Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH2:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[C:7]([CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:17]=O>S(=O)(=O)(O)O>[CH3:17][NH:6][C:5]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([CH2:11][CH3:12])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C=O
Reactant: CCc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCc1c([N+](=O)[O-])cc(C)c(NC)c1[N+](=O)[O-]

Procedure:
This compound is made according to Scheme 1. 2,4-Dinitro-3-ethyl-6-methylaniline is treated with paraformaldehyde in concentrated sulfuric acid to afford N-methyl-2,4-dinitro-3-ethyl-6-methylaniline. The synthesis is completed in the same manner as 4-ethyl-5-(2-imidazolinylamino)benzimidazole (see Example 2).
Reaction SMILES: [CH2:1]([N:8]([C:29]1[CH:34]=CC=C[CH:30]=1)[C:9]([C:11]1([C:15]([NH:17][S:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35]C1C=CC(NC(C)C)=CC=1>>[F:35][C:4]1[CH:5]=[CH:6][C:1]([N:8]([CH:29]([CH3:34])[CH3:30])[C:9]([C:11]2([C:15]([NH:17][S:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:19])=[O:20])=[O:16])[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:2][CH:3]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: O=C(NS(=O)(=O)/C=C/c1ccccc1)C1(C(=O)N(Cc2ccccc2)c2ccccc2)CCC1
Product: CC(C)N(C(=O)C1(C(=O)NS(=O)(=O)/C=C/c2ccccc2)CCC1)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.00 g) obtained in Example 570 (1) and 4-fluoro-N-isopropylaniline (490 mg). This was purified by silica gel column chromatography to give the title compound (71 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[O:15])=[CH:8][C:7]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4].[I-:26].[Na+]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][I:26])=[O:15])=[CH:8][C:7]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(/C=C/C(=O)OCCCCCCCl)cc1OC
Reactant: [I-]
Agent: [Na+]
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCI)cc1OC

Procedure:
Preparation can be carried out analogously to Example 1 using 4.00 g (10.84 mmol) 6-chlorohexyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate and 9.75 g (65.05 mmol) sodium iodide, to yield 6-iodohexyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([N:76]3[CH2:81][C@@H:80]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][C@@H:78]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:77]3)[N:73]=[C:72]([NH:98][C:99]3[CH:104]=[CH:103][C:102]([NH2:105])=[CH:101][CH:100]=3)[CH:71]=2)[CH2:57]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>CC(N(C)C)=O.CCOC(C)=O>[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:67])([CH3:68])[CH3:69])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([N:76]3[CH2:77][C@@H:78]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:79][C@@H:80]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:81]3)[N:73]=[C:72]([NH:98][C:99]3[CH:104]=[CH:103][C:102]([NH:105][C:12]([C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[OH:1])=[O:14])=[CH:101][CH:100]=3)[CH:71]=2)[CH2:57]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(NC(=O)c4ccc5ccccc5c4O)cc3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.018 g, 0.096 mmol) was dissolved in DMA (2 mL), iPr2EtN (0.096 mmol) was added followed by HBTU (0.036 g, 0.096 mmol) and the mixture was shaken in an 8 mL Teflon septum capped vial at room temperature for 20 minutes. 4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-2-(4-aminophenyl-amino)-pyridine (168) (0.055 g, 0.0677 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL) and the organic layer washed with water (15 mL), NaHCO3 (aqueous sat., 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane for 30 min) gave the desired product (170) as an off-white powder upon concentration (0.042 g, 0.043 mmol, 64% yield). LC-MS (ESI): (exact mass: 981.53) m/e=982.6 [M+H+].
Reaction SMILES: C(N)C1C=CC=CC=1.C(=O)(OCC=CC1C=CC=CC=1)OC.CC1C=CC(C2C(=O)C3C(CC(O)C(O)C3)OC=2)=CC=1.CC1(C)C(C=[CH:54][C:55]2CCC/[C:57](=[CH:58]/[CH:59]=C3/C(C)(C)C4C(N/3CCCCS(O)(=O)=O)=CC=CC=4)/[C:56]=2[O:82][C:83]2[CH:88]=[CH:87][C:86]([O:89][CH2:90]CCCNCC3OC(O)C(N)C(O)C3O)=[CH:85][CH:84]=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2>>[CH3:90][O:89][C:86]1[CH:87]=[CH:88][C:83]([O:82][CH:56]([CH2:57][CH2:58][CH3:59])[CH:55]=[CH2:54])=[CH:84][CH:85]=1
Reactant: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: COC(=O)OCC=Cc1ccccc1
Agent: Cc1ccc(C2=COC3CC(O)C(O)CC3C2=O)cc1
Solvent: NCc1ccccc1
Product: C=CC(CCC)Oc1ccc(OC)cc1
Reaction time: 10 h

