Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([N:18](CC)CC)C.CN>O1CCCC1>[CH3:16][NH:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Agent: CN
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Yield: 97.5 %

Procedure:
The method described in Part A of Example 4 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) with triethylamine (8.53 mL, 61.2 mmol) and methylamine (20.41 mL of a 2 M solution in tetrahydrofuran, 40.82 mmol) to provide 9.45 g of N-methyl-2-chloro-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:11]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][NH:32][C:33]([NH2:35])=[S:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:9]1[CH:14]=[C:13]([C:15](=[N:31][NH:32][C:33]([NH2:35])=[S:34])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:11]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(c1ccccc1)c1cc(C(=O)c2ccccc2)cc(C(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccccc1)c1cc(C(=O)c2ccccc2)cc(C(=O)c2ccccc2)c1

Procedure:
To a round bottom flask containing methanol (16 mL) was added 1,3,5-tribenzoylbenzene (0.250 g, 0.640 mmol). This was stirred under nitrogen and heated to reflux. Thiosemicarbazide (0.05536 g, 0.608 mmol) was then added to the flask, followed by p-toluenesulfonic acid (0.00122 g, 0.0064 mmol). The reaction mixture was stirred at reflux for 14 h. The crude mixture was purified using column chromatography, eluting with 35% ethyl acetate in hexanes, however the product still contained impurities and was submitted for testing without further purification. HRMS (ESI) calculated for C28H21O2N3SH+ (M+H)+ 464.14272, found 464.14267. Compound 25 was estimated to be approximately 80% pure by NMR, and was submitted for biological testing without further purification.
Reaction SMILES: [C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:24].O>CCOCC>[C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][OH:24])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CNC=O
Reactant: FC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: CCOCC
Solvent: O
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of C3F7OCF2CF2CH2CH2I (300 g, 0.68 mol) and N-methyl-formamide (300 mL), was heated to 150° C. for 26 h. Then the reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (77 mL) and p-toluene sulfonic acid (2.59 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 minutes. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude product was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in turn, then dried over magnesium sulfate. The product was then distilled to give 199 g of C3F7OCF2CF2CH2CH2OH in 85% yield. The boiling point was 71˜73° C. at 40 mm Hg (5333 Pa).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=O)[OH:3].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([O:3][C@@H:2]1[CH2:4][C:5](=[O:7])[O:8][C:1]1=[O:9])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: O=C(O)C[C@@H](O)C(=O)O
Product: CC(=O)O[C@@H]1CC(=O)OC1=O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
A mixture of D-malic acid (10 g, 75 mmol, Major Chemicals Co. Ltd. lot #KS00404) in acetyl chloride (30 mL, Aldrich cat #11, 418-9) was heated to 45° C. for 6 h. The excess acetyl chloride was evaporated in vacuo and the residue was taken up in dichloromethane (10-15 mL). The volatiles were removed in vacuo and the residual oil was stored at 4° C. for 18 h. Under cold storage, the oil crystallized, giving rise to (R)-(+)-2-acetoxysuccinic anhydride (95a) as a white solid (11.7 g, quant yield); m.p. 52° C.; [α]D+23.82° (c 5.44, acetone); 1H-NMR (300 MHz, CDCl3) δ: 5.51 (dd, 1H, J 6 Hz, 9 Hz), 3.36 (dd, 1H, J 19 Hz, 9 Hz), 3.00 (dd, 1H, J 19 Hz, 6 Hz), 2.17 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 169.61 (+), 167.66 (+), 166.21 (+), 67.51 (−), 35.10 (+), 20.16 (−).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1.CCO.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe].O>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:11]=[CH:12][C:13]=2[NH2:14])[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCC(F)CC3)c2)CC1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N3CCC(F)CC3)c2)CC1
Temperature: 100 °C
Yield: 99 %

Procedure:
A solution of 1-[3-(4-fluoro-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine (as prepared in the previous step, 0.20 g, 0.62 mmol) in 2:1 EtOH:water (6 mL) was treated with solid NH4Cl (0.33 g, 6.2 mmol) and iron powder (0.17 g, 3.1 mmol) then heated to 100° C. for 2.5 h. The reaction was cooled to room temperature, treated with 1 drop of glacial acetic acid, and heated again to 100° C. for 30 min. The reaction was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The product was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.19 g, 99%), which was used immediately in the next reaction. LC-MS (ESI, m/z): Calcd. for C16H25FN4, 293.2 (M+H), found 293.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCCCNc1c(C(=O)OCC)cnc2c(N)cccc12
Yield: 78 %

Procedure:
The compound prepared in Example 3 was reacted with butylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 78%).
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17]C1C=CC=CC=1C.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:17][C:4]1[CH:3]=[CH:2][CH:15]=[CH:14][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: Cc1ccccc1CBr
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccccc1C

