Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[S:7])#[N:4].Br[CH2:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].O>C(O)C>[CH3:13][C:12]([C:11]1[N:8]=[C:6]([CH2:5][C:3]#[N:4])[S:7][CH:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#CCC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1csc(CC#N)n1
Yield: 51.8 %

Procedure:
To a solution of 16.5 g of 85% KOH in 250 ml ethanol was added 25.0 g of 2-cyanothioacetamide. After all of this reagent had dissolved, 44.8 g of bromopinacolone was added dropwise over ca 5 min. The reaction temperature spontaneously climbed to 65° C. and a white solid began to deposit. The mixture was stirred and heated at reflux for 1 hour, cooled, poured into 1000 ml water, and extracted with ether. The extract was washed with brine, dried (MgSO4), and concentrated. Kugelrohr distillation of the residual oil gave 23.3 g of the desired product as a light yellow oil b.p. 90°-95° C. (1 mm Hg).
Reaction SMILES: C1CCCCC=1.C(OCC)(=O)C.C([O:20][C:21]1[C:28]([O:29][CH2:30][C@@H:31]2[O:33][CH2:32]2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])C1C=CC=CC=1>[Pd].C(O)C.O.C(N(CC)CC)C>[OH:33][CH2:32][C@@H:31]1[O:20][C:21]2[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: O=Cc1cccc(OC[C@H]2CO2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=Cc1cccc2c1O[C@@H](CO)CO2

Procedure:
The combined product from the previous reaction (57.27 g), palladium on carbon (10%; 2.75 g), cyclohexene (81.4 ml) and ethyl acetate (2 L) were heated and stirred together under reflux under nitrogen for 24 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (1 L) then filtered through a pad of Celite. The solvent was removed in vacuo to give an orange oil, which was dissolved in a mixture of ethanol (500 ml), water (500 ml) and triethylamine (55.2 ml). This mixture was stirred and heated under reflux for 3 hours. After cooling the ethanol was removed in vacuo and the remaining aqueous mixture extracted with ethyl acetate (2×250 ml). The combined extracts were washed with hydrochloric acid (1 M; 2×250 ml) then water then dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluting with a 3:1, followed by a 1:1, mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give (S)-2-hydroxymethyl-1,4-benzodioxan-8-carboxaldehyde (8.02 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:23]([NH:26][NH2:27])(=O)[CH3:24]>C(O)C>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13]3[N:14]([C:23]([CH3:24])=[N:26][N:27]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)NN
Reactant: CCSc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Solvent: CCO
Product: CCSc1cccc2c1C(c1ccccc1Br)=NCc1nnc(C)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-ethylthio-1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7-ethylthio-1-methyl-6-(o-bromophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:11])([F:10])[C:8]#[CH:9].I[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[CH3:22]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:22][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:13]=1[C:9]#[C:8][C:7]([F:11])([F:10])[F:6])[C:17]([OH:19])=[O:18]
Reactant: Cc1cc(C(=O)O)ccc1I
Reactant: C#CC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C#CC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The method is based upon a procedure detailed by Yoneda et al in Bulletin Chemical Society Japan 1990, 63, 2124-2126. A solution of n-butyl lithium (2.5M in hexanes; 1 eq) was added carefully to a solution of 3,3,3-trifluoroprop-1-yne (1 eq) in THF at −78° C. under nitrogen. The mixture was stirred at −78° C. for 30 min then a solution of ZnCl2 (3 eq) in THF was added slowly. The mixture was allowed to warm to room temperature, stirred for 30 min then Pd(Ph3P)4 (5 mol %) was added, followed by 4-iodo-3-methylbenzoic acid (0.5 eq). The mixture was heated to 50° C. and stirred for 15 h, then heated further to 80° C. for 5 h, and finally at 100° C. overnight. After allowing to cool to room temperature the mixture was concentrated under vacuum to a crude residue. The residue was purified by column chromatography on silica gel to give the product as a solid. m/z=227 (M−1).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>CC(C)=O>[N:9]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[N+:10]=[N-:11]
Reactant: CC(C)(C)C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN=[N+]=[N-]
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 2 L three-necked round-bottom flask fitted with a mechanical stirrer was added bromopinacolone A-1 (134 g, 747 mmol, 1.0 equiv), acetone (1.2 L), and sodium azide (63.2 g, 971 mmol, 1.3 equiv). The reaction mixture was stirred at room-temperature overnight and then filtered, and the solids were washed with acetone (2×100 mL). The filtrate was concentrated in vacuo to provide azidopinacolone (105.0 g, 100%) as an oil. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1]C1C2C(=CC=C(N(C)C)C=2)N=CC=1C#N.COC1C=C(C=CC=1)N.[CH3:26][N:27]([CH3:49])[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=1>>[ClH:1].[CH3:26][N:27]([CH3:49])[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=1
Reactant: CN(C)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: COc1cccc(N)c1
Agent: COc1cccc(Nc2c(C#N)cnc3ccc(N(C)C)cc23)c1
Product: Cl