Procedure:
Reaction of benzylamine with methyl cinnamyl carbonate catalyzed by Complex Ir-3 and [(COE)2IrCl]2 (FIG. 2, triangles): By the procedure for reaction of the combination of Ir-2 and [(COD)IrCl]2, the reaction of benzylamine (135 mg, 1.26 mmol) and methyl cinnamyl carbonate (192 mg, 1.00 mmol) catalyzed by [(COD)Ir(κ2-L1)(PPh3)] (Ir-3) (11.0 mg, 0.0100 mmol) and [(COE)2IrCl]2 (4.4 mg, 0.0050 mmol) was monitored by GC for 10 h. 1H NMR analysis of the crude reaction showed the ratios of products to be 98/1/1, and after purification of the product by the general procedure, HPLC analysis as described above indicated that the enantiomeric excess of the major product was 97.2%.
Reaction SMILES: ICI.[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[CH2:15]([Zn]CC)C.[NH4+].[Cl-]>CCCCCC>[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]12[CH2:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Product: C[Si](C)(C)OC12CCCCC1C2
Temperature: 0 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
Diiodomethane(120 μl, 1.5 mmol) was added slowly to perfluorohexanes (FC-72, 3 mL) in a test tube (14 mm×105 mm) and then trimethylsiloxycyclohexene (180 mg, 1.05 mmol) in hexane (3.5 mL) was slowly poured into the test tube. A hexane solution of diethylzinc (1.0 M, 1.5 mmol, 1.5 mmol) was added to the hexane layer, and the diiodomethane layer on the bottom was stirred gently so as not to mix the three phases. After 10 h at room temperature, additional diidomethane (40 μl, 0.5 mmol) was added to the bottom layer of the test tube by using a syringe. After 14 h, the reaction mixture was cooled to 0° C., and saturated NH4Cl (10 mL) was added. The hexane layer was decanted, washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by short column chromatography (17 mm×20 mm of florisil layer over 50 mm of silica gel layer) with benzene/hexane: ¼ to give 1-trimethylsiloxybicyclo[4.1.0]heptane in 63% yield (123 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[O:4].[C:19]1([C@@H:25]2[CH2:27][C@H:26]2[NH:28][C:29]2[S:30][CH2:31][C:32](=[O:34])[N:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:31]1/[C:32](=[O:34])[N:33]=[C:29]([NH:28][C@@H:26]3[CH2:27][C@H:25]3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:30]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1cnc2ccc(C=O)cc2c1OC
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OC
Temperature: 150 °C
Yield: 29.9 %

Procedure:
To the suspension of 6-formyl-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1e, 100 mg, 0.4 mmol), 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f, 93 mg, 0.4 mmol) and benzolic acid (5 mg, 0.04 mmol) in toluene (2 mL) were added and piperidine (5 uL, 0.04 mmol). The mixture was heated to 150° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with toluene and dried. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride in 30 min) afford 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid methyl ester (55 mg, 30%) as a light yellow solid. LC-MS m/e 460 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][C:19]=3[C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH:8]=2)[N:3]=1.C(O)=[O:38]>C(Cl)Cl>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:19]([C:30]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[O:31])=[CH:20][CH:21]=[CH:22][C:23]=3[C:24](=[O:38])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=2)[N:3]=1
Reactant: O=CO
Reactant: CC(C)(C)CCc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1

