Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]COC)=[N:11][C:12]([O:16][CH3:17])=[CH:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.Cl.[OH-].[OH-].[Pd+2]>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]1[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]=[C:12]([O:16][CH3:17])[N:11]=1
Reactant: COCOCCCCCCCCCCc1nc(OC)cc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(O)c(CCCCCCCCCCO)n1

Procedure:
To a stirred solution containing 18 mg (0.04 mmol) of 3-(benzyloxy)-6-methoxy-2-(10-(methoxymethoxy)decyl)-4-methylpyridine in 3 mL of methanol were added two drops of concentrated HCl. The reaction mixture was stirred at reflux for 16 h. To the mixture were added 3 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/N). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (5×1 cm). Elution with 3:1 hexanes-ethyl acetate afforded the expected product as white solid: yield 8 mg (67%); mp: 80-81° C.; silica gel TLC Rf 0.50 (3:1 hexanes-ethyl acetate); 1H NMR (methanol-d4) δ 1.27 (br s, 12H), 1.49 (br s, 2H), 1.64 (br s, 2H), 2.41 (br s, 3H), 2.81 (br s, 2H), 3.51 (br s, 3H), 4.02 (br s, 1H) and 7.05 (br s, 1H); 13C NMR (methanol-d4) δ 16.59, 25.51, 28.13, 28.57, 28.92, 28.97, 29.09, 29.14, 29.24, 32.22, 56.39, 61.56, 107.60, 142.26, 145.27, 148.68 and 155.10; mass spectrum (APCI+), m/z 296.2220 (M+H) (C17H30NO3 requires 296.2226).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 101 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel, heptane/EtOAc 7:3) to yield 118 mg (79%) product as a light yellow viscous oil. MS (ISP) 497.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[O:28][CH3:29]>>[CH3:29][O:28][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: COc1ncnc2ccc(Br)cc12
Product: COc1ncnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the minor product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.21 (m, 4H) 2.90-2.97 (m, 1H) 3.09-3.30 (m, 4H) 4.23 (s, 3H) 4.35 (s, 2H) 7.08-7.13 (m, 3H) 7.41-7.47 (m, 1H) 7.89 (dd, J=9, 2 Hz, 1H) 8.10 (d, J=9 Hz, 1H) 8.14 (d, J=2 Hz, 1H) 8.85 (s, 1H); MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1.C(O)=O>C(N(CC)CC)C.[Pd]>[NH2:13][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([NH:8][CH3:9])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CNc1cccc(N)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
59.5 mg of palladium at a concentration of 10% on charcoal are added to 0.014 mole (2.8 g) of 4-chloro-2-amino-6-methylaminonitrobenzene in 5.3 ml of triethylamine, and 1.16 ml of formic acid are then run in dropwise. A high exothermicity is noted. The reaction mixture is heated to 80° C. for 40 minutes. After dilution of the reaction mixture with ethanol, the catalyst is removed by hot filtration. The filtrate, evaporated under reduced pressure, enables a dry extract to be obtained. After dilution of the dry extract with water, the expected product precipitates. After being filtered off and washed with water, the precipitate is dried under vacuum in the presence of phosphorus pentoxide. After two recrystallizations from isopropanol in order to remove a gum, the product melts at 70° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C:32]([NH2:31])=[O:33])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(N)=O)CC2)c(C)c1
Yield: 72.8 %

Procedure:
(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (145 mg, 0.41 mmol) was dissolved in i-PrOH (4 mL) and treated with trimethylsilylisocyanate (78 μL, 0.58 mmol) at room temperature for 16 hours. The solution was then concentrated under reduced pressure and dried in vacuo. The crude material was purified by column chromatography with silica gel (15:1:0.1 CH2Cl2/MeOH/NH4OH) to give COMPOUND 301 as a colorless oil (118 mg, 73%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.6 Hz), 1.66 (q, 2H, J=11.1 Hz), 1.89 (br d, 2H, J=12.3 Hz), 2.17 (s, 3H), 2.28 (s, 3H), 2.68 (br t, 3H, J=12.3 Hz), 2.82 (sept, 1H, J=6.6 Hz), 3.77 (s, 2H), 3.83 (s, 2H), 4.00 (br d, 2H, J=12.6 Hz), 4.45 (br, 2H(NH2)), 7.15 (m, 1H), 7.24 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 8.19 (s, 1H), 8.32 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 17.91, 18.07, 23.21 (2C), 26.93 (2C), 27.00, 44.49 (2C), 53.97 (2C), 56.89, 122.79, 131.89, 132.84, 133.47, 138.68, 144.03, 145.03, 146.26, 154.10, 155.91, 157.78. ES-MS m/z 396 (M+H). Anal. Calcd. for C23H33N5O.0.8CH2Cl2: C, 67.39; H, 8.51; N, 17.08. Found: C, 67.33; H, 8.23; N, 17.27.
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40].O.C(OCC)(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:39]([N:7]1[CH2:8][C:9]2[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])[C:17]([O:29][CH3:30])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:31]=2[C:32](=[O:33])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Reaction time: 0.5 h

