Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][NH:3]1.C([Li])(CC)C.C1CCCCC1.[CH3:28][S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:28][S:29]([NH:32][C:33]([N:3]1[CH2:4][C@H:5]([NH:6][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[C:2]1=[O:1])=[O:34])(=[O:31])=[O:30]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: CS(=O)(=O)N=C=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: -75 °C
Reaction time: 0.03 h
Yield: 53.8 %

Procedure:
A stirred suspension of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (2.20 g; see example 1C) in 60 ml of dry tetrahydrofuran under nitrogen was warmed using a water bath at 40° C. until solution occurs. The solution was cooled to -75° C., and 7.4 ml of 1.35 M sec-butyl lithium in cyclohexane (10 mmol) was added. After stirring for 2 minutes, (methylsulfonyl) isocyanate (about 1.20 g) was added. This reaction was stirred at -75° C. for 10 minutes and poured into 100 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer. Ethyl acetate was added, and the pH was adjusted to 7. After several extractions with ethyl acetate, the aqueous layer was covered with ethyl acetate and adjusted to pH 2. Repeated extraction with ethyl acetate gave an acidic extract, which was dried (sodium sulfate) and evaporated to a residue (2.61 g). Chromatography of this residue on 250 g of silicAR CC-4 using dichloromethane and then 1% methanol in dichloromethane provided 1.82 g of product as a residue.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:15]=2[S:14]1.C(OCC)C.Cl>C(O)C>[ClH:1].[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:9])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:27][C:15]=2[S:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCS(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: -35 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
70-75% pure m-chloroperbenzoic acid (4.3 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-propylthioethyl)-6-trifluoromethoxybenzothiazoline (5.87 g) dissolved in absolute ethanol (80 cc) cooled to -35° C. The reaction is continued for 10 minutes at the same temperature. The reaction medium is then added to ethyl ether (300 cc) and treated with 4.2N ethereal hydrogen chloride (4.2 cc). The precipitate formed is filtered off, then taken up in distilled water (50 cc) and neutralized with 1N sodium hydroxide. After extraction with ethyl acetate, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), the crude product is purified by chromatography on a silica column, with ethyl acetate and then a mixture of ethyl acetate and methanol (90:10 by volume) as eluents. After conversion to hydrochlorides, 2-imino-3-(2-propylsulphonylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (0.33 g), subliming at about 200° C., and (RS)-2-imino-3-(2-propylsulphinylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (2.63 g), m.p. 125° C., are obtained.
Reaction SMILES: O/[N:2]=[C:3]1\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[NH:11][C:12](=[O:19])[C:13]3[N:14]([CH:16]=[CH:17][N:18]=3)[C:15]\1=2.C.[C:21](O)(=[O:23])[CH3:22]>O.CN(C)C=O.[Zn]>[C:21]([NH:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: O=c1[nH]c2c(n3ccnc13)/C(=N/O)c1ccccc1-2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 4 h

Procedure:
A suspension of 5.25 g of 10-(E-hydroxy-imino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 2.9 g of zinc powder in 100 ml of acetic acid is heated for 2 hours at a temperature between 80° C. and 90° C. After addition of 100 ml of acetic acid, the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (10 mmHg; 2 kPa) at 65° C. The product obtained (3.8 g) is suspended in 100 ml of distilled water, filtered, washed with 10 ml of distilled water and with 10 ml of acetone and then dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (2 g) is dissolved in 60 ml of boiling dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered while hot. The filter is washed with 10 ml of boiling dimethylformamide and the filtrate and the combined washings are then stored for 4 hours at a temperature in the region of 20° C. The crystals formed are separated out by filtration, washed successively with 10 ml of dimethylformamide, 10 ml of distilled water and 10 ml of acetone and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.43 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting at 330° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 2.00 (s, 3H: --CO--CH3); 6.13 (d, J=8.5 Hz, 1H: CH--N); 7.35 and 7.48 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.48 and 7.85 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.58 and 7.65 (2s broad, 1H each: --H of the imidazole); 8.58 (d, J=8.5 Hz, 1H: --NH--COCH3); 12.50 (cplx, 1H: --NH--)].
Reaction SMILES: [Cl:1][CH:2]([Cl:4])[CH3:3].[B:5](OC)([O:8][CH3:9])[O:6][CH3:7].C(NC(C)C)(C)C.C([Li])CCC.ClC(B(OC(C)C)OC(C)C)Cl>C1COCC1>[Cl:1][C:2]([B:5]([O:8][CH3:9])[O:6][CH3:7])([Cl:4])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(Cl)Cl
Agent: CC(C)OB(OC(C)C)C(Cl)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COB(OC)C(C)(Cl)Cl
Temperature: -78 °C

