Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C(O)C.[C-:16]#[N:17].[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH2:2][C:16]#[N:17])=[O:4])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 25.0 g. portion of α-bromo-p-methoxyacetophenone is suspended in 125 ml. of ethanol. A solution of 16.0 g. of sodium cyanide in 75 ml. of water is added, using an ice-water bath to keep the temperature at 25°-30° C. The mixture is stirred for 45 minutes at room temperature. A total of 1.2 liters of water is added in 200 ml. increments with filtration through celite until no more precipitate forms. The filtrate is acidified to pH 5 with acetic acid. The solid is collected, washed with water, dried and recrystallized from benzene giving p-methoxybenzoylacetonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C.C1(C)C(C)=CC=CC=1.N12CCN(CC1)CC2>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 100 ml of dry acetonitrile, and then 0.1 g of 1,4-diazabicyclo[2,2,2]octane was added thereto. To this mixture was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 30 ml of xylene over an hour. During this addition, the reaction was accompanied by slight heat generation, and therefore cooling was applied as necessary. After the addition, the reaction was continued at room temperature for 5 hours and then at 40° C. for 5 hours. After allowing the mixture to cool to room temperature, the precipitated colorless crystals were filtered, washed with ether and dried to obtain 33.9 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methyl-1,3,5-triazin-2yl) urea; m.pt. 190°-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[C:11]([N+:12]([O-])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[H][H]>[Pt].CN1CCOCC1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[C:11]([NH:12][OH:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccccc1OCc1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CN1CCOCC1
Product: Cc1ccccc1OCc1ncccc1NO
Yield: 161.3 %

Procedure:
A mixture of 5.0 g (21 mmol) of 2-(2-methylphenoxymethyl)-3-nitropyridine (Example 3.d) and 100 ml of N-methylmorpholine was hydrogenated at room temperature (approximately 25° C.) and an H2 pressure of approximately 1.1 bar in the presence of 1 g of 5% platinum/charcoal (51% water; manufactured by Degussa). The hydrogen uptake ceased after approximately 90 minutes. The catalyst was removed by filtration through active charcoal. The resulting solution was freed from solvent under reduced pressure, and the residue obtained was treated with approximately 50 ml of petroleum ether. This gave 7.8 g (90%) of the title compound as a white solid. The solvent was removed under reduced pressure ("high vacuum"), and the residue obtained was washed using hexane. This gave 4.5 g (94%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)(=O)C>[Br:20][CH2:17][C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(CO)c1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(CBr)c1

