Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CCCCCC.O1CCCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:18][C:17](=[O:19])[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)=[CH:15][N:14]([CH3:13])[CH3:30]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CN(C)C=C(C(=O)CC(=O)C(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 3.9 g. portion of diisopropylamine was dissolved in 200 ml. of dry tetrahydrofuran, and to the solution was added 16 ml. of 2.4-molar butyllithium solution in hexane. The mixture was stirred for 30 minutes and chilled to about -70°. To the mixture was added 10 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one suspended in 50 ml. of tetrahydrofuran. The temperature rose to about -60°, and the mixture was stirred for 50 minutes and chilled. To the mixture was then added over a period of 1 minute a 4.7 g. portion of pivaloyl chloride. The temperature of the reaction mixture was then about -70°. The mixture was allowed to warm slowly to ambient temperature while it was stirred for 16 hours. The mixture was then diluted with 200 ml. of diethyl ether, and was washed successively with 1 N hydrochloric acid, 1 N sodium hydroxide, and saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate, and was evaporated to dryness under vacuum to obtain 9.1 g. of a dark oil. The oil was chromatographed over a 300 g. silica gel column with 1:10 ethyl acetate:dichloromethane as the eluting solvent. The product-containing portions were combined and evaporated under vacuum to dryness to obtain 1.3 g. of the product, which was identified by nmr analysis, which showed (CDCl3) δ1.03 (s, 9H); 2.78 (s, 6H); 5.03 (s, >1H); 7.53 (broad s, 4H); 7.76 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:18])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN1CCCCCC1Cc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CC2CCCCCN2C)cc1

Procedure:
Add a solution of 0.75 g of acetyl chloride in 5 ml of benzene drop by drop to a solution of 1.9 g of the title compound of Example 22 and 1 g of triethylamine in 10 ml of benzene. After an hour concentrate the resulting product, take it up with water and diethyl ether, collect the organic phase and concentrate it to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>C(O)C.[Pd]>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccccc4)cc3c21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCc4ccccc4)cc3c21
Yield: 21.8 %

Procedure:
A solution of 1-(2-methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.37 g, 4.00 mmol) in ethanol (40 mL) was added to a Parr vessel charged with 10% palladium on carbon (137 mg). The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for six days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to provide 0.300 g of 1-(2-methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 175-178° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To a mixed solution of fuming nitric acid (3.5 ml) and conc. sulfuric acid (5.4 ml) was added p-toluenesulfonyl chloride (5.00 g, 26.2 mmol) in several portions under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. To the reaction mixture was added ice, and the mixture was extracted with diethyl ether. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 4-methyl-3-nitrobenzenesulfonyl chloride (5.43 g, yield 88.0%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3nnn[nH]3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(NC2CCNCC2)ncc1-c1nnn[nH]1

Procedure:
A solution of 4-[5-(1H-tetrazol-5-yl)-pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.32 mmol) in 4 M HCl in dioxane (60 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 246.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:22][CH:19]3[CH2:21][CH2:20]3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
4-(2,5-Dichloropyrimidin-4-yl)-benzoic acid methyl ester (85 mg, 0.30 mmol) was dissolved in ethanol with 0.2 mL cyclopropylamine and the reaction mixture heated to 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-(5-chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid methyl ester as a solid, 90 mg, 0.30 mmol, 100% yield. LCMS: ES+=304.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:29]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[N+:46]([O-:48])=[O:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:38]([N+:46]([O-:48])=[O:47])[CH:39]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-amino-benzoic acid ethyl ester (17 g, 103 mmol) in dichloromethane (500 mL) and triethylamine (20.8 g, 28.5 mL, 206 mmol) was treated with dimethylaminopyridine (0.63 g, 5 mmol) and 4-benzyloxy-3-nitro-benzoyl chloride (30 g, 103 mmol). The mixture was stirred at room temperature overnight, while a thick white precipitate formed. The slurry was diluted with water (10 mL) and stirred vigorously, then filtered, washing with dichloromethane and water. The solid was dried under high vacuum to yield 4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester as a white solid, 26.5 g (61%), MS (ISP): m/e=419.3 (M−H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1([CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:21]([NH2:23])=O)[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[NH4+].[OH-]>>[C:21]([CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:7]([CH3:24])([CH3:6])[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)#[N:23]
Reactant: CC1(C)c2ccccc2C(C(N)=O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)c2ccccc2C(C#N)c2ccccc21
Yield: 87.5 %