Procedure:
To 32 mg of 10q in 200 μl of pyridine 30 μl of acetic anhydride and 1 mg of DMAP were added. The mixture was stirred for ½ hr, then water and ethyl acetate were added and stirring was continued for ½ hr at RT. The product was extracted into ethyl acetate and washed twice with water, dried, concentrated and the residues were treated with diethyl ether to provide 25 mg of 10r, as white crystalline material. Mp: 178-180° C. Rf 0.15 (heptane/acetone 1/1). NMR (CDCl3) δ 1.33 (bm, 6, N-isoC3H7), 1.90+1.94 (2×s, 6, 2×CH3-pyrrazole), 2.00 (s, 3, N—CH3), 3.70 (s, 3, NCH3), 3.80 (s, 3, OCH3), 4.65 (m, 1, CH isoC3H7), 6.79 and 6.89 (2×s, 2, ArH), 6.93, 7.08 and 7.36 (3×m, 3, thiophene).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Product: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12

Procedure:
161 g of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.06 mol) are heated with stirring in 1 liter of phosphorus oxychloride at 80° for 48 hours. The mixture is decomposed by pouring onto crushed ice. The 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is filtered off and recrystallized from butyl alcohol, yield 148 g (86%); m.p. 179°-180°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:18][C:19]=1[Cl:20].FC(F)(F)C([O-])=O.[NH2:33][C@@H:34]1[C:41](=[O:42])[N:40]2[C@@H:35]1[S:36][CH2:37][C:38](/[CH:46]=[C:47]1/[C:48](=[O:71])[N:49]([CH2:52][C:53]3[CH:58]=[CH:57][N+:56]([CH2:59][C:60](=[O:70])[NH:61][C:62]4[CH:67]=[CH:66][C:65]([OH:68])=[C:64]([F:69])[CH:63]=4)=[CH:55][CH:54]=3)[CH2:50][CH2:51]/1)=[C:39]2[C:43]([OH:45])=[O:44]>CN(C)C(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][CH2:22][C:23]([NH:33][C@@H:34]2[C:41](=[O:42])[N:40]3[C@@H:35]2[S:36][CH2:37][C:38](/[CH:46]=[C:47]2/[C:48](=[O:71])[N:49]([CH2:52][C:53]4[CH:54]=[CH:55][N+:56]([CH2:59][C:60](=[O:70])[NH:61][C:62]5[CH:67]=[CH:66][C:65]([OH:68])=[C:64]([F:69])[CH:63]=5)=[CH:57][CH:58]=4)[CH2:50][CH2:51]/2)=[C:39]3[C:43]([O-:45])=[O:44])=[O:25])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)CSc1ccc(Cl)c(Cl)c1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccc(Cl)c(Cl)c5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 60.0 mg (0.36 mmol) 1,1′-carbonyldiimidazole, 85.0 mg (0.36 mmol) [(3,4-dichlorophenyl)thio]acetic acid and 200.0 mg (0.30 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2 .0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:38][CH:39]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)c1

Procedure:
Intermediate 4 was coupled with 4-(2-Amino-ethyl)-benzenesulfonamide following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 519. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.0 (m, 2H) 7.8 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 2H) 4.3 (s, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:39])[CH2:7][CH:6]([CH2:8][NH:9][C:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:11]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl>>[F:39][C:2]1([F:1])[CH2:3][NH:4][CH2:5][CH:6]([CH2:8][NH:9][C:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:24][CH:25]=3)[N:11]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)CC(F)(F)C1
Agent: Cl
Product: FC1(F)CNCC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
tert-Butyl 3,3-difluoro-5-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate from step A (227 mg, 0.42 mmol) was treated with HCl solution (in EtOAc, 5 N) at room temperature until the reaction was finished. The volatiles were removed under reduced pressure, dissolved in dichloromethane (5 mL), and neutralized with ammonium hydroxide. The dichloromethane phase was concentrated to afford N-((5,5-difluoropiperidin-3-yl)methyl)-7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-amine. MS (m/z): 441 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH2:29]([OH:31])C>O>[F:17][C:12]1[CH:13]=[C:14]([O:31][CH3:29])[CH:15]=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:11]=1[NH2:18]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: CCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(F)c(N)c(Nc2ccc(I)cc2F)c1
Temperature: 70 °C

