C:16]1([C@@H:1]([NH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[CH:18][C:17]=3[OH:31])[CH2:14][CH2:15]2)=[O:9])[CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1ccccc1)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)N1CCC(c2cc(F)c(O)cc2O)CC1)c1ccccc1
Yield: 144.7 %

Procedure:
A mixture of 174 mg (0.32 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid phenylamide in 1 ml of ethyl acetate and of 2 ml of methanol in the presence of 51 mg (30% by mass) of palladium-on-charcoal at 10% is stirred at ambient temperature under atmospheric hydrogen pressure for 8 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 30/70 heptane/ethyl acetate. 83 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ((S)-1-phenylethyl)amide are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:22][CH:21]=[N:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:32]([O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[S:22][CH:21]=[N:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1)([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: Oc1cccc(-c2nc(N3CCOCC3)c3scnc3n2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3scnc3n2)c1
Temperature: 70 °C

Procedure:
3-(7-morpholinothiazolo[4,5-d]pyrimidin-5-yl)phenol (1.0 eq.) was dissolved in DMF (5 ml). To this imidazole (8.0 eq.) and TBDMSCl (3.5 eq.) were added and the mixture was heated at 70° C. for 5 h. DMF was evaporated under reduced pressure and purification by flash chromatography (hexane:ethyl acetate, gradient from 100%-50% hexane in EtOAc) yielded the title compound as a white solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[C:13]([S:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[OH:20])=O)[CH3:2].COCCOC(/N=N/C(OCCOC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3][C:4]1[C:5]([C:6]2[O:20][C:10]3[CH:11]=[CH:12][C:13]([S:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:9]=3[N:8]=2)=[CH:21][CH:22]=[CH:23][N:24]=1)[CH3:2]
Reactant: CCSc1ncccc1C(=O)Nc1cc(SC(F)(F)F)ccc1O
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ncccc1-c1nc2cc(SC(F)(F)F)ccc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 2.13 g of 2-ethylsulfanyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]nicotinamide, 2.14 g of DMEAD, 2.24 g of triphenylphosphine and 20 ml of THF was stirred at 50° C. for 4 hours. A saturated aqueous ammonium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.52 g of 2-(2-ethylsulfanylpyridin-3-yl)-5-(trifluoromethylsulfanyl)benzoxazole (hereinafter, referred to as Compound of Present Invention 38).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1=[O:35].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:28]3/[C:27](=[O:35])[NH:26][C:34]4[C:29]/3=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 60 °C
Yield: 17.9 %

Procedure:
To a solution of (E)-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (25 mg, 0.0749 mmol), oxindole (10 mg, 0.0749 mmol), and MeOH (1 mL) was added piperidine (1 uL) and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and the product yellow solid was precipitated with MeOH (1 mL) and then filtered to give 11 mg. The filtrate was purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/MeOH) to give an additional 6 mg of product (17 mg total, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69-8.62 (m, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.00-7.91 (m, 3H), 7.77 (d, J=8.1 Hz, 1H), 7.72 (t, J=8.3 Hz, 1H), 7.63 (d, J=16.9 Hz, 1H), 7.53 (m, 2H), 7.44 (b.s., 1H), 7.25-7.17 (m, 2H), 6.92-6.86 (m, 2H), 5.77 (d, J=10.6 Hz, 1H), 4.09 (d, J=9.6 Hz, 1H), 3.84-3.74 (m, 1H), 2.67-2.53 (m, 1H), 2.24-2.13 (m, 2H), 1.85-1.66 (m, 3H); MS ESI 449.2 [M+H]+, calcd for [C28H24N4O2+H]+ 449.20.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[N:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:25])=[O:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:32][C:29]2[C:28]([O:33][CH3:34])=[N:27][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:31][N:30]=2)=[N:3][CH:4]=1
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1nc(P(C)(C)=O)cnc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
To a mixture of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared in Example 32: 0.120 g, 0.348 mmol) and 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348 mmol) was added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17.6 mg, 0.017 mmol), XANTPHOS (23.3 mg, 0.040 mmol), and cesium carbonate (0.228 g, 0.700 mmol), and dioxane (3.5 mL). The mixture was sealed and heated at 120° C. After 16 h, the reaction mixture was cooled to rt and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired product (11.4 mg, 6% yield). MS/ES+: m/z=511.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Cl)=[CH:20][CH:19]=1)([O-:17])=[O:16].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:24][CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)cc1

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.7 g), 2-[4-nitrophenoxy]ethyl chloride (0.73 g) (see C. A. [1955], 49, 3163e), sodium iodide (0.5 g) and potassium carbonate in acetonitrile (50 ml) were heated under reflux for 3 days. After cooling, the solvent was removed in vacuo, the residue dissolved in ethyl acetate and washed once with water, once with sodium carbonate and twice with brine. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give the product as an orange oil, yield 1.0 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCN)NC2=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCNC(=O)c3ccccc3)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of (3R,6R)-3-(3-aminopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (100 mg) in dry N,N-dimethylformamide (3 ml) was added benzoyl chloride (60 mg). The mixture was stirred at ambient temperature for 2 hours, diluted with water (15 ml) and allowed to stand overnight. The precipitated mass was collected, washed with water, and dried in vacuo to give (3R,6R)-3-(3-benzamidopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (45 mg).