Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([CH2:28][CH3:29])[CH2:26][NH2:27]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@@H:14]([OH:18])[CH2:15][C@@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([NH:27][CH2:26][CH:25]([CH3:24])[CH2:28][CH3:29])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Reactant: CCC(C)CN
Product: CCC(C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Following a procedure similar to that described in Preparation 7, 250 mg (0.76 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-3-methylbutyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 9) were dissolved in 500 mg (5.75 mmoles) of 2(RS)-methylbutylamine, and the solution was stirred at 100° C. for 3 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent). to give 270 mg (yield 85%) of the title compound as an amorphous substance.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:21]([C:20]3[CH:19]=[C:18]([CH:26]=[CH:25][CH:24]=3)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[O:1][N:2]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
N′-Hydroxynicotinimidamide (274 mg, 2.00 mmol) was coupled with 3-(tert-butoxycarbonyl)benzoic acid (Aldrich) according to the procedure described in Example 8. 1H NMR (300 MHz, CD3OD) δ 1.65 (s, 9H), 7.65 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.71-7.77 (m, 1H), 8.26 (ddd, J=7.7, 1.8, 1.6 Hz, 1H), 8.42-8.46 (m, 1H), 8.57 (dt, J=7.9, 2.0 Hz, 1H), 8.73-8.78 (m, 2H), 9.31 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 324 (M+H)+.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[CH:28][CH:27]=[C:26]([C:37]([O-:39])=[O:38])[CH:25]=2)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[CH:28][CH:27]=[C:26]([C:37]([O:39][CH3:1])=[O:38])[CH:25]=2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1[nH]c2cc(C(=O)[O-])ccc2c1C1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (137 eq) was added to a solution of methyl 2-(2-{[(tert-butoxycarbonyl)amino]phenyl}-3-cyclohexyl-1H-indole-6-carboxylate in DCM (0.1 M) at 0° C. and the solution was allowed to stir at RT for 1 h. The volatiles were removed in vacuo, and the residue diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (twice) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound (quant.). MS (ES+) m/z 349 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][O:10]C)[C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC=Cc1cccc(Br)c1C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cccc1CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 1-bromo-3-(2-methoxyvinyl)-2-methylbenzene [Aromatic Intermediate 22, step a] (1.75 g) in THF (25 mL) was added a solution of mercury(II) acetate (2.95 g) in water (30 mL) and the resulting solution was stirred in ice-water for 2.75 hours. Meanwhile, potassium carbonate (35 g) was dissolved in water (30 mL) and the solution was filtered. Sodium borohydride (1.17 g) was part dissolved/part suspended in 35 mL of the resulting potassium carbonate solution, and added to the reaction mixture from above. A grey, cloudy, two-phase mixture was formed, that was stirred at room temperature for 2.5 hours, then poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford the subtitled compound as a colourless oil. Yield 1.67 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>CCO.CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=[C:29]5[S:25][C:26](=[O:31])[NH:27][C:28]5=[O:30])=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (48 mg, 0.151 mmol) in 0.5 mL EtOH was added 2,4-thiazolidinedione (18 mg, 0.151 mmol) and piperidine (15 μL, 0.151 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and dissolved in DMF. Insolubilities were filtered off and the resulting filtrate purified by HPLC to yield 5-((5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=418)
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:35]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: CCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCCCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-3-n-hexyloxy-5-nitrobenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-n-hexyloxybenzoic acid is obtained with a melting point of 168°-169` C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=2)[CH:7]=[N:6][CH:5]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Li+].[CH:53]([Si:56]([CH:78]([CH3:80])[CH3:79])([CH:75]([CH3:77])[CH3:76])[O:57][C:58]1[CH:67]=[C:66]2[C:61]([CH:62]=[CH:63][CH:64]=[C:65]2[C:68]([NH:70][CH2:71][C:72]([O-])=[O:73])=[O:69])=[CH:60][CH:59]=1)([CH3:55])[CH3:54].C(N(CC)C(C)C)(C)C>C1COCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:4]([CH2:3][NH:2][C:72]([CH2:71][NH:70][C:68]([C:65]3[C:66]4[C:61](=[CH:60][CH:59]=[C:58]([O:57][Si:56]([CH:75]([CH3:77])[CH3:76])([CH:53]([CH3:55])[CH3:54])[CH:78]([CH3:79])[CH3:80])[CH:67]=4)[CH:62]=[CH:63][CH:64]=3)=[O:69])=[O:73])=[CH:5][N:6]=[CH:7]2)=[CH:11][C:12]=1[F:18])#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CN)cc1F
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)NCC(=O)[O-])c2c1)(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)NCC(=O)NCc3cncn3Cc3ccc(C#N)c(F)c3)c2c1)(C(C)C)C(C)C
Reaction time: 3 h

