Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22]C(C)([O-])C.[K+].CCl.Cl>C(O)(C)(C)C.O>[CH3:22][C:11]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]=1[CH2:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCl
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O

Procedure:
A solution of androst-4-ene-3,17-dione in t-butanol was heated to boiling and added to a boiling solution of potassium t-butoxide in t-butanol. Methyl chloride in t-butanol was added slowly. The solution was cooled, acidified with concentrated hydrochloric acid, and diluted with water. The excess t-butanol was removed under vacuum and the aqueous layer extracted with ethylacetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel and eluted with hexane/ethylacetate. The eluant was evaporated and the residue crystallized from ether to yield 4-methylandrost-4-ene-3,17-dione; I.R. (KBr): 1735 (17-oxo), 1660 (3-oxo), 1620 cm-1 (Δ4).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[CH2:24][CH2:25][P:26](=[O:29])([O-:28])[O-:27])(=O)C.[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38]>O.CO.CCN(CC)CC>[C@H:6]1([CH2:24][CH2:25][P:26](=[O:27])([O-:29])[O-:28])[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4].[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38]
Reactant: CC(=O)OC[C@H]1O[C@H](CCP(=O)([O-])[O-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[NH+](CC)CC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=P([O-])([O-])CC[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 57.5 %

Procedure:
A solution of 6 (49.3 mg, 0.11 mmol) in H2O/MeOH/Et3N (7:3:1, 11 mL) was stirred for 16 h at room temperature. The reaction was evaporated to dryness and the residual white powder was purified by Purification Method 1 (100% 0.05 M TEAB) to afford the triethylammonium salt of 7 as a colorless foam (30 mg, 99%): Rf 0.2 (iPrOH/H2O/aq. NH4OH 6:3:1); δH (400 MHz, D2O) 3.82-3.70 (m, 3H, H-3, H-6, H-7), 3.59 (dd, 1H, J1,2 3.4 Hz, J2,3 9.5 Hz, H-4), 3.54-3.43 (m, 3H, H-5, H-8a, H-8b), 2.97 (q, J=7.3 Hz, NCH2CH3, 1.4 equiv.), 1.70-1.20 (m, 4H, H-1a, H-1b, H-2a, H-2b), 1.04 (t, J=7.3 Hz, NCH2CH3, 1.4 equiv.); δC (100 MHz, D2O) 76.2 (d, JC,P 16.3 Hz, C-3), 71.6 (C-7), 69.6, 69.2 (C-5/C-6), 68.3 (C-4), 61.3 (C-8), 46.7 (NCH2CH3), 23.9 (d, JC,P 134.2 Hz, C-1), 18.4 (C-2), 8.3 (NCH2CH3); δP (161.9 MHz, D2O) 24.9. m/z (ESI) 271.0590 [M−H]−, C8H16O8P requires 271.0588.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:19])[C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](Cl)=[O:14])[CH:11]=1.[OH2:21]>N1C=CC=CC=1>[C:9]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:14])([OH:19])=[O:21]
Reactant: O
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: O=C(O)c1cccc(C(=O)Oc2cc[nH]c(=O)c2)c1
Yield: 43 %

Procedure:
1.00 g of 4-hydroxy-2-pyridone was suspended in 50 ml of pyridine. After the addition of 3.65 g of isophthaloyl chloride, the suspension was refluxed with heating for 1.5 hours. The reaction mixture was left to stand for cooling, to which water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was washed with ether to give 1.00 g of the title compound in a yield of 43%.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 36 %

