Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](C)[C:5]=1N.C[C:14]1[C:15](=[N:22]Cl)[C:16](C)=[CH:17][C:18](=[O:20])[CH:19]=1>C(O)(C)C>[CH:16]1[C:15](=[N:22][C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=2)[CH:14]=[CH:19][C:18](=[O:20])[CH:17]=1
Reactant: CC1=CC(=O)C=C(C)C1=NCl
Reactant: Cc1ccc(N)c(C)c1N
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
0.003 mole (0.627 g) of 1,3-dimethyl 2,4-diamino benzene dihydrochloride is dissolved in 11 cc of 0.82 N soda solution. To this solution, cooled to 0°, there is added 0.002 mole (0.339 g) of 2,6-dimethyl N-chlorobenzoquinone monoimine in solution in 6 cc of isopropanol. The reaction mixture rapidly turns blue. It is allowed to stand for one hour at 0.20. Then 0.400 g of the above indoaniline is isolated in the form of beautiful green flakes with golden glints by filtering. After washing with water and extended vacuum drying, the product melts at 196° (no drop of melting point is observed when used in mixture with the product prepared according to Example 22).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20].S([O-])([O-])=[O:24].[Na+].[Na+]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:17])([F:18])[F:19])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20])=[O:24]
Reactant: O=S([O-])[O-]
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S(=O)CC(F)(F)F
Yield: 37.1 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the present invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chlotoperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33][CH2:34]OS(C)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:34][CH2:33][CH2:32][C:22]1[N:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:25][C:21]=1[CH3:20])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2CCCc1nc(-c2ccccc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with methanesulfonic acid 3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl ester in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-1H-indol-4-yl}-propionic acid as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0.401 mmol) and sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and the residue was crystallized using ethanol/water and isolated as white solid (60 mg, 60%). 1H NMR (CDCl3): 8.19 (s, 1H), 7.32-7.26 (m, 2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]1.Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1
Reactant: CN(C)CCn1cc([N+](=O)[O-])cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)CCn1cc(N)cn1
Reaction time: 8 h

Procedure:
N,N-dimethyl-2-(4-nitro-1H-pyrazol-1-yl)ethanamine (1.19 g, 6.46 mmol)was dissolved in methanol (65 ml) and the flask was equipped with a hydrogenation stopcock apparatus. The flask was purged with N2 and 10% Pd/C (100 mg) was added. The flask was again purged with N2, then flushed with H2 and left overnight stirring under H2 (1 atm). The reaction was purged with N2 and filtered through Celite, rinsing with methanol. The filtrate was concentrated in vacuo to give a viscous oil, which was dissolved in dioxane and treated with excess 4N HCl-dioxane, whereupon a thick and somewhat gummy precipitate formed. The mixture was concentrated to dryness and dried under vacuum.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: NC1CCCOc2ccccc21
Product: O=C(CCCCl)NC1CCCOc2ccccc21

Procedure:
5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 4-chlorobutyryl choride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[Br:31])[C:24]([O:26][CH3:27])=[O:25].O1CCOCC1.C[Si](Cl)(C)C>CO>[CH2:1]([N:8]1[CH2:9][C:10]2[NH:20][C:21]3[C:30]([Br:31])=[CH:29][CH:28]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22]=3[C:14](=[O:16])[C:11]=2[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Temperature: 110 °C
Yield: 25.4 %

