Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][NH:40][CH2:41]2.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([N:40]1[CH2:41][CH:42]2[CH:38]([C:37]2([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH3:36])[CH2:39]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)c3cc4ccccc4o3)CC21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-benzofuran-2-carboxylic acid (201 mg, 1.24 mmol) in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazole monohydrate (200 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg, 1.77 mmol). After stirring at room temperature for 10 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220 mg, 2.6 mmol). The reaction mixture was stirred at room temperature overnight before concentrating in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were treated with water (15 ml) upon which a buff solid precipitated. The biphasic mixture was filtered to afford 380 mg of a buff solid. The biphasic filtrate was separated and the organic layer was dried (MgSO4), and concentrated in vacuo to afford a further 80 mg of buff solid. The combined buff solid was warmed to 60° C. in methanol and allowed to slowly cool to room temperature upon which the title compound was collected by filtration as an off-white solid (340 mg, 63%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=[O:10])=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=[O:10]
Reactant: [N-]=[N+]=NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.7 %

Procedure:
To a mixture of 3 (13.5 g, 48.7 mmol), THF (100 mL) and water (50 mL) was added triphenyl phosphine (14.05 g, 53.5 mmol). The resulting mixture was stirred at room temperature for 6 hours. The THF and water were removed in vacuo. The residue was dissolved in the minimal amount of dichloromethane and passed through a silica gel pad (50 g) and washed with dichloromethane (500 mL) followed by a 4:1 mixture of dichloromethane-5% ammonia in methanol (500 mL). The appropriate fractions were concentrated and recrystallized from ethyl acetate to yield 6.45 g of 4 as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11]O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.Cl.C(OCC)(=O)C>[N:27]([CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)=[N+:28]=[N-:29]
Reactant: OCc1cccc2ncccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of quinolin-5-yl-methanol (96 mg, 0.60 mmol) and DPPA (202 μL, 0.91 mmol) in toluene (2 mL) was added DBU (166 μL, 1.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 3M HCl (1.7 mL) and ethyl acetate (5 mL). The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 49 mg of 5-azidomethyl-quinoline as light brown oil (44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CCN(CC)CC.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>CCOC(C)=O>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOCCCNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (6.36 g, 40 mmol) in EtOAc (60 mL) were added Et3N (12.14 g, 120 mmol) and 3-ethoxypropan-1-amine (4.54 g, 44 mmol). The reaction mixture was refluxed overnight, then cooled to rt and concentrated in vacuo to give the title compound as yellow oil (8.68 g, 90%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)=[CH:4][C:3]=1[CH:17]([F:19])[F:18].[Li]CCCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[F:18][CH:17]([F:19])[C:3]1[CH:4]=[C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)[CH:15]=[CH:16][C:2]=1[CH:28]=[O:29]
Reactant: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)F)c2)O1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)F)c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution of (S)-4-((4-bromo-3-(difluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (65; 3 g, 0.089 mol) in THF (30 ml) was added n-BuLi (2.5M solution in hexane, 3.9 ml, 0.097 mol) at −78° C. The mixture was stirred at the same temperature for 1 h and DMF (0.929 g, 0.103 mol) was added dropwise. After stirring at −78° C. for an additional 20 min, saturated aqueous NH4Cl (30 ml) was added. The resulting reaction mixture was warmed to room temperature and extracted with Et2O (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtOAc=5:1) to afford the titled compound, namely (S)-2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde 66 (1.83 g, 72%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9](=[CH:19]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9]3[CH:19]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: CNN
Reactant: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=O)N1Cc2cnn(C)c2-c2cc(Cl)ccc21
Yield: 39.6 %

