Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 40, 0.427 g, 0.81 mmol) following the procedure described for Intermediate 21. The desired product was obtained as yellow foam (0.247 g, 71%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH:12](B1OC(C)(C)C(C)(C)O1)=[CH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CC1CCCO1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:12]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1)=[CH2:13]
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CC1CCCO1
Product: C=Cc1ccc([N+](=O)[O-])c(C)n1
Yield: 116.3 %

Procedure:
A suspension/solution of 6-bromo-2-methyl-3-nitropyridine (500 mg, 2.304 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.782 mL, 4.61 mmol), palladium(II) acetate (25.9 mg, 0.115 mmol), X-phos (110 mg, 0.230 mmol) and cesium carbonate (3.0 g, 9.22 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (8 mL) and water (2 mL) was stirred under nitrogen at 60° C. for 1 hour. The reaction mixture was cooled then separated between ethyl acetate and water. The organic phase was washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in DCM (5 mL). This was applied to a silica cartridge and eluted with a gradient of 0-100% ethyl acetate in cyclohexane. This gave the crude product (440 mg) as a brown liquid which was used directly in the next step with no further purification. LCMS (2 min, formic) Rt 0.91 min, m/z (ES+) 165 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[N:42]1([CH2:47][S:48][C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)[CH:46]=[CH:45][CH:44]=[N:43]1>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([S:48][CH2:47][N:42]5[CH:46]=[CH:45][CH:44]=[N:43]5)=[CH:50][CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(SCn2cccn2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCn4cccn4)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[(pyrazol-1-ylmethyl)sulfanyl]aniline (427 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 15 minutes at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(pyrazol-1-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (384 mg) (Compound 330) as yellow amorphous.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][CH:19]=[O:20])[CH3:2].[CH3:21][Mg]Br.CCOCC>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH2:18][CH:19]([OH:20])[CH3:21])[CH3:2]
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(C)O
Temperature: 0 °C
Yield: 70 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetaldehyde (0.253 g, 0.840 mmol), is dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. with stirring under nitrogen. Methylmagnesium bromide, 3.0M in ether, (0.300 mL, 1.00 mmol) is added and the ice bath removed. After slowly warming to room temperature, the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is quenched with saturated ammonium chloride solution and diluted with ether. The two phases are separated and the organic washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The 1-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-2-ol (0.222 g, 0.7049 mmol) is formed in 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][N:23]1[C:31]3[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24]1)[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCCCl)c1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2CCCn2ccc3cc([N+](=O)[O-])ccc32)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To 926 mg of 5-methoxyindole was added 30 ml of dimethylformamide and 230 mg of sodium hydride (in oil), this mixture was stirred under nitrogen gas stream at 60° C. for 1 hour. Then 1.5 g of 1-(3-chloropropyl)-5-nitroindole was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was further stirred at 60° C. for 5.5 hours, then water was added thereto, and the crystals being separated were collected by filtration, and washed with water. The washed crystals were subjected to a silica gel column chromatography (eluent: dichloromethane), there was obtained 1.8 g of 1-[3-(5-methoxyindol-1-yl)propyl]-5-nitroindole as in the form of yellow powdery product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].ClC1[N:14]=[C:13]2[CH:15]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17]C2=CC=1>CO>[O:1]=[C:5]1[NH:14][C:13]2[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:2]=2[CH:3]=[CH:4]1
Reactant: COC(=O)C1CCc2ccc(Cl)nc21
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2ccc(=O)[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a 15 mL mixture of tetrahydrofuran, methanol, and a 1.0 N aqueous LiOH solution in a 3:1:1 ratio was added 0.242 g (1.14 mmol) of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate from Step C above. The resulting mixture was stirred at ambient temperature for 1 h. The solution was evaporated in vacuo and the resulting light brown residue was purified by reverse phase HPLC (YMC Pack Pro C18, 100×20 mm I.D. column, 0-60% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in water gradient) to give the title compound as a brown oil (184 mg, 90%). LC-MS: m/z (E/S) 180.0 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(OCC)(=O)C>O1CCCC1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:11]([N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[C:7]=2[CH:8]=[CH:9]1)=[O:12]
Reactant: Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To an ice-cooled solution of (4-amino-1H-pyrrolo[3,2-c]pyridin-1-yl)(2,6-dichlorophenyl)methanone (50 mg, 0.16 mmol) and triethylamine (0.05 ml, 0.32 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (0.01 ml, 0.15 mmol) drop wise and stirred at room temperature for about 1 hour. Ethyl acetate was added and washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was taken up in methanol (5 mL), potassium carbonate (50 mg) was added and stirred for 10 minutes. The solvent was removed on a rotary evaporator at 20° C. and the residue was dissolved in dichloromethane, washed with water and brine, dried and concentrated to afford the crude product. Purification by silica gel column chromatography using ethyl acetate and dichloromethane gradient as eluent yielded N-[1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]acetamide (45 mg, 81%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C1COCC1.CO>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9](=[O:18])[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:11])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: O=C(C(=O)c1ccc(CBr)cc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C(=O)c1ccc(CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1)c1ccccc1