Procedure:
A modification of the procedure of Example 1 was followed. 1,1-Dichloroethane (25 ml, 0.30 mol) was used in place of dichloromethane and trimethyl borate (30 ml, 0.265 mol) was used in place of triisopropyl borate. The quantity of diisopropylamine was 40 ml and that of butyllithium was 0.25 mol. A -78° C. cooling bath was used. The yield of (I) (R3 =R7 =R8 =methyl), bp 48° C. (40 Torr), was 27 g, 55% taking into account the 14% THF indicated by NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate(5.422 g, 0.02 mol) and 1-phenylpiperazine(3.44 g, 0.02 mol) were dissolved in tetrahydrofuran(10 ml). After DBU(3.04 g, 0.02 mol) was added, the resulting solution was stirred at room temperature for 2 hrs, concentrated and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>>[CH:1]1([CH2:4][NH:5][C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[N:23]([CH3:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[O:13])[CH2:3][CH2:2]1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCC1CC1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CC2)cc1)c1ccccc1

Procedure:
The title product was prepared from cyclopropylmethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was used without further purification (100%, semi-crystal oil). HPLC-MS m/z=325.1 (M+1), Rt: 3.40 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[CH:26][N:25]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[CH:26][N:25]=[CH:24]4)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: Nc1cccc2cnccc12
Solvent: ClCCl
Product: CN1C(=O)C(NC(=S)Nc2cccc3cnccc23)N=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
As illustrated in the scheme above, to a solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 7) (0.035 g, 0.1 mmol) in dichloromethane (5 ml) was added 5-isoquinolinamine (0.015 g, 0.1 mmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (20 mg, 40%). 1H-NMR (CDCl3): δ 9.33 and 9.19 (2×s, 1H), 8.63 and 8.49 (2×d, J=5.6 Hz and J=6.0 Hz, 1H), 8.34 (br s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.92 (t, J=11.6 Hz, 2H), 7.58-7.32 (m, 10H), 6.03 (d, J=7.6 Hz, 1H) and 3.3 (s, 3H). MS (ESI) (M+H)+=486
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][O:31][CH2:32][CH2:33][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:28][CH:29]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCOCc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccc(Br)cc3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 46.2 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 1-bromo-4-{[(2-bromoethyl)oxy]methyl}benzene (42 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product was washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (19.4 mg, 32%). LC/MS ESI RT 2.07 min M+ 506
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[C@@H:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:11]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C@@H:10]([O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[CH:27]([CH3:29])[CH3:28])[C:9](=[O:30])[S:38][C:35]1[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[Si](O[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@H]1c1ncccc1F)(C(C)C)C(C)C
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(C)[Si](O[C@@H](C(=O)Sc1ccc(Br)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ncccc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 101.8 %

Procedure:
A concentrated residue (70.9 mmol) of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone (compound 20) was dissolved in diisopropyl ether (240 mL), and 4-bromothiophenol (15.5 g, 82.0 mmol) and potassium carbonate (3 g) were added thereto, and stirred at room temperature for 25 minutes. The disappearance of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone was confirmed, and then water (200 mL) and diisopropyl ether (120 mL) were added thereto and subjected to liquid-liquid separation. The organic layer was separated, washed with water (150 mL) and then with saturated saline water (150 mL), dried over magnesium sulfate, and concentrated under reduced pressure to obtain a residue of S-(4-bromophenyl) (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanethioate (compound 14) (45.3 g).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[C:9]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][N:38]=[C:37](SC)[N:36]=3)[C:10]=2[CH:11]=[C:12]2[C:25]=1[N:24]1[CH2:26][C@@H:27]([CH3:31])[O:28][C@@H:29]([CH3:30])[C@@H:23]1[C:14]1([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH2:13]2.[CH2:43]1COCC1.O>CO.C(Cl)Cl>[F:7][C:8]1[C:9]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([S:3]([CH3:43])(=[O:5])=[O:2])[N:36]=3)[C:10]=2[CH:11]=[C:12]2[C:25]=1[N:24]1[CH2:26][C@@H:27]([CH3:31])[O:28][C@@H:29]([CH3:30])[C@@H:23]1[C:14]1([C:15](=[O:22])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20])[CH2:13]2
Reactant: CSc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reaction time: 0.17 h

