Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CCc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CCc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 1.6 %

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-phenethylpiperazin-1-yl)pyridin-2-amine (0.058 g, 0.16 mmol) in EtOH (2.8 mL) and DMF (0.37 mL), 4-(dimethylamino)benzaldehyde (0.026 g, 0.18 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 mL, 0.48 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 99:1) to give the title compound as a solid (0.0012 g, 16%); 1H-NMR (500 Mz, DMSO-d6): δ 2.57-2.64 (m, 2H), 2.64-2.70 (m, 4H, piperazine N(CH2)2), 2.77-2.83 (m, 2H), 3.00 (s, 6H, NMe2), 3.65-3.70 (m, 4H piperazine N(CH2)2), 6.82 (d, J=9.0 Hz, 2H, ArH), 7.16-7.22 (m, 1H, ArH, C6H5), 7.25-7.32 (m, 4H, ArH), 7.98-8.04 (m, 3H, imidazo[4,5-b]pyridine 5-H and ArH), 13.09 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.59 min—461/463 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 461.2214, calculated for C26H30ClN6 (M+H)+: 461.2220;
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[N-:11]=[N+:12]=[N-:13].[Na+].O>CS(C)=O.[N-]=[N+]=[N-].[Na+]>[N:11]([CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCl)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
(S)-α-(Chloromethyl)benzenemethanol (2.38 g) in dry DMSO (50 ml) was treated with sodium azide (1.48 g) with stirring then heated at 60° C. for 24 h. More sodium azide (74 mg) was added and heating continued at 80° C. for a further 24 h. The reaction mixture was cooled, poured into water and extracted into ethyl acetate, which was washed with water (3×) then brine and dried (MgSO4). The solvent was evaporated to give the sub-title compound (2.40 g) as a yellow oil.
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[C:18]1([CH:24]([OH:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH:2]([NH:1][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][O:26][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:25]
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: CC(O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(COC(C)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a stirred solution of 1-benzyl 2-methyl (S)-(−)-1,2-aziridinedicarboxylate (1.88 g) in dichloromethane (30 ml) were added at 0° C. 1-phenyl-ethanol (9.77 g) and boron trifluoride etherate (2.0 ml). After stirring the mixture for one hour the cooling bath was removed and stirring was continued overnight. Then the reaction mixture was poured onto saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give S)-2-benzyloxycarbonylamino-3-(1-phenyl-ethoxy)-propionic acid methyl ester (1.34 g, 47%) as a light yellow oil. MS (ISP): 358.2 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[S:44][C:45]([CH3:48])=[CH:46][N:47]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:42][C:43]2[S:44][C:45]([CH3:48])=[CH:46][N:47]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1cnc(N)s1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ncc(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-5-methylthiazole (17 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (22.5 mg, yield 38.2%).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CS(O)(=O)=O.[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[CH2:62][NH2:63]>>[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[CH2:62][NH:63][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:43]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cc2ccccc2[nH]1
Agent: CS(=O)(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc2ccccc2[nH]1
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-indol-2-yl)methanamine methanesulfonate, the title compound was obtained as an off-white solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 9.18 (br s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 2H), 7.19-6.98 (m, 4H), 6.36 (s, 1H), 6.28 (t, J=5.9 Hz, 1H), 6.10 (s, 1H), 4.62 (d, J=5.9 Hz, 2H), 4.42 (s, 2H), 3.81-3.73 (m, 2H), 3.45-3.38 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 463.2 (M+1), 485.2 (M+23).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][N:20]3[C:29](=O)[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:22][CH:21]3[OH:31])[CH2:12][CH2:11]2)=[N:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(Cl)[Cl:47]>>[ClH:47].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][N:20]3[CH2:29][CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:22][C:21]3=[O:31])[CH2:12][CH2:11]2)=[N:2]1
Reactant: ClCCl