Procedure:
To 5-(aminomethyl)-1-(4-cyano-3-fluorobenzyl)imidazole hydrochloride, as described above in Step B, (54 mg, 0.18 mmol) in dry THF (2 mL) under argon were added PYBOP (219 g, 0.42 mmol), N-[7-(triisopropylsilyloxy)naphthalene-1-carbonyl]glycine lithium salt, as described above in Step D, (171 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.124 mL, 0.71 mmol). The reaction mixture was stirred for 3 hrs, then partitioned between CH2Cl2 (30 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2-1% MeOH −0.1% NH4OH to CH2Cl2-5% MeOH −0.5% NH4OH, to yield the desired product as a pale foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:8]([NH:10][CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:9].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O>[CH2:8]([N:10]([CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:9]
Reactant: CCCCCCC(=O)Cl
Reactant: CCNC(C)CCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCC(=O)N(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A 500 ml 3-neck round bottom flask fitted with a thermometer and addition funnel was charged with 7.65 g of sodium carbonate and 70 ml of water. To this mixture was added 6.8 g (0.029 mol) of N-ethyl-α-methyl-4-nitrobenzenebutanamine and 70 ml of acetone. The resulting mixture was cooled to slightly below 25° C. and 4.5 ml (0.029 mol) of heptanoyl chloride and 70 ml of acetone were added while maintaining the temperature of the mixture in the range of about 20°-25° C. The suspension was stirred at room temperature overnight and evaporated to dryness under reduced pressure. The residue was slurried in water and extracted three times with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, twice with water and finally a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 7.723 g of N-ethyl-N-[1-methyl-4-(4-nitrophenyl)butyl]heptanamide as an oil.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[CH2:19]([O:18][C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH2:5][CH2:4][S:3]1)=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N=C1SCCN1c1cccc(C(F)(F)F)c1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 40.5 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g) , dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3- (3-trifluoromethylphenyl) thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room temperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3- (3-trifluoromethylphenyl) thiazolidine.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]1([CH2:12]CC(O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)Cl>[CH:7]1([CH2:12][CH2:1][C:2]([Cl:4])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CCC1CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)CCC1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.0 g of oxalyl chloride in 15 ml of methylene chloride is added dropwise to a 0° C. solution of 0.65 g of 3-cyclopentylpropionic acid in 15 ml of methylene chloride. The solution is allowed to warm to room temperature and is stirred for 6 hours. The solution is concentrated at reduced pressure, rediluted with 25 ml of methylene chloride and reconcentrated to give 3-cyclopentylpropionyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH3:27])([CH3:26])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[CH:12]1([NH:11][C:4]2[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:15][C:16]3[CH:24]=[C:23]4[C:19]([C:20]([CH3:27])([CH3:26])[C:21](=[O:25])[NH:22]4)=[CH:18][CH:17]=3)[N:3]=2)[CH2:14][CH2:13]1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: Clc1nc(NC2CC2)c2occc2n1
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
Product: CC1(C)C(=O)Nc2cc(Nc3nc(NC4CC4)c4occc4n3)ccc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 26.1 %

Procedure:
To a flask was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.45 g, 2.14 mmol, Example #3, Step C), 6-amino-3,3-dimethylindolin-2-one (0.378 g, 2.14 mmol, Astatech), K2CO3 (0.89 g, 6.44 mmol) and t-AmOH (5 mL). To the mixture was added Pd2dba3 (0.118 g, 0.129 mmol) and X-Phos (0.123 g, 0.258 mmol). The mixture was heated to about 100° C. and stirred for about 15 h. The mixture was filtered and the filtrate was directly purified by column chromatography eluting with 0 to 70% of 10% MeOH/DCM (containing 2M 1.5% NH3 in EtOH) and DCM (25 g silica gel)). The material was then dried in a vacuum oven at about 65° C. for about 48 h. The solid was then suspended in Et2O (5 mL), sonicated for 2 min and filtered. The solid was dried in a vacuum oven at about 80° C. for about 16 h to give 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,3-dimethylindolin-2-one (0.195 g, 26%): LC/MS (Table 2, Method c) Rt=1.81 min.; MS m/z: 350 (M+H)+. Syk IC50=A
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8]1([Si:14]([Cl:17])([Cl:16])Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1([SiH](Cl)Cl)C=CC=CC=1.C1C=CC=CC=1>[C:8]1([Si:14]([C:7]2[CH:6]=[CH:10][CH:9]=[CH:8][CH:13]=2)([Cl:16])[Cl:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl[SiH](Cl)c1ccccc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Yield: 253.1 %

