Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH2:25][C@@H:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.BrC(Cl)(Cl)Cl.N12CCCC=C1CCCCN2>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1
Reactant: COC(=O)[C@@H]1COC(c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)=N1
Agent: C1=C2CCCCNN2CCC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)c1coc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Methyl (S)-2-{3-[(S)-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl]phenyl}-4,5-dihydro-1,3-oxazole-4-carboxylate (138 mg, 0.304 mmol) obtained in Step 1 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours after adding bromotrichloromethane (0.181 mL, 0.913 mmol) and diazabicyclo[5,4,0]undec-7-ene (0.137 mL, 0.913 mmol). The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give methyl (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylate (119 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH:23]([CH3:25])[CH3:24])[NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C(O)C.[Fe]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:7])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Yield: 93.5 %

Procedure:
To a solution of methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 1.9 mmol) in 85% ethanol (20 mL) was added iron powder (1.09 g, 19.6 mmol) and 2N aqueous HCl solution (1.0 mL). The resulting mixture was heated at reflux for 2 h. The mixture was then filtered through a pad of Celite® and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure to afford methyl N-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.58 g, 90%). 1H NMR (400 MHz, CD3OD) δ 1.03 (dd, 6H), 2.26 (m, 1H), 3.74 (s, 3H), 4.48 (d, 1H), 6.77 (d, 2H), 7.43 (d, 2H), 7.62 (d, 2H), 7.83 (d, 2H); LC-MS m/z 327.1 (MH+), retention time 2.27 minutes.
Reaction SMILES: [CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Methyl 2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate (0,9 g, 2.5 mmol) in THF (6 ml) and methanol (6 ml) were treated with 1N aqueous sodium hydroxide (7 ml), and stirred at ambient temperature overnight. The clear solution was evaporated to low bulk, treated with water and glacial acetic acid to pH4. The resultant white precipitate was stirred for 15 minutes, filtered, washed well with water, then sucked dry to yield the title product as a white solid (0.8 g, 92%). MS: (M+H)+ 347 (M.)+ 346
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:31])[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:21])[N:11]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[C:23]=2[F:30])=[CH:6][C:5]=1[N+:32]([O-])=O)=[N+]=[N-].O1CCCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[NH2:32][C:5]1[CH:6]=[C:7]([C:10]2([OH:31])[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:21])[N:11]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[C:23]=2[F:30])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc(N=[N+]=[N-])c([N+](=O)[O-])c2)c1F
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc(N)c(N)c2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of 3-(4-azido-3-nitrophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.50 mg, 3.20 mmol) in a mixture tetrahydrofurane-water (1:1, 30.0 mL) ammonium formate (2.0 g, 32.0 mmol) was added followed by the addition of iron (1.45 g, 26.0 mmol). The mixture was heated to reflux and stirred for 180 minutes. It was cooled to room temperature and diluted with ethyl acetate. The resulting slurry was filtered through a pad of Celite, and washed with ethyl acetate. It was partitioned with water and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an oily product. It was crystallized from diethyl ether by the addition of hexane. The product was collected by filtration, dried in vacuo, to provide 3-(3,4-diaminophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.16 g, 88% yield). 1H NMR (400 MHz, CD3OD): 7.57 (s, 1H), 7.42-7.23 (m, 3H), 7.16 (m, 2H), 6.75 (s, 1H), 6.61-6.57 (m, 1H), 3.78 (d, J=8.4 Hz, 1H); MS (EI) for C22H14F3N3O2: 408 (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[C:5]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[C:5]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a chloroform solution containing 280 mg of tert-butyl (1-(2-(7-methoxy-5-(pyridin-4-yl)-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.84 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added thereto, the resultant solution was adjusted to pH about 12 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 230 mg of a yellow oily substance, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 57 from (Z)-3-[1-(3-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:48])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:48])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 44.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.039 mmol) and sodium hydroxide (0.395 mL, 0.395 mmol) in dioxane (0.5 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and the clear solution was purified by HPLC to provide the title compound as a white solid (13 mg, 42%). LCMS: m/e 746.58 (M+H)+, 2.27 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.63-3.44 (m, 5H), 3.43-3.26 (m, 2H), 3.24-3.13 (m, 1H), 3.05 (d, J=4.3 Hz, 4H), 2.86 (br. s., 1H), 2.58-2.40 (m, 1H), 2.27-1.02 (m, 22H), 1.73 (s, 3H) 1.24 (s, 3H), 1.13 (d, J=4.5 Hz, 2H), 1.10 (s, 3H), 1.06 (s, 3H), 1.02 (d, J=4.5 Hz, 2H), 0.97 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+]>>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(=O)CCCCCCCCCCCOC1CCCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CCCCCCCCCCCOC1CCCCO1
Yield: 100 %

