Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([OH:17])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:23][CH3:24])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)c1cc(=O)c2cc(O)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Yield: 65.6 %

Procedure:
Into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is added 700 mg (2.24 mg, 1.0 equiv.) of 8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23a). This material is dissolved in 50 mL of toluene, then 689 mg, 586 μL (4.47 mmol, 2.0 equiv.) of diethyl sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K2CO3 were added. The reaction was then heated to reflux for 24 hr. At the end of this time, monitoring by LC/MS reveals that the reaction is >than 95% complete. The reaction is then cooled, 100 mL of ethyl acetate is added and the organic layer is washed with 0.5N HCl solution, dried over Na2SO4, filtered and concentrated. The residues were subjected to flash chromatography, using 40% ethyl acetate in hexane as eluent. The purified fractions were concentrated to yield 500 mg (65%) of a colorless solid.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:16][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])([C:12]([F:13])([F:14])[F:15])[C:8]([F:11])([F:10])[F:9])=[O:28]
Reactant: C=C(F)C(=O)Cl
Reactant: Cc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccccc1C)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 21 g (0.081 mol) of 2-tolylhexafluoro-2-propanol and 8.2 g (0.08 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 40 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.02 g of hydroquinone monomethyl ether. 19.6 g (73 percent of theory) of 2-tolylhexafluoro-2-propyl α-fluoroacrylate having a boiling point of 58° to 60° C. (under 0.27 mbar) were obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=O>C(O)C.N1CCCCC1>[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)[NH:14][C:13]1=[O:19]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (79.9 mg, 61%).
Reaction SMILES: C(O[C:4](=O)[C:5]([CH3:15])(C)CC1C=CC(S)=CC=1)C.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([C:27]2[CH:32]=[CH:31][C:30]([C@@:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:5][CH2:4]1
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccccc2Br)cc1)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S)cc1
Product: C[C@](O)(c1ccc(S(=O)(=O)c2ccccc2C2CC2)cc1)C(F)(F)F

Procedure:
Using the methods described above in Example 12, but substituting 2-Bromo-benzenethiol for 3-(4-mercaptophenyl)-2,2-dimethylpropionic acid ethyl ester in step a, 2-[4-(2-bromobenzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2C#N)CC1
Temperature: 110 °C

Procedure:
5-bromo-2-fluorobenzonitrile (2.00 g, 10.00 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.01 g, 25.0 mmol) were dissolved in a minimal amount of chloroform (3 ml) and heated at 110° C. for 20 h, during which all of the solvent evaporated. The resulting crude golden yellow oil was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, and dried (MgSO4). Flash chromatography with 25:10:65 and 35:10:55 EtOAc-CH2Cl2-Hexane of the concentrated organic layers gave the desired product, tert-butyl 4-(4-bromo-2-cyanophenylamino)piperidine-1-carboxylate as a light yellow glassy foam. MS m/e 379.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:22]>CCOC(C)=O.O>[ClH:22].[ClH:22].[CH3:1][O:2][C:3]1([C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COC1(c2nccn2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(c2nccn2C)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (182 mg) in EtOAc (0.7 ml) and water (0.09 ml) was added 4N hydrogen chloride in EtOAc (0.7 ml) and the mixture was stirred at room temperature for 2 hours. Solvent was removed in vacuo to give 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine dihydrochloride (122 mg) as a colorless powder. The obtained crude product was used in next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH:22]([NH:25][OH:26])([CH3:24])[CH3:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:25]([OH:26])[CH:22]([CH3:24])[CH3:23])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: CC(C)NO
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: CC(C)N(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-isopropyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (CDCl3) δ ppm 8.59 (s, 1H), 8.46 (s, 1H), 7.39 (s, 1H), 7.10 (m, 2H), 7.02 (d, 2H, J=8.6 Hz), 6.73 (s, 1H), 5.41 (s, 2H), 5.08 (m, 1H), 1.33 (d, 6H, J=6.6 Hz). LCMS (APCI, M+H+): 328.1 HRMS calcd for C18H18FN3O2 (M+H) 328.1456, found 328.1456. HPLC: 95.8% purity.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[F:22][C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:29][C:26]1[CH:25]=[CH:24][C:23]([F:22])=[N:28][CH:27]=1)[CH3:2]
Reactant: Oc1ccc(F)nc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(COc1ccc(F)nc1)OCC
Temperature: 100 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
Bromoacetaldehyde diethyl acetal (6.75 ml, 44.9 mmol) and cesium carbonate (30.9 g, 95.0 mmol) were added to an N,N-dimethylacetamide solution (60 ml) of 6-fluoropyridin-3-ol (3.0 g, 24.9 mmol, purity: at most 94%), and stirred under a nitrogen atmosphere at 100° C. for 15 hours. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=17:1 to 6:1) to obtain 5-(2,2-diethoxyethoxy)-2-fluoropyridine (5.67 g, yield: 99%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[CH:5]1([CH2:4][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24](=[O:25])[N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=3[CH3:44])=[CH:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CCCc1nc(C)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (bromomethyl)cyclopropane (0.17 mL), cesium carbonate (1.7 g) and 4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (0.56 g, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[CH3:14]>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc2ccccc2c1
Yield: 99.4 %

