Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([NH:9]C(=O)C)=[CH:7][CH:8]=1.Br[C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].CCCCCO>[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]([NH:9][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])=[CH:7][CH:8]=1
Reactant: Cc1cccc(C)c1Br
Reactant: COc1ccc(NC(C)=O)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2c(C)cccc2C)c(C)c1
Reaction time: 42 h
Yield: 28.6 %

Procedure:
A mixture of 14.3 g of 3-methoxy-6-acetylaminotoluene, 17.8 g of 2-bromo-m-xylene, 6.6 g of potassium carbonate, and 0.3 g of copper (I) iodide was stirred for 42 hours at 160°-210° C. After the reaction mixture was cooled, 22.9 g of potassium hydroxide and 66 ml of n-amyl alcohol were added to the mixture, which was then refluxed for 3.5 hours. Then the reaction mixture was cooled and washed with hot water. The n-amyl alcohol was removed by distillation, and the remaining reaction mixture was distilled under reduced pressure to obtain 5.5 g (28 percent of theoretical yield) of 3-methoxy-6-(2',6'-dimethylanilino)toluene.
Reaction SMILES: COC1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[N:31]1C=CC(C=O)=CC=1>>[N:31]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccncc1
Product: O=C(NCCNCc1ccncc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-pyridinecaboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.35-8.42 (2H, m) 8.00 (1H, d, J=5.61 Hz) 7.65 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.47 Hz) 7.36-7.41 (2H, m) 7.24 (1H, d, J=3.56 Hz) 6.86 (1H, d, J=5.66 Hz) 6.55 (1H, d, J=3.56 Hz) 3.82 (2H, s) 3.51 (2H, t, J=6.25 Hz) 2.79 (2H, t, J=6.17 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:22]1[C:25]2([CH2:30][CH2:29][O:28][CH:27](O)[CH2:26]2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:8]1([CH3:21])[CH:9]=[CH:10][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:29][CH2:30][C:25]3([CH2:26][CH2:27][OH:28])[CH2:22][CH2:23][CH2:24]3)[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: OC1CC2(CCC2)CCO1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine trifluoroacetate (418 mg) (synthesized in Preparation Example 4-5) in tetrahydrofuran (3 mL) was added triethylamine (0.28 mL). The solution was stirred at room temperature for 5 minutes. Then, 7-oxaspiro[3.5]nonan-6-ol (104 mg) (synthesized in Example 65) in tetrahydrofuran (3 mL) was added to the solution and it was stirred at room temperature for additional 10 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (424 mg) was added thereto. The solution was then 4lowed for its temperature to rise to room temperature. The solution was stirred for additional 4.5 hours. A 3N aqueous sodium hydroxide solution (5 mL) was added to the reaction solution and it was extracted with tert-butyl methyl ether. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3)] to give the title compound (175 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH:29]([CH3:31])[CH3:30])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.I[C:33]1[CH:38]=[CH:37][N:36]([CH3:39])[C:35](=[O:40])[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH:29]([CH3:31])[CH3:30])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:33]3[CH:38]=[CH:37][N:36]([CH3:39])[C:35](=[O:40])[CH:34]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cn1ccc(I)cc1=O
Reactant: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1

Procedure:
A mixture of 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 0.092 mmol), 4-iodo-1-methylpyridin-2(1H)-one (20 mg, 0.085 mmol), Pd(PPh3)2Cl2 (6 mg, 0.0085 mmol), and Cs2CO3 (2 N, 0.425 mL, 0.85 mmol) in 1,4-dioxane (2 mL) was refluxed for 3 h under N2. The reaction mixture was treated with EtOAc (20 mL) and water (20 mL), and the organic layer was dried and concentrated in vacuo. The residue was purified by preparative HPLC to give two isomers.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:36])[CH2:9][CH:10]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:11](=[O:24])[CH2:12][O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8](=[O:36])[CH2:9][C@H:10]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH:11]([OH:24])[CH2:12][O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)COc1c(F)c(F)cc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(O)COc1c(F)c(F)cc(F)c1F
Reaction time: 3 h

