Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=2[Cl:16])=[O:10])[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=2[Cl:16])=[O:10])[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2Cl)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide (200 mg, 0.480 mmol, prepared as described in the previous step) in DME (20 mL) and water (5 mL) was treated with 2-chlorophenylboronic acid (78.8 mg, 0.504 mmol) and cesium carbonate (469 mg, 1.44 mmol). The resulting mixture was degassed via sonication, placed under Ar, treated with PdCl2(dppf).DCM (19.6 mg, 0.0240 mmol), and heated to 90° C. for 3 h. The cooled mixture was then diluted with water (40 mL) and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 3:17 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-3-nitro-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C20H19Cl2N5O3: 448.1 (M+H); Measured: 448.0.
Reaction SMILES: C([O:4][C@@H:5]([C@H:23]([O:54]C(=O)C)[C@H:24]([O:50]C(=O)C)[C@@H:25]([NH:31][C:32](=[O:49])[C@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH:34]C(OCC1C=CC=CC=1)=O)[CH2:26][O:27]C(=O)C)[C:6]([NH:8][C@H:9]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13]CC)=[O:12])=[O:7])(=O)C>CO.[Pd]>[OH:4][C@@H:5]([C@H:23]([OH:54])[C@H:24]([OH:50])[C@@H:25]([NH:31][C:32](=[O:49])[C@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:34])[CH2:26][OH:27])[C:6]([NH:8][C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:7]
Reactant: CCOC(=O)C[C@H](NC(=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](COC(C)=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1ccc(C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc([C@H](CC(=O)O)NC(=O)[C@@H](O)[C@H](O)[C@H](O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C)cc1
Yield: 46.3 %

Procedure:
A solution of ethyl (S)-3-[(2S,3R,4 R,5S)-2,3,4,6-tetraacetoxy-5-(N-benzyloxycarbonyl-L-leucyl)aminohexanoyl]amino-3-(4-methylphenyl)propionate (184 mg) in methanol (10 ml) was stirred at room temperature with 10% palladium on activated carbon (100 mg) under hydrogen atmosphere for 2 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml) and to the solution was added 1N aqueous sodium hydroxide solution (2.2 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1hour, followed by addition of 1N hydrochloric acid (2.2 ml). After concentration under reduced pressure, the residue was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to afford the title compound (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH3:15])[C:7]=12
Reactant: CCI
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: CCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 42 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and iodoethane, the titled compound was obtained as a white solid. (Yield: 42%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](/[N:11]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cccc(Br)c1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: CN(C)/C=N/C(=S)Nc1cccc(Br)c1
Temperature: 100 °C

Procedure:
(3-Bromophenyl)thiourea (2.1 g, 9.1 mmol) was suspended in N,N-dimethylformamide dimethyl acetal and was heated to 100° C. for 2 d. The cooled mixture was diluted with ether and filtered and the solid washed with ether to give the title compound (2.42 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]#[N:10])([CH3:13])[CH2:11][O:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C#N)(CO)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C#N)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile (25 g, 104.17 mmol) in pyridine (225 mL) was added para-toluene sulphonyl chloride (29.79 g, 156.25 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with a 2N aqueous hydrochloric acid solution (2×50 mL), water (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (10% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-(4-bromo-phenyl)-2-cyano-2-methyl-ethyl ester as a colorless liquid (35 g, 73%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[C:13]1[N:14]=[CH:15][N:16]2[C:21]=1[C:20](=O)[NH:19][CH:18]=[N:17]2.C([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C.N1CCC1>C1(C)C=CC=CC=1>[N:26]1([C:20]2[C:21]3=[C:13]([C:8]4[CH:9]=[N:10][N:11]([CH3:12])[C:7]=4[Br:6])[N:14]=[CH:15][N:16]3[N:17]=[CH:18][N:19]=2)[CH2:27][CH2:31][CH2:30]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ncc(-c2ncn3nc[nH]c(=O)c23)c1Br
Agent: C1CNC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(-c2ncn3ncnc(N4CCC4)c23)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phosphorus oxychloride (0.046 mL, 0.503 mmol) was added to a mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.17 mmol) in toluene (1 mL). After addition of N,N-diisopropylethylamine (99.5%, 0.149 mL, 0.84 mmol), the reaction was allowed to stir at room temperature for 18 hours. After removal of solvent in vacuo, the residue was dissolved in dichloromethane and treated with azetidine (0.023 mL, 0.34 mmol). After 66 hours, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) to provide C8. Yield: 25 mg, 0.075 mmol, 44%. LCMS m/z 336.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.26-2.34 (m, 2H), 3.5-4.4 (v br m, 4H), 3.97 (s, 3H), 7.70 (s, 1H), 7.84 (s, 1H), 8.47 (s, 1H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[F:47].C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([F:47])[CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 74%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[C:19](=[O:30])[CH2:18][NH:17]1)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>CN(C)C=O>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[C:2]1[N:17]1[CH2:18][C:19](=[O:30])[N:20]2[CH2:29][CH2:28][C:27]3[C:22]([CH:21]2[CH2:16]1)=[CH:23][CH:24]=[CH:25][CH:26]=3
Reactant: O=C1CNCC2c3ccccc3CCN12
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CC(=O)N3CCc4ccccc4C3C2)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (313 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 4 hour and stood overnight. Ice-water was added to the solution and resulting precipitate was collected by filtration and washed with water and then dried to afford 2-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (555 mg, 96%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23]([CH3:47])([CH3:46])[O:24][CH2:25][CH2:26][CH2:27][CH:28]([C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH3:45])O)([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:28]([C:30]3[S:34][C:33]([C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=4)=[N:32][C:31]=3[CH3:45])[CH2:27][CH2:26][CH2:25][O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:47])[CH3:46])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO[Si](C)(C)C(C)(C)C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [rac]-4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain [rac]-(6-[4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(O)c1ccc(N(CCCl)CCCl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(N(CCCl)CCCl)cc1

