Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:10].O>C1(C)C=CC=CC=1>[CH2:15]([N:14]1[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:22])=[CH:7][C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=CC1=C(Cl)CCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2

Procedure:
46.7 g (0.358 mol) of 2-chloro-1-formylcyclopent-1-ene are dissolved in 400 ml of toluene. 138 g (0.716 mol) of N-benzylglycine ethyl ester are added. The mixture is refluxed for one hour, the water of reaction being separated off via a water separator. After cooling, any precipitate formed is filtered off with suction and the toluene solution is washed with water, dried and concentrated. The residue is taken up in 300 ml of ethanol, 600 ml of 2N hydrochloric acid are added and the mixture is extracted 3× with petroleum ether. The petroleum ether phase is washed with 2×175 ml of ethanol/2N hydrochloric acid 1:2 and then with 100 ml of saturated NaHCO3 solution, the organic phase is dried over MgSO4, stirred with active charcoal and filtered with suction, and the filtrate is evaporated in vacuo. Yield: 53.1 g of oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH2:12]([S-:15])[CH2:13][CH3:14].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][S:15][CH2:12][CH2:13][CH3:14])([O-:11])=[O:10]
Reactant: CCC[S-]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 1-(chloromethyl)-3-nitrobenzene (10.0 g, 58.1 mmol) in DMF (30 mL) was stirred at room temperature, then sodium propane-1-thiolate (5.7 g, 58.1 mmol) was added, followed by stirring at 60° C. overnight. After water was added, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give (3-nitrobenzyl)(propyl)sulfane (11.2 g, yield 91%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>ClCCl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26]
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of N,N-dimethyl-1,3-diaminopropane (0.92 g) and triethylamine (0.95 mL) in dichloromethane (10 mL) was added 2-nitrobenzenesulfonyl chloride (1 g), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (1.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3c(F)cccc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added thereto at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](N)[CH2:25][NH2:26].C(O)C.C>ClC1C=CC=CC=1Cl.C(Cl)Cl.O>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9]2[NH:26][CH2:25][CH2:24][N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#CCOc1ccc(C#N)cc1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: Clc1ccccc1Cl
Product: N#Cc1ccc(OCC2=NCCN2)cc1
Temperature: 5 °C

Procedure:
A mixture of 15.8 g of 4-cyanophenoxyacetonitrile and 23.3 g of ethylenediamine p-toluenesulfonate in 50 ml of 1,2-dichlorobenzene was heated at from about 130°-145° C. for about an hour. After reaction the mixture was cooled, diluted with CH2Cl2 and filtered to obtain the crude product. The crude product was dissolved in boiling absolute ethanol, treated with activated charcoal and filtered through a fluted paper. The filtrate was cooled to 5° C. for 1.5 hours and the crystals which formed removed by filtering. After drying in a vacuum oven, off-white crystals were obtained having a melting point of 190°-192° C. The off-white crystals were put in solution in 200 ml of boiling water and treated with activated charcoal and filtered. The filtrate was cooled to 5° C. for 1 hour and the crystals which formed removed by filtration. Upon drying, the product 2-((4-cyanophenoxy)methyl)-2-imidazoline p-toluenesulfonate was obtained as white crystals, m.p. 196°-198° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([I:19])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2nccc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1cnn(Cc2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 65E (270 mg) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (259 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous sodium bisulfite, water, and brine. The organic layers were combined, and evaporation of the solvent provided the title compound.
