Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethyl sulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 80 ml methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 189°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[O:9][CH3:10].N([O-])=O.[Na+].[I-:15].[K+]>O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:15])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: [I-]
Reactant: COc1cc(N)ccc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Dissolve 4-fluoro-3-methoxyphenylamine (5.0 g, 35 mmol) in water (25 mL) and concentrated sulfuric acid (8 mL). Cool to less than 0° C. in an ice/methanol bath and add sodium nitrite (2.7 g, 39 mmol) dropwise in a solution in water (20 mL) and stir one h. Dissolve potassium iodide (9.9 g, 60 mmol) in water (35 mL) and add dropwise. Warm to room temperature and stir 18 h. Extract with ethyl acetate (300 mL), wash with water (200 mL), saturated aqueous sodium thiosulfate (300 mL), and saturated aqueous sodium chloride (300 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as an orange oil (8.8 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
A suspension of 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide (Step 2 of Example 33-1, 100 mg, 0.314 mmol) and TEA (0.110 mL, 0.786 mmol) in DMF-THF-DCM (25:25:50, 6 mL) was treated dropwise with methanesulfonyl chloride (37 μL, 0.471 mmol) and the resulting mixture was stirred at rt for 3 h. The mixture was partitioned between NaHCO3 (aq) and EtOAc, and the organic phase was washed with brine, dried and concentrated to provide crude 4-bromo-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide as a yellow solid (130 mg, 88%). Without purification, using the procedure of Example 3-2, this material (25 mg, 0.063 mmol) and 6-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one (Intermediate 50-5, 27.8 mg, 0.076 mmol) were converted into 4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide (22 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (1H, s), 8.20 (1H, br. s.), 8.03 (1H, d, J=7.9 Hz), 7.70-7.78 (2H, m), 7.45-7.67 (6H, m), 7.36 (1H, dd, J=7.7, 1.1 Hz), 7.00-7.07 (2H, m), 6.93-7.00 (1H, m), 4.86-5.04 (2H, m), 4.26 (2H, d, J=6.2 Hz), 2.87 (3H, s), 1.84 (3H, s). Mass spectrum m/z 557.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:13][CH:15]1[CH2:16][O:17]1
Reactant: ClCC1CO1
Reactant: COc1ccc(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(I)c(OCC2CO2)c1
Temperature: 5 °C
Yield: 93 %

Procedure:
A 5.0 g (0.02 mole) sample of 2-iodo-5-methoxyphenol was added in portions to a suspension of 1.01 g (0.021 mole) of 50% sodium hydride (from which the oil had been removed by washing with hexane) in 40 ml of dry DMF. The resulting solution was cooled to 5° C. and 9.14 g (0.099 mole) of epichlorohydrin was added. The mixture was heated at 60° C. for 15 minutes. The mixture was cooled and filtered through diatomaceous earth. The solvent was evaporated in vacuo from the filtrate. The residue was taken up in ether, the ether washed with water and brine, dried (MgSO4) and the solvent evaporated in vacuo to give 5.72 g (93% yield) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[C:8](=[CH:18]\[N:19](C)C)/[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.O.[NH2:23]N>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:23][NH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: CN(C)/C=C(/C(=O)c1ccc(F)cc1)c1ccnc(Cl)n1
Solvent: O
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Yield: 48.1 %

Procedure:
A solution of the compound prepared in step 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirred at room temperature for 6 hours. The yellow precipitate was collected by filtration and air-dried to give 1.85 g of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine as a yellow solid, mp: 204-205° C.; Anal. Calc'd for C13H8ClFN4: C, 56.84; H, 2.94; N, 20.40; Cl, 12.91. Found: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][Cl:23])[P:5]([N:14]([CH2:18][CH2:19][Cl:20])[CH2:15][CH2:16][Cl:17])(=[O:13])[O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].CC(C)([O-])C.[K+].[Cl:30][CH2:31][CH2:32][N:33]([CH2:44][CH2:45][Cl:46])[P:34](Cl)([N:36]([CH2:40][CH2:41][Cl:42])[CH2:37][CH2:38][Cl:39])=[O:35]>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([P:5]([N:14]([CH2:15][CH2:16][Cl:17])[CH2:18][CH2:19][Cl:20])([O:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][P:34]([N:33]([CH2:32][CH2:31][Cl:30])[CH2:44][CH2:45][Cl:46])([N:36]([CH2:37][CH2:38][Cl:39])[CH2:40][CH2:41][Cl:42])=[O:35])=[O:13])[CH2:21][CH2:22][Cl:23]
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=P(OCCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
