Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[C:8]2[CH:13]=[N:12][C:11]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 28.8 %

Procedure:
8-Cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.051 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (10 mg, 0.051 mmol) were combined in i-PrOH (2 mL) and heated to 80° C. After 14 h, the solution was concentrated and purified by preparative HPLC (30 mL/min 0-100% H2O/MeCN gradient over 10 min) to provide 7.2 mg (29%) of 8-cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCl3:) δ ppm 9.32 (s, 1H), 8.31 (s, 1H), 7.57 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=8.9 Hz), 4.40 (q, 2H, J=7.1 Hz), 3.25-3.46 (m, 8H), 2.82-2.84 (m, 3H), 1.49-2.0 (m, 8H), 1.41 (t, 3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H34N6O3: 490.27, found: (M+H) 491.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.[N+](C1C=CC(C=C[N+]([O-])=O)=CC=1)([O-])=O>C1(C)C=CC=CC=1>[CH2:26]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc([N+](=O)[O-])cc3)cn2Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccc([N+](=O)[O-])cc1
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reaction time: 0.17 h

Procedure:
1-Benzyl-3-(4-nitro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.69 g) in toluene (5 mL) was added 378 μL of benzylamine. The mixture was stirred for 10 min and then 0.70 g of silica gel (SiO2) was added. After stirring at RT for 8 h, 0.77 g of 1-nitro-4-(2-nitro-vinyl)-benzene in toluene (5 mL) was added and the mixture was stirred for 14 h at RT. The mixture was then filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Chromatography on SiO2 (8 to 20% EtOAc/hexanes) afforded 0.48 g of the desired compound. MS (ESI): exact mass calculated for C25H27N3O4, 433.20; found, m/z 434.2 [M+H]+, 456.2 [M+Na]+.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[N+:25]([O-])=O)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1[NH2:25])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Yield: 109.5 %

Procedure:
α-(2-Propenyl)-[2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (50.49 g; 0.102 mole) was dissolved in methanol (350 ml) under argon at room temperature. Powdered stannous chloride dihydrate (119.67 g; 0.53 mole; 5.2 eq.) was added followed by concentrated hydrochloric acid (155 ml with stirring. Celite, ethyl acetate, and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a Celite pad (rinsed three times with ethyl acetate), rotary evaporated, and suction-filtered. The collected white solid was rinsed with 10% methanol:water and dried giving 51.97 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[N:25][OH:26])=[C:16]1[CH3:27]>>[Br:12][C:5]1[CH:6]=[C:7]([CH2:10][O:26]/[N:25]=[CH:24]/[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH3:14])[C:16]=2[CH3:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:13]
Reactant: Cc1c(C=NO)c2ccccc2n1C
Reactant: COC(=O)c1ccc(CBr)cc1Br
Product: Cc1c(/C=N/OCc2ccc(C(=O)O)c(Br)c2)c2ccccc2n1C
Yield: 43.8 %

Procedure:
This compound was produced using similar methods as that used in Step 4, example 6, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.28 g, 0.91 mmol) and 1,2-dimethyl-1H-indole-3-carbaldehyde oxime (0.18 g, 0.96 mmol). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (50/50 with 1% formic acid) followed by HPLC (65% acetonitrile in 0.1% trifluoroacetic acid solution) and one final recrystallization from ethyl acetate/hexanes to give 2-bromo-4-[({[(1E)-(1,2-dimethyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]benzoic acid (0.16 g, 45%) as a white solid. mp=165-166° C. 1H NMR (400 MHz, DMSO-d6); δ 13.34 (bs, 1H), 8.53 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.44 (d, 1H), 7.16 (t, 1H), 7.08 (t, 1H), 5.17 (s, 2H), 3.67 (s, 3H), 2.47 (s, 3H). Mass spec; (ES+) m/z 401.1, (ES−) m/z 399.0. Elemental analysis; Calculated for C19H17BrN2O3: C, 56.87; H, 4.27; N, 6.98. Found: C, 56.84; H, 4.3; N, 6.92.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][CH:44]3[CH2:46][CH2:45]3)[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[CH:44]1([NH:43][C:41]2[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=[C:37]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:12]4[CH:11]=[CH:10][C:9]([C:7]([N:1]5[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]5)=[O:8])=[CH:14][CH:13]=4)[CH:32]=3)[CH:42]=2)[CH2:46][CH2:45]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(c1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1)N1CCNCC1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.163 mmol, 0.052 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.2 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 0.050 g) and PdCl2dppf (0.1 eq, 0.0136 mmol, 0.001 g). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours 30. The reaction mixture is dissolved in DCM and washed with water. The organic layer is dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 477.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(c2ccc(O)c([N+](=O)[O-])c2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH2Cl2 (100 mL) was added BBr3 (12.0 g, 47.8 mmol) at −70° C. The mixture was stirred at −70° C. for 1 hour, then allowed to warm to −30° C. and stirred at this temperature for 3 hours. Water (50 mL) was added dropwise at −20° C., and the resulting mixture was allowed to warm room temperature before it was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/EtOAc 15:1) to afford 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 78%). 1H NMR (CDCl3, 400 MHz) δ 10.5 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.0, 8.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 3.64 (s, 3H), 1.68-1.64 (m, 2H), 1.20-1.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.N1C=CC=CC=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>CO>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Solvent: c1ccncc1
Solvent: CO
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.2 %