Procedure:
NaBH4 (1.65 g) was added portionwise to a stirred solution of 3-benzyloxycarbonylamino-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (21.1 g) in anhydrous THF (220 mL) at −20° C. under nitrogen. After stirring at this temperature for 3 hours, the reaction was quenched by the addition of saturated ammonium chloride solution and diluted with DCM. The organic layer was removed and the aqueous layer re-extracted with DCM. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography (10%-20% ethyl acetate/hexane). The sub-title compound as a white solid (14.6 g, 73%); 1H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 2.61-2.77 (2H, m), 3.16-3.36 (1H, 2×brd d), 4.12-4.22 (2H, m), 4.30-4.33 (1H, m), 5.44-5.69 (1H, 2×d), 6.78-6.86 (1H, m), 7.35-7.36 (5H, m); 19F NMR (346 MHz, CDCl3) (proton decoupled) δ −139.87, −139.89, −139.93, −139.95, −139.98, −157.02, −157.05, −157.06, −157.08, −157.09, −157.10, −157.12; ES (+) 488.27 (M+H).
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[S:27][C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH3:35])[C:30]=1[C:31]([O:33][CH3:34])=[O:32].C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:25][C:26]2[S:27][C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:29]([CH3:35])[C:30]=2[C:31]([O:33][CH3:34])=[O:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(N)sc(-c2ccccc2)c1C
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(-c2ccccc2)c1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate and benzenesulphonyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC1=CCCCCCC1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCC1
Yield: 69.8 %