Procedure:
Prepared from VII and 4-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 36%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2225, 2218, 1722, 1628, 1590, 1562, 1495, 1461, 1387, 1261, 1228, 1132, 966, 847, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 7.77 (m, 3H), 7.40 (d, 2H, J=9.0 Hz); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0612.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C([N:15]([CH2:18][CH3:19])CC)C.[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>>[NH2:15][C:18]1[CH:19]=[CH:22][CH:21]=[CH:20][CH:24]=1.[N-:15]=[C:5]=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Product: Nc1ccccc1
Product: [N-]=C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 68 (200 mg, 0.44 mmol) was treated with hydrogen in the presence of 10% Pd on carbon (20 mg). After 16 h stirring, the mixture was filtered through Celite and the solvent was evaporated off in vacuo to give the intermediate amino aniline product. This was then reacted with triphosgene (195 mg, 0.70 mmol) in the presence of triethylamine (260 uL, 0.70 mmol) in THF (15 mL). After 1 h stirring at room temperature a white precipitate was filtered off and the solvent was evaporated off in vacuo to give a crude residue of isocyanate aniline. This was used straight away in the following step. Isocyanate intermediate was dissolved in THF (10 mL). The solution was cooled to 0° C. Benzofuran-2-ylmethanol 59 (100 mg, 1.35 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The mixture was cooled on ice and TBAF (996 μL, 3.38 mmol) was added dropwise over 5 min. The resulting mixture was allowed to warm to room temperature and then stirred for 20 min. THF was evaporated off in vacuo. The intermediate was dissolved in pyridine (5 mL) and to this was added methane sulphonyl chloride (12.5 μL, 0.16 mmol). The mixture was stirred at room temperature for 1 h. Pyridine was evaporated off in vacuo and the crude product was purified by flash chromatography, eluting with hexane:EtOAc (3:1) to give 69 (5 mg, 2%) as a white solid. m/z=408.07 (M+H), 837.16 (2M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:2])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[C:13](=[O:24])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Yield: 41.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,6-dichloro-2-[2-(4-methoxy-phenyl)-propionylamino]-benzoic acid methyl ester (1.44 g, 3.77 mmol) and LiHMDS (11.0 mmol, 1M solution in THF). After normal workup, the pure objective compound (0.55 g, 42%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.52 (s, 3H, CH3), 3.67 (s, 3H, CO2CH3), 6.89 (d, J=8.9 Hz, 2H, ArH), 6.99-7.08 (m, 3H, ArH), 7.23 (d, J=1.9 Hz, 1H, ArH), 11.25 (s, 1H, NH); m.p. 210-212° C.; MS(EI) m/e 349 [M+], 162, 134; HRMS m/e cacld. for C17H13NO3Cl2 349.0272, found 349.0278.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: COCCN
Solvent: CN1CCCC1=O
Product: COCCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-Methoxy-ethylamine (90 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 341 (105.5 mg, yield: 20%). 1HNMR (DMSO-d6, 400 MHz): δ8.63 (s, 1H), 8.31 (s, 1H), 7.94-7.88 (m, 2H), 7.76-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.21 (s, 2H), 6.99 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.49 (s, 4H), 3.29 (s, 3H), 3.15 (s, 2H). ESI-MS: m/z=533 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].O>ClCCl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2ccc(C(=O)Cl)cc2)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2ccc(C(=O)N3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) was dissolved in dichloromethane (0.9 mL), and a saturated aqueous solution (0.9 mL) of sodium hydrogencarbonate was added to the solution. 4-(3,4,5-Trimethoxyphenyl)benzoyl chloride (55 mg) was then added dropwise to the mixture under ice cooling, and the resultant mixture was stirred for 1 hour. After water was added to the reaction mixture to conduct extraction with chloroform, the resultant organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][C:17]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.[Hg](Cl)Cl>[C:27]([O:26][C:24]([NH:23][C:20](=[N:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[NH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: Nc1cc2ccccc2cn1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cc2ccccc2cn1
Reaction time: 26 h
Yield: 84 %

Procedure:
Mercury (II) chloride (192 mg, 0.707 mmol) was added in one portion to a stirred mixture of 3-aminoisoquinoline (84.5 mg, 0.586 mmol), N,N′-di-t-butoxycarbonyl-S-methylisothiourea (Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52, 1700-1703) (204 mg, 0.703 mmol), and triethylamine (250 μL, 1.79 mmol) in CH2Cl2 (3.0 mL) under N2 at 23° C. The mixture was stirred for 26 hours and then directly purified by column chromatography upon silica gel using hexanes-EtOAc (98:2 to 95:5) as eluant to give 3-(N′,N″-di-t-butoxycarbonyl-N-guanidinyl)isoquinoline (189.4 mg, 0.492 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC(OC)=CC=3)=[CH:20][CH:19]=2)[C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(COc2ccc(Nc3c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c3C(=O)O)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: O=c1c2cc(O)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 5.0 g of 2-chloro-6-[[4-[(4-methoxyphenyl)methoxy]phenyl]amino]-3,5-dinitrobenzoic acid, 10 ml of phosphorus oxychloride, 0.2 ml of N,N-dimethylaniline and 50 ml of 1,2-dichloromthane was heated at reflux for 15 minutes and the reaction mixture was filtered hot. The filter cake was washed with 1,2-dichloroethane to provide the title compound, mp 278°-281° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CCN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of tert-butyl 2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (3.11 g, 6.8 mmol) in methanol (50 mL) was added to 10% Pd/C (0.32 g) and stirred in a hydrogen atmosphere (@ ambient pressure) for 5 h. The reaction was filtered through Celite and the filtrate concentrated under reduced pressure to yield tert-butyl 2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (2.2 g) as an oil. MS (ESI+) for C17H29N3O3 m/z 324.3 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@@H:8]([OH:16])[CH2:7]1)=O.[O:19]1[CH2:21][C@@H:20]1[C@@H:22]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:38](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)[CH:39]=[CH2:40]>>[CH2:40]([O:16][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C@@H:6]([NH:5][CH2:21][C@@H:20]([OH:19])[C@@H:22]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7]1)[CH:39]=[CH2:38]
Reactant: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c2cc(C)ccc21
Yield: 86 %