Procedure:
The title compound was prepared from 13-[(tetrahydro-2H-pyran-2-yl)oxy]-2-tridecanone (2.0 g, 0.006 mol), 2,6-diisopropylphenyl isocyanate (1.36 g, 0.006 mol), and lithium diisopropylamide (0.006 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 3.11 g (0.006 mol, 93%) of the desired product.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[CH3:17][S:18]([NH:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[N:27]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])(=[O:20])=[O:19]>CN(C=O)C>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:21]([CH2:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[N:27]([CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C:26]3=[O:41])[S:18]([CH3:17])(=[O:19])=[O:20])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CN(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 4-(2-chloroethyl)morpholine hydrochloride (0.195 g, 1.050 mmol), K2CO3 (0.242 g, 1.751 mmol) and tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.258 g, 0.700 mmol), (prepared in an analogous manner as described in Example 46, Scheme 46, Steps 1, 2, 3, 4), was heated to 80° C. for 5 hours in DMF (10 ml) and then stirred at room temperature overnight. The insoluble inorganic salts were filtered off and then washed with ethyl acetate. The filtrate was concentrated to dryness, and the resulting crude was purified by filtration through a silica gel cartridge (100% DCM to DCM:MeOH=98:2) to afford tert-butyl 2-(5-((N-(2-morpholinoethyl)methylsulfonamido)methyl)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.415 mmol, 59.3% yield, MS/ESI+ 482.1 [MH]+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:16][C:17](=O)[NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:2]=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:16][C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[CH:25][C:20]3=[CH:19][N:18]=2)[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)NCc1cnccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a mixture of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-oxo-4-(pyrazin-2-ylmethylamino)butyl isoquinolin-3-ylcarbamate (650 mg, 1.12 mmol) and DCM (50 mL) were added phosphoryl chloride (0.514 mL, 0.00561 mol). The resulting mixture was stirred at RT for overnight. The resulting solution was concentrated. The resulting residue was purified on prep-HPLC (ACN/H2O with 0.1% HCOOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(imidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (0.27 g, 43%). LRMS (M+H+) m/z 562.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:20]#[N:21])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Temperature: 90 °C
Yield: 67 %

Procedure:
A solution of 1B (250 mg, 0.76 mmol) and zinc cyanide (88 mg, 0.75 mmol) in DMF (2.5 mL) was bubbled with argon for 10 min, then tetrakis-(triphenylphosphine)palladium(0) (65 mg, 0.057 mmol) was added and the solution was deoxygenated. The reaction mixture was then heated at 90° C. for 4 h, cooled to RT, and partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 60%) in hexane to give the title compound (140 mg, 67% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17](C(C)C)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)=O.[CH3:35][C:36]([CH3:38])=O>C(Cl)Cl>[CH3:27][C:10]1[S:9][C:8]2[CH:1]=[C:2]3[C:3](=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:36]([CH3:38])[CH3:35])[CH:16]=4)[C:12]=2[C:11]=1[CH3:26])[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: CC(C)=O
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Product: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Reaction time: 2 h
Yield: 27 %