Procedure:
The compound 8 (450 mg, 1.2 mmol) was converted to the enol ether with 1-methoxycyclooctene (1.51 g, 12 mmol) in the same manner as the example 10 to give the compound 11 (405 mg, 70%) as oil. Rf 0.50 (Al2O3 60, Type E, 10:1 toluene -EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][CH2:14][CH:15]=O)=[CH:5][CH:4]=1.[NH2:18][C@H:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=3[N:33]=2)[C:21](=[O:35])[CH2:20]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][CH2:14][CH2:15][NH:18][C@H:19]2[CH2:23][N:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=4[N:33]=3)[C:21](=[O:35])[CH2:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCCN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
In N,N-dimethylformamide (5 ml) was dissolved 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (Reference Example 8,200 mg, 0.86 mmol). 6-[(4R)-4-Amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 262 mg, 1.03 mmol) was added thereto and subsequently acetic acid (65 mg, 1.12 mmol) was added. The obtained mixture was stirred at room temperature for 1 hour, cooled on ice and sodium triacetoxyborohydride (237 mg, 1.12 mmol) was added thereto. After stirring at room temperature for 2 hours, sodium hydrogen carbonate aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 80 mg (20%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:40]=[CH:39][C:17]([C:18]([NH:20][C@@H:21]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=3)[CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])=[C:16]([F:41])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:39]=[CH:40][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:41])[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-bromo-5-fluorophenyl)ethyl)carbamate (69 mg, 0.110 mmol) in DCM (1.0 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, then dissolved in DMSO and subject to prep HPLC. Pure fraction was combined and lyophilized to yield final product as a TFA salt. LCMS (m/z): 532.1/534.1 (MH+), 0.69 min; 1H NMR (400 MHz, Methanol-d4) δ ppm 7.94-7.84 (m, 2H), 7.73 (dd, J=1.4, 8.0 Hz, 1H), 7.66 (dd, J=1.4, 11.9 Hz, 1H), 7.55 (s, 1H), 7.49-7.39 (m, 1H), 7.29 (d, J=9.4 Hz, 1H), 5.48 (t, J=7.2 Hz, 1H), 4.04 (dd, J=2.9, 11.5 Hz, 2H), 3.57 (dt, J=2.2, 11.6 Hz, 2H), 3.51-3.41 (m, 2H), 3.01-2.85 (m, 1H), 1.97-1.76 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[F:38]C1C=CC=CC=1S>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:38])=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccccc1S
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2F)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromommethyl-2-methoxybenzoate (Intermediate 89) and 2-fluorothiophenol.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:9]([NH:25][C:26]2[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=2)=[N:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH:13]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].Cl[C:91]1[N:96]=[C:95]([CH3:97])[N:94]=[C:93]([NH2:98])[N:92]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:98][C:93]1[N:94]=[C:95]([CH3:97])[N:96]=[C:91]([C:8]2[C:9]([NH:25][C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]3)[CH:13]=2)[N:92]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cnc(Nc3cccc(O)c3)c(Cl)c2)CC1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2cccc(O)c2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
1,4-Dioxane (4.00 mL, 46762 μmol) was added to a mixture of 3-(3-chloro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenol (390 mg, 983 μmol), bis(pinacolato)diboron (299 mg, 1179 μmol), X-Phos (46.8 mg, 98.3 μmol), tris(dibenzylideneacteone)dipalladium(0) (45.0 mg, 49.1 μmol) and potassium acetate (0.154 ml, 2457 μmol) and the mixture was stirred at 100° C. for 3 h. After cooling to room temperature, 4-chloro-6-methyl-1,3,5-triazin-2-amine (213 mg, 1474 μmol) and bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (61.1 mg, 98.3 μmol) was added and the mixture was resealed and continued heating at 100° C. overnight. The mixture was allowed to cool to room temperature, filtered through a short path of Celite® (diatomaceous earth), and the filter cake was washed with EtOAc (2×20 mL). The combined organic phases were concentrated with SiO2 and purified by flash column chromatography (ISCO CombiFlash® system, Teledyne ISCO, Lincoln, Nebr.), pure DCM to 10% 2 M NH3/MeOH in DCM) to give 3-(3-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenol (7 mg, 1.5%) as a yellow solid. LCMS (API-ES) m/z 471 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.98 (br. s., 1H) 9.27 (d, J=4.89 Hz, 1H) 8.59-8.78 (m, 1H) 8.26 (d, J=2.93 Hz, 1H) 7.61-7.92 (m, 1H) 7.50 (d, J=1.76 Hz, 1H) 6.81-7.26 (m, 2H) 6.24-6.50 (m, 1H) 3.49 (br. s., 2H) 3.11 (br. s., 4H) 2.87 (d, J=5.87 Hz, 3H) 2.37-2.48 (m, 7H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N+:14]([O-])=O>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH2:14]
Reactant: Cc1cccc(C2=NCCN2C)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C2=NCCN2C)c1N
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of the title compound of Step A (3.37 g, 75% pure) in ethanol (15 mL) was added palladium hydroxide (170 mg, 20 wt % on carbon). The flask was twice evacuated and flushed with nitrogen and then twice evacuated and flushed with hydrogen. The mixture was vigorously stirred under a balloon of hydrogen for 3 hours before being evacuated, exposed to air and filtered through a pad of Celite®. The solution was concentrated and filtered through a pad of silica gel, eluting with 1% then 5% then 10% methanol in dichloromethane, then 5% triethylamine, 10% methanol, 85% dichloromethane. The material eluting in triethylamine/methanol/dichloromethane was concentrated to give the title compound of Step B (1.5 g) as an off white solid.
Reaction SMILES: [CH2:1]([N:4]([CH:22]([C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:29][SiH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]([OH:27])(C)[CH:24]=C)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C(OCC=C)C=C>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.C(Cl)Cl>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:1][CH:2]=[CH:3][C:23]([CH3:24])([OH:27])[CH:22]2[C:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:29][SiH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])(=[O:6])=[O:7])=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCN(C(C(C)(O)C=C)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Ru]Cl
Agent: C=CCOCC=C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CC=CC1(C)O
Yield: 73.1 %