Procedure:
Methylhydrazine(30.56 g) was added dropwise to a mixture of 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(160.3 g) and acetic acid (75.8 ml) in methanol(1.6 liters) with stirring and cooling over a period of 10 minutes. After being stirred for 1 hour at room temperature, the mixture was filtered by sunction and the filtrate was evaporated in vacuo after addition of acetic acid (160 ml) to it. The residue was neutralized with aqueous sodium hydroxide under ice cooling. The resulting precipitate was collected by filtration, washed with water and recrystallized from aqueous methanol and then ethanol to give 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H -pyrazolo[4,3-c]-quinoline (65.84 g). The physical data of the compound was identical to that of the object compound of Example 3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([CH2:6][CH:7](C(O)=O)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4]1>N1C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4]1
Reactant: O=C(O)C(CC1(C(F)(F)F)CC1)C(=O)O
Solvent: c1ccncc1
Product: O=C(O)CCC1(C(F)(F)F)CC1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 2-((1-(trifluoromethyl)cyclopropyl)methyl)malonic acid (1.13 g, 5.00 mmol) in pyridine (25 mL) was heated at 100° C. overnight, cooled to RT and concentrated to dryness. The residue was dissolved in 3N HCl, extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid (664 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 2.32 (t, J=8.0 Hz, 2H), 1.79 (t, J=8.0 Hz, 2H), 0.86 (m, 2H), 0.75 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][C:18]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[N:17][N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].[Cl-].[NH4+]>C1COCC1.O>[C:1]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][C:18]([C:20]([CH3:27])([CH3:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCC(C)(C)c1nnc(Nc2cccnc2Oc2ccccc2C(C)(C)C)s1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(C(C)(C)CCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of methyl 4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-4-methylpentanoate (Example 96) (450 mg, 1.0 mmol), lithium hydroxide hydrate (125 mg, 3 mmol) in THF (10 mL) and water (2 mL) was stirred at rt for 2 h. A solution of saturated ammonium chloride was added and mixture was extracted twice using ethyl acetate. The organic phase was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by preparative HPLC to give the title compound (430 mg, TFA salt) as a white solid. (M+H)+=441.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1)=[O:4].CCCCCCC.C(O)C.C(NCC)C>>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][C@@H:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1)=[O:4]
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2n1C)CCC(c1ccccc1)O3
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCNCC
Product: Cc1nc2c3c(c(C(=O)N(C)C)cc2n1C)CC[C@@H](c1ccccc1)O3

Procedure:
Resolution of racemic 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid dimethylamide (0.5 g, 1.4 mmol) was achieved by preparative chromatography using a 275×110 mm CHIRALPAK® AS-V 20 μm column. The mobile phase consisted of a n-heptan/ethanol/diethylamine mixture [95/5/0.1 (v/v/v)]. The separation was performed at room temperature with a flow rate of 1 ml/min. The products were detected at a wavelength of 225 nm. The separation afforded 0.19 g (39%; ee 98.9%) of the title compound ((8S)-enantiomer) as a white solid. m.p. 227°-228° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:25])C.[Li+].[OH-].Cl>C1COCC1.CO>[C:21]([C:17]1[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:26][CH2:27][CH3:28])[C:4]([OH:29])=[O:3])=[C:8]([CH3:25])[CH:9]=2)[N:16]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1C)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of [rac]-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2-methyl-phenyl]-2-ethoxy-propionic acid ethyl ester (50 mg, 0.124 mmol) in THF/methanol 2/1 (0.75 ml) was added a 1 N aqueous LiOH solution (0.75 ml, 0.72 mmol). The reaction mixture was stirred for 2 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (44 mg, 0.117 mmol, 95%) as colorless crystals.
Reaction SMILES: O[CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][N:6]2[CH2:9][CH2:10][CH2:11][C:12]([CH3:23])([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH3:13])[CH2:3]1.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:24]([CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][N:6]2[CH2:9][CH2:10][CH2:11][C:12]([CH3:23])([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH3:13])[CH2:3]1)#[N:25]
Reactant: CC(C)(CCCN1CC2CC(O)C1C2)S(=O)(=O)c1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(CCCN1CC2CC(C#N)C1C2)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
6-Hydroxy-2-[4-methyl-4-(phenylsulfonyl)pentyl]-2-azabicyclo[2.2.1]heptane (1 g, 2.97 mmol), potassium cyanide (386 mg, 6 mmol) and 18-crown-6 (78 mg, cat.) were suspended in acetonitrile and the mixture was cooled in ice-water. Tri-n-butylphosphine (1.2 ml, 5 mmol) was added followed by dropwise addition of carbon tetrachloride (0.57 ml, 6 mmol). The mixture was allowed to stir at room temperature for 12 h. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica using a gradient elution of 10–100% ethyl acetate in i-hexane, to give the product (600 mg, 58%) as an oil which crystallised on standing.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28].C(OC)(C)(C)C>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CO)cc2)c(=O)c1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 280 mg (0.80 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1a) in 8.0 mL of DCM is added 75 μL (0.80 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and tert-butylmethylether is added. The formed precipitate is collected, washed with tert-butylmethylether and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH:10]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Oc1ccccc1-c1cccnc1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
2-Bromophenol (0.5 g, 2.9 mmol) was dissolved in dimethoxyethane/water (2:1). Pyridin-3-ylboronic acid (0.71 g, 5.8 mmol) and Pd(dppf)Cl2 (0.12 g, 0.14 mmol), sodium carbonate (1.2 g, 14 mmol) were added thereto, followed by stirring for 1 hour under reflux. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2-(pyridin-3-yl)phenol (0.25 g, 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:17])[CH2:12][S:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:17])[CH2:12][S:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC1=NC(C)(c2ccc(N)cc2)CS1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC1=NC(C)(c2ccc(NS(C)(=O)=O)cc2)CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20 mmol) is dissolved in dimethylformamide (1 ml) and treated by a solution of methylsulfonyl chloride (0.0232 g, 0.20 mmol) in dry dimethylformamide (1 ml) followed by 2M aqueous sodium carbonate solution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by chromatography to give the title compound. MH+ (ESMS): 326.1
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1.[ClH:25]>ClCCl.O1CCCC1>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:15][Cl:25])[CH:11]=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccnc(Nc2ccccc2)n1
Reactant: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccnc(Nc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This ketone (1.3 g, 6.1 mmol) was dissolved in dichloromethane (40 mL), then TEA (5.1 mL, 36.6 mmol) and tert-butyl-dimethyl-trifluoro methansulphonate (4.2 mL, 18.3 mmol) were added. The orange solution was stirred overnight, then diluted with more dichloromethane (150 mL), washed twice with a 5% sodium hydrogencarbonate solution (50 mL), with water, with brine, then dried over sodium sulphate and concentrated to give the bis-silylated derivative (2.67 g). To half of the material (1.32 g, 2.94 mmol) dissolved in tetrahydrofuran (THF, 25 mL) and cooled to 0° C., a solution of NBS (0.549 g, 3.09 mmol) in THF (10 mL) was added dropwise in 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour, then 2 N HCl was added and the reaction mixture was stirred for 24 hours at r.t. The crude was purified by flash chromatography (eluant: hexane/ethyl acetate 5:1) to yield 0.325 g of title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18](=[O:20])[NH2:19])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([NH2:19])=[O:20])=[C:9]([CH:14]=1)[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(Cl)ccc1OCC(N)=O
Yield: 96.1 %

