Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:29]O>C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([O:24][CH3:29])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: -2.5 °C

Procedure:
A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (23.5 g, 0.0636 mol) in methanol (235 ml, 10 vol) was stirred and cooled to 0 to −5° C. under nitrogen. Thionyl chloride (9.3 ml, 0.1272 mol, 0.40 vol) was charged dropwise over 20 minutes, maintaining the temperature −5 to +5° C. The resulting slurry was then heated and stirred at reflux under nitrogen for 16 h after which time LC analysis showed 1.4% by area of acid remaining. The solution was evaporated to dryness in vacuo at 40° C. to give a brown sludge. The sludge was dissolved in ethyl acetate (118 ml, 5 vol) and water (235 ml, 10 vol) and the layers separated. The aqueous layer was washed with ethyl acetate (118 ml, 5 vol) and basified to pH 11 with saturated aqueous potassium carbonate (118 ml, 5 vol). The product was extracted into dichloromethane (3×118 ml, 3×5 vol) and the combined extracts dried over magnesium sulfate (23 g, 1 wt) and concentrated in vacuo at 40° C. to yield title compound (21.7 g, 98% from the nitrile) as a cream solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([S:17]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (1.6 g, 10.3 mmol) in CH2Cl2 (70 mL) was added with TEA (1.1 mol eq, 1.6 mL) and the mixture was stirred at r.t. for 10 minutes. Then 3-fluorobenzensulfonyl chloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethylic ether to afford 2F as a pale yellow solid (2.80 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 3.41 (s, 3H), 3.48 (m, 2H), 4.01 (m, 1H), 5.20 (t, 1H), 7.58 (m, 2H), 7.81 (m, 2H), 8.52 (d, 1H, J=8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]([C:17]([OH:19])=O)[C:7]=2[CH:20]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:17]([CH:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:15][O:16][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][C:7]1=2)=[O:19])([CH3:33])[CH3:32]
Reactant: COc1ccc2c(c1)C(C(=O)O)c1cccnc1CO2
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: COc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccnc1CO2
Yield: 73.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 0.74 g of 5,11-dihydro-7-methoxybenzoxepino[3,4-b]pyridin-5-carboxylic acid obtained in Example 58 (Compound W) in place of Compound A and 0.72 g of 2,6-diisopropylaniline in place of aniline to obtain 0.86 g of Compound 41.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.O[C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][C@H:24]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)n1CCc1ccc(Br)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCc2ccc(Br)cc2)cc1
Yield: 54 %

Procedure:
To a solution of 4-[1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl]phenol (3.00 g, 8.42 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.96 g, 10.1 mmol) and triphenylphosphine (2.65 g, 10.1 mmol) in toluene (30 ml) was added diethyl azodicarboxylate (1.76 g, 10.1 mmol) and refluxed for 20 hours under heating. The insoluble matter was filtered out and the filtrate was diluted with ethyl acetate. The obtained solution was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 2.40 g (yield: 54.0%)
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1.C(N(S(F)(F)[F:32])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:32][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CO)ccn23)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CF)ccn23)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a cooled (−78° C.) suspension of 3′-(7-hydroxymethylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (96 mg, 0.30 mmol) in dichloromethane (20 ml) was added (diethylamino)sulfur trifluoride (50 mg, 0.31 mmol) dropwise over 5 min. The mixture was stirred at −78° C. for 20 min then allowed to warm to −40° C. for 5 min before quenching the reaction with a pre-cooled −40° C. solution of acetic acid (0.5 ml) in dichloromethane (5 ml). The mixture was warmed to ambient temperature, made basic with saturated sodium hydrogencarbonate solution (30 ml) and extracted with dichloromethane (2×75 ml). The combined organics were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) gave a solid which was triturated with diethyl ether to give the title compound (84 mg, 87%) as a white powder. 1H NMR (400 MHz, CDCl3) δH 5.45 (2H, d, J 47), 6.90 (1H, dd, J 7 and 2), 7.50 (1H, dt, J 8 and 1), 7.57-7.60 (2H, m), 7.61-7.72 (4H, m), 7.78-7.84 (3H, m), 8.61 (1H, dd, J 7 and 1); m/z (ES+) 328 (M++H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:30](O)=[O:31])[N:20]=[C:21]3[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:43])[C@@H:37]([NH2:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:35][C:36](=[O:43])[C@@H:37]([NH:42][C:30]([C:19]1[N:20]=[C:21]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([C:12](=[O:13])[NH:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:23]=2)=[O:31])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(C)(C)C
Yield: 21.6 %