Procedure:
Prepared from 0.400 g of 4-chloro-6-dimethylaminoquinoline-3-carbonitrile and 0.256 g of 3-methoxyaniline in the same manner as EXAMPLE 395. The yield of 6-dimethylamino-4-(3-methoxyphenylamino)quinoline-3-carbonitrile was 0.532 g of brown powder: mass spectrum (electrospray, m/e): M+H 318.9.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42]Br>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:16][C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:20][CH2:42][C:41]2[CH:44]=[CH:45][C:46]([F:47])=[C:39]([F:38])[CH:40]=2)[N:19]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an oven-dried round bottom flask was added DMF (5 mL), the product of Step E (0.500 g; 1.27 mmol), Cs2CO3 (0.910 g; 2.79 mmol), and 3,4-difluorobenzyl bromide (0.162 mL; 1.27 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution (3×), and brine. The organic portion was dried (Na2SO4), filtered, and concentrated in vacuo. Purification done by MPLC (silica gel; 0-10% ethyl acetate/hexane gradient) afforded the desired product: m/e=518 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2].[S-:14][C:15]#[N:16].[Na+].[Br-].[Na+].BrBr>CO>[CH:1]([C:4]1[C:5]([S:14][C:15]#[N:16])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: N#C[S-]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(N)c1
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])cc1SC#N

Procedure:
The title compound was prepared according to General Method 13 using 5-isopropyl-2-nitro-phenylamine (prepared in Example PP-1; 5.4 g, 30 mmol), sodium thiocyanate (14.6 g, 180 mmol), sodium bromide (3.7 g, 35.99 mmol), bromine (5.75 g, 36.0 mmol), and MeOH (100 mL). The crude reaction mixture was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 238 (M+H).
Reaction SMILES: CSC.ClCl.[Cl:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:8]=1[NH2:9].N1C2C(=CC=CC=2)C=CC=1.Cl[S:26]([C:29]1[N:37]=[C:36]2[N:31]([CH:32]=[N:33][C:34]([Cl:39])=[C:35]2[Cl:38])[N:30]=1)(=[O:28])=[O:27]>ClCCl.[SH2]=N.CO>[Cl:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:8]=1[NH:9][S:26]([C:29]1[N:37]=[C:36]2[N:31]([CH:32]=[N:33][C:34]([Cl:39])=[C:35]2[Cl:38])[N:30]=1)(=[O:28])=[O:27]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)c1nc2c(Cl)c(Cl)ncn2n1
Agent: ClCl
Agent: N=[SH2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Solvent: CSC
Product: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2c(Cl)c(Cl)ncn2n1
Temperature: 0 °C