Procedure:
Step BK (3): The product from Step BK (2) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (271 mg, 1.03 mmol) following a procedure analogous to Step AW (1) to afford 415 mg (86% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. LC-MS (M+H)+=467.29; 1H NMR (500 MHz, CDCl3) δ ppm 7.39-7.16 (m, 7H) 5.93-5.87 (m, 1H) 5.33-4.60 (m, 8H) 4.08 (d, 2H) 3.94 (m, 1H) 3.62 (m, 1H) 3.46 (d, 1H) 3.10-3.06 (m, 2H) 3.6 (m, 1H) 2.59-2.54 (m, 2H) 2.37 (s, 3H) 1.25 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:9][C:8]#[CH:7])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
Potassium carbonate (1.04 g, 7.5 mmol) and propargyl bromide (654 mg, 5.5 mmol) were added to a solution of tert-butyl-1-piperazinecarboxylate (931 mg, 5.0 mmol) in acetone (5 ml). The reaction mixture was heated at 60° C. for 1 hour, and then filtered to remove the inorganics. The solvent was removed under vacuum to give a crude product which was purified by column chromatography (10-30% ethyl acetate/hexane) yielding 4-propargylpiperazine-1-carboxylic acid tert-butyl ester (894 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH:17]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[NH2:18].C(OCC)C>CO>[ClH:1].[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: NNc1nccs1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccccc2c1NNc1nccs1
Product: Cl

Procedure:
A solution of 1.63 g of ethyl 4-chloroquinoline-3-carboxylate and 0.80 g of 2-hydrazinothiazole in 22 ml of methanol is stirred for 26 hours at 23°; 22 ml of diethyl ether is added to the resulting slurry, which is then filtered. The precipitate is washed once with methanol-ether (1:1) and once with ether to yield ethyl 4-(2-thiazolylhydrazino)-quinoline-3-carboxylate hydrochloride as a yellow solid which is used directly in the above cyclization.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1)=[O:35]
Reactant: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 3-[2-(methylthio)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (0.82 g, 2.26 mmol) in DCM (22 mL) was added a solution of 50% mCPBA (818 mg, 2.37 mmol) in DCM (6 mL) through an addition funnel. The reaction was stirred for 10 minutes and saturated aqueous NaHCO3 and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (50% EtOAC/hexanes eluant) to provide the product (567 mg) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 8.93 (d, 1H, J=6.8), 8.68 (d, 1H, J=5.6), 8.57 (d, 1H, J=8.8), 8.44 (s, 1H, 8.37-8.35 (m, 1H, 8.08 (d, 1H, J=7.6), 7.78 (t, 1H, J=8.0), 7.61-7.65 (m, 1H), 7.21-7.26 (m, 2H), 2.84 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29].C(N(C(C)C)CC)(C)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>CN(C=O)C>[C:39]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29])(=[O:41])[CH3:40]
Reactant: NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 0 °C

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.019 g, 0.047 mmol) and diisopropyl ethylamine (0.075 mL, 0.43 mmol) in DMF (1 mL) under nitrogen was treated with acetic anhydride (0.004 mL, 0.042 mmol) at ambient temperature. The reaction was warmed slightly to solubilize then reacted at ambient temperature for 10 min. Water was added (2 mL) and the reaction was cooled to 0° C. and concentrated in vacuo. The resulting residue was treated with 1 N NaHSO4 and filtered then triturated with Et2O and dried in air to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.7 (s, 3 H), 3.3 (dd, J=3.1, 1.3 Hz, 2 H), 3.4 (m, 2 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (m, 2 H), 4.9 (t, J=4.8 Hz, 1 H), 7.1 (t, J=8.8 Hz, 2 H), 7.4 (m, 2 H), 8.0 (m, 1 H), 8.2 (s, 1 H), 8.5 (s, 1 H), 10.4 (d, J=6.2 Hz, 1 H), 17.2 (s, 1 H); ES+ MS: 443 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]([OH:25])[CH3:24])[C:11]1=[O:26])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:26])[C@@H:12]([CH2:22][C@@H:23]([OH:25])[CH3:24])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC(C)O)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)C[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (420 mg, 0.91 mmol, 1.0 equiv) in THF (8 mL), MeOH (4 mL) and water (4 mL) was added LiOH.H2O (115 mg, 2.73 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for one hour. The volatile solvent was removed under vacuum and the residue was acidified by addition of 3.0 N HCl aqueous solution until pH=1. The mixture was extracted with EtOAc (50 mL). The separated organic layer was washed with brine (10 mL), dried (over Na2SO4) and concentrated. The residue was purified by HPLC (0.1% NH4OH) to give product (68 mg, 16.7%). MS: 448.2 [M−H+]. 1H NMR (400 MHz, CD3OD) δ 1.07-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.60 (m, 2H) 1.63-1.85 (m, 4H) 1.87-1.98 (m, 1H) 2.02-2.11 (m, 1H) 3.60-3.66 (m, 1H) 3.93-4.03 (m, 2H) 4.15 (d, 1H) 4.26-4.35 (m, 1H) 6.94 (s, 1H).