Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30](Br)[CH:29]=[C:28](Br)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C.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>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:38]3[CH:39]=[N:34][CH:35]=[N:36][CH:37]=3)[CH:29]=[C:28]([C:38]3[CH:39]=[N:34][CH:35]=[N:36][CH:37]=3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)O
Reactant: OB(O)c1cncnc1
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: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3cncnc3)c2)c1CCC(=O)O
Temperature: 160 °C
Yield: 55.9 %

Procedure:
To a solution of 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-dibromo-phenoxy)-hexyl]-phenoxy}-butyric acid (150 mg, 0.26 mmol) in ethanol (2 mL) in a 20 mL microwave tube were added tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.03 mmol), pyrimidin-5-ylboronic acid (189 mg, 3.0 mmol), and potassium carbonate (212 mg, 1.53 mmol) at room temperature. The microwave tube was sealed and heated to 160° C. in a microwave oven for 30 minutes. Then, the reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The two layers were separated and the ethyl acetate layer was discarded. Then, the aqueous layer was acidified with 1.0 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-di-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (85 mg, 57%) as a light yellow solid: ES(+)-HRMS m/e calculated for C33H36N4O6 (M+Na)+ 607.2527, found 607.2527.
Reaction SMILES: C(O[C:4](=[O:8])[CH:5]([F:7])[F:6])C.[NH2:9][C@H:10]([CH2:20][F:21])[C@@H:11]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[OH:12]>>[F:7][CH:5]([F:6])[C:4]([NH:9][C@H:10]([CH2:20][F:21])[C@H:11]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)=[O:8]
Reactant: CCOC(=O)C(F)F
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(F)F

Procedure:
Using the same procedure as Step 1 of Example 4 and reacting ethyldifluoroacetate with commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol the title compound is obtained (18.3 g): m/z 373 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.CN1CCC(N2C3C(=CC(NC(C4SC=CC=4)=N)=CC=3)CC2)C1.O1CCN(CCN2C3C(=CC(NC(C4SC=CC=4)=N)=CC=3)CCC2)CC1.CN1CCC(N2CCCCC3C=C(NC(C4SC=CC=4)=N)C=CC2=3)C1>CO.Cl>[CH3:1][NH:2][CH:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Agent: CN1CCC(N2CCCCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: CN1CCC(N2CCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: CNC1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Yield: 55 %

Procedure:
A solution of compound 5 (250 mg, 0.533 mmol) in MeOH (10 mL) and 1M HCl (10 mL) was refluxed for half an hour and then concentrated. The residue was partitioned between 3N NaOH (50 mL) and CH2Cl2 (25 mL) and the product was extracted into CH2Cl2 (2×25 mL). The combined organic layers were dried (Na2SO4), and concentrated. This residue was subjected to flash chromatography on silica gel: 2% methanol: 98% CH2Cl2 followed by 2.5% 2M ammonia in methanol; 97.5% CH2Cl2 to give a yellow-brown solid. (108 mg, 55% yield) 1H NMR (DMSO-d6) δ 7.67 (d, J=3.0 Hz, 1H), 7.54 (d, J=5.1 Hz, 1H), 7.07 (dd, J=3.9, 5.1 Hz), 6.62-6.47 (m, 3H), 6.21 (s, 2H), 3.57-3.50 (m, 1H), 3.11 (t, J=5.4 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 2.28 (s, 3H), 2.24-2.20 (m, 1H), 1.98-1.92 (m, 2H), 1.82-1.77 (m, 2H), 1.70-1.65 (m, 2H), 1.59-1.47 (m, 2H), 1.24-1.11 (m, 2H). ESI-MS (m/z, %): 369 (MH+, 82), 338 (100), 258 (21), 185 (50), 148 (64), 140 (46); ESI-HRMS calculated for C21H29N4S (MH+): 369.2107, Observed: 369.2104; HPLC purity: 95.3%.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.[NH2:34][CH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([NH:34][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: NC1CCc2ccccc21
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NC1CCc2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added 2.5 g triethylamine, and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed to come to room temperature and then stirred 2 hours. To the reaction mixture is then added, dropwise, 3.4 g 1-aminoindan, and the reaction mixture then stirred for 16 hours. The reaction mixture is then extracted several times with 2 N hydrochloric acid, then with 2 N aqueous sodium hydroxide solution, washed well with saturated aqueous sodium chloride, dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The resulting residue is rapidly filtered over silica gel, with methylene chloride as solvent. The necessary fractions indicated to contain reaction product by thin layer chromatography of samples are pooled and solvent removed by evaporation under vacuum to give title product as a viscous oil, characterized by NMR (in CDCl3); triplet at 5.15 ppm (4 protons) and doublet at 6.4 ppm (1 proton).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.P(Br)(Br)[Br:15].P(Br)(Br)(Br)=O.[OH-].[Na+]>>[Br:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=[C:2]([NH2:1])[CH:11]=1
Reactant: BrP(Br)Br
Reactant: Nc1cc(O)c2cc(Cl)ccc2n1
Agent: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)c2cc(Cl)ccc2n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
2-Amino-6-chloro-4-hydroxyquinoline (CAS 64319-84-2, 6.0 g, 31 mmol) were added portionswise to phosphorus tribromide (25 g, 92 mmol). Phosphorus oxybromide (10 g, 37 mmol) were added and the mixture was stirred at 150° C. for 16 h. The mixture was poured into 300 mL ice water and the pH was adjusted to 11 by addition of 32% sodium hydroxide solution. The solid was filtered off and washed with water and cyclohexane. 4-Bromo-6-chloro-quinolin-2-ylamine was obtained as a yellow solid (7.8 g, 98%), MS: m/e=258.9 (M+H+).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B(F)(F)[F:16].F>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([F:16])[CH:7]=1
Reactant: FB(F)F
Reactant: Nc1cc(Br)ccc1-c1ccccc1
Agent: F
Product: Fc1cc(Br)ccc1-c1ccccc1

