Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)(O)=[O:14].ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:11][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)c1cc(Cl)cc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cc(Cl)cc(C(N)=O)c3N)cc2)CC1

Procedure:
A solution of 2,3-diamino-5-chlorobenzamide (0.75 g), tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (0.17 g), 1-hydroxybenzotriazole (HOBT, 0.22 g), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 0.85 g) and diisopropylethylamine (DIPEA, 0.85 mL) in DMF (5 mL) was stirred for 18 hours and concentrated. The concentrate was flash chromatographed on silica gel with 10% methanol/dichloromethane.
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[F:1][C:2]1[C:17]([F:18])=[C:16]([CH2:19][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reactant: CCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(F)c1F
Reaction time: 2 h
Yield: 83 %

Procedure:
Combine 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol), n-pentylamine (105 mg, 1.20 mmol), and MeOH (3 ml) in a round bottom flask equipped with nitrogen inlet and stir for two hours. Add NaBH4 (57 mg, 1.50 mmol) and stir for an additional two hours before concentrating. Dissolve concentrate in EtOAc and wash with 5% aq. KOH and brine, dry (Na2SO4), and concentrate. Purify on silica gel (5% (1 M NH3/MeOH)/DCM) to give the title compound (290 mg) as a white solid. Mass spectrum (ion spray): m/z=350 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.28 (d, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.22 (d, 1H), 7.15 (m, 1H), 3.73 (s, 2H), 2.48 (t, 2H), 1.41 (m, 2H), 1.25 (m, 4H), 0.84 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](O)=[O:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=CO
Product: O=CNc1ccc(F)cc1

Procedure:
Was prepared according to Example 2 from 4-fluoroaniline and formic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cccc(Cl)c1F
Product: CCOC(=O)C(C)=NNc1cccc(Cl)c1F

Procedure:
The title compound, EI-MS: m/e=258.1 (M+), was prepared in accordance with the general method of example 32d) from (3-Chloro-2-fluoro-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>C([O-])(O)=O.[Na+].C1COCC1>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[C:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[CH:10][CH:9]=2
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccccc3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccccc3)c21
Yield: 65.9 %