Reactant: O=C1CC2(CCCC2)CC(O)N1OCCCN1CCN(c2nsc3ccccc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1CC2(CCCC2)CCN1OCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution prepared from 8-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyloxy]-7-hydroxy-8-azaspiro[4.5]decan-9-one (4.7 g), 80 ml of CH2Cl2 and 40 ml of trifluoroacetic acid was added triethylsilane (1.8 ml) dropwise. The mixture was stirred at room temperature. After 1.5 hours, no starting material remained as judged by TLC.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:21]([C@@H:28]1[CH2:33][C@@H:32]([N:34]([CH2:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=[CH:44][CH:43]=2)[C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:31][CH2:30][NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N>C(Cl)Cl.CO>[CH2:21]([C@@H:28]1[CH2:33][C@@H:32]([N:34]([CH2:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=[CH:44][CH:43]=2)[C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])[CH2:31][CH2:30][N:29]1[C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
248 mg (1.17 mmol) of diphenylacetic acid are reacted in analogy to Example 2j first with 128 μl (1.76 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =621.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1ccccc1CC1(N)CC1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccccc1CC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 161 mg (1 mmol) 1-(2-methyl-benzyl)-cyclopropylamine. Yield: 60 mg (16%, trifluoroacetate); mass spectroscopy: [M+H]+=369.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28](CO)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:35])=O.[O:37]1[CH2:41][CH2:40][CH2:39]C1>CN(C)C=O>[ClH:35].[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:21][N:25]5[CH2:24][CH2:23][C:41](=[O:37])[CH2:40][CH2:39]5)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1)C1CC1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cl
Product: O=C1CCN(Cc2cnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a mixture of [2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]methanol (0.30 g), N,N-dimethylformamide (two drops) and tetrahydrofuran (6 mL) was added thionyl chloride (0.09 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated. The obtained residue was dissolved in tetrahydrofuran (2 mL) and the solution was added to a mixture of piperidine-4,4-diol hydrochloride (0.19 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give a yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). The obtained amorphous solid was dissolved in ethyl acetate, and 4M hydrogen chloride-ethyl acetate solution (1.0 mL) was added. The precipitated crystals were collected by filtration, and dried to give the title compound (0.21 g, yield 57%) as yellow crystals. melting point 146-148° C. MS: 554 (MH+).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>C(OCC)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1
Reactant: c1cc2c(s1)CCNC2
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=Cc1ccccc1Cl
Solvent: CCOCC
Product: Clc1ccccc1C(N1CCc2sccc2C1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (0.5 g, 3.59 mmol), benzotriazole (428 mg, 3.59 mmol), and 2-chlorobenzaldehyde (504 mg, 3.59 mmol) were dissolved in diethyl ether and stirred for 3 days in the presence of molecular sieves (4 Å) under an argon atmosphere at room temperature. After 3 days, the ether was filtered and washed with saturated sodium bicarbonate solution (20 mL). The ether was dried over sodium sulfate, filtered and concentrated. The remaining colorless foam was dissolved in heptane/diethyl ether (5 mL/1 mL) and stored in a freezer (−10° C.) overnight. After 20 hours at −10° C., the heptane was decanted and the remaining oil was dried under high vacuum at room temperature until a constant weight was achieved to provide 1-[(2-Chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-methyl]-1H-benzotriazole (Compound IVa, 0.84 g, 61.7% yield) as a colorless foam that appeared to be an 80:20 mixture of isomers by NMR. 1H NMR (300 MHz, CDCl3/TMS): δ=8.08 (d, 1H, J=8.1 Hz), 7.91-7.79 (m, 2H), 7.55 (d, 1H, J=8.4 Hz), 7.53-7.24 (m, 4H), 7.11 (s, 1H), 7.04 (d, 1H, J=5.1 Hz), 6.61 (d, 1H, J=5.1 Hz), 3.90 (d, 1H, J=14.4 Hz), 3.69 (d, 14.4 Hz), 3.21-2.95 (m, 2H), 2.88 (m, 2H). (major isomer). 13C NMR (75 MHz, CDCl3/TMS): δ=145.48, 133.78, 133.45, 132.94, 132.65, 130.10, 129.40, 127.50, 126.98, 126.56, 124.97, 124.00, 122.79, 119.80, 110.39, 84.85, 49.59, 47.28, 25.50. (major isomer). MS (HR, DIP-CI): Calculated for (MH+): 379.0779. found 379.0752.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)=O.[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[S:27])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>O1CCOCC1>[O:19]1[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][N:25]([C:26]2[S:27][CH:2]=[C:3]([C:5]3[S:6][C:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)=[CH:8][CH:9]=3)[N:28]=2)[C:43]([C:39]2[S:38][CH:42]=[CH:41][CH:40]=2)=[O:44])[CH2:21][CH2:20]1
Reactant: O=C(CBr)c1ccc(-c2ccccn2)s1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=S)NCCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2ccc(-c3ccccn3)s2)cs1
Temperature: 80 °C
Yield: 107.4 %

Procedure:
A mixture of 2-bromo-1-[5-(2-pyridinyl)-2-thienyl]-1-ethanone (169 mg, 0.6 mmol) (167 mg, 0.6 mmol) and (3-morpholin-4-yl-propyl)-thiourea (122 mg, 0.6 mmol) in dry dioxane (5 ml) was heated at 80° C. for 2 h, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5 mL) followed by the addition of N,N-diisopropylethylamine (209 μL, 1.2 mmol) and thiophene-2-carbonyl chloride (96 μL, 0.9 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (320 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 497.5 [M+H]. HPLC retention time (Method B)=2.55 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(N3CCN(C(=O)OCc4ccccc4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 40 °C
Yield: 94 %

Procedure:
A solution of 6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in the previous step, 2.0 g, 7.8 mmol) in DMF (40 mL) was treated with solid Na2CO3 (0.99 g, 9.4 mmol) and piperazine-1-carboxylic acid benzyl ester (1.5 mL, 7.8 mmol), then heated to 90° C. for 1 h and to 40° C. for 15 h. The reaction was concentrated to 20 mL volume, diluted with EtOAc, and washed well with water. The combined aqueous layers were further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% EtOAc in hexane) afforded the title compound (3.2 g, 94%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 7.39-7.31 (m, 5H), 6.01 (d, 1H, J=9.2 Hz), 5.16 (s, 2H), 3.84-3.76 (m, 2H), 3.71-3.65 (m, 4H), 3.64-3.58 (m, 4H), 3.02-2.93 (m, 2H), 1.74-1.65 (m, 2H), 1.66-1.60 (m, 1H), 1.38-1.26 (m, 2H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C23H29N5O4, 440.2 (M+H), found 439.9.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].[N:13]([O-])=O.[Na+]>Cl.O>[C:2]([C:6]1[CH:7]=[C:8]([NH:9][NH2:13])[CH:10]=[CH:11][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cccc(NN)c1
Reaction time: 1 h

Procedure:
3-t-Butylaniline hydrochloride (5 g) in concentrated hydrochloric acid (8 ml) was stirred at 0° whilst a solution of sodium nitrite (1.86 g) in water (2.4 ml) was slowly added. The mixture was kept at 0° for 1 hour and, after filtering (at 0°), it was treated dropwise with a solution of stannous chloride dihydrate (18.2 g) in concentrated hydrochloric acid (18.8 ml). A pink-coloured solid separated. After 1 hour, this solid was filtered off and washed with saturated aqueous sodium chloride. The resulting salt was converted into base in the usual way to give 3-t-butylphenylhydrazine, b.p. 88°-90°/0.25 mm Hg.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:19]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60]([N:21]1[CH2:22][C@H:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH2:19][C@H:20]1[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50]
Reactant: C=CCOC(=O)N[C@@H](CCCC)C(=O)O
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a flask containing 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5 (45 mg, 0.08 mmol) was added a 4 M solution of HCl in dioxane (1.4 mL, 5.6 mmol). After 1 h, LC-MS analysis indicated complete consumption of the starting material (5) and formation of the desired -Boc product. The volatile components were then removed in vacuo, and the crude material was taken up in DMF (1 mL). To this mixture was added alloc-Nle-OH (4) (26 mg, 0.12 mmol), DIPEA (0.144 mL, 0.8 mmol), and TBTU (39 mg, 0.12 mmol). After stirring at RT for 30 min, complete consumption of the amine was evidenced via LC-MS. The reaction mixture was then worked-up with 1N HCl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The solvent was then removed in vacuo and the crude product was purified on silica (10-50% EtOAc/hexanes) to yield 50 mg (95% yield) of 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate 6. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.07 (m, 3H), 7.97 (br s, 1H), 7.88 (m, 1H), 7.54-7.47 (m, 3H), 7.07 (s, 1H), 6.92 (dd, J=17.5 Hz, 10.5 Hz, 1H), 5.90 (d, J=17.5 Hz, 1H), 5.83 (m, 1H), 5.43-5.63 (m, 3H), 5.25-5.13 (m, 2H), 4.79 (app t, J=8 Hz, 1H), 4.65-4.37 (m, 4H), 4.26 (m, 2H), 4.10 and 4.08 (2 d, J=4.0 Hz and 4.5 Hz, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.44-1.33 (m, 4H), 1.05-0.98 (m, 2H), 0.92 (m, 3H), 0.05 (s, 9H). LRMS (CI, [M+H]) Calc'd=658.4. Found=658.4. HRMS (APCI, [M+H]+) Calc'd for C37H48N3O6Si: 658.3307. found: 658.3348.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([OH:25])=O)#[N:11].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:32]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:32]=[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH2:13][CH2:12][C:10]#[N:11])[C:23]2=[O:25]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CN(C)C=O
Reactant: N#CCCCOc1ccccc1CC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N#CCCCOc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.125 g, 0.87 mmol), [2-(3-Cyano-propoxy)-phenyl]-acetic acid (0.19 g, 0.87 mmol), BF3Et2O (5 ml), PCl5 (0.27 g, 1.3 mmol), DMF (8 ml and 5 ml). Crude 4-[2-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile was obtained as an oil which was taken onto the next stage without further purification.