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 2-bromomethyltoluene (10 g), a 2M ethanolic solution of sodium ethylate (30 cc) and ethyl 2-mercaptoacetate (6.5 g), in ethanol (100 cc). Ethyl (2-methylbenzylthio)acetate (8.9 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C@H:11]1[C:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]([CH2:33][C:34]([F:37])([F:36])[F:35])[N:19]=1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[F:17][C:14]1([F:16])[CH2:15][C@@H:10]([CH2:9][OH:8])[C@H:11]([C:18]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[CH:21][N:20]([CH2:33][C:34]([F:37])([F:36])[F:35])[N:19]=2)[CH2:12][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2COCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2CO)cc1

Procedure:
A mixture of 3-{(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.15 g, 3.97 mmol) and Pearlman's catalyst (1.0 g) were stirred together in ethyl acetate (50 mL) containing acetic acid (5 mL) under an atmosphere of hydrogen at rt for 20 h. The reaction mixture was then filtered through a Celite® pad and the filtrate was washed with saturated aqueous solutions of NaHCO3 and NaCl before drying over Na2SO4. Solvent removal in vacuo yielded {(1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexyl}methanol as a faint-yellow, thick syrup. 1H NMR (400 MHz, acetone d6) δ 8.06 (1H, s), 7.96 (2H, d, J= 8.4 Hz), 7.79 (2H, d, J= 8.4 Hz), 5.08 (2H, q, J=8.8 Hz), 3.70 (1H, m), 3.47 (1H, m), 3.36 (1H, m), 3.16 (3H, s), 3.09 (1H, m), 2.38 (1H, m), 2.25 (1H, m), 2.15-1.30 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:23]([C:24]([N:26]=[C:27]=[O:28])=O)=[C:22]([F:29])[C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([F:29])[C:23]=1[C:24]1[NH:26][C:27](=[O:28])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.130 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=6.0 Hz, 2H), 7.24-7.47 (m, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 8.16 (m, 1H), 12.10 (br s, 1H); MS (m/z): 437.16 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][C:45]1([CH3:56])[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]5([CH3:56])[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and DIEA (83 mg, 0.64 mmol) in 6 mL of DMF were added EDCI (98 mg, 0.51 mmol) and DMAP (88 mg, 0.72 mmol) at room temperature. 20 minutes later, tert-butyl 3-amino-3-methylazetidine-1-carboxylate (95 mg, 0.51 mmol) was added in one portion and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylazetidine-1-carboxylate (75 mg, 76.9%) as a yellow solid. MS: (M+H)+=480.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[Cl-].[NH4+].O>C(O)(C)C>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CNc1ccccc1N

Procedure:
A mixture composed of 15.2 g (0.1 mol) of N-methyl-2-nitroaniline, 24 g of reduced iron, 0.8 g of ammonium chloride, 20 ml of water and 200 ml of isopropanol was stirred with heating at about 100° C. for 30 minutes in a 1 liter 3 necked flask. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of N-methylphenylenediamine. The compound was dissolved in 100 ml of tetrahydrofuran, to which was added 8.7 g (0.11 mol) of pyridine and to which was added dropwise 36 g (0.1 mol) of tribromoacetyl bromide under cooling with ice. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and then under heating on a steam bath for about 2 hours. The reaction solution was poured into about 500 ml of ice water and the crystals thus-deposited were collected by filtration to obtain 10.6 g of Compound (II-15). A melting point was 108° to 112° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].Cl.[OH-].[Na+]>CO.O>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of tert-butyl ethyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (0.4 g, 0.896 mmol) in methanol (10 mL) was treated with 3 N HCl (3.88 mL, 11.64 mmol) and stirred at reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and basified with 1N NaOH. The product was extracted into dichloromethane (2×25 mL). The combined organic layer was dried (Na2SO4) and concentrated. The crude material was subjected to column chromatography on silica gel (5:95 (2M NH3 in MeOH):CH2Cl2) to give a yellow solid (0.142 g, 45.8%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=0.9, 3.6 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.07 (dd, J=3.6, 4.8 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.49 (dd, J=2.1, 8.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 6.31 (brs, 2H), 3.55-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.04-3.00 (m, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.56 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); ESI-MS (m/z, %): 347 (MH+, 75%), 276 (100%); HPLC purity: 99.5% by area.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:40][CH2:39]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 3.6 g of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoro-methyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 3.7 ml of 1-methylpiperazine in 80 ml dichloromethane is stirred at 40° C. for 2 hours. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [silica gel, eluent: dichloromethane/methanol/triethylamine, elution gradient 99.7/0/0.3 (v/v/v) to 89.7/10/0.3 (v/v/v)]. The obtained product is filtered through a short plug of Flash-NH2 silica gel [eluent: dichloro-methane/methanol, 9/1 (v/v)] in a further purification step. After evaporation of the solvents, the resulting oil is treated with 5 ml diethyl ether, resulting in precipitation of the product. After filtration the title compound is obtained as white solid.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl.[CH3:37][OH:38]>>[CH3:37][O:38][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: CO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OC
Temperature: 25 °C