Procedure:
A solution of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (65 mg, 0.148 mmol) in DMF(1.5 mL) was treated with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCL (35 mg, 0.193 mmol), HBTU (73 mg), and DIEA (0.106 mL) by the General Procedure A. The crude product was purified by flash column chromatography on silica gel using 88:12 Hexanes/EtOAc to give 18 mg of 2(S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}3,3-dimethylbutyric acid methyl ester as a colorless oil. This was used for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=4)[CH2:31]3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[NH2:15][C:4]1[N:3]=[C:2]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=4)[CH2:31]3)=[CH:26][CH:25]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(c2ccc(C#N)nc2)CC3)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)nc3)CC4)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.075 g, 0.33 mmol), 5-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carbonitrile (0.12 g, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.01 g, 0.02 mmol) and potassium carbonate (0.14 g, 0.99 mmol) in 1,4-dioxane (2 mL), and water (1 mL) was heated at 120° C. for 2 h. After cooled to r.t., the mixture was diluted with MeOH, filtered, concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 10% MeOH in DCM to give the desired product. The product was further purified by RP-LCMS (pH=10) to afford the desired product (0.10 g, yield: 71%). Analytic LCMS (M+H)+: m/z=427.3.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C>[CH2:20]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[CH3:21]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
A mixture of 25.0 g (137 mmol) methyl vanillate, 38.87 g (274 mmol) potassium carbonate, 500 ml DMF, and 16.5 ml (206 mmol) ethyl iodide was heated to 100° C. under N2. At 2.5 hours, cooled and removed solids. Stripped solvent, and partitioned between water and methylene chloride. Stripped solvent and dried in vacuo, giving 25.85 g of white solid: mass spectrum (EI m/e): M=210.0.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]N1CCNCC1>>[CH3:27][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[CH:17]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Product: CN1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3c2)CC1

Procedure:
The title compound was prepared following the procedure described for 7a using 1-methylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.41 (3H, s), 3.52 (4H, br), 7.12 (1H, t, J=7.47 Hz), 7.39 (3H, m), 7.45 (1H, m), 7.68 (1H, m), 8.22 (2H, dd, J=8.55, 0.98 Hz), 8.60 (1H, d, J=5.86 Hz), 9.12 (1H, br). m/z 346.4 (MH+). m/z 360.4 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=2)[N:13]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[C@@H:12]([CH3:26])[CH2:11]1.[CH:27]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:33]3[CH:32]=[N:31][N:30]([CH:27]4[CH2:29][CH2:28]4)[CH:34]=3)[CH:18]=2)[N:13]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[C@@H:12]([CH3:26])[CH2:11]1
Reactant: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1C(=O)C1CC1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(c2nc3ccccc3o2)c2cc(-c3cnn(C4CC4)c3)ccc2N1C(=O)C1CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of (S)-(4-(benzo[d]oxazol-2-yl)-6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)(cyclopropyl)methanone (0.019 g, 0.046 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.012 g, 0.051 mmol), tris(dibenzylideneacetone)dipalladium (2.1 mg, 2.3 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (2.2 mg, 4.6 μmol) and cesium carbonate (0.045 g, 0.138 mmol) in dioxane (1.0 mL) and water (0.20 mL) was heated in the microwave at 100° C. for 1.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-(4-(benzo[d]oxazol-2-yl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (0.014 g, 69%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.65-1.05 (m, 11 H), 1.85-2.02 (m, 1 H), 3.58-3.80 (m, 1H), 3.90-4.16 (m, 2 H), 5.02-5.18 (m, 1 H), 7.01-7.26 (m, 2 H), 7.31 (dd, J=8.21, 1.76 Hz, 1 H), 7.35-7.58 (m, 3 H), 7.79 (s, 1 H), 8.18 (s, 1 H), 8.36 (d, J=2.05 Hz, 1 H). MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([C:37]3[CH:41]=[C:40]([C:42]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[NH:43])[S:39][C:38]=3[S:52][CH3:53])(=[O:36])=[O:35])[CH:29]=2)=[C:23]([NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]2[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=2)[CH:22]=1>CC(O)=O.CO>[C:48]([O:47][C:45]([NH:44][C:42](=[NH:43])[C:40]1[S:39][C:38]([S:52][CH3:53])=[C:37]([S:34]([C:30]2[CH:29]=[C:28]([C:24]3[C:25]([CH3:27])=[CH:26][C:21]([NH:20][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:22][C:23]=3[NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][C:66]([C:67]([OH:69])=[O:68])=[CH:70][CH:71]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:35])=[O:36])[CH:41]=1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 22.9 %

