Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH3:12][C:13]([CH3:15])=[O:14]>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:13]([OH:14])([CH3:15])[CH3:12]
Reactant: Brc1nccs1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of n-butyllithium (2.5 M in diethyl ether, 160 ml, 0.40 mol) in diethyl ether (300 mL) was added slowly 2-bromo-1,3-thiazole (50 g, 0.30 mol). After 30 minutes, acetone (25 g, 0.43 mol) was added dropwise at −78° C. The reaction mixture was then warmed to ambient temperature, quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (20% ethyl acetate/hexanes) to give 2-(1,3-thiazol-2-yl)propan-2-ol.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccnc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (12.28 mg, 0.307 mmol), 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile (60.2 mg, 0.205 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one (38 mg, 0.205 mmol).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[CH:27][C:26]=3[CH3:32])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cl)cc1-c1ccc(CN2CCNC(Cc3ccccc3)C2)cc1
Temperature: 85 °C
Yield: 68 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 5-chloro-2-methylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.077 g of the title compound. Yield 68% ES MS (+) m/z 391.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BH4-].[Na+]>CO>[CH2:1]([NH:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH3:3]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
1.51 g of propanal dissolved in 5 ml of methanol was added dropwise to 6.15 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 60 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, 1.03 g of sodium borohydride was added to the mixture. The resulting mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 1 hour. After methanol was removed, water was added to the residue, and the residue was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol (15:1)) to obtain 5.22 g of 2-(propylaminomethyl)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([NH:21][CH2:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:13]([NH:21][CH2:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:29])=[O:30])=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccccc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-[(benzoylamino)methyl]thiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (8.6 mg) with purity >70%. MS (pos) m/z 466.2.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([O:21]C)=O)[C:16]([O:23]CC3C=CC(OC)=CC=3)=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2].O.[C:35](O)([C:37]([F:40])(F)F)=O>C(#N)C>[C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([NH:14][CH2:15][C:10]3[CH:11]=[CH:35][C:37]([F:40])=[CH:8][CH:9]=3)=[O:21])[C:16]([OH:23])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(C2CCN(C)N2C(C)=O)c2cccnc2c1OCc1ccc(OC)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)N1C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CCN1C
Temperature: 120 °C

Procedure:
A solution of the above acetylpyrazolidine (50 mg, Step 1), water (0.25 mL), and TFA (0.15 mL) in acetonitrile (5 mL) was stirred at room temperature for 6 hours. The resultant mixture was concentrated under vacuum. Residual water and TFA was removed by co-evaporation with additional acetonitrile (3×5 mL). Without further purification, the residual oil was treated with 4-fluorobenzylamine (0.2 mL) in a mixture of methanol (1 mL) and toluene (8 mL) in a sealed tube was heated in an oil bath at 120° C. for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[F:1][C:2]1[C:3]([O:13][CH2:21][CH2:22][O:23][CH3:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: COCCBr
Reactant: Cc1ccc2ccc(O)c(F)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a mixture of 8-fluoro-2-methylquinolin-7-ol (0.30 g, 1.69 mmol) and potassium carbonate (0.70 mg, 5.08 mmol) in acetone (7 mL) was added 1-bromo-2-methoxyethane (0.47 g, 3.39 mmol) and the mixture heated at 70° C. for 18 hours. Additional bromo-2-methoxyethane (0.150 mL) and potassium carbonate (0.35 g) were added and heating was continued for 16 hours. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 25M; 25% ethyl acetate:hexanes) to afford 8-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.217 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]=[CH:9][N:10](C)C)=[O:7])=[C:4]([CH3:15])[CH:3]=1.Cl.[CH3:17][O:18]N>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:18][CH3:17])=[O:7])=[C:4]([CH3:15])[CH:3]=1
Reactant: CON
Reactant: Cc1cc(Br)ccc1C(=O)N=CN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CON=CNC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
In a solution of 0.67 g of 4-bromo-N-(dimethylaminomethylidene)-2-methyl benzoic acid amide in 10 mL of 1,4-dioxane, a solution of 0.36 g of methoxyamine hydrochloride in 2 mL of water was added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with 50 mL of ethyl acetate, washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.70 g of the aimed product as white crystal.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:40])([CH3:41])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Trifluoroacetic acid (0.18 mL) was added to a solution of {5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 62-(1); 23.3 mg, 0.0370 mmol) in dichloromethane (0.9 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1 to 2/1) to give the title compound (17.0 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Br:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[N:21]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH:30][C:12]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:14])[N:21]=1
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(C2(C(=O)Nc3cc4ccccc4c(Br)n3)CC2)cc1
Temperature: 50 °C
Yield: 75 %