5-Hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate, 174 mg (0.387 mmol), and N,N,N′N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 363 mg (0.996 mmol), were dissolved in 15 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 0.4 mL of 1 M solution in tetrahydrofuran (0.4 mmol), was added over a 10-15 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 43 hours. Additional potassium tert-butoxide and N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidoyl chloride were added over the next 4 days to drive the reaction to completion. After 4.5 days, the reaction mixture was diluted with ethyl acetate; and the ethyl acetate layer separated, washed with water and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, 630 mg, was twice purified by preparative HPLC, and the product fractions combined and lyophilized, giving di[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfide, compound 1CC, as a colorless oil, compound 1CC, 56 mg (18% yield), identified by HPLC and 1H and 31P NMR. Mass spectrum: 779 (C20H40Cl8N4O4P2S+4+H+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([CH:18]=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:4])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.[BH4-].[Na+]>CO.ClCCl>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([CH2:18][NH:31][CH:28]3[CH2:30][CH2:29]3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:4])[CH3:3]
Reactant: NC1CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C=O)c2ncccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc(CNC2CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a dichloromethane (0.12 M) solution of 6-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-8-quinolinecarbaldehyde (1 eq.) from the previous step was added magnesium sulphate (1 eq.) and cyclopropyl amine (2 eq.). The resulting suspension was stirred at RT for 16 h. The insolubles were removed via filtration and rinsed with dichloromethane before the combined filtrate was concentrated in vacuo. The crude imine thus obtained was taken up in methanol (0.12 M) and then added sodium borohydride (1.5 eq.) portionwise. The reaction mixture was stirred at RT for 2 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][C:32]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a cold (0° C.), stirred solution of COMPOUND 249 (69 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added benzyl isocyanate (35 μL, 0.28 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 45 minutes, the mixture was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 93 mg (87%) of COMPOUND 271 as a white solid. 1H NMR (CDCl3) δ 1.60-1.71 (m, 2H), 1.88-1.93 (m, 2H), 2.08 (s, 6H), 2.61-2.69 (m, 3H), 3.81 (s, 4H), 4.05 (d, 2H, J=12.9 Hz), 4.42 (d, 2H, J=5.4 Hz), 4.74 (br t, 1H, J=5.4 Hz), 7.08 (dd, 2H, J=7.5, 5.1 Hz), 7.25-7.38 (m, 7H), 8.34 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.36, 27.35, 44.58, 45.30, 54.99, 57.83, 122.81, 127.47, 128.03, 128.87, 133.82, 138.45, 140.13, 146.20, 157.52, 157.83; ES-MS m/z 444 (M+H). Anal. Calcd. For C27H33N5O.0.4CH2Cl2: C, 68.91; H, 7.13; N, 14.66. Found: C, 69.19; H, 7.37; N, 14.64.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ncccn2)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC=C(c2ncccn2)C1
Reaction time: 16 h

Procedure:
1.56 g of the compound of step 1 of Example 29 was dissolved in 15 ml of pyridine, 0.8 ml (1.5 equivalents) of phosphorus oxychloride was added under ice cooling and the result was agitated for 16 hours.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])COCC[Si](C)(C)C)=[O:16])[N:11]=[CH:10][N:9]=1)(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[C:62](O)(=[O:66])[C:63]#[C:64][CH3:65].O>C(Cl)Cl>[Cl:37][C:27]1[C:28]([O:35][CH3:36])=[CH:29][C:30]([O:33][CH3:34])=[C:31]([Cl:32])[C:26]=1[NH:17][C:15](=[O:16])[N:14]([C:12]1[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[NH:45][C:62](=[O:66])[C:63]#[C:64][CH3:65])[CH:13]=1)[CH3:38]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccccc3N)ncn2)c1Cl
Reactant: CC#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC#CC(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of (2-amino-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (50 g, 0.075 mmol) and DCC (42 g, 0.2 mmol) in DCM (50 mL) was added a solution of but-2-ynoic acid (13 g, 0.15 mmol) in DCM (10 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. Water (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by reverse phase chromatography to obtain the title compound (20 mg, yield: 34%). MS (ESI): 659 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1>>[N:23]1([CH2:22][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCn1nnc2ccccc21
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cn2nnc3ccccc32)c(=O)[nH]c1=O
Yield: 33.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (135 mg, yield: 33.5%).
