Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[N:21]=[C:20](F)[CH:19]=[CH:18][CH:17]=1)([C:9]1[N:14]=[C:13](F)[CH:12]=[CH:11][CH:10]=1)[CH3:8].[CH:23]1[CH:28]=[CH:27][C:26]([P-:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[K+].[Cl-].[NH4+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[N:21]=[C:20]([P:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:26]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=1)([C:9]1[N:14]=[C:13]([P:29]([C:26]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: CC(c1ccccn1)(c1cccc(F)n1)c1cccc(F)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)(c1cccc(P(c2ccccc2)c2ccccc2)n1)c1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: -60 °C
Reaction time: 72 h
Yield: 132.3 %

Procedure:
14.0 g (48.0 mmol) of 6,6′-(1-(pyridin-2-yl)ethane-1,1-diyl)bis(2-fluoropyridin) were dissolved in 300 ml of tetrahydrofurane and cooled to −60° C. 200 ml (100 mmol) of potassium diphenylphosphide (0.5 M solution in tetrahydrofurane) were added and the mixture was stirred for three days at room temperature. The reaction was hydrolysed with 200 ml of saturated ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed two times with saturated ammonium chloride solution and dried with sodium sulphate. The solvent was removed under reduced pressure to yield 40 g (>100%) of crude product which was used in the next synthesis without further purification.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:6]([OH:8])=[O:7].BrC1C=CC([C:22](OC)=[O:23])=C(OC)C=1>>[CH3:22][O:23][C:4]1[CH:3]=[C:11]([C:12]2[CH:16]=[N:15][NH:14][CH:13]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-c1cn[nH]c1
Reactant: COC(=O)c1ccc(Br)cc1OC
Product: COc1cc(-c2cn[nH]c2)ccc1C(=O)O

Procedure:
Intermediate 2 was synthesized by following a similar route to Intermediate 1 using methyl 4-bromo-2-methoxybenzoate in step 1A. LCMS (ESI) m/z: 219.1 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.O>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium azide was added to a solution of 4-benzyl-1-(3-p-toluenesulfonyloxypropyl)piperidine (0.216 g, 0.56 mmol) in DMF (5 mL). The resulting solution was stirred at 80° C. for 3 h then cooled at 25° C., diluted with water (50 mL) and extracted with diethyl ether (2×50 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum to afford crude title compound as an oil (0.15 g). 1H-NMR (CDCl3): 1.2-1.4 (m, 2H), 1.4-1.6 (m, 1H) 1.628 (dd, J=13.2 Hz, 2H), 1. 761 (t, J=7.2 Hz, 2H), 1.857 (t, J=11.4 Hz, 2H), 2.367 (t, J=7.2 Hz, 2H), 2.53 (d, J=7.2 Hz, 2H), 2.86 (bd, J=11.4, 2H), 3.314 (t, J=6.9 Hz, 2H), 7.14 (d, J=7.5 Hz, 2H), 7.19 (d, J=6.9, 1H), 7.275 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].C(N(CC)CC)C.O>O1CCOCC1>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.1 %

Procedure:
To a stirred solution of neopentylamine (0.86 g ml, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from ethyl acetate/hexane to yield 3-nitro-N-(2,2-dimethyl-propyl)-benzenesulfonamide (2.14 g, 87%) as a white solid. MS (ISP) 271.1 [(M−H)−]; mp 117° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[CH:11]=2)[CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH2:33].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH:33][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[CH:11]=2)[CH:3]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Temperature: 140 °C
Yield: 13.2 %