Procedure:
Compound 79 (200 mg, 0.63 mmol) was treated with a solution at 15% of TFA in CH2Cl2 at room temperature for 45 min. The solution was concentrated in vacuo and water (10 mL) was added. The aqueous phase was washed with Et2O, basified with aqueous 2N NaOH, and extracted with CHCl3 (10 mL×3) obtaining 130 mg of a white solid (80) (yield 96%). 1H NMR (CDCl3, 300 MHz) δ8.37 (br s, 1H), 7.29-7.22 (m, 2H), 6.82 (d, J=9.3 Hz, 1H), 5.44 (br s, 1H), 3.8(s, 2H), 3.89 (s, 2H). MS (m/e) (API-ES) 215 (M+H)+, m.p. 135-137° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[OH-].[K+:15]>>[C:1]([O-:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[K+:15]
Reactant: C=CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: C=CCCCCCCCCC(=O)[O-]
Temperature: 0 °C

Procedure:
Undecylenic acid (18.8 g, 0.102 mol) was added dropwise gradually to ½ N ethanolic solution of potassium hydroxide (200 mL) with stirring at 0° C. The volatile matter was distilled off under reduced pressure to give a crude product. The crude product was washed with acetone and heated under reduced pressure to give potassium undecylenate represented by the formula given below as a white solid (8.88 g, yield 88%). CH2═CH—(CH2)8—CO2−K+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1ccc(-c2ccc3c(c2)C(C)NCC3)o1
Product: Cc1ccc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:24][NH:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>>[C:1]([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:24][N:23]([C:50](=[O:51])[CH2:49][N:48]([CH3:53])[CH3:47])[CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)CC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@@H]1CNC[C@H]1OC(=O)CCCCCCC/C=C\C/C=C\CCCCC
Agent: Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@@H]1CN(C(=O)CN(C)C)C[C@H]1OC(=O)CCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound 26 (297 mg, 87.2%) was obtained in the same manner as that in Example 25, by using compound 2 (300 mg, 0.478 mmol) obtained in Example 2, and N,N-dimethylglycine hydrochloride (Tokyo Chemical Industry Co., Ltd.; 133 mg, 0.955 mmol).