Azzindani/Open_Reaction_Data huggingface dataset:
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]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23](OC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].O1CCCC1.[NH3:33]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([Cl:27])[C:23]([NH2:33])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCOc1ccc(CC(Cl)C(N)=O)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (2.36 g), tetrahydrofuran (40 mL), methanol (40 mL) and aqueous ammonia solution (specific gravity 0.88; 40 mL) was stirred at room temperature for 2.5 hrs. The organic solvents were evaporated in vacuo and the residue was diluted with water (1 L) and extracted with dichloromethane (3×400 mL). The combined dichloromethane layers were washed with dilute hydrochloric acid solution (2M; 400 mL), water (1 L), brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, mp 149°-151° C. after recrystallisation from dichloromethane-hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)cc1
Yield: 53.1 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {4-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 53%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(OC(N1C=C(C2N(C(OC(C)(C)C)=O)C3C=C(NC4C=CC(C(=O)N(C)C)=CC=4)N=CC=3C=2)C=N1)=O)(C)(C)C>>[C:30]([N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH:43][C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[C:9]([C:18]5[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=5)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]=4[CH:15]=3)=[CH:41][CH:40]=2)[CH2:37][CH2:38]1)(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Product: CC(=O)N1CCN(c2ccc(Nc3cc4c(cn3)cc(-c3cnn(C(=O)OC(C)(C)C)c3)n4C(=O)OC(C)(C)C)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from compound (17) and 4-(4-acetylpiperazin-1-yl)aniline using the method described for compound (49). 1H-NMR (500 MHz, CDCl3) 1.47 (s, 9H), 1.69 (s, 9H), 2.17 (s, 3H), 3.13 (t, J=5.0 Hz, 2H), 3.15 (t, J=5.3 Hz, 2H), 3.65 (t, J=5.8 Hz, 2H), 3.81 (t, J=5.2 Hz, 2H), 6.45 (br s, 1H), 6.56 (d, J=0.6 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 7.29 (d, J=8.9 Hz, 2H), 7.42 (s, 1H), 7.81 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.4 Hz, 1H), 8.41 (d, J=0.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(=O)(O)[O-:17].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: O=C([O-])O
Reactant: COC(=O)C(C)(C)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To an ambient temperature solution of 2-(4-Bromomethyl-phenyl)-2-methyl-propionic acid methyl ester (275 mg, 1.01 mmol) in DMSO (8 mL) is added sodium bicarbonate (127 mg, 1.52 mmol). The reaction mixture is heated to 120° C. After 3 h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (179 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.85 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=8.4 Hz), 3.67 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH2:25]([C:27]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:42][CH3:43])([OH:41])[CH2:39][CH3:40])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([C:27]([C:45]1[CH:46]=[CH:47][C:48]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[CH:49][CH:50]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:39][CH3:40])([OH:41])[CH2:42][CH3:43])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(O)cc2)cc1C)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1C)CC
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N,N-Diisopropylethylamine (0.83 mL, 2 mmol) and trifluoromethanesulfonic anhydride (0.26 mL, 1.6 mmol) were added to a solution of 4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-phenol (Example 39-(3); 0.52 g, 1.4 mmol) in dichloromethane (7 mL) at −78° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (0.65 g, 92%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:23][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][C:11]([C:20](=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=4)=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cccc(C(=O)c2ccc3oc4ccc(C(=O)c5cccc(C)c5)cc4c3c2)c1

Procedure:
2,8-Bis(3-methylbenzoyl)dibenzofuran is prepared according to the procedure of Step 1, Example 1. Dibenzofuran (42 g, 0.25 mole), m-toluoyl chloride (82 g, 0.53 mole), and anhydrous aluminum chloride (73 g, 0.55 mole) are reacted in carbon disulfide (250 ml) for twenty-four hours at 20°. The desired compound is obtained after recrystallization of the crude product from toluene, yield 22 g (23% of theory), mp 180°-1°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CS(C)=O.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:34][C@H:35]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=1
Reactant: COc1ccc2cc(-c3cnc4ccc(Cl)nn34)sc2c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 33 mg of the yellow solid, 75%.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][NH2:35])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:38][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>C(N(CC)CC)C>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][NH:35][S:41]([CH:39]([CH3:40])[CH3:38])(=[O:43])=[O:42])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
Using 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (248 mg), triethylamine (135 μl) and 2-propanesulfonyl chloride (65.5 μl), the same reaction as Example 31 was carried out to yield the titled compound (55 mg) as colorless needle crystals.
Reaction SMILES: Cl.Cl.[CH2:3]([NH2:8])[CH2:4][CH2:5][CH2:6][NH2:7].CN(C=O)C.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:8][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5 N NaOH, (clear solution) and stirred for 2 hr. 10 The reaction mixture was acidified to pH=1.25, extracted with ether (2 X), made basic (pH>10) with 5 N NaOH, and extracted with dichloromethane (2 X). The dichloromethane fractions were combined and washed with water (2 X), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc2ncnc(Cl)c2cc1C
Reactant: Clc1ccc2c(c1)NCC2
Product: Cc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1C
Yield: 16 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 16% yield from 6-chloro-indoline and 4-chloro-6,7-dimethyl-quinazoline. (M.P. 199° C.; LC-MS: 310 (MH+)).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:21]([O:23][CH:24]([CH2:30][O:31][CH:32]([CH3:34])[CH3:33])[CH2:25][O:26][CH:27]([CH3:29])[CH3:28])=[O:22])=[CH:17][CH2:18][S:19](=O)[C@H:14]23)=[O:11])[N:8]=1)=[O:2].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:21]([O:23][CH:24]([CH2:25][O:26][CH:27]([CH3:28])[CH3:29])[CH2:30][O:31][CH:32]([CH3:33])[CH3:34])=[O:22])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS(=O)[C@H]12)c1csc(NC=O)n1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 1.2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 6.5 g) and sodium iodide (5 g) in dried acetone (130 ml) was dropwise added trifluoroacetic anhydride (7 g) at -2° C. over 16 minutes, and stirred at 0° to 5° C. for 1.2 hours. The resultant mixture was poured into ice water (650 ml), and then extracted with ethyl acetate (200 ml). The extract was washed with an aqueous solution of sodium sulfite (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) in turn. The solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diethylether (100 ml). The precipitates were collected by filtration to give 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.6 g).
Reaction SMILES: CN(C)[C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[C:13]=1[F:27].[OH-:30].[Na+]>CCO.O>[F:18][C:17]1[C:16]([F:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([F:26])=[C:13]([F:27])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:30])=[O:28]
Reactant: [OH-]
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F