Procedure:
A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (16.1 g, 70 mmol), methyl 3-amino-4-bromobenzoate (21.9 g, 84 mmol), polyphosphoric acid (120 g) and dioxane (120 mL) was heated at 110° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, filtered and the filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried, and concentrated to give crude residue, which was chromatographed on silica gel using gradient eluant of 20% to 50% ethyl acetate in petroleum ether to give the crude product. Then the crude product was dissolved in MeOH (1 L), TMSCl (150 mL) was added, and the mixture was stirred at reflux for 12 h. After cooling to room temperature, the solvent was evaporated and the residue was recrystallized from MeOH to afford methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (7.6 g). 1H NMR (CDC3-d1) δ 10.9 (s, 1H), 8.06 (d, 1H, J=7.8 Hz), 7.51-7.74 (m, 5H), 7.20 (d, 1H, J=7.8 Hz), 4.36-4.62 (m, 4H), 3.82 (s, 3H), 3.67-3.72 (m, 2H), and 2.82-2.83 (m, 2H). MS (ESI) m/e [M+1]+427.0.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-c3cccnc3)nc2c1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
To a mixture of 0.40 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g of 3-pyridine boronic acid, 8 ml of 1,4-dioxane and 0.07 g of dichlorobis(triphenylphosphine)palladium (II), a mixture of 0.40 g of sodium carbonate and 3 ml of water was added and heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 4-(5-trifluoromethyl-benzoxazole-2-yl)-[3,3′]bipyridinyl (hereinafter, referred to as “active compound 128”).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[C:17](=O)(O)[O-].[Na+]>Cl.CO>[CH3:17][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
The solution of 4.2 g (17.9 mmol) 4-nitro-3-(trifluoromethyl)benzoic acid (commercially available) in 5.1 mL 1.25 M hydrochloric acid in methanol was refluxed for 5 h. After cooling down to room temperature the solution was poured on saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers washed with brine, dried over magnesium sulfate and evaporated. After filtration the solvent was evaporated and the residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 60:40 v/v) to afford the title compound as a light yellow solid (90%) which was pure enough for the next step without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:10]([CH3:25])[C:9]2=[O:26])=CC=1.O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:25][N:10]1[C:11]([CH3:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9]1=[O:26]
Reactant: COc1ccc(CN2C(=O)N(C)C(C)(c3ccccc3)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)Nc2ccccc2C1(C)c1ccccc1

Procedure:
To a solution of 1-(4-Methoxy-benzyl)-3,4-dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (1.00 g, 2.6 mmol) in trifluoroacetic acid (8 mL) and DCM (8 mL) is stirred at room temperature for 1 h. Then H2O is added and is extracted with DCM/H2O. The organic layer is concentrated and is purified by chromatography on silica gel to give product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)[CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1C=O
Reactant: Cn1ccnc1CNCCCCNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nccn1C

Procedure:
Using General Procedure B, reaction of {4-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester in CH2C2, 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 and NaBH(OAc)3 gave {4-[(1-methyl-1H-imidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.01 (s, 3H), 2.05-2.08 (m, 4H), 2.30 (s, 3H), 2.64 (t, 1H, J=7.5 Hz), 2.94-3.04 (m, 2H), 3.56 (s, 2H), 3.82 (s, 2H), 4.20 (s, 2H), 6.81 (d, 1H, J=1.7 Hz), 7.09-7.15 (m, 2H), 7.43-7.45 (m, 1H), 8.40 (d, 1H, J=3.5 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 230 as a white solid. 1H NMR (CDCl3) δ 1.22-1.32 (m, 2H), 1.41-1.49 (m, 4H), 2.21 (s, 3H), 2.48-2.55 (m, 4H), 3.41 (s, 3H), 3.64 (s, 2H), 3.72 (s, 2H), 6.76 (s, 1H), 6.87 (s, 1H), 7.06-7.10 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 8.35 (d, 1H, J=4.2 Hz). 13C NMR (CDCl3) δ 16.98, 22.56, 30.18, 31.41, 40.63, 49.44, 53.11, 57.94, 120.31, 121.43, 125.99, 131.96, 136.99, 144.58, 145.13, 155.90. ES-MS m/z 288 (M+H). Anal. Calcd. for C16H25N5.0.1H2O.0.2CH2Cl2.0.1CH4O: C, 63.28; H, 8.47; N, 22.64. Found: C, 63.59; H, 8.58; N, 22.30.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:28]C(C)(C)C(C)(C)[O:25]2)=[C:20]([CH3:33])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].O1CCCC1.C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.Cl.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]([OH:28])[OH:25])=[C:20]([CH3:33])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(B(O)O)c(C)c1)NC(=O)OCc1ccccc1
Yield: 100.1 %