Procedure:
A solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)phenyl)(pyrrolidin-1-yl)methanone (188 mg, 0.390 mmol, see Example 45) in formic acid (>96%) (10 mL, 265 mmol) was heated to 110° C. After 4 days CH2Cl2 was added and the solution was washed with water and sodium carbonate solution. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a white powder. MS (ESI, pos. ion) m/z: 501 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:18]1=[O:19].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:17][C:18](=[O:19])[CH:20]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=c1ccc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Oc2ccccc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (1.54 mL, 0.00600 mol) in methylene chloride (0.50 mL) was added to a mixture of coumarin (0.731 g, 0.00500 mol) and of trifluoroacetic acid in DCM (1M, 10 mL) at rt. The resulting mixture was stirred at rt for 1 h and was then washed with NaHCO3 (2 mL) and brine (2 mL) successively. The organic phase was dried (over Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash (ethyl acetate/hexane 20%) to give the desired product (0.99 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12].[Li+].[OH-].CCOC(C)=O>CO.C1COCC1>[C:17]1(/[CH:16]=[CH:15]/[CH2:14][O:13][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:23])=[O:2])=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1NC(=O)OC/C=C/c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1C(=O)O)OC/C=C/c1ccccc1
Reaction time: 0.67 h

Procedure:
Compound 72 (7.989 g, 26 mmol) was dissolved in aqueous methanol (3:1, 1200 mL) with THF (2-3 drops) to aid solubility. A solution of LiOH (3.12 g, 130 mmol) was added as a solid to the stirring reaction mixture at 0° C. and stirred for 40 minutes. The reaction was allowed to return to room temperature and stirred for 16 hours, at which time TLC (70% Pet ether:EtOAc) revealed complete reaction. Excess methanol and THF were evaporated in vacuo and the remaining solution acidified to pH 2 with conc. HCl, to furnish a colourless precipitate (73), which was collected by filtration and dried (92%). 1H NMR (250 MHz, CDCl3) δ 10.85 (s, 1H, acid OH), 10.80 (s, 1H, carbamate NH), 8.34-8.32 (d, 1H, aromatic H), 8.00 (dd, 1H, J=1.5, 7.9 Hz, aromatic H), 7.70-7.55 (m, 1H, aromatic H), 7.53-7.10 (m, 5H, aromatic coc), 6.75 (d, 1H, J=16 Hz, 3′-H), 6.46 (dt, 1H, J=6.2, 16 Hz, 2′-H), 4.82 (d, 2H, J=6.3 Hz, 1′-H); 13C NMR (62.9 MHz, CDCl3) δ 170.6 (ester carbonyl), 153.2 (CO carbamate), 142.0 (aromatic quat), 137.1 (aromatic quat), 135.1 (methine), 134.5 (alkenic methine), 132.5 (methine), 131.0 (methine), 127.7 (methine), 125.0 (alkenic methine), 122.6 (methine), 119.0 (methine), 116.5 (aromatic quat), 66.5 (methylene Coc). MS m/z 297 (M+. +1), 265, 252, 236, 224, 205, 189, 176, 149, 138, 117.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:2]2[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1c[nH]cn1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-imidazoleacetate hydrochloride, as described above in Step A, (4.30 g, 24.3 mmol) in dry DMF (50 mL) were added triethylamine (7.45 mL, 53.5 mmol), then triphenylmethyl bromide (8.64 g, 26.7 mmol). The mixture was stirred at ambient temperature for 18 hours, then partitioned between H2O (250 mL) and EtOAc (250 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with EtOAc, to yield the product as a pale solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (S)-morpholine-3-carboxylic acid (2 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (7.26 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.O1[CH2:20][CH2:19]OCC1>>[CH3:4][N:3]1[CH2:20][CH:19]=[C:6]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=2)[CH2:7][CH2:2]1
Reactant: C1COCCO1
Reactant: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Product: CC(C)Oc1cc(C2=CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
800 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are introduced into 62 ml of 1,4-dioxane. After sparging for 10 min with argon in the reaction mixture, 1.25 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride, 6.02 g of caesium carbonate, 6.2 ml of water and 467 mg of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated at 100° C. for 16 h. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (90/10 to 80/20). 401 mg of 1′-methyl-5-nitro-4-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine are obtained in the form of a yellow gum.
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[O:43]1CCOCC1.Cl>O>[NH2:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:18])[OH:21])[C:6]([OH:43])=[O:7]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: NC(CCCCB(O)O)(C(=O)O)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 100 °C
Yield: 23 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (500 mg, 0.8 mmol) in 1,4-dioxane (3 mL, 40 mmol) was treated with a 6M aqueous solution of hydrogen chloride (6 mL, 40 mmol) followed by heating to 100° C. for 24 h. At the end of the 24 hour period, the reaction mixture was diluted with water and filtered. The filtrate that was obtained was purified by HPLC using 5%-50% acetonitrile in water over 30 min. The product-containing fractions were concentrated, then dissolved in 1N HCl and frozen prior to lyophilization to afford 2-amino-6-borono-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)hexanoic acid (79 mg, 20%) as a white foam. 1H NMR (400 MHz, DMSO-d6, Mixture of diastereoisomers) δ 8.55-8.35 (2H), 8.05-7.98 (m, 2H), 7.96-7.85 (m, 2H), 5.83 (t, J=6.5 Hz, 2H), 3.70-3.14 (m, 4H), 2.78-2.65 (m, 1H), 2.19-1.60 (m, 4H), 1.47-1.23 (m, 3H), 1.14-1.00 (m, 1H); ESI MS found for C16H24BN3O8S m/z 412.1 [M−OH)+; 410.2 (M−H2O)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>C(#N)C.O>[C:20]([CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])[CH:11]=2)[NH:15][CH:14]=1)#[N:21]
Reactant: CCOC(=O)N=C=S
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CC#N
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.33 h