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-phenyl-2H-indol-2-one (26.5 mg, 0.08 mmol) (from Example 43 infra) was acylated with 2-thiopheneacetyl chloride (25.7 mg, 0.16 mmol) (Aldrich) in saturated aqueous NaHCO3 (0.16 mL) and THF (2 mL) at room temperature for 3 h to give (Z)-N-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-phenyl-1H-indol-5-yl]-2-thiopheneacetamide (yield: 24 mg, 67%).
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])(O)=[O:2].B.O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:8]2[C:9]3[C:14](=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[C:6]([S:5][CH2:4][CH2:1][OH:2])=[C:7]2[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)(C)Cc1c(SCC(=O)O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(SCCO)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the acid from Step 4 (3.8 g, 8.23 mmol) in THF (200 mL) there was added 0.9M borane in THF (25 mL) and the mixture was stirred at r.t. for 1.5 hours. Water (25 mL) was added and the THF removed by evaporation. More H2O was added along with 2N HCl (15 mL) and the mixture was extracted with Et2O 3 times. These extracts were washed with H2O 4 times, dried and evaporated to leave a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of hexane and EtOAc. The title compound was obtained as a thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]2[CH:44]=[C:43]([N:45]([CH3:47])[CH3:46])[S:42][C:41]=2[CH:48]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:44]2[C:40]3[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:48][C:41]=3[S:42][C:43]=2[N:45]([CH3:46])[CH3:47])=[O:7])[CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:14]([CH3:15])[CH3:16]
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: COc1cc(C(=O)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3-methoxy-4-triisopropylsilyloxybenzoic acid (9.75 g, 30 mmol; Part A) in 300 mL of dichloroethane and 1 drop of DMF was treated with oxalyl chloride (13.1 mL, 150 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and suspended in 300 mL of chlorobenzene. 6-Benzyloxy-2-(N,N-dimethylamino)benzo[b]thiophene (8.5 g, 30 mmol) was added, and the resulting mixture was heated at 105° C. for 5 h. After cooling to ambient temperature, the reaction mixture was poured into 500 mL of saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CHCl3 (3×150 mL). The combined organics were dried over K2CO3, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; gradient of 5% to 10% EtOAc in hexanes) afforded 6.05 g (10.3 mmol; 34%) of the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH:29][CH3:30])[CH3:28]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([N:29]([CH2:27][CH3:28])[CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCNC
Solvent: ClCCl
Product: CCN(C)C(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.10 g, 2.8 mmol) in CH2Cl2 (10 mL) was added neat ethyl(methyl)amine (310 μL, 3.6 mmol) dropwise. The mixture was stirred at room temperature for 1 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-ethyl-3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (1.09 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 1.15 (t, 3H, J=7.0 Hz), 2.05 (s, 3H), 2.06 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 3.08 (s, 3H), 3.74-3.81 (m, 3H), 4.16 (dd, 1H, J=2.0, 12.5 Hz), 4.27 (dd, 11, J=4.5, 12.5 Hz), 5.14 (t, 1H, J=10.0 Hz), 5.26 (t, 1H, J=10.0 Hz), 5.34-5.40 (m, 2H), 5.78 (d, 1H, J=8.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: NCCN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCOCC2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 4-(2-aminoethyl)morpholine. m/e (ESI) 500 (MH+)
Reaction SMILES: [OH-].[Na+].[CH:3]([CH:6]([C@H:16]1[CH2:19][C@H:18](C2C=C([N+]([O-])=O)C=CC=2C([O-])=O)[CH2:17]1)[C:7]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:8][SiH3:9])([CH3:5])[CH3:4].CC(O)=[O:34]>O1CCOCC1>[CH:3]([CH:6]([C@H:16]1[CH2:17][C@H:18]([OH:34])[CH2:19]1)[C:7]([CH:10]([CH3:11])[CH3:12])([CH:13]([CH3:15])[CH3:14])[O:8][SiH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)C([C@H]1C[C@H](c2cc([N+](=O)[O-])ccc2C(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C([C@H]1C[C@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Aqueous NaOH (0.4 mol/L, 12 mL, 4.56 mmol) was added to a stirred solution of trans-3-(triisopropyl-siloxyethyl)cyclobutyl-4-nitrobenzoate (0.96 g, 2.28 mmol) in 18 mL 1,4-dioxane at ambient temperature. After 1 hr, AcOH was added drop by drop. After 5 min, the reaction mixture was concentrated by rotovap. The residue was partitioned between EtOAc (10 mL) and saturated NaHCO3 (2×10 mL). The organic phase was dried over MgSO4 and solvent evaporation gave light yellow oil (0.57 g, 92.3%, Rf=0.23 (Hexane: EtOAc=9:1)). 1H NMR (CDCl3, 300 MHz): δ 1.00-1.07 (m, 21H), 1.63-1.70 (m, 2H), 1.78 (bs, 1H), 1.99-2.10 (m, 4H), 2.24-2.38 (m, 1H), 3.61-3.65 (t, J=6.6, 2H), 4.35-4.44 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 12.23, 18.29, 24.24, 38.05, 39.37, 62.27, 66.82. MS (FAB): expected for C15H32O2Si (M+H)+ 273.50. Found 273.22456.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21].O1CCCC1>CN(C)C=O>[CH3:18][NH:19][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A solution of 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.046 mL (0.78 mMol) methyl isocyanate in 6 mL 5:1 tetrahydrofuran:dimethylformamide was stirred at room temperature for 5 hours. At this point an additional 0.020 mL methyl isocyanate were added and stirring continued for another 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between 3:1 chloroform:isopropanol and 1N sodium hydroxide. The phases were separated and the aqueous phase extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica gel plate), eluting with dichloromethane containing from 20-40% methanol and 1% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 0.043 gm (34%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]([CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1>>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:31])[CH2:30][CH2:29]2)=[O:12])[N:7]([CH3:13])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Product: Cn1nc(C(C)(C)C)cc1C(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Yield: 91.9 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (27.3 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (35.5 mg) as a yellow solid. Exact mass calculated for C21H27FN4O2: 386.2. Found: LCMS m/z=387.5 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:1][NH:30][C:28]2[CH:29]=[C:24]([C:18]3[NH:19][C:20]4[C:16]([CH:17]=3)=[CH:15][C:14]([F:13])=[C:22]([F:23])[CH:21]=4)[CH:25]=[CH:26][C:27]=2[O:31][CH3:32])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Methyl 4-formylbenzoate (0.21 g, 1.28 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.34 g, 1.24 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 3.33 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.3 g, 1.42 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated, and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product as off-white crystals (140 mg), mp 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1
Reactant: NN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)cc1NN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 45 g of 4-chloro-1,2-dinitrobenzene, 25 g of 4-aminomorpholine and 30 g of triethylamine in 250 ml of 96° EtOH is stirred for 48 hours at RT. The precipitate formed is filtered off and washed with iso ether to give 30.2 g of the expected product. M.p.=155° C.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21](SC)=[N:22][S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[N:13]=1>O1CCCC1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21]([NH:22][S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[O:7])[N:13]=1
Reactant: CCOCC
Reactant: COc1cc(OC)nc(NC(=NS(=O)(=O)c2cccnc2)SC)n1
Agent: FB(F)F
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2)n1
Reaction time: 0.33 h