Procedure:
A solution of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (6.90 g, 15.2 mmol), sodium periodate (16.3 g, 76.1 mmol), tetrahydrofuran (156 mL), ammonium acetate (4.69 g, 60.9 mmol) and water (156 mL) was stirred at 25° C. for 24 h. The reaction was diluted with ethyl acetate and 1 N HCl solution. The aqueous solution was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was crystallized in ethyl acetate to yield the desired product (5.65 g, 80%). 1H NMR (400 MHz, CD3OD): δ 7.3 (m, 5H), 7.16 (d, 1H), 7.0 (m, 2H), 5.02 (m, 2H), 4.42 (m, 1H), 3.68 (s, 3H), 3.10 (m, 1H), 2.88 (m, 1H), 2.28 (s, 3H); MF=C19H22BNO6; LCMS found for C19H23BNO6 (M+H)+: m/z=372.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].N#N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C>CC(N(C)C)=O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[C:24]([S:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:22])=[O:23])=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: N#N
Solvent: CC(=O)N(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a nitrogen flushed flask containing 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (82.8 g, 370 mmol), (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid (100.0 g, 388.9 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (5.83 g, 7.41 mmol) were added N2 sparged THF (926 mL) and sparged 0.5 M K3PO4(aq) (1.65 L, 825 mmol). The mixture was stirred for 15 hours at room temperature. The layers were separated and the organic layer was washed with 600 mL brine, dried over MgSO4, filtered, and concentrated to dryness to give a solid residue. The solid was dissolved in 900 mL DMA, stirred with 60 g activated charcoal at 80° Celsius for 2 hours, and then stirred at room temperature for an additional 16 hours. The charcoal was removed by filtration and then washed with 150 mL DMA. The combined filtrates were treated three times with fresh Silicycle brand SiliaMetS Thiol Pd Scavenger (30 g, 15 g, 7.5 g) in DMA at 80° Celsius for 8 hours to 16 hours. Upon cooling to rt the scavenger was filtered off and the filtrate was concentrated to dryness. The resulting solid was triturated in toluene (1.2 L) at 90° Celsius for 2 hours. Upon cooling to rt the solid was collected by filtration and washed twice with toluene (700 mL) and twice with hexanes (700 mL) yielding the title compound (120.0 g, 80.9%). MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.42-8.37 (m, 1H), 8.10-8.02 (m, 2H), 7.95-7.86 (m, 1H), 7.70-7.63 (m, 1H), 7.63-7.58 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.26 (m, 2H), 7.00-6.92 (s, 1H), 6.79-6.66 (s, 2H), 1.10-0.95 (s, 9H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:8]=[C:9]([CH3:23])[CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[N:12]=3)[CH:6]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.71) (0.43 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.08 g) which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].[CH3:24][O:25]C1C=CC=CC=1NC1N=C(C2C=C(O)C=CC=2)C=CC=1[N+]([O-])=O>C(O)(=O)C.[Fe]>[OH:23][C:19]1[CH:18]=[C:17]([C:5]2[N:6]=[C:7]3[N:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[O:15][CH3:16])[C:24](=[O:25])[NH:1][C:2]3=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)ccc1[N+](=O)[O-]
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)ccc1N
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(=O)[nH]c2ccc(-c3cccc(O)c3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(5-Amino-6-(2-methoxyphenylamino)pyridin-2-yl)phenol. 3-(6-(2-Methoxyphenyl-amino)-5-nitropyridin-2-yl)phenol (1.48 g, 4.39 mmol) was dissolved in glacial acetic acid (120 mL). Iron powder (0.489 g, 8.78 mmol) was then added and the solution heated to 80° C. The reaction was monitored via thin layer chromatography for starting material consumption. After 2 h, the solution was cooled and filtered through celite and condensed under reduced pressure. The resultant oil was partitioned between sodium bicarbonate solution and ethyl acetate (3×). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (1.15 g, 85%). MS (ESI) m/z 308.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH3:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[H-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CN(C)C=O>[C:19]([N:10]1[CH:11]([CH3:13])[CH2:12][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:14])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)N(C(=O)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen stream, 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (300 mg) described in Preparation Example 52 was dissolved in N,N-dimethylformamide (3 mL), sodium hydride (60 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Then, benzoyl chloride (0.17 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (220 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](OC)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C=C(COS(C)(=O)=O)[C:34](=O)[N:35](CC(C)C)N=2)=CC=1C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][NH:35][CH3:34])[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Product: CNCc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Yield: 96.2 %

Procedure:
Following the procedure of Example 9 (4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow oil (yield: 96.2%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2]>CO.[Ni]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of 1-ethyl-4-(5-nitro-pyridin-2-yl)-piperazine (1.4 g) and Raney-Nickel (140 mg) in MeOH (30 mL) is stirred for 10 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford the title compound as a purple oil: ESI-MS: 207.1 [MH]+; TLC: Rf=0.26 (DCM/MeOH/NH3aq, 94:5:1).