Procedure:
1,3-bis(tert-Butoxycarbonyl)-2-methyl-2-thiopseudourea (433 mg, 1.49 mmol) was added to a solution of 4-[5-(3-{4-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-pentyloxy]-benzoic acid (233 mg, 0.298 mmol, Example 283: step e) in 5% AcOH/MeOH (10 mL) over 2 days at 35° C. The solvents were removed in vacuo and the residue was purified by flash chromatography (1–6% MeOH/methylene chloride) to afford the title compound as a yellow solid (70 mg, 23%). ESI-MS (m/z): Calcd. for C48H61N7O12S3: 1024.4 (M+1); found: 1024.0.
Reaction SMILES: Cl[C:2]([C@:4]1([CH3:19])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:3].[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].N1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O.[Cl-].[Na+].O>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]([C@:4]1([CH3:19])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:3]
Reactant: Nc1ccccc1Br
Reactant: C[C@@]1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@]1(C(=O)Nc2ccccc2Br)CCCN1C(=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of EXAMPLE 5A in toluene (20 mL) and N,N-dimethylformamide (10 mL) was added 2-bromoaniline (0.891 g) and pyridine (1.38 mL) and the mixture heated at 40° C. for 4 hours. The mixture was treated with ethyl acetate and brine and the organic layer was washed with 5% aqueous citric acid and aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to afford the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH3:15])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C-]#N.[Na+].CN(C)[CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)=[O:24]>CN(C=O)C>[I:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH3:15])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([C:7](=[O:8])[CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)=[O:24])[CH:9]=1
Reactant: COc1cc(C(=O)CCN(C)C)cc(OC)c1OC
Reactant: CCCOc1c(I)cc(C=O)cc1OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-iodo 3-methoxy-4-n-propoxybenzaldehyde (26 g, 0.08 mol) in DMF (75 ml) was added over 15 minutes to a stirred solution of sodium cyanide (4 g, 0.08 mol) in DMF (100 ml) at 35° C. After stirring for 20 minutes, a solution of 3-dimethylamino-1-(3,4,5-trimethoxyphenyl)-1-propanone (18 g, 0.07 mol) in DMF (100 ml) was added over 0.5 hour. The mixture was stirred at 35° C. for 1 hour and kept at room temperature overnight. It was poured into ice-cold 20% hydrochloric acid (2 1), and the solid was filtered, dried by suction, and taken up in ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness. Crystallization from Et2O-hexane gave 1-(5-iodo-3-methoxy-4-n-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione, m.p. 120°-121° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:27]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturoted aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product (307 mg), mp 165-166° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=1)#[CH:16]>C(O)(C)C>[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1)#[CH:16]
Reactant: C#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9.54 mmol), isopropanol (30 mL), and 3-ethynylbenzenamine (1.2 g, 10.00 mmol) was refluxed for 5 h. The reaction mixture was cooled to room temperature and refrigerated. The solid was filtered, washed with cold isopropanol several times, and dried in vacuo to give 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][S:13][C:14]=1[C:15]([OH:17])=[O:16])([OH:3])=[O:2].O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)C>CO.CCCCCC>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][S:13][C:14]=1[C:15]([OH:17])=[O:16])([O:3][CH3:19])=[O:2]
Reactant: O=C(O)CCCCCCc1ncsc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CCCCCCc1ncsc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.2 g of 4-(6carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = H) and 10.2 g of p-toluenesulphonic acid monohydrate were dissolved in 400 ml of methanol. The obtained reaction mixture was stirred for 2 hours at room temperature, then poured onto one liter of water. After saturating the aqueous solution with ammonium sulphate it was extracted with 3 × 400 ml of ethyl acetate, then the ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated in vacuo. Recrystallization of the obtained crude product from a mixture of diethyl ether and n-hexane afforded 7.9 of 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid (X, R1 = H). M.p.: 113°-114° C.