Procedure:
POCl3 (25 mL, 00 mmol) was added to crystalline 10,10-Dimethyl-9,10-dihydroanthracene-9-carboxamide [8] (1.25 g, 4.9 mmol) while stirring. The solution was then heated at reflux (30 min), when TLC showed complete absence of starting material. The solution was then poured into a mixture of crushed ice and NH4OH with vigorous stirring. The solution was stirred for 15 minutes and excess of NH4OH was added to keep the solution alkaline. A solid substance separated out which was extracted with ether (3×50 ml). The combined ether extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give an light yellow oil which crystallized immediately. The product obtained was chromatographically pure and recrystallized readily from EtOH to give 1.0 g (86%) of the product as colorless prisms. mp. 91-92° C. 1H NMR (CDCl3)d: 1.54 (s, 3H, CH3), 1.79 (s, 3H, CH3), 5.32 (s, 1H, CH), 7.32-7.68 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 30.22, 30.33, 36.95, 125.77, 127.43, 127.92, 129.28. Anal. Calcd. For (C17H15N): C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:13]O.Cl.CC(OC(C)=O)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-bromo-1H-indole-3-carbaldehyde (1.2 g, 5.36 mmol) in pyridine (10 mL) was added NH2OH.HCl (0.424 g, 6.11 mmol) portionwise and the resulting mixture was stirred at rt for 1.5 h. 25 mL of Ac2O was added and the mixture was heated at reflux overnight. After this time the reaction mixture was cooled to rt and poured into ice. The resulting solid was filtered and the product was purified by flash column chromatography to give 6-bromo-1H-indole-3-carbonitrile slightly impure but was used for the next step. Mass Spectrum (ESI) m/e=222 (M+1).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of cyclopent-3-en-1-ol (CAS number 14320-38-8; 15 g, 178 mmol) in dry THF (357 ml) at 0° C. under nitrogen was added sodium hydride (60%, 9.27 g, 232 mmol). After fizzing had ceased, to this was then added drop wise 1-(chloromethyl)-4-methoxybenzene (CAS number 824-94-2; 31.4 ml, 232 mmol). The reaction was allowed to warm to room temperature and stirred for 17 hours then quenched by the addition of methanol and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-50% DCM/petrol) to afford the title compound.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH2:7][CH3:8]>CO>[CH2:6]([O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1)[CH2:7][CH3:8]
Reactant: CCCOc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 75 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 8.63 g(0.05 mol) of 3-(n-propoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oily residue.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]3[C:9](=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=3[OH:28])[S:18][N:19]=2)=[CH:22][CH:23]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-Fluoro-phenyl)-4-hydroxy-7-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 422.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22](O)([CH2:25][CH3:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.CN(S(F)(F)[F:32])C>>[CH2:23]([C:22]([C:4]1[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1)([F:32])[CH2:25][CH3:26])[CH3:24]
Reactant: CN(C)S(F)(F)F
Reactant: CCC(O)(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Product: CCC(F)(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 3-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pentan-3-ol with dimethylaminosulfur trifluoride using the procedure described in Example 12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH2:39]>>[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH:39][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:24]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1ncn(-c2ccc(CN)c(F)c2)n1
Product: Cc1ncn(-c2ccc(CNC(=O)c3nc4n(c(=O)c3OCc3ccccc3)CCOC4(C)C)c(F)c2)n1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 87, (2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. White crystals; mp 183-185° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65 (6H, s, 2×CH3), 2.52 (3H, s, CH3), 4.05 (4H, m, 2×CH2), 4.64 (2H, d, J=6.1 Hz, NCH2), 5.33 (2H, s, OCH2), 7.29-7.55 (8H, m, aromatics), 7.84 (1H, broad t, NH), 8.45 (1H, s, CH). Anal. Calcd for C27H27FN6O4: C, 62.54; H, 5.25; N, 16.21. Found: C, 62.41; H, 5.40; N, 16.23.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1C=CC=CC=1>[CH3:14][O:13][C:3]1[C:4]([CH3:12])=[C:5]([CH3:11])[C:6]([O:9][CH3:10])=[C:7]([CH3:8])[C:2]=1[CH:23]=[O:24]
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: COc1c(C)c(C)c(OC)c(C=O)c1C
Reaction time: 0.03 h
Yield: 112 %