Reaction SMILES: [OH-].[Na+].[CH2:3]=[CH:4][CH2:5][SH:6].[CH2:7]([CH:9]1[CH2:12][N:11](OC(=O)C)[C:10]1=[O:17])[CH3:8]>O>[CH2:5]([S:6][CH:12]1[NH:11][C:10](=[O:17])[CH:9]1[CH2:7][CH3:8])[CH:4]=[CH2:3]
Reactant: CCC1CN(OC(C)=O)C1=O
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1NC(=O)C1CC
Reaction time: 0.17 h

Procedure:
To a solution of 1.06 g of sodium hydroxide in 14 ml of water were added 2.82 ml of allylthiol. The solution was stirred under an argon atmosphere for 10 minutes. To this solution was added, over a period of 1 minute, a solution of 3.79 g of ethyl acetoxyazetidinone in 6 ml of water. After about 15 minutes, when the starting material had been consumed, the solution was extracted three times with dichloromethane. The combined organic extracts were back-extracted with water, then dried over magnesium sulphate, evaporated in vacuo, and chromatographed over silica gel, eluting with ethyl acetate/hexane mixtures. The main product (2.84 g) was trans 4-allylthio-3-ethylazetidinone, which contained a trace amount of the cis isomer. (Yield 2.84 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)C(C)C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 3.18 mmol) in 25 mL of CH2Cl2 was placed under an atmosphere of nitrogen and then chilled in an ice water bath. The solution was treated with triethylamine (0.89 mL, 6.7 mmol) and then slowly with isobutyryl chloride (0.35 mL, 3.3 mmol). The reaction was stirred and allowed to slowly come to ambient temperature. After 16 h, the reaction was diluted with 15 mL of CHCl3 and 15 mL of 10% Na2CO3 solution and the layers were separated. The organic portion was washed with H2O (15 mL). The combined aqueous washes were back-extracted with CHCl3 (10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. The foam was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a white foam. The foam was triturated with hexanes and filtered to yield N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.821 g) as a white solid. mp 108–110° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J=7.5 Hz, 1H), 7.72 (t, J=5.4 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.46–7.41 (m, 1H), 7.26–7.21 (m, 1H), 6.97 (t, J=5.5 Hz, 1H), 6.62 (s, 2H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.17–3.13 (m, 4H), 2.29 (h, J=6.9 Hz, 1H), 1.71 (p, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.4, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2, 121.2, 114.7, 65.8, 63.1, 50.2, 36.6, 34.4, 28.0, 19.9, 15.3; MS (APCI) m/z 385 (M+H)+; Anal. Calcd for C20H28N6O2•0.25H2O: C, 61.76; H, 7.38; N, 21.61; Found: C, 61.67; H, 7.55; N, 21.72.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([OH:51])=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:44]=2)[N:37]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:51][C:41]2[C:40](/[CH:39]=[CH:38]/[C:36]3[N:37]=[C:33]([CH3:32])[S:34][CH:35]=3)=[CH:44][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[O:12][C:13]=1[CH3:14]
Reactant: Cc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.49 g), 4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.05 g), potassium carbonate (1.01 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.25 g, yield 53%) as pale-yellow crystals. melting point: 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:26][C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:32]Br>C(Cl)(Cl)Cl>[Br:32][C:26]1[C:13]2[C:14](=[N:15][C:16]([CH3:23])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]=2[NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:9])=[O:10])[S:24][C:25]=1[C:27]1[CH:28]=[N:29][NH:30][CH:31]=1
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a stirred solution of ethyl 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 73) (870 mg, 1.824 mmol) in CHCl3 (30 mL) at 60° C. was added bromine (0.10 mL, 2.01 mmol), prediluted in CHCl3 (5.25 mL), dropwise. The resulting mixture was stirred at 60° C. for ca. 4 h and was then cooled to RT. The resulting precipitate was filtered and the solid rinsed with DCM and dried, to give the title compound (920 mg). LCMS (A) m/z: 556/558 [M+1]+, Rt 1.25 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[NH2:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:44]2)=[C:36]2[CH:42]=[CH:41][S:40][C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])[CH2:44]2)=[C:36]2[CH:42]=[CH:41][S:40][C:37]2=[N:38][CH:39]=1)=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2sccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6, 176.4 mg, 0.4950 mmol) in THF (0.5 mL), a solution of 1-chloro-N,N,2-trimethylpropenylamine (169.8 mg, 1.271 mmol) in THF (1.0 mL) was added slowly. The mixture was stirred at room temperature for 5 h. A solution of tert-butyl [(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (139.6 mg, 0.4006 mmol) in THF (2.0 mL) was then added to the resulting mixture, followed by pyridine (316.1 mg, 3.996 mmol), and the mixture was stirred at room temperature for a further 2 h. The mixture was then concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a dark semi-solid (230.7 mg, 84%). LCMS calc. for C32H37F2N6O5S2 (M+H)+: m/z=687.2. found 687.2.