Procedure:
To 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (4.07 g, 21.17 mmol), thionyl chloride (4.64 mL, 63.52 mmol) and DMF (64 μL) were stirred at 50° C. for 3 hours, after which additional thionyl chloride (4 mL) and DMF (60 μL) were added and the mixture was stirred at 50° C. for 1 additional hour. The excess thionyl chloride was evaporated under reduced pressure. The resulting acid chloride was dissolved in anhydrous DCM (20 mL) and was slowly added to a cooled suspension of (0° C.) of 1-bromoisoquinolin-3-amine in DCM (50 mL) and Et3N (14.05 mL, 100.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with DCM and washed with water (1×30 mL), 1 N NaOH (2×30 mL), 1 N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-50% ethyl acetate in hexane) to yield N-(1-bromoisoquinolin-3-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (6.0 g, 75%) as a yellow solid. ESI-MS m/z calc. 396.05. found 397.3 (M+1)+. Retention time 2.24 minutes. 1H NMR (400.0 MHz, CDCl3) d 8.55 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.56-7.52 (m, 1H), 7.46-7.42 (m, 2H), 7.01-6.98 (m, 2H), 3.90 (s, 3H), 1.75 (dd, J=3.7, 6.8 Hz, 2H) and 1.21 (dd, J=3.7, 6.9 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.C(O[CH:14](OCC)[CH2:15][CH:16](OCC)OCC)C>C(O)C.O>[CH3:8][N:7]1[C:2]2[N:1]=[CH:14][CH:15]=[CH:16][C:3]=2[C:4](=[O:10])[NH:5][C:6]1=[O:9]
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Solvent: O
Solvent: CCO
Product: Cn1c(=O)[nH]c(=O)c2cccnc21
Temperature: 25 °C
Yield: 19.4 %

Procedure:
14.34 g (101.7 mmol) 6-amino-1-methyluracil and 26 mL (108 mmol) 1,1,3,3-tetraethoxypropane are dissolved in a mixture of 250 mL ethanol and 1 liter water and refluxed for 3 hours. After cooling down to room temperature, the precipitated intermediate is isolated by filtration washed with water and dried. 7.71 g of the condensation product of the acetal and the amino group is added to 12.5 mL concentrated sulfuric acid and the mixture is heated to 160° C. After cooling down to room temperature, the mixture is poured into 125 g ice. The crude product precipitates from the medium, is isolated by filtration, washed to neutral pH and dried. 4.84 g of the crude product is dissolved in 2 l refluxing methanol. 300 mL silicagel is added and the mixture is evaporated under reduced pressure. The crude product loaded onto the silicagel is purified by preparative column chromatography using chloroform/methanol 9:1. 3.49 g (19%) 1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is isolated (m.p. 277–285° C., Lit. 285° C.).
Reaction SMILES: [CH2:1]([N:5]([CH2:19]CCC)[S:6][N:7]([CH3:18])[C:8]([O:10][N:11]=[CH:12][C:13]([CH3:17])([S:15][CH3:16])[CH3:14])=[O:9])CCC.CN(C)SCl>>[CH3:19][N:5]([CH3:1])[S:6][N:7]([CH3:18])[C:8]([O:10][N:11]=[CH:12][C:13]([CH3:14])([S:15][CH3:16])[CH3:17])=[O:9]
Reactant: CCCCN(CCCC)SN(C)C(=O)ON=CC(C)(C)SC
Agent: CN(C)SCl
Product: CSC(C)(C)C=NOC(=O)N(C)SN(C)C

Procedure:
2-Methyl-2-(methylthio)propanal O-[(dimethylaminosulfenyl)-(methyl)carbamoyl]oxime is prepared in the same manner as the compound of Example III except that dimethylaminosulfenyl chloride is used instead of dibutylaminosulfenyl chloride.
Reaction SMILES: N([CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=2[F:23])[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])=[CH:7][CH:6]=1)=[N+]=[N-].C1(NC(=O)C2C=CC(F)=C(C3N=NC(C)=CC=3)C=2)CC1.[Cl:44]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCCl.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>[Cl:44][CH2:4][C:5]1[N:10]=[N:9][C:8]([C:11]2[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=2[F:23])[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])=[CH:7][CH:6]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: [N-]=[N+]=NCc1ccc(-c2cc(C(=O)NC3CC3)ccc2F)nn1
Agent: Cc1ccc(-c2cc(C(=O)NC3CC3)ccc2F)nn1
Solvent: ClCCCl
Product: O=C(NC1CC1)c1ccc(F)c(-c2ccc(CCl)nn2)c1
Temperature: 90 °C
Yield: 47 %