Reaction SMILES: [C:1]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([N:19]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:33]3)[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Product: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 36.7 %

Procedure:
By using a method similar to the method of Example 460, using 2-tert-butyl4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.934 g, 3.44 mmol) and (S)-2-phenethyl-piperazine (0.655 g, 3.44 mmol) gives 0.561 g of the title compound as a yellow solid: mp 93–96° C.; mass spectrum (ion spray): m/z=445 (M+1); Analysis for C27H32N4S(0.5 H2O): calcd: C, 71.49; H, 7.33; N, 12.35; found: C, 71.27; H, 6.88; N, 12.29.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(O)cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 174 mg of the title compound (85%) as a yellow solid in 99.8% purity by HPLC (Rt: 4.7, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:22])[N:6]=1)[CH2:3][CH3:4].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH3:22][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13](=[O:21])[N:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([CH:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH2:3][CH3:4])=[N:6]2
Reactant: CCC(N)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Compound 17 (100 mg, 0.341 mmol) was combined with 6-bromo purine (75 mg, 0.375 mmol) and diisopropylethylamine (65 uL, 0.375 mmol) in n-butanol (1.0 mL). The reaction was sealed, heated to 120° C., and stirred for 18 hours. The solution was allowed to cool, then concentrated in vacuo. The resulting residue was purified by prep HPLC to provide compound 14 as an olive solid. (ES): m/z 412 (M+H), 206. 1H NMR (300 MHz, DMSO-d6) δ 8.96-9.06 (br. m, 1H), 8.53 (br. s, 1H), 8.51 (s, 1H), 7.68 (t, 1H, J=7.8 Hz), 7.45-7.62 (m, 6H), 7.31 (d, 1H, J=7.3 Hz), 4.76-4.86 (m, 1H), 2.73 (s, 3H), 1.98-2.11 (m, 1H), 1.76-1.94 (m, 1H), 0.79 (t, 3H, J=7.2 Hz). The reaction described above and compound 14 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:28][C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)=[N:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-n2cccn2)ccc1-c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 1] (132 mg, 0.441 mmol) and tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (140 mg, 0.401 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (23 mg, 20 μmol) followed by a solution of Na2CO3 (85 mg, 0.802 mmol) in water (0.5 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL), washed with water (10 mL), then the organic phase was separated and concentrated in vacuo to afford the crude product as a pale brown solid. The crude material was purified by flash chromatography using a 12 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow/off-white solid (138 mg, 78% yield). LC-MS: Rt 1.34 min; MS m/z 443.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=2.53 Hz, 1H), 8.21 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.60 (dd, J=8.59, 2.02 Hz, 1H), 6.59-6.62 (m, 1H), 4.05 (s, 3H), 3.51 (s, 8H), 1.43 (s, 9H).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]34O[C:17]3([CH:18]([O:35][Si](C(C)(C)C)(C)C)[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:35])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:43][C:44](=[O:49])[C:45]([CH3:47])([CH3:46])[CH3:48])=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(O[Si](C)(C)C(C)(C)C)C21O3
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(=O)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
To a solution of Compound 210 (9.5 g, 13.6 mmol) in wet CHCl3 (150 mL) cooled at zero degrees C was added BF3.OEt2 (8.4 mL, 68.0 mmol) followed by stirring at 25° C. for 10 minutes. The reaction mixture was diluted with CH2Cl2 (400 mL), washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was then dissolved in THF (50 mL) and treated with 48 percent aqueous HBr (5 mL) at 25° C. for 40 minutes with stirring. The reaction mixture was diluted with ethyl ether (400 mL), washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash column chromatography of the residue (silica gel, 33 percent ethyl ether in petroleum ether) gave Compound 211 (2.80 g, 34 percent) and Compound 212 (1.30 g, 18 percent). Compound 211: Rf =0.52 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2970, 1719, 1681, 1606, 1494, 1381, 1307, 1179, 1123, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=8.7 Hz, 1 H, H1), 7.45-7.18 (m, 6 H, H4and aromatic), 6.98 (dd, J=8.7, 2.4 Hz, 1 H, H2), 6.11 (d, J=0.9 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.72 (dd, J=11.1, 1.7 Hz, 1 H, olefinic), 2.90 (dt, J=18.9, 4.5 Hz, 1 H, H9), 2.77-2.53 (m, 3 H, H7 and H9), 2.24-2.12 (m, 2 H, H8), 1.34 (s, 9 H, COC(CH3) ), 0.21 (s, 9 H, Si(CH3)3); MS (FAB+) m/e (rel intensity) 698 (M+Cs, 100), 565 (6); HRMS for C34H35NO5SiCs (M+Cs), calcd 698.1339, found 698.1339.