Procedure:
A mixture of N-allyl-4-benzyloxy-N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-2-hydroxy-2-methyl-but-3-enyl]-benzenesulfonamide (compound of formula VII, 4.0 g, 6.1 mmol), diallyl ether (0.82 ml, 0.66 g, 6.7 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (0.34 g, 0.4 mmol) and methylene chloride (116 ml) was stirred at reflux for about 3 hours. The mixture was concentrated in vacuo then purified using a Flash 40 system (silica gel cartridge, eluting with 10% ethyl acetate in hexane) to afford 2.8 g of 1-(4-benzyloxy-benzenesulfonyl)-2-(tert-butyldiphenyl-silanyloxymethyl)-3-methyl-1,2,3,6-tetrahydro-pyridin-3-ol (compound of formula VIII) as a colorless solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[CH2:13][CH2:12][CH:11](I)[C:10](=[O:15])[C:9]=1[CH3:16].S(OC)(OC)(=O)=O>C1COCC1>[CH3:1][O:15][C:10]1[C:9]([CH3:16])=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)[O-]
Reactant: CC1=C(N)CCC(I)C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COc1cccc(N)c1C
Temperature: -15 °C
Yield: 89 %

Procedure:
2.24 g (20 mmol, 2 eq) of potassium tert-butoxide is dissolved in 60 ml of anhydrous THF and the resulting solution is cooled to −15° C. with stirring. A solution of 2.51 g (10 mmol, 1 eq) of 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one in 25 ml anhydrous THF is added to the potassium tert-butoxide solution and the temperature is kept below −5° C. during addition. The cooling bath is removed after addition and the reaction is allowed to warm up to 5° C. within 1 hour. HPLC shows complete elimination. 1.20 g (9.5 mmol, 0.95 eq) of dimethyl sulfate is added to the reaction mixture with vigorous Stirring. The reaction is shown to be complete by HPLC (˜2 h). Then an HPLC weight assay indicates an 89% yield of the product. The isolation of the product was not optimized.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH2:28][CH2:29][OH:30])=[N:25][CH:26]=1.ClC1C=CC(C(F)(F)F)=CN=1.NC(O)C>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([O:30][CH2:29][CH2:28][NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:19])[F:31])=[CH:26][N:25]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: OCCNc1ccc(C(F)(F)F)cn1
Agent: CC(N)O
Agent: FC(F)(F)c1ccc(Cl)nc1
Product: FC(F)(F)c1ccc(NCCOc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
In analogy to the procedure described for Example 90, 46 mg (59% of theory) of the product are obtained starting from 50 mg (0.17 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo-[1,2-c]pyrimidine (Example 6A) by reaction with 48 mg (0.23 mmol) of 2-{[5-(trifluoro-methyl)pyridin-2-yl]amino}ethanol, which can be prepared in analogy to the synthesis of Example 48A from 2-chloro-5-(trifluoromethyl)pyridine and aminoethanol, after subsequent purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1>O1CCCC1>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Solvent: C1CCOC1
Product: Cc1nc2cc(Cl)c(N)cc2o1
Reaction time: 1.5 h

Procedure:
Compound (2), (30 g), was dissolved in tetrahydrofuran (150 mL), and Raney-Nickel which had been pre-washed with water (×3) and tetrahydrofuran (×3), was added. The mixture was then hydrogenated at room temperature and 352 kg/dm2 (50 psi) of hydrogen. The reaction is complete in approximately 1.5 hours. After this period, the catalyst is filtered off and the solution concentrated under reduced pressure. The residue is triturated with heptane, cooled and the solid filtered off. Yield 22 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:14]Br>CO>[Br:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: BrBr
Reactant: Nc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCO3 (5.2 g, 62 mmol). The reaction mixture was stirred for 30 minutes at RT then Br2 (4.9 g, 31 mmol) was added drop wise. Then the resulting reaction mixture was stirred additionally for 16 h at RT. After completion of reaction, the reaction mass concentrated under reduced pressure, crude purified by silica gel (100-200 mesh) chromatography using EtOAc/Hexane (8:2) to afford 4-Bromo-6-chloro-pyridazin-3-ylamine (2.3 g, 36%) as a solid.