Procedure:
A mixture of 1-[4-(bromomethyl)phenyl]-2-phenylethane-1,2-dione (6.06 g, 20.0 mmol), 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (4.56 g, 21.0 mmol), PS-DIEA (20 g, 74 mmol), and TEA (50 mg, 0.5 mmol) was stirred overnight at rt in THF-MeOH (1:1, 300 mL). After this time, the resin (PS-DIEA) was filtered and washed with MeOH (2×100 mL). The combined solution was concentrated to afford the desired product. This product is pure enough (by LCMS) for next step reaction. Analytical LCMS: single peak (ELSD), 2.483 min.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[CH:11][C:3]=12.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[CH:11][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2cnn(-c3ccccc3)c2n1
Product: Cc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Temperature: 92.5 °C
Yield: 89 %

Procedure:
A suspension of 4-hydroxy-6-methyl-1-phenyl-pyrazolo-[3,4-d]pyrimidine (350 mg, 1.55 mmol) (Ind. J. Chem. 31B, 163, 1992) in phosphorus oxychloride (10 mL) was heated under to 90-95° C. for 9 h. The mixture was cooled to rt and concentrated. The residue was slowly poured into crushed ice. The precipitated solid was filtered, washed with water, and dried in air to obtain 4-chloro-6-methyl-1-phenyl-pyrazolo-[3,4-d]pyrimidine (compound 3B, 335 mg, 89%) as an off-white solid. HPLC Retention time=3.70 min.; LC/MS (M+H)+=245.13.
Reaction SMILES: [F:1][C@@H:2]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@@H:4]([O:5]C)[C@@H:3]1[OH:13]>Cl.O>[F:1][C@@H:2]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][CH:4]([OH:5])[C@@H:3]1[OH:13]
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@@H](F)[C@H]1O
Agent: Cl
Solvent: O
Product: OC[C@H]1OC(O)[C@H](O)[C@H](F)[C@@H]1O
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Methyl 3-deoxy-3-fluoro-β-D-allopyranoside (24.5 g) [compound (1); this compound is described in "J. Org. Chem.", 48, pp. 4734-4743 (1983) by Peter J. Card et al.] was dissolved in 6M hydrochloric acid (500 ml) and the solution was allowed to stand at 70° C. for 8 hours (for hydrolysis reaction). The resulting reaction solution was concentrated and the syrup so obtained was dissolved in water (400 ml). The solution was neutralized with addition of ion-exchange resin, Dowex 1×2(OH- form) (100-200 mesh) (apparently 800 ml), then filtered and the filtrate was concentrated to afford the titled compound (2) (22.1 g) as a colorless syrup. Yield: 97%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].C(#N)C.C1C(=O)N([Cl:31])C(=O)C1>CCOC(C)=O>[Cl:31][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(Cl)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 49 %

Procedure:
The procedure of Nickson, T. E. et al. (Synthesis 1985, 669-670) was used. 3-Nitro-2′-trifluoromethyl-biphenyl-4-ylamine (12.7 g, 45.0 mmol, as prepared in the previous step) was placed in a 250 mL round-bottom flask equipped with a magnetic stir bar and a reflux condenser, and dry acetonitrile (150 mL) was added. The solid was allowed to dissolve, and NCS (1.5 eq., 9.02 g, 67.5 mmol) was added as a solid. The reaction was heated at 80° C. for 3 days. The reaction was cooled to RT, diluted with EtOAc, then washed twice with water (20 mL) and once with brine (30 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was chromatographed on an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 6.96 g (49%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.10 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.57-7.62 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.44-7.54 (m, 1H), 7.32 (d, J=7.3 Hz, 1H), 6.64 (br. s., 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2>Cl.O.[Pt](=O)=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ccccc2cn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Product: COc1cc2c(cn1)CCCC2
Reaction time: 5 h
Yield: 73.1 %