Procedure:
2-Amino-4-bromo-biphenyl was subjected to a Schiemann reaction using hydrofluoroboric acid. The product had a b.p. of 106°-109°C./0.6mm, and a m.p. of 38°-39°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23])=[CH:6][CH:5]=2
Reactant: CSC(=N)c1cccs1
Reactant: Cc1cc2cc(N)ccc2n1CCN1CCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2cc(NC(=N)c3cccs3)ccc2n1CCN1CCCC1
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A solution of compound 27 (0.37 g, 1.520 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.86 g, 3.040 mmol) at room temperature and stirred for overnight (16 h). The reaction was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 28 (0.43 g, 81%) as a foam. 1H NMR (DMSO-d6) δ 1.64-1.76 (m, 4H), 2.39 (s, 3H), 2.46-2.58 (m, 4H), 2.66 (t, 2H, J=7.2 Hz), 4.16 (t, 2H, J=7.2 Hz), 6.09 (s, 1H), 6.20 (brs, 2H), 6.61 (dd, 1H, J=1.8, 8.5 Hz), 6.87 (d, 1H, J=1.2 Hz), 7.08 (dd, 1H, J=3.9, 4.9 Hz), 7.27 (d, 1H, J=8.7 Hz), 7.57 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz); ESI-MS (m/z, %) 253 (MH+, 100), 177 (56); ESI-HRMS calculated for C20H25N4S (MH+), calculated: 353.1794; observed: 353.1804; HPLC purity: 97% by area.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21][C:22](=[O:30])[CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=O)=[C:4]([F:31])[CH:3]=1.[C:32](O)(=[O:34])[CH3:33].[O-]C#N.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:21]2[C:32](=[O:34])[CH:33]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH2:23][C:22]2=[O:30])=[CH:6][C:7]=1[O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)O
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Agent: N#C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(N2C(=O)C=C(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide and 2 ml of acetic acid was added sodium cyanate, and the mixture was stirred at 50° C. for 1 hour and then at 110° C. for 1.5 hours. After cooling, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyridin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2([CH2:4][OH:3])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(4-bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester (10.0 g, 37.2 mmol) in THF (100 mL) at 0° C. was added lithium aluminum hydride (2.11 g, 55.7 mmol) and the reaction was stirred for 1 hour at room temperature. The mixture was quenched with H2O (2 mL), followed by 4 N aqueous NaOH (2 mL) and additional H2O (6 mL). After stirring for 15 minutes, the solid precipitate was removed by filtration and the filtrate was concentrated and dried to give the title compound.
Reaction SMILES: CS([CH2:5][CH:6]=[CH:7][CH2:8]S(C)(=O)=O)(=O)=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>ClCCl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:20]2[CH2:8][CH:7]=[CH:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)CC=CCS(C)(=O)=O
Solvent: ClCCl
Product: COc1ccc(CN2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a solution of 1,4-dimethylsulphonyl-2-butene (2.15 g, 11.64 mmol) in dichloromethane (40 ml), 4-methoxybenzylamine (6 ml, 44.24 mmol) was added dropwise and the solution was stirred 20 hours at r.t. The solid was filtrated and the filtrate was washed with water (2×30 ml), dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography: silica gel, gradient hexane:ethyl acetate 3:1 to 1:1 to afforded the product (1.4 g, 63%) as yellow oil.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:33](=[O:34])[C:32]1[CH:36]=[C:37]([C:40]([CH3:41])([CH3:42])[CH3:43])[C:38]([OH:39])=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:31]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, di-n-dodecylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoyl chloride to produce N,N-di-n-dodecyl-3,5-di-t-butyl-4-hydroxybenzamide; an oil product. When tested by the procedure of Example 2, the sample containing this compound lasted 600 hours, about 2.0 times as long as the control.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15](F)[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([NH:28][CH3:27])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1cc2c(c(C)c1F)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (210 mg) of methylamine were added to pyridine (1 ml), and the mixture was heated and stirred overnight at 60° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol was added to the residue to collect solids. The solids were washed successively with ethanol and diethyl ether to obtain the title compound (115 mg) as a colorless powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:20]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)[OH:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=2)=[O:21])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C(O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a 250 mL round bottomed flask charged with (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol (2.1 g, 4.9 mmol) in dichloromethane (200 mL) was added Dess-Martin periodinane (2.5 g, 5.9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone (1.9 g, 90%) as a light yellow oil: LC/MS m/e calcd for C21H15FN2O3S2 [M+H]+ 427.49, observed 426.7.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].ClC(OCC(C)C)=O.[CH3:40][N:41]1CCOCC1.CN>CN(C)C(=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:41][CH3:40])=[O:14])[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(C)c(-n2c(NC)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 27 %