Procedure:
A solution of 0.6 mL (8 mmol) of dimethyl sulfide in 65 mL of dichloromethane was cooled to -20° C. and then 0.4 g (6 mmol) of chlorine was slowly sparged in with stirring and cooling to maintain the temperature below -15° C. A mixture of 5.0 g (31 mmol) of 2,6-dichloroaniline and 6.3 g (49 mmol) of quinoline was then added with cooling and stirring to form a mixture of the sulfilimine catalyst, unreacted 2,6-dichloroaniline, and quinoline. The mixture was allowed to warm to 0° C. and 10 g (45 mmol) of 2-chlorosulfonyl-7,8-dichloro[1,2,4]triazolo[1,5-c]pyrimidine was added with stirring and cooling. The mixture was allowed to warm to about 20° C. and stir for about 16 hours. It was then diluted with 50 mL of methanol and the solids that formed were collected by filtration, washed 2×30 mL with methanol, and dried to obtain 6.2 g (80 percent of theory) of the title compound as a white solid having uv maxima at 210 and 270 nm.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[C:9]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1)#[N:10]>C(O)C>[F:19][C:17]([F:20])([F:18])[C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:9]([NH2:10])=[O:2])[CH:16]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)ccn1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)ccn1
Yield: 75.4 %

Procedure:
To 72 ml of ethanol were added 6.18 g of sodium bicarbonate and 5.11 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 45 minutes. After allowing to cool, 6 g of 2-cyano-4-trifluoromethylpyridine was added at 0° C., and the mixture was stirred, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5 g of 4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH:7]([CH2:13][C:14](=O)[CH3:15])[CH2:6]2.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:14]([CH3:15])=[CH:13][C:7]=1[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CC(C)=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Cc1cc(C)n(CC(C)O)c1-2
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1.2 g of (RS)-5-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 1.65 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 3 hours, during which the solvent was reduced to a volume of 30 ml. The cold reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.17 g (82%) of (RS)-1-(6-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)c2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (25 mg, 0.057), 2-furancarbonyl chloride (5.8 μL, 0.059 mmol) and DIEA (49 μL, 0.282 mmol) was combined in anhydrous DMF (1.5 mL). After stirring under nitrogen at ambient temperature for 0.5 hrs, the reaction mixture was evaporated in vacuo and partitioned between EtOAc and 1N NaHSO4. The aqueous layer was separated and back-extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The product was crystallized from MeOH/Et2O and collected by filtration providing a white solid: ES+ MS: 537 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][CH:9]=2)[CH:4]=1)=O.[CH3:22][NH:23][CH3:24].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(OCC)(=O)C.C(O)(=O)C.O>[CH3:22][N:23]([CH2:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][CH:9]=2)[CH:4]=1)[CH3:24]
Reactant: CC1CC(=O)NN=C1c1ccc(-n2ccc(C=O)c2)cc1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(CN(C)C)c2)cc1