Procedure:
1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene from Step 1 (5 g, 19.3 mmol, 1 equiv.) was dissolved in benzene (2×20 mL) and the solvent removed in vacuo to remove residual water. The dry solid was dissolved in toluene (100 mL) and the resulting solution cooled in an ice-water bath. To the colorless solution was added n-BuLi (1.6 M in hexanes, 16 mL, 26.9 mmol, 1.4 equiv.) dropwise over 1 min. After 2 min stirring, the resulting aryllithium species was quenched with DMF (7 mL, 90 mmol, 4.5 equiv.). Following an additional 30 min, excess base was quenched with 1 M aqueous citric acid (20 mL), and the mixture diluted in ethyl acetate (100 mL). The organics were removed, rinsed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4.5 g 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde as an orange solid, which was used without further purification. 1H NMR (CDCl3, 400 MHz) 10.5 (s, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Br-].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Zn+].C1COCC1>C([O-])(O)=O.[Na+].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]>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:11]2[S:10][CH:14]=[CH:13][N:12]=2)=[CH:3][CH:4]=1
Reactant: [Zn+]c1nccs1
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Fc1ccc(-c2nccs2)cn1
Reaction time: 2.5 h

Procedure:
To a 7 mL dram vial equipped with a stir bar was added 5-bromo-2-fluoropyridine (500 mg, 2.84 mmol) and Pd(dppf)Cl2 (104 mg, 0.142 mmol). The vial was sealed with a septum cap and then placed under N2 atm. To the vial was added thiazol-2-ylzinc(II) bromide in THF (6 mL, 3.00 mmol). The vial was placed in a 65° C. heating block with stirring for 2.5 h. The reaction solution was transfered to a 125 mL separatory funnel and was diluted with sat. aq. NaHCO3 (50 mL) upon which a significant amount of a white solid precipitated. The mixture was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (50 mL); dried over MgSO4; filtered; then concentrated in vacuo. The resulting was subjected to silica gel chromatography (hexanes:EtOAc) to afford 2-(6-fluoropyridin-3-yl)thiazole as a white solid, 303 mg (59%). 1H-NMR (500 MHz, CDCl3) δ 8.80 (d, J=2.5 Hz, 1H), 8.39 (ddd, J=8.5, 7.4, 2.5 Hz, 1H), 7.92 (d, J=3.3 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 7.07-7.03 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.[Cu][C:22]#[N:23].C(OCC)(=O)C.N>CN1CCCC1=O>[CH2:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:22]#[N:23])[N:7]=1)[CH2:9][CH3:10]
Reactant: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(Cl)n1
Reactant: N#C[Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 200 °C
Yield: 8.5 %

Procedure:
To a solution of 2-chloro-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine (50 mg) in 1-methyl-2-pyrrolidinone (2 mL), was added copper(I) cyanide (60 mg). The suspension was heated in the microwave at 200° C. for 20 min, than poured into a mixture of ethyl acetate (10 mL) and ammonia solution (5 mL). The organic layer was separated, washed with water (10 mL), dried over sodium sulphate and evaporated at reduced pressure. Preparative HPLC afforded the title compound 4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a brown gum (4.1 mg).
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: OB(O)c1ccnc(Cl)c1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)cnc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
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: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+]>O.Cl>[Br:8][C:7]1[C:2](=[O:11])[NH:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Cl)cc1Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
A solution of 2-amino-3-bromo-5-chloropyridine (4.0 g, 19.3 mmol) in water (30 mL) and conc. HCl (5.2 mL) was cooled with an ice bath to 0° C. and was treated with a solution of sodium nitrite (1.33 g, 19.3 mmol) in water (12 mL) over 10 min. The mixture was stirred for an additonal 10 min and allowed to warm to room temperature over 48 hr. The mixture was filtered. The solids were washed with water, then with CCl4 and were dried under vacuum at 50° C. for 3 hr to give 3-bromo-5-chloro-1H-2-pyridone (2.77 g, 69%), mp 173.5-175° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2C(F)(F)F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 40.6 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.19 g of 2-trifluoromethylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(2-trifluoromethylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (18)).