Procedure:
At -78° C., to a stirred solution of (2-benzyl-4,5-dimethylthiophen-3-yl)-(4-methoxy-3-isopropyl-phenyl)-methanone (6.48 g, 0.0178 mol) in CH2Cl2 (75 mL) was added dropwise boron tribromide (9.4 mL, 0.099 mol). After the addition was complete the dry ice/acetone bath was removed and the reaction was stirred for 2 h. The reaction was quenched into KH2PO4 (100 mL), extracted with CH2Cl2 and concentrated. Purification on silica gel, eluting with 5% EtOAc/pet. ether, gave 1.67 g (27%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) β 9.49 (s, 1 H), 8.42 (s, 1 H), 7.94 (d, 1 H), 7.47-7.32 (m, 3 H), 7.01 (s, 1 H), 6.93 (s, 2 H), 3.32 (m, 1 H), 2.39 (s, 3 H), 1.59 (s, 3 H), 1.19 (d, 6 H).
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[ClH:40].C(OCC)(=O)C>C(O)=O>[ClH:40].[CH2:37]([C:34]1[CH:33]=[N:32][C:31]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[N:36][CH:35]=1)[CH3:38]
Reactant: CCC(=O)Nc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(propionylamino)benzyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (100 mg) synthesized in Example 439-3 was dissolved in formic acid (2.5 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was dried by heating at 60° C. to give the title compound (98 mg) as a white amorphous solid.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Product: c1ccc(NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure A was used to convert benzophenone hydrazone (3.42 g, 20 mmol; Aldrich) and 1-bromobenzene (3.14 g, 20 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1ccc(Br)cc1
Reactant: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCSc1ccc(I)cc1
Reaction time: 16 h

Procedure:
The Grignard reagent from the product of Step 2.1 (15 g) was prepared using magnesium in tetrahydrofuran (60 ml). Iodine (16.2 g) was added over 10 min and the mixture was stirred for 16 hrs. Water was added and then 10% sodium metabisulphite (100 ml). The product was extracted into petroleum ether and distilled. Yield 10.5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:25]3[C:24]([Cl:23])=[CH:29][C:28]([Cl:30])=[CH:27][N:26]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=495.1 [M+H]+ and 497.2 [M+2+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=1.O=[CH:16][C:17](=[CH2:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].O>[CH3:19][C:17]1[CH:16]=[N:14][C:9]2[C:10]([CH:18]=1)=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH3:6]
Reactant: COc1ccccc1N
Reactant: C=C(C)C=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: O
Product: COc1cccc2cc(C)cnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
94 ml of concentrated sulfuric acid and 70 ml of water are placed in a 1 l triple-necked flask equipped with a mechanical stirrer. The mixture is cooled to 0° C. with an ice bath and the dropwise addition is carried out of 45 g (366 mmol) of ortho-anisidine, followed by 0.54 g of sodium iodide. The mixture is then heated with an oil bath to 115° C. and 50 ml (604 mmol) of methacrolein are added using a syringe driver at the rate of 25 ml/h. Heating is continued for 1 h after the addition. The mixture is cooled to ambient temperature and then thrown onto a mixture of ice and of sodium carbonate. Extraction is carried out with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 98/2) to provide 18.7 g of 3-methyl-8-methoxyquinoline. (Yield: 29.5%)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1)[CH3:9].[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1.O>CN1C(=O)CCC1.CCOC(C)=O>[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([N:25]2[CH2:24][CH2:23][NH:22][C@@H:21]([CH3:20])[CH2:26]2)=[N:14][CH:13]=1)[CH3:9]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C[C@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN[C@@H](C)C2)nc1
Yield: 52 %

Procedure:
Triethylamine (3.7 mL, 27 mmol, 5.0 eq) is added to a solution of 6-chloronicotinic acid ethyl ester (1.0 g, 5.4 mmol, 1 eq), (S)-2-methyl-piperazine (540 mg, 5.4 mmol, 1 eq) in NMP (6 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 150° C. (high absorption setting) for 30 min. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (5-60% EtOAc/Heptane, then 10% MeOH/Heptane), (700 mg, 52% yield).