Procedure:
Ethoxycarbonyl isothiocyanate (1.2 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry acetonitrile (50 ml). After 10 min. the resulting suspension was diluted with water (40 ml) and stirred for 20 min.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Temperature: 97 °C

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid dimethylamide (473 mg, 1.43 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (814 mg, 3.56 mmol) and diisopropylethylamine (0.747 mL, 4.29 mmol) in 1,4-dioxane (5 mL) is heated at 97° C. under nitrogen for 2 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with MeOH in dichloromethane 0-2%, to give 4-{2-[4-(6-dimethylcarbamoyl-benzo[b]thiophen-2-yl)-5-methylpyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving in dichloromethane (20 mL) and treating with triethylsilane (0.9 mL) and TFA (4 mL). The resultant yellow solution is stirred at room temperature for 1 hour. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 3-12%, the fractions containing the desired product are collected and concentrated to give yellow foam. This foam is dissolved in MeOH (20 mL), treated with 0.5 N LiOH (20 mL) then concentrated to give the crude product of the title compound as yellow foam. It is used for next reductive methylation without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8](=[O:20])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([O:17][CH3:18])[C:10]=2F)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[NH4+].[Cl-]>O1CCCC1.CN(C)C=O>[CH:1]1([N:4]2[C:10]3[C:9](=[CH:14][C:13]([F:15])=[C:12]([F:16])[C:11]=3[O:17][CH3:18])[C:8](=[O:20])[NH:7][C:5]2=[O:6])[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc(C(=O)NC(=O)NC2CC2)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(F)c(F)cc2c(=O)[nH]c(=O)n(C3CC3)c12

Procedure:
A solution of 1-cyclopropyl-3-(3-methoxy-2,4,5-trifluorobenzoyl)urea (Example 27b, 0.94 g, 3.26 mmol) in tetrahydrofuran (20 mL) and N,N-dimethylformamide (5 mL) is treated with sodium hydride (0.275 g, 6.8 mmol, 60% in mineral oil dispersion) and heated at reflux for 16 hours. The mixture is cooled, treated with saturated NH4Cl and extracted with dichloromethane. The organic layer is then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Flash column chromatography (1:3 ethyl acetate/hexanes) afforded the title compound. MS (EI, M+1) m/z 269.