Procedure:
A mixture of N-[6-(6-chloro-2-methoxy-pyrimidin-4-yl)-benzothiazol-2-yl]-acetamide (160 mg, 0.48 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (362 μL, 2.4 mmol), and K2CO3 (359 mg, 2.6 mmol) in N-methylpyrrolidinone (2.6 mL) is heated to 140° C. Water (20 mL) is added after 1 hour of heating and extracted with EtOAc (20 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. This residue is subjected to chromatography on silica gel eluting with 90% ethyl acetate:heptane to afford a solid which is triturated with 1:1 methanol:ethyl acetate. The solid is collected to afford N-(6-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzothiazol-2-yl)-acetamide [31 mg, 13%, Example 94]. LCMS RT=2.49 minutes, MS: 488 (M+H). IC50=11 nM
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.CCCCCC.[F:15][C:16]1[C:17]([CH3:25])=[N:18][C:19]([F:24])=[C:20]([F:23])[C:21]=1[F:22].C(I)C>C1COCC1.[Cl-].[Na+].O>[CH2:25]([C:17]1[C:16]([F:15])=[C:21]([F:22])[C:20]([F:23])=[C:19]([F:24])[N:18]=1)[CH2:2][CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(F)c(F)c(F)c1F
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A 1.5M solution of LDA in hexane (100 mL, 150 mmol) is cooled to -60° C. in an isopropyl alcohol/dry ice bath. To the stirred LDA solution, under nitrogen, is added, dropwise over a 0.5 hours period, a solution of 22.617 g (137 mmol) of 3,4,5,6-tetrafluoro-2-picoline, the product of Step 1, in 80 mL of dry THF. The reaction mixture is stirred for 0.5 hours at -60° C. and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF is added, dropwise over a 20 minute period. After the reaction mixture is stirred at -60° C. for 0.5 hours, the cooling bath is allowed to slowly (1.5 hours) warm to -30° C. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is distilled to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[N:33]=[CH:34][O:35][C:36]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:36]6[O:35][CH:34]=[N:33][C:32]=6[CH3:31])[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ncoc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. HPLC. Yield: 25 mg (25%) 1HNMR (400 MHz, DMSO-d6): δ 1.21 (broad s, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 2.83 (d, J=4.8 Hz, 3H), 7.37-7.43 (m, 4H), 7.56 (d, J=1.6 Hz, 1H), 7.74-7.79 (m, 3H), 7.98-8.02 (m, 2H), 8.0 (s, 1H), 8.44-8.45 (m, 1H), 9.20 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]1([C:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:16][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CS
Reactant: O=C(c1ccccc1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a stirring solution of (2-fluorophenyl)(phenyl)methanone 87 (2 g, 9.99 mmol) and methyl 2-mercaptoacetate in DMF (30 mL) was added potassium carbonate (4.14 g, 30.0 mmol) and the reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 3-phenylbenzo[b]thiophene-2-carboxylate 88 as a white oily solid (0.62 g, 23% yield) after purification by ISCO (0 to 40% ethyl acetate in hexane). LRMS (ESI): (calc) 268.33 (found) 269.156 (MH)+
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[N:9]([CH3:13])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)COc2ncc(Br)cc21
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a suspension of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (500 mg, 2.183 mmol) in acetone (8 mL) at RT was added potassium carbonate (905 mg, 6.55 mmol) followed by methyl iodide (0.341 mL, 5.46 mmol). This was heated to 60° C. under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to RT, solvent removed in vacuo. The residue was partitioned between water/ethyl acetate (ca. 25 mL each). The aqueous layer was extracted with ethyl acetate (ca. 25 mL twice). The combined organic layers were dried over MgSO4 and solvent removed in vacuo. The residue was purified on silica gel (eluted with 20-60% ethyl acetate/cyclohexane) to afford the title compound (334 mg). LCMS (A): m/z (M+H)+ 243/245, C8H7BrN2O2 requires 242/244 (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.3 %

Procedure:
(R)-tert-butyl 2-((S)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)morpholine-4-carboxylate (120 mg, 0.28 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 20 min and a solution of satd aq NaHCO3 was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford methyl 2-((S)-(3-chlorophenyl)((R)-morpholin-2-yl)methoxy)ethylcarbamate (120 mg, 100%), which was used without purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CCc4ccccc4)C3)cc2)nc1
Yield: 64.2 %

Procedure:
Combine 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (compound of example 322) (0.0237 g, 0.0797 mmol), (2-bromoethyl)benzene (0.0108 mL, 0.0791 mmol), and potassium carbonate (0.0237 g, 0.171 mmol) in dimethylformamide (0.96 mL) and stir for 15 min. Then purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia in methanol) to provide 0.0204 g (64%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2182; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.28 (dd, 1H, J=2.9.8.3 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.33-7.27 (m, 2H), 7.27-7.18 (m, 3H), 7.12 (d, 2H, J=8.3 Hz), 7.01 (d, 1H, J=8.8 Hz), 3.15 (d, 2H, J=11.2 Hz), 2.97-2.85 (m, 3H), 2.73-2.65 (m, 2H), 2.19 (q, 2H, J=11.2 Hz), 2.03-1.74 (m, 3H), 1.59 (dq, 1H, J=4.4, 12.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[I:15]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:15][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: II
Reactant: COC(=O)CCc1ccc(OC)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 3-neck 5 L RBF equipped with mechanical stirrer, thermometer, and a nitrogen bubbler, was charged with 3-(4-methoxyphenyl)propionic acid methyl ester (100 g, 515 mmol), silver sulfate (161 g, 515 mmol) and iodine (131 g, 515 mmol) in methanol (2 L). The reaction mixture was stirred vigorously at room temperature for 1 hour. The reaction was filtered through Solka-Floc® (ethyl acetate wash). The filtrate was concentrated and the residue was taken up in ethyl acetate (4 L). The organic was washed with water, saturated aq. NaHSO3 (50 mL), and brine (50 mL) before drying over Na2SO4, filtering, and concentrating to dryness. The crude reaction was purified by column chromatography to yield methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol) as a clear oil. MS ESI calc'd. for C11H14IO3 [M+H]+ 321.0, found 321.0.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1I)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cu][C:47]#[N:48]>CN(C)C=O>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1[C:47]#[N:48])[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1I)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1C#N)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Yield: 13.9 %