Procedure:
A mixture of 3-methoxyisoquinoline (800 mg, 5.03 mmol) and platinum dioxide (100 mg) in concentrated hydrochloric acid (10 ml) was shaken under an atmosphere of hydrogen at 40 psi for 5 h. The mixture was diluted with water, filtered through Celite™, basified with sodium hydroxide then extracted four times with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated to afford the title compound (600 mg) as a clear oil, MS (ES+) 164 (MH+). δH (CDCl3) 7.85 (1H, s), 6.43 (1H, s), 3.87 (3H, s), 2.65 (4H, m) and 1.75 (4H, m).
Reaction SMILES: C(OC([N:8]=[C:9]([NH:41]C(OC(C)(C)C)=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:13][CH2:12]1)=O)(C)(C)C.[ClH:49]>C(OCC)(=O)C>[ClH:49].[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:18]=1[NH:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:9]([NH2:41])=[NH:8])[CH2:12][CH2:13]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC(=N)N)CC2)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-{trans-4-[2,3-bis(tert-butoxycarbonyl)guanidino]cyclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg) in ethyl acetate (4 mL) was added 4N-hydrochloric acid in ethyl acetate (8 mL). The mixture was stirred for 15 hours at ambient temperature. After evaporation of the solvent, the residue was triturated with ethyl acetate to give N-(3,4-dimethoxybenzyl)-2-(trans-4-guanidinocyclohexylamino)-5-nitrobenzamide hydrochloride as yellow powders (145 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.C(OCC)(=O)C>CN(C=O)C.O>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(F)c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
In a 50 mL 3-neck RBF equipped with reflux condenser, magnetic stirrer and thermo pocket were charged 2-fluoro-5-nitrophenol (2.4 g), K2CO3 (3.16 g) and dry DMF (20 mL). The reaction mixture was heated at 50° C. for 30 min. followed by addition of benzyl bromide (2.87 g) in DMF and the reaction mixture was heated to 80° C. for 18 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. The reaction was complete after 30 minutes. After completion, the reaction mixture was poured into cold water. The solid precipitate was filtered and washed with water and dried under reduced pressure at 45° C. to give 3.20 g of 2-(benzyloxy)-1-fluoro-4-nitrobenzene. 1H NMR: DMSO-d6 (400 MHz): 5.35 (s, 2H), 7.358-7.397 (m, 1H), 7.415-7.454 (m, 2H), 7.448-7.530 (m, 2H), 7.553-7.579 (m, 1H), 7.900-7.939 (m, 1H), 8.091-8.116 (dd, 1H, J=2.8, 4.4).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](OS(C(F)(F)F)(=O)=O)[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]=12.C([O-])([O-])=O.[K+].[K+].[CH2:30]([SH:32])[CH3:31]>CN(C=O)C.O>[CH2:30]([S:32][C:6]1[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]2=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:31]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2sccc2c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(SCC)nc2sccc2c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a solution of ethyl 4-methyl-6-(trifluoro-methyl-sulfonyloxy)thieno[2,3-b]pyridine-5-carboxylate (1.84 g, 4.9 mmol, 1 eq.) in DMF (30 ml) were added K2CO3 (2.70 g, 19.6 mmol, 4 eq.) and ethanethiol (3.73 ml, 49.8 mmol, 10 eq.) at RT. The reaction mixture was stirred at 80° C. for 2 h. Afterwards the mixture was diluted with water (50 ml) and was extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over Na2SO4 and evaporated. The crude product was purified by CC (EtOAc/hexane 1:49) to yield ethyl 6-(ethylthio)-4-methylthieno[2,3-b]pyridine-5-carboxylate (0.26 g, 0.92 mmol, 19%).
Reaction SMILES: [Na].[CH3:2][C:3]1[O:4][C:5](=O)[C:6](=[CH:8][OH:9])[N:7]=1.Cl.[CH3:12][O:13][C:14](=[NH:16])[NH2:15]>C(#N)C>[CH3:12][O:13][C:14]1[NH:16][C:8](=[O:9])[C:6]([NH:7][C:3](=[O:4])[CH3:2])=[CH:5][N:15]=1
Reactant: COC(=N)N
Reactant: CC1=NC(=CO)C(=O)O1
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: COc1ncc(NC(C)=O)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
Acetonitrile (20 ml) was added to 2-methyl-4-hydroxymethylene-5-oxazolone sodium salt (1.00 g, 6.71 mmol) and O-methylisourea hydrochloride (0.74 g, 6.71 mmol), and the mixture was stirred at 80° C. for 2 days. The mixture was concentrated, and methanol (5 ml) and water (3 ml) were added. The mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-acetylamino-1,6-dihydropyrimidine (0.91 g, 4.97 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)c(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(-c4nnn[nH]4)s3)CC2)c(Cl)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 3,4-dichloro-N-[1-(5-cyano-1,3-thiazol-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 321, 0.100 g, 0.26 mmol) in DMF (3 ml) was added sodium azide (0.169 g, 2.60 mmol) followed by the addition of ammonium chloride (0.139 g, 2.60 mmol) at room temperature. The reaction was stirred at 120° C. for 3 hrs. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) (0.025 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[NH:21][N:20]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:16][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[C:19]([C:18]([F:17])([F:29])[F:28])=[N:20]2)=[CH:3][CH:4]=1)[C:9](=[O:10])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(C(=O)N1CCCC1)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C(=O)N1CCCC1)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 190 °C
Reaction time: 1.5 h
Yield: 4.1 %

Procedure:
A mixture of 1-[2-(4-bromophenyl)propanoyl]pyrrolidine (140 mg, 0.5 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (95 mg, 0.5 mmol), copper (I) iodide (10 mol %, 10 mg, 0.05 mmol), N,N-dimethylglycine (20 mol %, 10 mg, 0.1 mmol) and potassium carbonate (138 mg, 1 mmol) in dimethylsulfoxide (2 ml) was stirred at 190° C. in a microwave reactor for a total of 1.5 h. The reaction mix was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure. The resulting product was purified firstly by adding the material in dichloromethane to a 5 g pre-packed silica column and eluting with ethyl acetate, followed by mass directed auto-prep to give a crop of the title compound as a brown oil (8 mg, 4%).