Procedure:
A solution of N-(N',N'-dimethylaminoethyl) 1-methyl-4-{1-methyl-4[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamido}imidazole-2-carboxamide (248 mg, 0.510 mmol) in methanol (35 mL) was hydrogenated over 5% Pd on carbon (118 mg) at room temperature and atmospheric pressure until TLC analysis indicated complete reduction of the starting material (5 h). The catalyst was removed by filtration. Concentration of the filtrate gave a residue which was coevaporated with dry THF (20 mL, twice) to give N-(N',N'-dimethylaminoethyl)-2-methyl-4-{1-methyl-4[1-methyl-4-aminoimidazole-2-carboxamido]imidazole-2-carboxamido}imidazole-2-carboxamide as an off-white powder. p-N,N-Bis(2-chloroethyl)aminobenzoyl chloride was prepared by dissolving p-N,N-Bis(2-chloroethyl)aminobenzoic acid (13.4 mg, 0.510 mmol) in benzene (2 mL) and thionyl chloride (2 mL) and heating to reflux under a drying tube for 1.25 h. (The solution turned from purple to green upon addition of thionyl chloride). The excess thionyl chloride and solvent were then removed under reduced pressure and the residue coevaporated with dry CH2Cl2 (10 mL, once).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2nc(Cl)ncc2C)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)c1
Yield: 20 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-methoxyphenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 20% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.59 (d, 2H, J=8.2 Hz), 7.37 (t, 1H, J=8.0 Hz), 7.24 (d, 2H, J: not calculated due to overlapping peaks), 7.16 (m, 2H), 6.98 (d, 1H, J=8.2 Hz), 3.85 (s, 3H), 3.49 (s, 2H), 2.57 (bs, 8H), 2.36 (s, 3H), 2.24 (s, 3H); MS (ESI): 404.4 [M+H]+, 202.9 [M+2H]2+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][C:23](=O)[CH3:24].C(O)(=O)C>C(O)C>[CH3:24][C:23]1[CH:22]=[CH:21][N:13]2[N:12]=[C:11]([NH2:16])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)=[C:14]2[N:15]=1
Reactant: CC(=O)C=CN(C)C
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Temperature: -10 °C

Procedure:
The product from Example 1B (200 mg, 0.775 mmol) was charged to a microwave vial with a stir bar. A solution of 4-(dimethylamino)but-3-en-2-one (175 mg, 1.55 mmol) in ethanol (2 mL) was added, and the mixture was stirred at room temperature as acetic acid (25 ΞL, 0.437 mmol) was added. The solution was irradiated in the microwave at 150° C. for 35 minutes, then cooled to room temperature and finally to −10° C. The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc, 70:30-40:60) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 5.71 (s, 2H), 6.69 (d, J=7.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.87-7.98 (m, 2H), 8.62 (d, J=7.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][N:9]1NC(CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1NC(=O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1
Reaction time: 2 h