Procedure:
A solution of 3.00 g of 2-naphthaldehyde and 6.69 g of ethoxycarbonylmethylenetriphenylphosphorane in 100 ml of acetonitrile was heated under reflux for 1 hour, after which the reaction mixture was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.32 g (yield 99%) of ethyl 3-(2-naphthyl)-2-propenoate as a colorless solid.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[N:18][C:19]=3[O:28][CH3:29])[N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[H][H]>CCO.[Pd]>[CH3:29][O:28][C:19]1[N:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[C:22]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]([NH2:1])([CH3:6])[CH3:5])=[CH:12][CH:11]=1)=[N:14]2
Reactant: COc1nccc2nc(-c3ccc(C(C)(C)N=[N+]=[N-])cc3)c(-c3cccs3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1nccc2nc(-c3ccc(C(C)(C)N)cc3)c(-c3cccs3)cc12

Procedure:
A mixture of 2-[4-(1-azido-1-methylethyl)phenyl]-5-methoxy-3-(2-thienyl)-1,6-naphthyridine (2-5, 78 mg, 0.194 mmol) and 10% Pd/C (9 mg) was stirred under 1atm hydrogen in EtOH (5 mL) for 2 h. The mixture was filtered through celite and concentrated to give the title compound as a clear oil. LRMS m/z (M+1) Calcd: 376.1,. Found 376.2.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:23][C:6]1[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]2[CH:9]=[N:10][NH:11][C:12](=[O:14])[C:13]=2[C:5]=1[Cl:4]
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reaction time: 8.5 h
Yield: 83 %

Procedure:
To 30 ml of acetonitrile solution containing 903 mg (3.00 mmol) of 3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(c) was added 703 mg (3.95 mmol) of N-bromosuccinimide at room temperature, and the mixture was stirred for 8.5 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, 5% aqueous sodium hydrogen sulfite solution and then a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate were added diisopropyl ether and cyclohexane, precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane and then with hexane, and dried under reduced pressure to obtain 943 mg of the title compound as a pale yellowish solid. (Yield: 83%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH3:27]OC(C1C=C(OC2C=CC(C(O)=O)=NC=2)C2CC(C)(C)OC=2C=1)=O.C(N)C>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH2:25][CH3:27])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Agent: CCN
Product: CCNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (166a) (74 mg, 0.22 mmol) and ethyl amine (2.0 M in THF, 1 mL) to give a white solid (28 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.78 Hz, 1 H) 8.18 (d, J=8.59 Hz, 1 H) 7.82-7.91 (m, 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.25 (s, 1 H) 7.19 (d, J=1.01 Hz, 1 H) 3.87 (s, 3 H) 3.52 (dd, J=7.33, 6.06 Hz, 2 H) 2.90 (s, 2 H) 1.49 (s, 6 H) 1.22-1.33 (m, 3 H); LCMS for C20H22N2O5 m/z 371.00 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@H:13]2[O:17][CH2:18][C:19]([O:22][CH3:23])([O:20][CH3:21])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:13]2[O:17][CH2:18][C:19]([O:22][CH3:23])([O:20][CH3:21])[C@@H:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OCc3ccccc3)[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@H]2OS(C)(=O)=O
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a stirred solution of compound 12d (500 mg, 1.55 mmol) in CH2Cl2 (20 mL) was added triethyl amine (332 μL, 2.32 mmol) and mesyl chloride (266 mg, 2.32 mmol). After stirring for 30 minutes the reaction was washed with saturated NaHCO3 (1×20 mL), 2M HCl (1×20 m), dried MgSO4 and concentrated to give the title compound (655 mg, 99%) as a yellow oil. MS M+H 402.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[C:17]([O:26][CH3:27])[CH:16]=2)[N:3]=1.C1COCC1.[CH3:33][NH2:34]>>[CH3:27][O:26][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:34][CH3:33])[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:20]=[CH:19][C:18]=1[C:21]1[O:25][CH:24]=[N:23][CH:22]=1
Reactant: COc1cc(Nc2nc(Cl)nc(-c3ccccc3)n2)ccc1-c1cnco1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-c3cnco3)c(OC)c2)nc(-c2ccccc2)n1
Temperature: 80 °C
Yield: 83 %