Procedure:
Triethylamine (3.9 g) was added to a flask containing 83.3 g of the crude product mixture described in Example 1. This mixture was stripped by the process described in Example 1. The volatiles were condensed and analyzed by GC-TCD. About 77.4 g of a liquid was recovered comprising 24.7 g of diphenyldichlorosilane (yield of 77 percent), 1.4 g of phenyldichlorosilane, 24.5 g of phenyltrichlorosilane, and 10.1 g of benzene.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:38])=[O:37]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cc(Cl)ccc1Cl)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 28 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,5-dichlorobenzenesulfonyl chloride under the conditions used in example 2 giving 28% of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1
Reactant: CS(=O)(=O)OCc1cnccn1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cnccn4)c(Cl)c3)c12
Yield: 61 %

Procedure:
The procedure described in Example 4.1 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide and pyrazin-2-ylmethyl methanesulfonate to give the title compound in 61% yield; NMR spectrum (DMSO-d6) 1.3 (d, 3H), 1.95 (s, 3H), 3.03 (s, 3H), 3.37 (1H obscured by H2O), 4.21 (dd, 1H), 5.08 (m, 1H), 5.37 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 8.11 (d, 1H), 8.46 (s, 1H), 8.66 (m, 2H), 8.85 (s, 1H), 9.94 (s, 1H); Mass Spectrum MH+ 493.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16]>C(Cl)Cl>[OH:6][CH2:7][C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: COCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCCCC(CO)(c2cccc(O)c2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1M solution of BBr3(1.48 mL, 1.48 mmol) in CH2Cl2 was added to 3-methoxymethyl-3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Step A above) (0.391 g, 1.35 mmol) dissolved in anh. CH2Cl2 (5 mL) at −78° C. After 24 h of stirring at RT, the reaction was quenched with H2O, extracted with CH2Cl2 (3×), dried (MgSO4), concentrated and purified using SiO2 chromatography (1-1.5% MeOH/CH2Cl2with HOAc) to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:17]=1[O:18][CH:19]([C:21]1[S:25][C:24]([N:26]=[C:27]=[O:28])=[N:23][N:22]=1)[CH3:20]>CCCCCC.C(OCC)C>[Cl:15][C:16]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:17]=1[O:18][CH:19]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:28])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:23][N:22]=1)[CH3:20]
Reactant: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)cc2Cl)s1)OC
Yield: 81.7 %

Procedure:
A 200 milliliter flask was charged with 2.1 grams (0.018 mole) of methylaminoacetaldehyde dimethylacetal, 50 milliliters of benzene and 5.8 grams (0.018 mole) of the 5-[1-(2,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting slurry was refluxed for 15 minutes to form a yellow solution and cooled with formation of a few crystals. A minimum amount of hexane-diethylether was added, and crystallization occurred. The crystals were filtered off, and dried in a vacuum oven at 80°0 C. to give 6.4 grams of white crystals of 3-[5-[1-(2,4-dichlorophenoxy)-ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 125°-127° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C]=O.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[CH3:63][OH:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]2[N:18]([C:17]3[N:16]=[C:15]4[CH2:22][O:23][C:63](=[O:64])[C:14]4=[CH:13][C:12]=3[CH2:11]2)[C@H:19]([CH3:21])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CO)nc3N21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc4c(nc3N21)COC4=O

Procedure:
The product of step 1 was carbonylated in methanol with carbon monoxide (35 bar) at 110° C. (24 h) in the presence of palladium acetate (0.02 eq), dppp (0.025 eq) and triethylamine (3 eq). The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate:heptane to yield the title compound as with crystals (MS: 346.3 (M+H+))
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C(O)C>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[N:26]=1
Reactant: COC(OC)C(=O)CC(=O)c1ccncc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: COC(OC)c1cc(-c2ccncc2)n(-c2ccc(F)cc2)n1
Yield: 9.6 %

Procedure:
A stirred solution of 4,4-dimethoxy-1-pyridin-4-yl-butane-1,3-dione (20 g, Reference Example 2) in ethanol (500 ml) was treated with 4-fluorophenylhydrazine hydrochloride (29 g). The mixture was refluxed for 0.5 hour then evaporated. The residual yellow oil was subjected to flash chromatography on silica eluting with a mixture of methanol and dichloromethane (99:1, v/v) to give the title compound as a brown oil (2.7 g). MS: 314 [MH]+. RF=0.27 (ethyl acetate, determined by thin layer chromatography on silica).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)(O)[O-].[Na+]>ClCCl>[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCCn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCCn1ccnc1)c1ccccc1

Procedure:
Following the general procedure of Example 8 and reacting the appropriate benzenesulfonyl chloride with 1H-imdazol-1-propanamine or 1H-imidazol-1-butanamine in the presence of saturated sodium bicarbonate in dichloromethane for 16-48 hours, then crystallizing the respective products with ether and, if necessary, recrystallization from ethyl acetate or ethanol/dichloromethane gave the compounds of Examples 9-12 found in Table III below and gives the compounds of Examples 13-15 in Table III.