Procedure:
3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide. A solution of N-cyclopropyl-4-fluoro-3-(6-methylpyridazin-3-yl)benzamide (430 mg, 1.58 mmol) in 35 mL of DCE was treated with trichloroisocyanuric acid (122 mg, 0.52 mmol) and heated at 90° C. for 1.5 h. Additional trichloroisocyanuric acid (16 mg, 0.07 mmol) was added to the reaction mixture, which was heated for another 30 min at 90° C. The reaction mixture was cooled to RT and the white solid was filtered and rinsed with 2×25 mL of DCM. The filtrate was washed with 5 mL of 0.5 N NaOH followed by 5 mL of brine. The organic layer was concentrated and the residue was purified by silica gel chromatography (35-95% EtOAc in hexanes) to give 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 47% yield). MS (ESI, pos. ion) m/z: 306.2 (M+1). A solution of 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 0.75 mmol) in 1 mL of DMF and 1 mL of acetone at RT was treated with NaN3 (68 mg, 1.04 mmol) and the mixture stirred at RT for 5 h. The reaction mixture was filtered through a fritted funnel and the solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated. The brown residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (215 mg, 92% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 313.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1 H, d, J=3.7 Hz), 8.46 (1 H, dd, J=7.3, 2.1 Hz), 8.15 (1 H, dd, J=8.8, 1.8 Hz), 8.07 (1 H, m), 7.90 (1 H, d, J=8.8 Hz), 7.52 (1 H, dd, J=10.5, 8.9 Hz), 4.87 (2 H, s), 2.88 (1 H, m), 0.72 (2 H, m), 0.60 (2 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −114.48.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCCCCc1ccc(N)c(Br)c1
Product: CCCCCCc1ccc(N)c(-c2ccccc2)c1

Procedure:
2-bromo-4-(n-hexyl)aniline and benzene boronic acid can be combined to form 2-phenyl-4-(n-hexyl)aniline,
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[Mg]Br>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][C:21]=1[O:23][CH3:24])=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)c1F
Reactant: COc1ccc([Mg]Br)c(OC)c1
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (3.22 g, 16.0 mmol) and 2,4-dimethoxyphenylmagnesium bromide (29 mL, 0.5 M in THF) to give 1.21 g of the title compound as a white solid.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([Cl:2])[C:4]=3[C:5]3=[N:22][O:21][C:20]([CH3:23])=[C:6]3[C:7]2=[O:19])[CH2:14]1)[CH3:25]
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: CCOC(=O)CBr
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (446 mg, 1.0 mmol) in tetrahydrofuran (20 mL) add ethylbromoacetate (0.11 mL, 1.0 mmol) and follow by potassium carbonate (346 mg, 2.5 mmol). Stir the mixture at room temperature under nitrogen overnight. Concentrate the mixture, partition between water and 20% isopropanol/chloroform, and separate. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 261 mg of the title compound as a clear oil, 65% yield. 1H NMR: consistent with structure. MS (ion spray) 404 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH3:10])=[C:5]([CH3:17])[C:4]=1[CH3:18].[OH-].[Na+].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:14]2[CH2:13][CH2:12][N:11]([CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:18])[C:5]=3[CH3:17])[CH3:10])[CH2:16][CH2:15]2)=[O:28])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(C)N2CCNCC2)c(C)c1C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)N2CCN(C(=O)c3ccc(C(F)(F)F)cc3)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine (0.02 g, 0.081 mmole) was dissolved in anhydrous toluene and 1N NaOH (1:1) at room temperature. The 4-trifluoromethyl benzoyl chloride (0.013 ml, 0.081 mmole) was added into the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was washed with 1N NaOH, extracted with EtOAC. The combined organic layers were dried over MgSO4. After removal organic solvent, the residue was purified by SCX column eluted with MeOH and 10% MeOH (NH3) in dichloromethane. (4-Trifluoromethyl-phenyl)-{4-[1-(4-Methoxy2,3-Dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone (compound 10) was obtained as a pale yellow oil (0.010 g 30%). Analysis H1 NMR (400MHz, CDCl3): 7.65 (2H, d), 7.495 (2H, d), 7.19 (1H, d), 6.689 (1H, d), 3.764 (3H, s), 3.682 (1H, q), 3.317 (2H, m), 2.506 (6H, m), 2.266 (3H, s), 2.164 (3H, s) 1.286 (3H, d). MS (LC-MS): Calculated for C23H27F3N2O2 420.47, found 421.26 (M+). XII. {5-[1-4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(4-trifluoromethyl-phenyl)-methanone (compound 11)
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21]COC)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[ClH:26]>CO>[ClH:26].[CH2:1]([C:3]1[S:4][C:5]([CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([OH:21])=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)c(C)s1
Agent: Cl
Solvent: CO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)c(C)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazole (3.21 g) in methanol (75 mL) was added concentrated hydrochloric acid (1.5 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-methanol to give 4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (3.02 g, yield 96%) as pale-yellow prism crystals. melting point: 184-186° C.