Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:27])[C@@H:12]1[CH2:16][S:15][CH2:14][N:13]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CO>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][S:15][CH2:16][C@H:12]1[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:5]([OH:28])=[O:4])=[O:27])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
1N Sodium hydroxide (45 ml) was dropwise added to a methanol solution (120 ml) of N-(benzyloxycarbonyl)-L-thioprolyl-L-proline methyl ester (11.84 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was dissolved in water. The aqueous solution was acidified with concentrated hydrochloric acid under ice-cooling and extracted with chloroform. The extract was washed with water and concentrated to give the title compound (6.47 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=O)[CH3:16])[C:8]1=[O:18])[CH3:2].[NH2:27][C:28]1[C:33]([CH:34]=O)=[CH:32][CH:31]=[CH:30][N:29]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCC(C)=O)C1=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 2-7 (430 mg, 1.18 mmol), 2-amino-3-formylpyridine (144 mg, 1.18 mmol; for prep., see JOC 1983,48, 3401) and proline (136 mg, 1.18 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform -70:25:5 chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[C:24](O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([O:18][C:24]2[C:25]([CH3:27])=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(O)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: COc1ccc(OC(CC(C)C)[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(C)n1
Temperature: 70 °C
Yield: 13.8 %

Procedure:
Purge nitrogen through a solution of (3S)-3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-1) (0.5 g, 1.94 mmol) and 6-methoxy-2-methyl-pyridin-3-ol (0.41 g, 2.91 mmol) in toluene (10 mL) at room temperature for 10 minutes. Add tri-n-butylphosphine (0.73 mL, 2.91 mmol) followed by azodicarboxylic acid dipiperidide (0.59 mg, 2.91 mmol). Heat the reaction mixture to 70° C., and stir over night. Cool the mixture to room temperature and pour onto saturated aqueous NaHCO3 (50 mL). Extract with ethyl acetate (2×), combine the organic extracts and dry (Na2SO4), filter and concentrate. Purify the crude residue by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to afford (3S)-3-[1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-2) (101 mg, 13%). The deprotection and the L-tartarte formation are performed essentially as in EXAMPLE 1 to afford the title compound. MS (m/z)=279 [M+1]
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:34])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:32][C:30]([F:31])([F:33])[O:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:34])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(OC(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-[2-(4-Trifluoromethoxy-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01064, 0.3 g, 0.62 mmol) was dissolved in anhydrous DCM (7 ml), cooled to 0° C. and to this was added TFA (2.8 ml), and the reaction mixture was stirred under nitrogen for 1.5 h. The reaction mixture was poured onto solid potassium carbonate (6 g), and water (25 ml) added. Extracted with DCM and the organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, 0.21 g, 87%. Rf: 0.35 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.64 (2H, m, CH2), 1.79 (2H, dd, J=2.7, 12.9 Hz, CH2), 2.32 (1H, m, CH), 2.61 (2H, td, J=2.7, 12.3 Hz, NCH2), 2.94 (1H, s, NH), 3.10 (2H, td, J=3.3, 12.6 Hz, NCH2), 6.79 (1H, dd, J=1.2, 8.1, ArHD), 6.95 (2H, m, ArHE), 6.95 (1H, m, ArHE), 7.08 (1H, td, J=1.5, 7.8 Hz, ArHc), 7.13 (2H, d, J=8.4 Hz, ArHF), 7.62 (1H, s, NH), 8.34 (1H, dd, J=1.2, 8.1 Hz, ArHA).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS (ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:9][C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].Cl>N1C=CC=CC=1.CO>[CH:6]([N:9]([C:10]1[C:11]([CH3:41])=[C:12]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([C:38]([NH2:40])=[O:39])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)[S:2]([CH3:1])(=[O:4])=[O:3])([CH3:8])[CH3:7]