Procedure:
To 8 ml of 15% aqueous tetrahydrofuran was added with stirring 0.8 g of mercuric acid oxide and 0.56 ml of borontrifluoride etherate. The mixture was stirred for 20 minutes, and then 0.8 g of N-(4,6-dimethoxypyrimidin-2-yl)-N'-(3-pyridinylsulfonyl)carbamimidothioic acid, methyl ester was added. The slurry was stirred at room temperature for 1 hour, filtered, and the solid was rinsed with 50 ml of water, followed by 40 ml of dichloromethane, and dried to give 0.3 g of the desired product, m.p. 176° C. dec.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]([CH3:32])([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][C:17]([OH:16])([CH3:32])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: CC(C)NCC(C)(O)COc1ccc(N)cc1
Product: CC(C)NCC(C)(O)COc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine (Method 13) and 4-[2-hydroxy-2-methyl-3-(isopropyl amino)propoxy]aniline (Method 118), the product was obtained. MS (MH+): 486, 488; HPLC (RT): 4.26.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15]O.[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[SH:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[S:23][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2
Reactant: Cn1ccnc1S
Reactant: OCc1cccc2cc(-c3nccs3)[nH]c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1SCc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A solution of [2-(1,3-thiazol-2-yl)-1H-indol-7-yl]methanol (0.095 g), 1-methyl-1H-imidazole-2-thiol (0.047 g) and tributylphosphine (0.251 g) in tetrahydrofuran (7 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.312 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.089 g, yield 66%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34](S(C1C=CC=CC=1)(=O)=O)[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])([CH3:30])([CH3:29])[CH3:28]>O>[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])[C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:19])([F:20])[F:3])[CH:6]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Sodium hydride (60% in mineral oil, 154 mg, 3.85 mmol) is added in portions to a mixture of 3-(3-trifluoromethyl-phenylamino)-cyclohex-2-enone (INTERMEDIATE 3; 960 mg, 3.76 mmol) and 2-methyltetrahydrofuran (8 mL). After 30 min [benzenesulfonyl-(4-cyano-2-methylsulfanyl-phenyl)-methyl]-carbamic acid tert-butyl ester (Step 1, 1.56 g, 3.73 mmol) is added and the mixture is stirred at room temperature for 50 min. Water and 2-methyltetrahydrofuran are added and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 2.13 g. ESI mass spectrum: [M+H]+=532; Retention time HPLC: 1.22 min (Z018_S04).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][CH:14]=[C:7]1[CH:6]=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:20]=[C:21]([SH:23])[CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=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:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:20]=[C:21]([S:23][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[C:12]([CH3:15])=[N:13][CH:14]=[C:7]2[CH:6]=[CH:5]3)[CH:22]=1
Reactant: N#CC1(c2cc(F)cc(S)c2)CCOCC1
Reactant: Cc1ncc2ccc3cc(Br)ccc3n12
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: CCN(C(C)C)C(C)C
Product: Cc1ncc2ccc3cc(Sc4cc(F)cc(C5(C#N)CCOCC5)c4)ccc3n12
Temperature: 80 °C

Procedure:
4d (80 mg, 0.3 mmol) and 4-(3-Fluoro-5-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (4e, 88 mg, 0.37 mmol) were dissolved in 1,4-dioxane (3 mL) and degassed for 10 minutes with N2. iPr2NEt (0.10 mL, 0.6 mmol), Pd2dba3 (14 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol) were added, and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 4f.