Procedure:
Oxone (5902 mg, 9.60 mmol) was added to a solution of (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylthio)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 168, 984 mg, 1.92 mmol) in MeOH:THF:H2O (30 ml)(1:1:1), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with DCM (50 ml), stirred for 10 minutes, filtered, and the filter cake was washed with EtOH. The filtrate was washed with water and brine, concentrated under reduced pressure to give the desired product used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Cn2ccnc2C(C)c2cccc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) and N, N-diisopropylethylamine (77 mg, 0.6 mmol) in dichloromethane, under nitrogen, was added 4-methoxybenzyl bromide (151 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 90 min and water (10 ml) was added. The layers were separated, and the aqueous layer washed with dichloromethane (15 ml). The combined organics were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [N:1]([C@@H:4]([C@H:46]1[CH2:50][CH2:49][O:48][CH2:47]1)[C:5]([NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28]C(OC)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)=[O:6])=[N+]=[N-].N1C=CC=CC=1.Cl[C:58]([O:60][CH3:61])=[O:59]>CO.C(OCC)(=O)C.[Pd]>[CH3:61][O:60][C:58](=[O:59])[NH:1][C@@H:4]([C@H:46]1[CH2:50][CH2:49][O:48][CH2:47]1)[C:5](=[O:6])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:58](=[O:59])[O:60][CH3:61]
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N=[N+]=[N-])[C@H]1CCOC1)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H]1CCOC1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of the product of Example 142A (0.038 g, 0.055 mmol) in a mixture of methanol (0.40 mL) and ethyl acetate (0.40 mL) was added 10% Pd on C (0.038 g), and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 2 hours. The mixture was filtered through celite and the solvent was evaporated. The residue was dissolved in dichloromethane (0.40 mL) and pyridine (0.007 mL, 0.087 mmol) and methyl chloroformate (0.004 mL, 0.052 mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate and the organic layer was washed with dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 5% methanol in ethyl acetate to give the title compound (0.017 g, 43% yield). 1H NMR (300 MHz, MeOH-d4), δ ppm 0.87 (s, 9 H), 1.51-1.66 (m, 4 H), 2.31-2.43 (m, 1 H), 2.66 (dd, J=13.4, 9.0 Hz, 1 H), 2.83-2.96 (m, 3 H), 3.44 (dd, J=6.4, 9.0 Hz, 1 H), 3.52 (s, 3 H), 3.55-3.85 (m, 5 H), 3.65 (s, 3 H), 3.91 (d, J=9.6 Hz, 1 H), 4.24-4.30 (m, 1 H), 4.34-4.42 (m, 1 H), 7.11-7.35 (m, 8 H), 7.78-7.90 (m, 4 H), 8.57 (m, 1 H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-])=O.[NH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16]([O-])(O)=[O:17].[Na+]>>[C:16]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCC(=O)O
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ccccc1
Reaction time: 18 h

Procedure:
To a nitrophenol resin (TG-2a) (10 mg, 3.5 μmol) was added 0.1 M glycin in 0.1 M NaHCO3. The reaction was stirred for 18 hours. The reaction mixture was filtered and washed with H2O. The washer was combined and acidified with acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9]O)=[O:5].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S(O)(=O)=[O:34])=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([O:34][CH:26]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH3:9])=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: ClCCl
Product: CC(CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl)OC1CCCCO1
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of 13 (1.22 g, 4.0 mmol) in 50 mL of CH2Cl2 was cooled in an ice-bath, and 3,4-dihydro-2H-pyran (1.0 mL) and p-toluenesulfonic acid (0.1 g) were added. The reaction mixture was stirred for 2 h, then concentrated under reduced pressure. Chromatography of the residue on silica gel, eluting with EtOAc/petroleum ether (from 1:2 to 2:1), gave 2-chloro-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)propyl]benzamide (21) (1.45 g, 94%): as a pale yellow oil; 1H NMR [(CD3)2SO] δ 8.99 (d, J=2.7 Hz, 1 H, H-4), 8.81 (m, 1 H, CONH), 8.51 (d, J=2.7 Hz, 1 H, H-6), 4.57 (m, 1 H), 3.72 (m, 2 H), 3.46-3.25 (m, 4 H), 1.82-1.44 (m, 8 H). 13C NMR δ 162.7, 148.4, 145.9, 140.3, 128.2, 125.8, 120.5, 98.0, 64.2, 61.3, 36.5, 30.2, 28.9, 24.9, 19.1. HRMS (FAB) Calcd. For C15H1935ClIN3O7 [M+H+] m/z 388.0912. Found; 388.0915.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33].C(N(CC)CC)C.Cl>C(#N)C>[CH3:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and 3,4-dimethylphenylisocyanate (0.15 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.30 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.02 min (97.86%); mp: 254-256° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.30-2.47 (m, 1H), 2.60 (d, J=17.2 Hz, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.36-4.50 (m, 3H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 6.66 (t, J=5.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.11 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.62, 22.49, 31.20, 42.77, 47.10, 51.56, 115.35, 119.15, 121.86, 122.91, 126.89, 128.67, 129.49, 130.26, 136.08, 138.03, 142.36, 144.96, 155.26, 167.95, 170.98, 172.85; Anal Calcd for C23H24N4O4: C, 65.70; H, 5.75; N, 13.33. Found: C, 65.48; H, 5.62; N, 13.20.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.FC1C(C(C2N3N=C(C(=O)C)C=CC3=NC=2)C)=C(F)C=C2C=1C=NN2C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:11]([F:23])([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 35.2 %

Procedure:
The title compound as a light yellow oil (180 mg, 30%, 80% pure) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (500 mg, 1.507 mmol), tributyl(1-ethoxyvinyl)stannane (2.55 ml, 7.54 mmol) and PdCl2(PPh3)2 (106 mg, 0.151 mmol) in 1,4-dioxane using the same procedure as described in the synthesis of compound 31.4. 1H-NMR (400 MHz, MeOH-d4) δ ppm 9.17 (s, 1H), 8.91 (d, 1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m, 1H), 2.61 (s, 3H). LCMS (method B): [MH]+=340.1, tR=2.16 min.