Procedure:
Sodium (181 mg) was dissolved in 10 ml of methanol and 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added with stirring at room temperature. The reaction mixture was stirred at room temperature for three hours and poured into a mixture of 1N hydrochloric acid and ice. The crystals separated out therefrom were collected by filtration and the resulting crystals were purified by a silica gel column chromatography (chloroform-methanol=40:1). The resulting yellow amorphous substance was crystallized in ether and collected by filtration to give 273 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [Na].[SH:2][CH:3]([CH3:5])[CH3:4].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:4][CH:3]([S:2][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]
Reactant: CC(C)S
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSC(C)C
Reaction time: 12 h

Procedure:
To sodium (4.2 g, 0.18 mol) in ethanol (100 mL) was added 2mercaptopropane (20 mL), 0.21 mol) followed by ethyl bromoacetate (10 mL, 0.090 mol). The mixture was stirred for 12 hours, concentrated, partitioned between ether and water and washed with water. The organic phase was dried over MgSO4, evaporated and distilled to afford the desired product. B.P. 58°-62° C. (1 mm).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (24.4 g, 0.14 mol) in 200 mL DMF was added morpholine (25.7 mL, 0.28 mol), followed by the addition of K2CO3 (23.6 g, 0.17 mol). The mixture was stirred at room temperature for 48 h. The mixture was poured into 0.7 L H2O and the precipitate was collected by filtration. The precipitate was further rinsed with 0.5 L H2O. The resulting solid was air dried by purging with a flow of air for 24 h, thus affording 29.3 g of 4-(3-methoxy-4-nitrophenyl)morpholine (0.12 mol, 86%).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([C:34]([C:36]3[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)=[O:35])[CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si](C(C)C)(C(C)C)C(C)C)[CH:14]=2)=CC=1.B(F)(F)F.CCOC(C)=O.C([O-])(O)=O.[Na+]>CSC>[OH:8][C:9]1[CH:10]=[C:11]([C:34]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[O:35])[CH:12]=[C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][NH:19]3)[CH:14]=1
Reactant: COc1ccc(COc2cc(C(=O)c3ccc(OC)nc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Product: COc1ccc(C(=O)c2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To compound [3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-(6-methoxy-pyridin-3-yl)-methanone in dimethylsulfide (2 mL) at 0° C. was added excess BF3 etherate. The resulting reaction mixture was stirred at 0° C. for 20 min. TLC indicated that the disappearance of the starting material. EtOAc was added to dilute the reaction mixture and sat. NaHCO3 was added to adjust the pH of the aqueous phase to 6-7. The aqueous phase was then extracted with EtOAc three times. The combined organic phases were dried over Na2SO4 and concentrated. The crude product was again dissolved in THF (1 mL) and treated with TBAF (1M in THF, 1 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature. At the end of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water three times. The organic phase was then dried and concentrated to afford the crude product which was further purified by preparative SFC to afford [3-hydroxy-5-(1H-indol-4-yl)-phenyl]-(6-methoxy-pyridin-3-yl)-methanone (29 mg, 75%). 1H NMR (400 MHz, CD3OD): δ 8.57 (d, J=2.3 Hz, 1H), 8.04 (dd, J=8.6, 2.3 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.36-7.30 (m, 2H), 7.17 (d, J=3.1 Hz, 1H), 7.12-7.08 (m, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:27][O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>O1CCCC1>[CH3:27][O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 3.56 g. of 3-benzoylpropionic acid and 3.24 g. of N,N-carbonyldiimidazole in 30 ml. of tetrahydrofuran is stirred at room temperature for 30 minutes. A 3.32 g. portion of L-proline methyl ester hydrochloride is added and the mixture is stirred at room temperature for 2.5 days. The solvent is removed in vacuo. Water and dichloromethane are added to the residue and the organic layer is separated, washed with water, then with 0.1 N hydrochloric acid and dried over magnesium sulfate. The solvent is removed in vacuo, giving 5.0 g. of the desired product as off-white crystals, m.p. 66°-70° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:25]>CO.O1CCOCC1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:25]
Reactant: COC(=O)CNC(=O)[C@H](CSCNC(C)=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CNC(=O)[C@@H](N)CSCNC(C)=O
Reaction time: 0.17 h

Procedure:
5 g of Boc-Cys(Acm)-Gly-OMe are dissolved in 20 ml of methanol and 50 ml of 4.4 N HCl in dioxane are added. After 10 minutes at 25°C, the mixture is concentrated to half its volume and 100 ml of ether are added. The mother liquor is separated from the resulting amorphous precipitate and the latter is dried.