Reactant: Cc1c(NC(C)C)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)cccc1N(C(C)C)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.3 μL, 0.016 mmol) was added to a stirred solution of 4-(3-(isopropylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, TFA salt (Example 9-1, 13 mg, 0.016 mmol) in pyridine (0.2 mL) at rt. After 30 min, additional methanesulfonyl chloride (2.4 μL) was added and the mixture was stirred overnight. The mixture was treated with 1 M hydrochloric acid (0.56 mL), dissolved in methanol and purified by preparative HPLC to provide two rotational isomers of 4-(3-(N-isopropylmethylsulfonamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide, isolated separately as TFA salts after lyophilization. Isomer A (3.3 mg, 31%) 1H NMR (400 MHz, chloroform-d) δ 9.58 (1H, s), 7.81 (1H, d, J=7.70 Hz), 7.68 (1H, s), 7.41-7.47 (1H, m), 7.32-7.37 (2H, m), 7.11 (1H, d, J=7.70 Hz), 7.05 (1H, d, J=8.14 Hz), 6.86 (1H, d, J=8.14 Hz), 4.60-4.72 (1H, m), 3.66 (3H, br. s.), 3.05 (8H, br. s.), 2.90 (3H, s), 1.91 (3H, s), 1.40 (3H, d, J=6.60 Hz), 1.12 (3H, d, J=6.82 Hz). Mass spectrum m/z 562.1 (M+H)+. Isomer B (2.9 mg, 27%) 1H NMR (400 MHz, chloroform-d) δ 9.41 (1H, br. s.), 7.84 (1H, d, J=7.70 Hz), 7.69 (1H, s), 7.46 (1H, t, J=7.81 Hz), 7.36 (2H, t, J=8.25 Hz), 7.13 (1H, d, J=7.70 Hz), 7.05 (1H, dd, J=8.25, 1.21 Hz), 6.92 (1H, d, J=8.36 Hz), 4.71-4.82 (1H, m), 3.67 (3H, br. s.), 2.59-3.07 (11H, m), 1.90 (3H, s), 1.43 (3H, d, J=6.60 Hz), 1.10 (3H, d, J=6.60 Hz). Mass spectrum m/z 562.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C1[C:62]2(OCCC[O:63]2)[CH2:61][C@@H](C(OC)=O)N1C(OCC1C=CC=CC=1)=O>>[C:62]([N:38]1[CH2:37][C:36]2([CH2:40][CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:2]([CH3:57])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[N:34]([C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[CH2:35]2)[CH2:39]1)(=[O:63])[CH3:61]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCCO2
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)CN(C(C)=O)C2)C(C)C
Yield: 83 %

Procedure:
This compound was prepared in an analogous fashion to Example 21 from methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate Example 24 (40 mg, 0.05 mmol) to afford the title compound as a yellow solid (35 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67-12.33 (m, 1H) 7.19-7.99 (m, 12H) 5.07 (br. s., 1H) 3.92-4.25 (m, 4H) 3.67-3.94 (m, 4H) 3.45-3.66 (m, 8H) 2.20-2.46 (m, 3H) 2.17 (br. s., 2H) 1.80-2.06 (m, 5H) 1.60-1.82 (m, 3H) 0.78-1.02 (m, 12H). HRMS for C44H56N9O7 (M+H)+ calc: 822.4303. found: 822.4300. Purity (LC-MS): 91%.
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.ClC1C(=O)C(C#N)=C(C#N)C(=[O:25])C=1Cl>O1CCCC1.O>[C:1]1(=[O:25])[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: c1ccc2c(c1)c1c3n2CCCC3CCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC2CCCn3c2c1c1ccccc13
Temperature: 0 °C

Procedure:
7.2 g (0.034 mol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazole prepared according to A. S. Baily et al. J. C. S. Perkin I (1980) 97, were dissolved in 300 ml of tetrahydrofuran. The mixture was diluted with 30 ml of water and cooled to 0° C. A solution of 17.0 g (0.075 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of tetrahydrofuran was added dropwise in 10 minutes while stirring thoroughly at a reaction temperature between 0° and 5° C. The reaction mixture was stirred for 1 hour and evaporated in vacuum. The residue was extracted with methylene chloride. The methylene chloride solution was washed with 200 ml of 0.5N sodium hydroxide solution and evaporated in vacuum. The residue was chromatographed over 500 g of silicagel using ethyl acetate as an eluent. After evaporating the good fraction, the desired ketone was obtained in a yield of 4.6 g (60%) having a melting-point of 172°-173° C.