Procedure:
To a mixture of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.00 g) and pyridine (30 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction methanol (98:2-95:5, volume ratio) to give the title compound (250 mg, yield 27%) as orange crystals.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11]C(=O)C)[C:7]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].Cl>C(O)C>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnc(-c2nc3ccccc3[nH]2)n1CCO

Procedure:
3.5 mg. of 2-[5-nitro-1-(2-acetoxyethyl)-2-imidazolyl]-benzimidazole are boiled for 1 hour in 8 ml. of ethanol with 4 ml. of concentrated aqueous hydrochloric acid. After concentrating the reaction mixture to dryness, the residue is digested with methanol. After vacuum-filtering, 226 mg. of 2-[5-nitro-1-(2-hydroxyethyl)-2-imidazolyl]-benzimidazole is obtained, m.p. 217°-219° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]=[C:29]=[O:30])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][C:29](=[O:30])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Product: O=C(Nc1ccc2c(c1)OCCO2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 2,3-dihydro-1,4-benzodioxin-6-ylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a solid (29.1 mg, 50%) having the following characteristics.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44](COS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:44]2[C:45](=[O:46])[N:40]([CH2:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[N:41]=[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)[CH:43]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:20](=[O:21])[NH:19][CH2:18][C:17]([CH3:23])([CH3:22])[N:14]3[C:15]=2[CH:16]=1)=[O:7])C.Cl>CCO.O>[CH3:22][C:17]1([CH3:23])[N:14]2[C:15]3[CH:16]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][C:11]=3[CH:12]=[C:13]2[C:20](=[O:21])[NH:19][CH2:18]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A 3M aqueous solution of NaOH (0.27 mL) was added to 58 mg (0.20 mmol) of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester in 5 mL of EtOH. After 3 h an additional 0.27 mL of NaOH (3M) was added followed by 1 mL of H2O, and the mixture was heated to 50° C. for 3 h. The mixture was diluted with water, chilled to 0° C., and concentrated HCl was added until the pH reached 2. The resulting suspension was stirred for 1 h at 0° C. then filtered and washed with water. The filter was dried in the vacuum oven at 60° C. overnight to provide 51 mg of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH2:6]1)=[N+]=[N-].[C:17]([OH:20])(=S)[CH3:18]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:17](=[O:20])[CH3:18])[O:9][N:8]=2)=[N:11][CH:12]=1
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(O)=S
Product: CC(=O)NCC1CC(c2ccc(Br)cn2)=NO1
Reaction time: 52 h

Procedure:
5-Azidomethyl-3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazole (3 g, 10.6 mmol) and thioacetic acid (10 ml) were combined and stirred for 52 hours. The reaction mixture was concentrated in vacuo and then ethyl acetate (20 ml) was added. The resulting precipitate was filtered and washed with ethyl acetate (2×20 ml) to give the desired product (1.8 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCCCCc1ccc(N)c(Br)c1
Product: CCCCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-pentylaniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-pentylaniline,
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@H:17]([C:22]([N:24]([C@@H:26]([CH:33]([CH3:35])[CH3:34])/[CH:27]=[C:28](/[C:30](O)=[O:31])\[CH3:29])[CH3:25])=[O:23])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[C:4]([CH3:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(#N)C>[CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@H:17]([C:22]([N:24]([C@@H:26]([CH:33]([CH3:35])[CH3:34])/[CH:27]=[C:28](\[CH3:29])/[C:30]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:31])[CH3:25])=[O:23])[C:18]([CH3:20])([CH3:21])[CH3:19])=[O:15])[C:4]([CH3:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N1CCOCC1)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
By using an analogous procedure to that described in General Procedure I Method A, N,β,β,3-tetramethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropyl-2-butenyl]-N1,3-dimethyl-L-valinamide (100 mg, 0.205 mmol) is treated with hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) in anhydrous acetonitrile (3 ml) at room temperature for 15 hours, followed by addition of morpholine (0.036 ml, 0.41 mmol). After stirring at room temperature for 15 hours, the product is purified using the aqueous work-up method, to provide the title compound (89 mg, 78%) as a orange amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:35])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](Cl)=[O:30])[O:20]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:23]1([CH3:25])[C:19]([CH3:18])([CH3:35])[O:20][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:30])[O:22]1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CC1(C)OB(c2cccc(C(=O)Cl)c2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cccc(C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 13 h
Yield: 41.7 %