Procedure:
To 1.20g (2.86 mmol) of N-t-butyl-4-(1,1-dimethylethoxycarbonylamino)-1-(phenylmethylcarbonylamino)piperazine-2(S)-carboxamide and 1.1g (0.086 mmol) of 10% Pd/C was added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>>[ClH:44].[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29](=[O:32])[C:30]#[CH:31]>C(Cl)Cl.C1N2CCN(CC2)C1>[CH2:1]([C@@H:8]1[C@@H:16]([O:17]/[CH:31]=[CH:30]/[C:29](=[O:32])[CH3:28])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: C#CC(C)=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CC(=O)/C=C/O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (622 mg, 1.64 mmol, 1.00 equiv) in CH2Cl2 (16 mL, 0.10 M) at 0° C. (ice water bath) were added but-3-yn-2-one (0.192 mL, 2.46 mmol, 1.50 equiv) and DABCO (9 mg, 0.08 mmol, 0.05 equiv). The dark solution was removed from the cold bath, stirred at room temperature for 2 h, concentrated, and purified by automated silica gel column chromatography (5-50% EtOAc in hexanes) to provide tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(((E)-3-oxobut-1-en-1-yl)oxy)-1,5-dioxonan-3-yl)carbamate (617 mg, 84%) as an amorphous white solid: IR (ATR) 1753, 1707, 1631, 1600, 1497, 1367, 1158, 1077, 1021, 956, 909, 730, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47-7.35 (d, J=12.3 Hz, 1H), 7.35-7.25 (m, 1H), 7.25-7.16 (m, 1H), 7.16-7.04 (m, 2H), 5.84-5.71 (d, J=12.3 Hz, 1H), 5.16-5.07 (d, J=8.2 Hz, 1H), 5.07-4.95 (dq, J=9.3, 6.4 Hz, 1H), 4.72-4.57 (q, J=7.4 Hz, 1H), 4.01-3.85 (dd, J=11.6, 7.5 Hz, 1H), 3.82-3.67 (t, J=9.2 Hz, 1H), 2.14-2.05 (m, 1H), 3.59-3.49 (m, 1H), 3.49-3.40 (m, 1H), 3.36-3.23 (dd, J=11.1, 7.6 Hz, 1H), 2.97-2.86 (dd, J=13.8, 3.7 Hz, 1H), 2.45-2.30 (m, 1H), 2.21-2.14 (s, 3H), 2.14-2.05 (s, 1H), 1.49-1.41 (s, 9H), 1.41-1.36 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 197.25, 172.15, 162.57, 138.45, 129.07, 128.58, 126.52, 108.48, 89.17, 80.33, 73.86, 72.57, 71.38, 52.71, 46.43, 35.29, 28.69, 28.26, 18.73, 14.20; HRMS-ESI (m/z) [M+Na]+ calc'd for C24H33NO7Na, 470.2149. found, 470.2160.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9][CH3:10])(=[O:4])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9]([CH3:10])=[O:16])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CC(=O)OCCCS(C)=O
Temperature: 0 °C
Yield: 65.8 %

Procedure:
To an ice-cold solution of 3-methylthio-1-propyl acrylate (18) (5.95 g, 37.1 mmol) in CH2Cl2 (80 mL), m-chloroperoxybenzoic acid (76.5 wt % 8.37 g, 37.1 mmol) was added in portions over a period of 1.5 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the solvent was evaporated under reduced pressure. The resulting sticky white solid was washed with water (2×100 mL) and filtered. The water washings were evaporated under reduced pressure to yield the crude product as a yellow oil. The crude product was purified by column chromatography (silica gel, ether, 20 wt % acetone/ether, 70 wt % acetone/ether) to afford colorless oil compound 23, namely methyl 3-(acryloyloxy)propyl sulfoxide (4.3 g, 66 wt %) (23).
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[S:35][CH:39]=[CH:38][CH:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: O=Cc1cccs1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3cccs3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.280 g, 0.610 mmol) in anhydrous methanol (6 mL), at room temperature, was added thiophene-2-carboxaldehyde (0.25 mL, 2.67 mmol) followed by NaBH3CN (0.081 g, 1.30 mmol) and the resultant solution was stirred at room temperature. After 1 day, an additional amount of NaBH3CN (0.083 g, 1.31 mmol) was added and the solution was stirred at room temperature for an additional 3 days. The solvent was removed under reduced pressure and CH2Cl2 (30 mL) and water (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (2 mm plate, 40:1 CH2Cl2-MeOH) provided 0.173 g of the desired amine as a yellow oil.