Reaction SMILES: CC(C)(OC(=O)[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([C:45]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[C:46]([OH:48])=[O:47])=[O:44])C.C1C(=O)N(O[C:83]([C@@H:85]([NH:91][C:92]([O:94][CH2:95][C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)=[O:93])[CH2:86][CH2:87][C:88]([NH2:90])=[O:89])=[O:84])C(=O)C1.CCN(C(C)C)C(C)C.O>C1COCC1.C(#N)C>[NH2:90][C:88](=[O:89])[CH2:87][CH2:86][C@@H:85]([C:83](=[O:84])[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([C:45]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[C:46]([OH:48])=[O:47])=[O:44])[NH:91][C:92](=[O:93])[O:94][CH2:95][C:96]1[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=1
Reactant: CCCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A solution of 2-((2,2-Dimethyl-4-oxo-3,8,11,14,17,20,23,26,29,32, 35,38-dodecaoxa-5-azatetracontan-40-yl)carbamoyl)-2-undecyltridecanedioic acid (20 mg, 0.018 mmol) in THF (Volume: 2 mL) was added to Z-L-Gln-Osu (Santa Cruz Biotechnology, CAS 34078-85-8, 11 mg, 0.029 mmol), then DIPEA (75 μl, 0.429 mmol) was added. Stirred at room temperature under a nitrogen atmosphere over weekend. Complete conversion was observed by LCMS (Acidic Eluent A: Water+0.05% Trifluoroacetic Acid, Eluent B: ACN, column Sunfire C18 3.5 μm 3.0×30 mm −40° C., 5-95% gradient 2 minutes, retention time 1.77 min) The reaction mixture was concentrated under reduced pressure and then dissolved in acetonitrile. Purified on a MS-triggered HPLC (Sunfire 30×50 mm Sum column ACN/H2O w/0.1% TFA 75 ml/min 1.5 ml injection, 55-80% ACN 3.5 min gradient, retention time 2.70 minutes) and the fractions pooled and lyophilized to give 10.5 mg clean product ZQ-FA in 46% yield as a clear colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([Cl:22])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
Part B. A solution of the pyridone from Part A (6.72 g, 25.9 mmol) in phosphorus oxychloride (52 mL, 25.5 mmol) was stirred at ambient temperature for 3 d. The reaction mixture was poured into a mixture of ice (150 g) and dichloromethane (200 mL). After the ice had melted, 100 mL more dichloromethane was added, and the pH of the mixture was adjusted to 7 with solid NaHCO3. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to afford the product (4-benzylamino-2-chloro-6-methyl-3-nitropyridine) as a bright yellow crystalline solid (6.45 g, 23.2 mmol, 90%). TLC RF 0.76 (ethyl acetate). 1H NMR (300 MHz, CDCl3): d 7.43-7.26 (5H, m), 7.04 (1H, br), 6.47 (1H, s), 4.48 (2H, d, J=5.5 Hz), 2.40 (3H, s). MS (NH3—CI): m/e 281 (5), 280 (35), 279 (17), 278 (100).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:38])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CN(Cc1ccc(CO)cc1)C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1ccc(CBr)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Into a solution of N-methyl-N-(tetrahydropyran-4-yl)-4-(hydroxymethyl)benzylamine (0.68 g) and triphenylphosphine (0.91 g) in dichloromethane (10 ml) was added under ice cooling carbon tetrabromide (1.44 g), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/hexane 1/9) and further to washing with diethyl ether/hexane to obtain N-methyl-N-(tetrahydropyran-4-yl)-4-(bromomethyl)benzylamine (687 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:16](=[O:17])[NH:15][CH3:14])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN=C=O
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CNC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 104 °C
Reaction time: 14 h

Procedure:
300 mg (1.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 8 ml toluene and 4 ml petroleum ether 60/80 are treated with 0.097 ml (1.65 mmol) methyl isocyanate. The mixture is stirred in a pressure tube at 104° C. for 5 hours and at room temperature for 14 hours. The suspension is filtrated to give 302 mg (corresponding to 78% of theor.) of the product.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>CO>[CH3:17][N:18]1[CH2:19][CH:20]=[C:21]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH2:22][CH2:23]1
Reactant: CN1CCC(=O)CC1
Reactant: c1cc2ccc(N3CCCC3)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3cc(N4CCCC4)ccc23)CC1
Temperature: 72 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
6-(pyrrolidin-1-yl)-1H-indole (500 mg, 2.68 mmol) was added to a solution of potassium hydroxide (1.55 g, 27.62 mmol) in methanol (20 mL). 1-methylpiperidin-4-one (610 mg, 5.39 mmol) was then added, and the resulting solution was stirred at 72° C. overnight. The mixture was concentrated and the residue was poured into water (40 mL). After filtration, the filter cake was washed with water (1×50 mL) and diethylether (1×50 mL), to afford 400 mg (47.6%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(pyrrolidin-1-yl)-1H-indole as a white solid.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.CC1(C)CCCC(C)(C)N1.N#N.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25].C(=O)C>C1COCC1>[Br:18][C:19]1[C:27]2[CH:2]([CH3:3])[O:25][C:24](=[O:26])[C:23]=2[CH:22]=[N:21][CH:20]=1
Reactant: [Li]CCCC
Reactant: O=C(O)c1cncc(Br)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CC=O
Agent: N#N
Solvent: C1CCOC1
Product: CC1OC(=O)c2cncc(Br)c21
Temperature: -50 °C
Reaction time: 1 h

Procedure:
n-BuLi (1375 μl, 2.200 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (407 μl, 2.400 mmol) in THF (5 mL) at −78° C. under inert gas (N2). The resulting mixture was stirred at ˜−50° C. for 1 hr. 5-bromonicotinic acid (202 mg, 1 mmol) in THF (5 mL) was added at this temperature. The resulting mixture was stirred for 45 min at −50° C. acetaldehyde (56.5 μl, 1.000 mmol) was added and the resulting mixture was stirred for 60 min. The reaction was quenched by NH4Cl (saturated solution) and warmed up to room temperature. After acidified to pH 2 with HCl, the resulting mixture was heated to reflux for 8 hrs. After concentration, acid-base extraction and concentration again, the residue was purified by column (Heptane/ethyl acetate v/v, 10-20%) yielded colorless solid. 1H NMR (400.3 MHz, CDCl3): δ 1.77 (d, J=6.7 Hz, 3H), 5.56 (q, J=6.7 Hz, 1H), 8.91 (s, 1H), 9.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:11][C:12](=[O:43])[C@@H:13]([CH:40]([CH3:42])[CH3:41])[NH:14][C:15](=[O:39])[C@H:16]([CH:28](CC1C=CC=CC=1)[C:29](=[O:31])[OH:30])[NH:17]C(OCC1C=CC=CC=1)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.O.[Pd].[C]>[CH3:1][O:2][CH2:3][C@H:4]([NH:11][C:12](=[O:43])[C@@H:13]([CH:40]([CH3:41])[CH3:42])[NH:14][C:15](=[O:39])[C@H:16]([CH2:28][C:29](=[O:30])[OH:31])[NH2:17])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(C)C)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)C(C)C)c1ccccc1
Temperature: 40 °C
Yield: 70.1 %

Procedure:
To a suspension of 6.20 g (10.5 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine (R)-α-methoxymethylbenzylamide in 200 ml of methanol and 50 ml of water was added 1.50 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen under heat at 40° C. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to 15 ml. The crystal thus precipitated was removed by filtration and dried to obtain 2.69 g (7.36 mmols, 70.0% ) of α-L-aspartyl-D-valine (R)-α-methoxymethylbenzylamide.