Procedure:
A suspension of 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (Intermediate 17, 550 mg, 1.35 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution was added dropwise a freshly prepared solution of Na2S2O4 (707 mg, 4.0 mmol) in water (2 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated and residue dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield 3-fluoro-N1-(2-fluoro-4-iodophenyl)-5-methoxybenzene-1,2-diamine (448 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (3H, s), 6.43-6.50 (2H, m), 6.56-6.61 (1H, m), 7.26-7.27 (1H, m), 7.37 (1H, d, J=10.0).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[C:26]([O:30][NH2:31])([CH3:29])([CH3:28])[CH3:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:31][O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)ON
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 200 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 10 and 199 mg of O-(tert-butyl)hydroxylamine hydrochloride in 2.6 ml of ethanol, 167 mg of pyridine was added, and the mixture was stirred at 70° C. for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 2 ml of water and extracted with ethyl acetate (2 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 207 mg of the desired product as a colorless resinous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([N:35]([CH3:34])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)Cc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylbenzylamine. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:18][CH2:17]2)=[O:15])[CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[O:15])[CH2:10][C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
To a solution of (3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-4-oxobutanoic acid (Step 6) (0.63 g, 0.97 mmol), tert-butyl piperazinecarboxylate (0.272 g, 1.46 mmol), HOBt (0.131 g, 0.97 mmol) and TEA (0.135 mL, 0.97 mmol) in 10 mL of CH2Cl2 at 0° C. was added EDC (0.28 g, 1.46 mmol). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd. NaHCO3, and extracted with 50 mL of EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude compound was further purified by silica gel column chromatography (EtOAc) to afford tert-butyl 4-[(3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]-phenyl}piperazinyl)-4-oxobutanoyl]piperazinecarboxylate as a white foam (0.3 g). MS (ESI, pos. ion) m/z: 702.5 (M+1). Calc'd for C35H48ClN5O6S: 701.30. Anal. Calcd for C35H48ClN5O6S 0.5H2O: C, 59.10; H, 6.94; N, 9.85; Cl, 4.98. Found: C, 59.32; H, 6.94; N, 9.81; Cl, 5.17.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]Cl.CN(C=O)C.C(Cl)(C(Cl)=O)=O.OC1C=[C:19]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:20]2[C:25]([CH3:26])=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[C:21]=2[N:22]=1>O>[Cl:1][C:2]1[CH:3]=[C:19]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:20]2[C:25]([CH3:26])=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:33]=3)[C:21]=2[N:22]=1
Reactant: CCOC(=O)c1cc(O)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: ClCCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(see, e.g., Sercel, A. D., et al., Synthetic Communications 2007, 37, 4199-4208). Fresh Vilsmeier's reagent was prepared as follows: to a stirring solution of 1.2 DCE (4 mL) was added DMF (0.2 mL, 2.6 mmol). The resulting solution was cooled down to 0° C. and (COCl)2 (0.22 mL, 2.6 mmol) was added dropwise. The viscous suspension was stirred at room temperature for 10 min, and then 49 (104 mg, 0.26 mmol) was added to the mixture. The suspension was heated to reflux overnight. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL×2). The organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to provide the title compound (120 mg, quantitative yield) as a yellow oil. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.31 (t, J=8.2 Hz, 4H), 7.08 (t, J=7.4 Hz, 1H), 6.97 (d, J=7.7 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 5.59 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 1.46 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.34, 157.00, 156.91, 151.20, 150.30, 141.77, 135.67, 131.25, 129.71, 129.54, 123.37, 119.00, 118.78, 117.69, 110.41, 62.31, 50.03, 16.16, 14.20.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC1C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:19][CH:32]=[N:31][CH:30]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 85 °C

Procedure:
To 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid (230 mg, 0.881 mmol) and TosMIC (172 mg, 0.881 mmol) in DME (8.0 mL) was added DBU (0.29 mL, 1.9 mmol). The mixture was heated to 85° C. for 2.5 hours in a sealed tube. After concentrated, the residue was diluted with saturated sodium carbonate and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and the resulting solid was filtered and dried to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid as a beige solid. MS m/z=301 [M+1]+. Calc'd for C15H9FN2O4: 300.25.
Reaction SMILES: [CH2:1]([N:6]([CH2:10][CH:11]=[CH2:12])C(=O)C)/[CH:2]=[CH:3]/[CH:4]=[CH2:5]>C1(C)C(C)=CC=CC=1>[CH:11]12[CH2:10][NH:6][CH2:1][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:12]2
Reactant: C=C/C=C/CN(CC=C)C(C)=O
Solvent: Cc1ccccc1C
Product: C1=CC2CNCC2CC1

Procedure:
Dissolve 33.1 g (0.2 mol) of N-[(E)-2,4-pentadienyl]-N-(2-propenyl)-acetamide (title compound from Example A.3.) in 200 ml of xylene, introduce a vigorous stream of nitrogen for 15 min, add 0.1 g of 4-hydroxyanisole, then heat to reflux overnight and distil in a high vacuum.