Procedure:
A solution of 335 mg (0.44 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-iodoimidazole-4-propionamide and 79 mg (0.88 mmol) of copper-(I) cyanide in 25 ml of dimethylformamide is stirred at 120° overnight under argon. Subsequently, the reaction mixture is evaporated under reduced pressure, the residue is suspended in 30 ml of a 95:5 mixture of methylene chloride and methanol and filtered over Dicalite. The filtrate is evaporated and, for purification, the residue is chromatographed on 50 g of silica gel using a 160:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. After precipitation from a methylene chloride-ether mixture there are obtained 40 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-cyanoimidazole-4-propionamide as a colourless powder; MS: 656 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:17](=[O:29])[C:18]1[C:23]([O:24][CH:25]([F:27])[F:26])=[CH:22][CH:21]=[CH:20][C:19]=1F)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:19]2[C:18](=[C:23]([O:24][CH:25]([F:27])[F:26])[CH:22]=[CH:21][CH:20]=2)[C:17](=[O:29])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10]1
Reactant: CCOC(=O)C(=NNc1ccc(Cl)cc1F)C(=O)c1c(F)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2F)c2cccc(OC(F)F)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Ethyl 2-[(2-fluoro-4-chlorophenyl)-1,1-diazanediyl]-(2-fluoro-6-difluoromethoxybenzoyl)acetate (460 mg) and potassium carbonate (137 mg) were added to N,N-dimethylformamide (10 ml), and the resultant mixture was heated at 100° C. for 1 hour. The mixture was cooled to room temperature, and was poured into ice-water (about 50 ml). After allowing it to stand overnight, the precipitated crystals were collected by filtration, washed with water (5 ml) two times and were dried under reduced pressure to give 410 mg of desired ethyl 1-(2-fluoro-4-chlorophenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylate (yield: 93.8%). m.p., 140°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:37]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:38])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCCC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (648 mg, 2 mmol) in dichloromethane (5 mL) and pyridine (1 mL, 12 mmol) was added a solution of piperidine-1-carbonyl chloride (0.275 mL, 2.2 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(piperidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (870 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H33N3O3 (M+H)+: 436.57, observed: 436.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:18](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:17]=2[C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>[OH-].[K+].C(Cl)(Cl)Cl.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:35]([C:26]1[C:27](=[O:34])[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:29][C:24](=[C:17]2[C:18](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:16]2=[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2)[CH:25]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cc(C2=C(c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=C(C#N)C#N)cc(C(C)(C)C)c1O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C1=CC(=C2C(=C(C#N)C#N)C2=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of 1.00 g (3.04 mmol) of potassium ferricyanide in 20 ml of 1N KOH solution was added to a solution of 0.51 g (1.0 mmol) of 6a in 20 ml of chloroform. The deep blue two-phase mixture was stirred vigorously at room temperature for 1 hr under a nitrogen atmosphere. The organic layer was separated, washed with water, dried (MgSO4) and evaporated in vacuo to give 0.50 g (98%) of 5a as golden plates after recrystallization from hexane; mp 210-215° (dec); ir (KBr) 2960-2860(m), 2227(w), 2217(w), 1753(m), 1600(s), 1525(w), 1510(w), 1470(s), 1360(m), 1345(m), 1260(w), 1115(s), 1020(w), 950(w), 910(m), 830 cm-1 (w); nmr (CDCl3) δ 1.34(s, 18H), 1.38(s, 18H0); 7.45(d,J = 2Hz, 2H), 7.71 (d, J = 2Hz, 2H); uv-visible, λmax (benzene) 319(sh) (3.77), 345(sh) (3.90), 364(4.03), 387(sh) (4.01), 415(sh) (3.88), 498 (sh) (3.96), 548(sh) (4.40), 587(4.79), 609 (4.80), 640(sh) (4.25); mass spectrumm/e 508.31003 (calcd 508.30897); Anal. Calcd for C34H40N2O2 : C, 80.27; H, 7.93; N, 5.51. Found: C, 80.40; H, 8.09; N, 5.48.
Reaction SMILES: C[O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(OCC)(=O)C>[OH:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2nc3c(O)ccc(-c4ccccc4)c3s2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
A solution of 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (630 mg, 1.7 mmol) is slowly trated with boron tribromide (16 ml, 1.0 M in dichloromethane) at 0° C. The reaction is slowly warmed to ambient temperature and stirred for further 72 h. The mixture is diluted with ethyl acetate and extracted twice with water and once with brine. After drying over sodium sulfate, the solvent is removed in vacuo. Flash chromatography (silica, eluent ethyl acetate/hexane 1:1) and final recrystallization from tetrahydrofurane/hexane yields 118 mg (19%) of the product as white solid. MS: m/e=367 (M+H+).