Procedure:
A mixture of N,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoro-4′-phenylanilino)phenylacetamide (2.7 g, 6.7 mmol) and NaOH (3.0 g, 72 mmol) in EtOH (100 mL) and water (20 mL) is heated at reflux temperature for 14 hours. After cooling to room temperature, most of the ethanol is removed by rotary evaporator. Ice water (250 mL) and ice cold Et2O (250 mL) are added and the organic phase is separated and washed with ice cold 1 N HCl (200 mL) and then brine (100 mL). The organic solution is dried (MgSO4) and evaporated by rotary evaporator taking care not to warm above 50° C. The title compound is obtained by trituration of the residue with hexane (m.p. 180–181° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23].C([O:28][CH2:29][CH2:30][O:31][NH2:32])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:32][O:31][CH2:30][CH2:29][OH:28])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)c2n(c1=O)CCC2
Reactant: CC(C)(C)OCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)NOCCO)c2n(c1=O)CCC2
Temperature: 75 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]1[N:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@H:9]3[CH2:10][O:11][CH2:12][CH2:13][N:8]3[CH3:6])=[N:15][N:16]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1c1nnc2ccc(F)cn12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCOC[C@@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of Intermediate 83b (297 mg, 0.92 mmol) in DCM (8.0 mL) at 0° C. was added TFA (400 μL) and the reaction stirred at RT overnight. Further TFA (600 μL) was added and the reaction stirred for 1 h then partitioned between DCM and sat. aq. NaHCO3 solution. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in DCM (4.0 ml) and MeOH (3 drops) added. Formaldehyde solution (37 wt % in water, 162 μL, 2.00 mmol) was added followed by sodium triacetoxyborohydride (372 mg, 2.40 mmol). The reaction was stirred overnight then loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (75.0 mg, 34%). 1H NMR (400 MHz, d4-MeOD): 2.09 (3H, s), 2.49 (1H, td, J 11.4, 3.8), 2.98 (1H, dt, J 11.9, 2.0), 3.79-3.90 (3H, m), 3.94 (1H, m), 4.01 (1H, dd, J 10.1, 4.0), 7.50 (1H, ddd, J 10.0, 7.7, 2.2), 7.81 (1H, ddd, J 10.1, 4.9, 0.8), 8.98 (1H, ddd, J 4.0, 2.3, 0.8).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[Cl:23][C:24]1[CH:25]=[C:26]([NH2:38])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH:16]4[CH2:20][CH2:19][O:18][CH2:17]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:21]#[N:22])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 85 °C
Yield: 73.9 %

Procedure:
To a single-neck reaction flask (500 ml) were added 4-chloro-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (5 g, 15.649 mmol), 3-chloro-4-(pyridin-2-yl-methoxy)benzenamine (4.037 g, 17.214 mmol) and pyridine hydrochloride (421 mg). To the flask was added isopropanol (150 ml). The mixture was stirred and refluxed for 2 hr at the temperature of 85° C. The reaction was stopped and cooled to the room temperature. The resultant mixture was filtered in vacuo. The filter cake was washed with mother liquor and dried in vacuo to give a yellow solid (5.988 g). Yield: 73.9%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid* (0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.249, 1.47 mmol) in dichloromethane was stirred for 45 minutes before the addition of ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reaction mixture was stirred for 2 hours, solvent removed under reduced pressure and residue was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford the title compound (0.091 g, 36% yield). LC/MS: (PS-A2) Rt 3.08 [M+H]+ 339.93.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:22][CH2:23][CH:18]([O:17][C:15]3[CH:16]=[C:11]4[CH:10]=[C:9]([C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:28])[NH:8][C:12]4=[N:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OC3CCN(C4CC4)CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2cc(OC3CCN(C4CC4)CC3)cnc2[nH]1)N1CCOCC1
Yield: 79.4 %

Procedure:
The solution of 0.16 g (0.34 mmol) 5-(1-cyclopropyl-piperidin-4-yloxy)-2-(morpholine-4-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 2 ml dichloromethane was cooled down to 0° C. and treated with 0.52 ml (0.8 g, 6.8 mmol) trifluoroacetic acid. The cooling bath was removed and after 1 hour at room temperature the solution was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.1 g (83%) of the desired compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.O>CS(C)=O>[O:18]1[CH2:4][CH:17]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1csc(-c2ccc(C3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of 0.063 g (1.5 mmol) of sodium hydride in DMSO (10 mL) was added 0.300 g (1.47 mmol) of trimethylsulfonium iodide as a solution in DMSO (5 mL). After stirring at room temperature for 5 min 0.130 g (0.687 mmol) of the above aldehyde was added as a solution in DMSO (5 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was poured into H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.129 g (92.3%) of 2-(4-oxiranyl-phenyl)-thiazole as a clear oil.