Procedure:
4.2 g (15 millimoles) of 6-[p-(3-formylpyrrol-1-yl)-phenyl]4, 5-dihydro-5-methylpyridazin-3-one (compound from Example 1A) in 30 ml of methanol were stirred with 3.36 g (30 millimoles) of 40% strength aqueous dimethylamine solution, 1.8 g (30 millimoles) of acetic acid and 0.75 g (12 millimoles) of sodium cyanoborohydride for 5 hours at room temperature (conversion monitored by thin layer chromatography using SiO2 and 5:2:2 ethyl acetate/acetic acid/water). 50 ml of H2O were added, the mixture was rendered alkaline with 2N NaOH and extracted with ethyl acetate, the organic phase was washed with water, dried with Na2SO4 and purified over a silica gel column using a 4:1 methylene chloride/methanol mixture, and the crystalline residue from the product-containing fractions was recrystallized from ethyl acetate/petroleum ether. 1.4 g of 6-[p-(3-dimethylaminomethylpyrrol-1-yl)-phenyl]-4, 5-dihydro-5-methylpyridazin-3-one of melting point 167°-168° C. were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)ccc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a solution of Intermediate 48a (198 mg, 0.24 mmol) in THF (4 mL) was added TBAF (1M in THF, 0.29 mL, 0.29 mmol) and the red solution was stirred at RT for 15 min. The solution was concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. FCC, using 4-8% MeOH in DCM, gave the title compound (124 mg, 78%). LCMS (Method 5): Rt 4.50 min, m/z 655 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.60-1.63 (2H, m), 1.70-1.75 (4H, m), 1.84-1.96 (2H, m), 1.99-2.13 (2H, m), 3.14 (4H, t, J=5.2 Hz), 4.82 (1H, m), 5.55 (1H, t, J 4.4), 6.33 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.08 (1H, d, J=8.5 Hz), 7.12 (1H, d, J=2.4 Hz), 7.16 (1H, dd, J=9.8, 2.2 Hz), 7.27-7.39 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.60-7.63 (2H, m), 8.13 (1H, s), 10.59 (1H, br s).
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(OC([N:29]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:41]([N:29]1[C:3]2[C@@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc3ccccc3c2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 15.8 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 240 mg, 1.12 mmol) in 1,2-dichloroethane (8 mL) was added to a cooled (0° C.) solution of triethylamine (210 μL, 1.5 mmol) and N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 37; 285 mg, 0.82 mmol) in 1,2-dichloroethane (4 mL) over 1 min. The reaction mixture was stirred at room temperature for 75 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the reaction mixture was heated at reflux for 1 h, allowed to cool, and concentrated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions containing the product were evaporated and purified again using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions containing the product were evaporated, then co-evaporated with methanol and then with diethyl ether and dried under high vacuum at room temperature overnight to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (53 mg, 16%) as a white foam. ES(+)-MS (M+H) 409.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[C:18]([NH2:20])[S:19][C:15]=4[CH:14]=3)[N:10]=[C:4]2[CH:3]=1.[BrH:23].[NH+]1C=CC=CC=1.Br.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OCC)C.C(OCC)(=O)C.O>[Br:23][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][C:9]=1[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH2:20])[S:19][C:15]=2[CH:14]=1
Reactant: Br
Reactant: Cc1ccn2cc(CCc3ccc4nc(N)sc4c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccn2c(Br)c(CCc3ccc4nc(N)sc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzothiazole (0.4 g), pyridinium hydrobromide perbromide (0.5 g) and 25% hydrogen bromide-acetic acid (0.1 ml) in acetic acid (4 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated to give a residue, which was triturarted with a solution of ethyl acetate and diethyl ether to give a precipitate. The precipitate was collected by filtration and dried to give 6-[2-(3-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzothiazole (0.38 g).
Reaction SMILES: [C:1]([CH2:5][CH2:6][S:7][C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:10][CH2:11][N:12]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>>[C:1]([CH2:5][CH2:6][S:7][C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH2:10][CH2:11][N:12]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCSC1=NCCN1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCSC1=NCCN1Cc1cc(F)cc(F)c1

Procedure:
2-(2-Carbomethoxyethylthio)-1-(3,5-difluorobenzyl)imidazoline prepared as in example 12 is stirred with aqueous sodium hydroxide and the reaction mixture is heated at reflux for one hour, cooled, and neutralized with concentrated hydrochloric acid. The mixture then is extracted three times with ether and the combined ether extracts are concentrated. Trituration of the residue with boiling hexane and recrystallization from ethylacetate-hexane, yields 2-(2-carboxyethylthio)-1-(3,5-difluorobenzyl)imidazoline.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.[CH2:12]([C:14]([CH2:19]O)([CH2:17][OH:18])[CH2:15][OH:16])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:12]([C:14]1([CH2:17][OH:18])[CH2:15][O:16][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[O:8][CH2:19]1)[CH3:13]
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1(CO)COC(c2c([N+](=O)[O-])cnn2C)OC1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (370 mg, 2.39 mmol, intermediate 3) in toluene (50 mL) was added 2-ethyl-2-(hydroxymethyl)propane-1,3-diol (315 mg, 2.35 mmol) followed by p-toluenesulfonic acid (20 mg, 0.10 mmol). The reaction mixture was heated at reflux for 36 hr whilst azeotropically removing the water. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) as the first eluting isomer as a colourless solid (244 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 6.38 (s, 1H), 4.16 (s, 3H), 4.02 (d, J=11.5 Hz, 2H), 3.97 (d, J=5.2 Hz, 2H), 3.42 (d, J=3.8 Hz, 2H), 1.90 (m, 3H), 0.99 (t, J=7.6 Hz, 3H).