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[CH3:34][CH:35]([CH3:71])[C@H:36]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][C:45]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][S:57]([C:60]4[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=4)(=[O:59])=[O:58])=[CH:52][CH:51]=3)=[CH:46][CH:47]=2)[C:42]1=[O:70])[C:37]([O:39]C)=[O:38]>>[CH3:34][CH:35]([CH3:71])[C@H:36]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][C:45]([C:50]3[CH:51]=[CH:52][C:53]([NH:56][S:57]([C:60]4[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=4)(=[O:59])=[O:58])=[CH:54][CH:55]=3)=[CH:46][CH:47]=2)[C:42]1=[O:70])[C:37]([OH:39])=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 92 was prepared analogous to compound of example 78 by hydrolysis of compound of example 91.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].CCO[C:30]([CH3:32])=[O:31]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:10]4[CH2:9][CH2:8][N:6]([CH3:5])[C:30](=[O:31])[CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: CCOC(C)=O
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 4 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 50.0 mg, 0.144 mmol), KF (42.6 mg, 0.719 mmol) and 1-methylperazine-2-one hydrochloride (67.0 mg, 0.431 mmol) were suspended in NMP (0.4 mL). The RM was stirred at 180° C. for 4 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.75 min (conditions 5), (tR 11.35 min (conditions 2), MH+=425.9, 1H-NMR in DMSO-d6: 8.07 (s, 1H); 7.80 (d, 1H); 7.52 (s, 1H); 7.36 (d, 1H); 7.05 (d, 1H); 4.85 (m, 1H); 4.01 (d, 1H); 3.95 (s, 3H); 3.78 (d, 1H); 3.62 (m, 2H); 3.27 (m, 2H); 2.81 (s, 3H); 1.79 (d, 3H)).
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:17])[CH:6]=1)(=O)C>Cl>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:17])[CH:6]=1
Reactant: CC(=O)Nc1cc(O)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(O)c(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A mixture of 4-acetamido-2-hydroxy-5-nitrobenzoic acid (5 g, 20.8 mmol, 1.00 equiv) and HCl (aq.) (110 mL, 6N) in a 500-mL round-bottom flask was allowed to react, with stifling, for 2 hrs while the temperature was maintained at reflux. The mixture was cooled. The solids were collected by filtration, yielding 3.4 g (82%) of 4-amino-2-hydroxy-5-nitrobenzoic acid as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([O:25]C)[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:20]=1
Reactant: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2-methyl-phenoxy]acetate (300 mg, 0.66 mmol, 1 eq) and AlCl3 (526 mg, 3.95 mmol, 6 eq) in CH2Cl2 (10 mL) was added ethanethiol (245 mg, 3.95 mmol, 5 eq) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 2 h and the resulting mixture was quenched by the addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 15:1) to give the title compound as a colorless oil (120 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19](Br)=[CH:20][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1)[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.CCO.CCO.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[CH:20][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2cnc3cc(Br)ccc32)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnc3cc(-c4ccc(OC)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of [4-(5-bromo-benzoimidazol-1-yl)-phenyl]-acetic acid ethyl ester (0.300 g, 0.84 mmol), 4-methoxyphenylboronic acid (0.152 g, 1.00 mmol, 1.2 equiv), PdCl2(dppf) (18 mg, 0.025 mmol, 0.03 equiv), Na2CO3 (2 M solution in H2O, 1.7 mL, 3.34 mmol, 4 equiv) in toluene/EtOH (12 mL; 5:1, v/v) is stirred and refluxed for 2 h. After further addition of boronic acid (0.100 g, 0.66 mmol) in EtOH (1 mL), the reaction mixture is stirred and refluxed for 30 min, allowed to cool to rt, diluted with EtOAc and H2O, and filtered through a pad of Celite. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Silica gel column chromatography purification (Hexane/EtOAc, 3:1) provides the title compound as a yellow solid: ES-MS: 387.1 [M+H]+; single peak at tR=4.27 min (System 1); Rf=0.24 (Hexane/EtOAc, 3:1).