Procedure:
4-Chloro-N-[3-methoxy-4-(5-oxazolyl)phenyl]-6-phenyl-1,3,5-triazin-2-amine, 103, (27 mg, 0.07 mmol) was suspended in 2M methylamine in THF (1 mL, 2 mmol) was added and the reaction mixture heated in a sealed tube at 80° C. overnight. The product was filtered and purified by flash column chromatography (2% methanol in methylene chloride) to yield 22 mg (83%) of the title compound LCMS (Ret Time=3.15 min, HPLC condition B) M+H+=375.23 (100%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[I:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CN(C=O)C>[I:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(I)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2cccc(I)c2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 57.5 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitril (1.82 g, 10 mmol) in dry DMF (25 ml) is added triethylamine (1.54 ml, 11 mmol) and 3-iodoaniline (1.2 ml, 10 mmol) and the mixture is heated to 80-100° C. over night. After cooling the mixture is poured into four volumes of ice-water. The precipitate is filtered off, washed with water and dried. This crude product is washed with hot ethanol to yield 2.1 g (58%) of the title compound. Mp. 211-212° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:10][S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 122.5 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Benzoic acid (250 g, 2.05 mol) was placed in a 1-L round-bottom flask, and chlorosulfonic acid (1L, 1760 g, 15.1 mol) was added. The mixture was heated with stirring at 120-125° C. for 2 h, allowed to cool to 40-50° C., and added dropwise to an excess of crushed ice. The precipitated product was collected by filtration and dissolved in 1 L of ethyl acetate; then the aqueous layer that formed was separated, and the organic layer was washed with 100 mL of water, dried over sodium sulfate, and concentrated by evaporation to near dryness. After trituration with 300 mL of hexane, the product was collected by filtration, washed on the filter with 200 mL of hexane, and dried in air to give 384.1 g (85%) of 3-chlorosulfonylbenzoic acid, mp 134-135° C. (lit. mp 134-135° C.); 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 11.43 (broad s, CO2H), 7.81 (t, J=8.0 Hz, H-5), 8.32 and 8.50 (2d, J=8.0 Hz, H-4 and H-6), 8.79 (t, J=1.6 Hz, H-2); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 170.00 (C═O), 145.06 (C-3), 136.71 (C-6), 131.92 (C-4), 131.31 (C-1), 130.63 (C-5), 128.91 (C-2).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([NH:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=4)[C:14]([NH:16][CH3:17])=[O:15])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)cnc3c2)c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)cnc3c2)c1

Procedure:
To a mixture of 3-(3-Bromo-imidazo-[1,2-b]-pyridazin-7-yl)-N-methyl-benzamide (Intermediate A) (1 eq, 0.353 mmol, 117 mg) and 2-chloropyridine-4-boronic acid (1.2 eq, 0.424 mmol, 66.7 mg) in DME (3 ml) are added water (1 ml) and Na2CO3 (2 eq, 0.707 mmol, 87.6 mg). PdCl2(PPh3)2 (0.1 eq, 0.035 mmol, 24.8 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-N-methyl-benzamide as a yellow solid; [M+H]+=364
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:29]>CO>[NH2:29][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC1CO1
Reactant: N
Solvent: CO
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazole (250 mg, 0.657 mmol) in 7 N NH3 in methanol (10 mL) is stirred at 60° C. for 16 h. The solvent is evaporated and the remaining residue is dried under HV to give 1-amino-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (278 mg) as a beige oil; LC-MS: tR=0.86 min, [M+1]+=398.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:23]1[C:24]([CH3:31])=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][CH2:40][CH2:41][OH:42]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:39][CH2:40][CH2:41][OH:42])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:10])=[O:11])=[CH:4][C:3]=1[C:23]1[C:24]([CH3:31])=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1
Reactant: OCCCBr
Reactant: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCCO)cc1Cl
Temperature: 45 °C
Yield: 60.5 %

Procedure:
To 5-[2-chloro-4-hydroxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile (90 mg, 0.2 mmol) in dry acetonitrile (1.5 mL), was added Cs2CO3 (130 mg, 0.4 mmol), followed by an addition of 3-bromo-1-propanol (36 mg, 0.26 mmol). The mixture was heated at 45° C. for 24 hrs and partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, washed with brine (2×5 mL) and dried over MgSO4. After filtration, the mixture was concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/1) to give 5-[2-chloro-4-(3-hydroxy-propoxy)-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 9-1 as a white solid (62 mg). MS: 511.9 (M+H)+; tR=8.07 min (method 2). NMR (CDCl3), δ, 8.344 (1H, s), 7.634 (1H, s), 7.597 (1H, s), 7.235 (1H, s), 7.164-7.184 (2H, m), 7.008-7.060 (1H, m), 6.871 (1H, d, J=7.8 Hz), 4.287 (2H, t), 3.769-3.805 (4H, m), 2.775-2.786 (2H, m), 2.064 (3H, s), 1.850-1.905 (2H, m), 1.959-1.995 (2H, m), 1.653 (2H, s).