Procedure:
A mixture of benzyl 4-aminobenzoate (4.39 g, 19.3 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (4.30 g, 16.1 mmol) and N,N-diisopropylethylamine (7.49 g, 57.9 mmol) in methylene chloride (50 mL) was stirred at ambient temperature for 13 h. After this time, the reaction was concentrated under reduced pressure and purified by chromatography (silica, heptane to 1:3 ethyl acetate/heptane) to afford benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.07 g, 78% pure by mass, 27% yield) as a light yellow sticky foam that was used without further purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(=O)C>CO>[C@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(F)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3ccc(F)cc3)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A 4.0 g portion of 4-fluorophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was reacted as described in Example 8, giving 2.2 g of the intermediate as a white solid, [α]D26 =+52°±1° (0.872%, methanol).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 49.4 %

Procedure:
The title compound (74 mg) was prepared as in Example 177, Steps C and D, using 215 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 296 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C18H22ClN3, 315.15; found, m/z 316.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.59-7.53 (m, 2H), 7.36-7.30 (m, 2H), 4.48 (m, 1H), 3.44-3.37 (m, 2H), 3.34-3.27 (m, 2H), 3.22-3.15 (m, 2H), 2.81-2.74 (m, 2H), 2.06-1.84 (m, 6H), 1.65-155 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[S:15])[NH2:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].Cl[CH2:19][C:20](=O)[CH3:21]>C(O)C>[CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[S:15][CH:19]=[C:20]([CH3:21])[N:14]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCc1c(OC)nc2nc(C(N)=S)cn2c1C
Solvent: CCO
Product: CCc1c(OC)nc2nc(-c3nc(C)cs3)cn2c1C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A mixture of 4.30 g (0.017 mol) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-thiocarboxamide and 3.18 g (0.0344 mol; 2 eq) of chloroacetone in 300 ml of ethanol was heated under reflux. After 5 hours, 3.18 g of more chloroacetone were added. After 29 hours, the solvent was evaporated, and the residue was dissolved in 2000 ml of water. The solution was made alkaline with concentrated ammonia and was extracted 3 times with chloroform. The chloroform extracts were dried over MgSO4, filtered and evaporated to dryness. The residue was purified by flash chromatography using chloroform as eluent and the resulting solid was recrystallized from ethyl acetate to obtain 3.37 g (68%) of 6-ethyl-7-methoxy-5-methyl-2-(4-methylthiazol-2-yl)-imidazo[1,2-a]pyrimidine as a buff powder melting at 184°-186° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([N:29]4[CH2:28][CH2:27][O:26][CH2:31][CH2:30]4)=[N:33][CH:34]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-morpho-lin-4-yl-nicotinamide was prepared starting from intermediate A and 6-morpholinonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (d, J=1.76 Hz, 1H) 8.33 (d, J=8.28 Hz, 1H) 8.12 (t, J=4.50 Hz, 1H) 7.98 (d, J=0.75 Hz, 1H) 7.85 (dd, J=9.03, 2.51 Hz, 1H) 7.47-7.57 (m, 4H) 7.36-7.44 (m, 2H) 7.17 (s, 1H) 6.79 (d, J=9.03 Hz, 1H) 6.73 (d, J=2.01 Hz, 1H) 4.24 (d, J=4.52 Hz, 2H) 3.63-3.71 (m, 4H) 3.48-3.55 (m, 4H). MS calcd. for C29H24ClN5O4 [(M+H)+] 542.2, obsd. 542.0.