Procedure:
To a cooled (0° C.) solution of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.18 g, 0.38 mmol) in N,N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.60 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.46 mmol) and 4-methylmorpholine (0.55 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.50 mmol). Stirred at 0° C. for 35 min. Added methylamine (0.29 mL of 2M solution in THF, 0.57 mmol). After 1 h, distilled DMA and purified the crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ7.86 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H, J=8.0 Hz), 6.98 (m, 2H), 5.52 (q, 2H, J=12.8 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 2.09 (s, 3H). ESHRMS m/z 493.0659 (M+H calculated for C21H20BrF2N4O3 requires 493.0681).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1.S(=O)(=O)(O)O>>[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]=[C:14]1[NH:15][CH2:16][CH2:17][NH:18]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6.4 gm (0.0234 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine nitrate were added slowly over a period of 15 minutes to 10 ml of concentrated sulfuric acid at 20° C., while slightly cooling and vigorously stirring. The viscous reaction mixture was allowed to stand at room temperature for two hours, whereupon ice was added thereto, and the precipitate formed thereby was filtered off, recrystallized from methanol and dried. Yield: 2 gm (33.5% of theory) of 2-(2-chloro-4-methyl-5-nitro-phenylimino)-imidazolidine, m.p. 198°-201° C.; Rf -value 0.7 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts ammonium hydroxide; carrier: silicagel G; visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[CH:75]=C(C(OCC)=O)[O:73][N:72]=2)=[CH:67][CH:66]=1>>[Cl:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[CH:75]=[C:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([O:6][CH3:7])=[O:5])[C:9]5=[O:37])=[CH:14][CH:13]=4)=[CH:22][CH:21]=3)=[O:25])[O:73][N:72]=2)=[CH:69][CH:70]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)no1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(Cl)cc5)no4)cc3)cc2C1=O
Yield: 48 %

Procedure:
The compound of example 617 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 3-(4-chlorophenyl)isoxazole-5-carboxylate.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:15]/[C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])=[CH:20][CH:19]=1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: O=Cc1ccc(F)cc1
Product: O=C(/C=C/c1ccc(F)cc1)c1cnc2sc3c(n12)CCCCC3

Procedure:
This compound was prepared as in EXAMPLE 15 by condensation of 1-(6,7,8,9-tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl ethanone (Formula N-4) with 4-fluorobenzaldehyde to provide 6,7,8,9-Tetrahydro-[2-(4-fluorophenyl)-E-ethenyl]-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl methanone (Formula N-5, X=4-fluoro), 3.1 g, m.p. 187-188°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([NH:35][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NC1CCCc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(NC1CCCc2ccccc21)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (6.3 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1,2,3,4-tetrahydro-1-naphthylamine (63.0 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was re-dissolved in CH2Cl2 (50 mL). The organic layer was washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the crude mixture. Flash column chromatography of the crude (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (87.0 mg, 100%): m.p. 164-165 ° C.