Procedure:
12 g of the N-(4-chloro-3-hydroxymethylphenyl)-2-methyl-3-furancarboxamide prepared in Step 5 above, was dissolved in 180 ml ethyl acetate. 1.8 ml of phosphorus tribromide was then added. The resultant mixture was stirred for 90 minutes at room temperature. 100 ml of water was then added to the mixture. The resultant organic phase was separated, washed with water, aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. The solvent was evaporated off to produce 12.97 g of N-(3-bromomethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide as a solid.
Reaction SMILES: [NH2:1][CH:2]1[C:7](=[N:8][C:9]2[CH:14]=[CH:13]N=CC=2)[CH:6]=[N:5][N:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:19].[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3](=[O:19])[N:4]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:14]1[CH:13]=[CH:15][N:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)N1N=CC(=Nc2ccncc2)C(N)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(N)c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
Into 150 ml of an absolute methanol solution of 10.8 g of 4-amino-2-tert-butyl-5-(4-pyridylimino)pyridazin-3-(2H)-one, 0.76 g of sodium borohydride was added in a few times under cooling with ice. Then, the mixture was stirred at room temperature for 40 minutes, and the 0.76 g of sodium borohydride was further added thereto. The mixture was stirred for 0.5 hour. Methanol was distilled off under reduced pressure, and 200 ml of water and 400 ml of ethyl acetate were added to the residue, followed by shaking. The insoluble powder was collected by filtration. The organic layer in the filtrate was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 4.7 g of a residue. The residue was combined to the previously obtained insoluble powder, and the mixture was thoroughly washed with a solvent mixture comprising 150 ml of n-hexane and 50 ml of methylene chloride, and then dried to obtain 8.7 g of the desired product (Compound No. 10) having a melting point of from 219° to 225° C.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH2:1]([NH:7][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-hexylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.62 g, yield 48%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.75. (m, 1H), 7.52-7.65 (m, 2H), 7.30-7.36 (m, 1H), 6.98-7.06 (m, 1H), 4.00-4.09 (m, 1H), 3.81-3.91 (m, 1H,), 3.62-3.70 (m, 2H), 3.48-3.55 (m, 2H), 3.29-3.43 (m, 4H), 1.52-1.62 (m, 2H), 1.20-1.40 (m, 6H), 0.80-0.90 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.6, 158.2, 156.0, 134.0, 133.9, 132.4, 129.6, 129.0, 127.0, 126.9, 121.8, 49.5, 49.0, 45.9, 40.7, 39.7, 31.4, 29.4, 26.5, 22.5, 14.0. MS (ES+) m/z 470 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[S:27][CH:28]=2)\[C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.[NH2:50][CH:51]1[C:76](=[O:77])[N:53]2[C:54]([C:60]([O:62][CH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]12>C(Cl)Cl>[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[S:27][CH:28]=2)\[C:21]([NH:50][CH:51]2[C:76](=[O:77])[N:53]3[C:54]([C:60]([O:62][CH:63]([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]23)=[O:23])[CH2:15][CH2:16][CH2:17]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (1.46 g, 7 mmoles) was added to a suspension of (Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid [IVe'] (4.09 g, 7 mmoles) in 70 mL of dry methylene chloride, and the mixture was stirred for 1 hour at room temperature. The acid chloride solution was added at -20° C. to a solution of silylated 7-ACA ester, which was prepared by adding BSA (5.6 mL, 21 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride [V] (3.16 g, 7 mmoles) in dry methylene chloride (70 mL). The mixture was stirred for 20 minutes at -10° C. and then at room temperature for 40 minutes. The reaction mixture was evaporated and diluted with ethyl acetate (300 mL), and the organic layer was washed with 5% aqueous sodium bicarbonate, water and a saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (Wako gel C-200, 60 g); elution with chloroform. The fractions containing the desired product were combined and evaporated to obtain 5.88 g (86%) of VIe' as a yellow powder.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][NH2:26]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: NCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC#CCOc1cc(NCC(F)(F)C(F)(F)F)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
To 4 ml of dimethylsulfoxide were added 365 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 442 mg of potassium carbonate, and 495 mg of 2,2,3,3,3-pentafluoropropylamine, followed by stirring at 80° C. for 4 hours. Then, 596 mg of 2,2,3,3,3-pentafluoropropylamine was further added, and the mixture was stirred at 100° C. for 6 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 73 mg of 4-(2-butynyloxy)-6-(2,2,3,3,3-pentafluoropropylamino)pyrimidine (the present compound (111)).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][NH2:18].CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCC(F)(F)F
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CCCNc1ccc2ncc(Br)n2n1
Yield: 93.7 %

Procedure:
A stirred solution of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (1.7 g, 7.6 mmol), 4,4,4-trifluoro-butylamine hydrochloride [84153-82-2] (1.3 g, 7.6 mmol), and Hunig's base [7087-68-5] (4.0 mL, 23.0 mmol) in 2-propanol (40 mL) was heated to 65° C., under N2 blanket for 3d, cooled, and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to provide 2.3 g of yellow solid. LRMS (ESI) m/z 323.1/325.1 [(M+H)]+, calc'd for C10H10BrF3N4: 323.12.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[OH:18][CH:16]1[CH2:17][N:14]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CC(O)C2)cc1
Temperature: 180 °C
Yield: 72.7 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (0.841 g, 5.00 mmol, Aldrich: Cat. #102644), azetidin-3-ol hydrochloride (0.438 g, 4.00 mmol, Aldrich: Cat. #680079) and potassium carbonate (1.38 g, 9.98 mmol) in dimethyl sulfoxide (4 mL) was heated at 180° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (0.643 g, 72.6%). LCMS (M+H)+: m/z=222.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([C:20](OCC)=[O:21])=[CH:6][N:5]2[C:25]=1[CH3:26].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])=[CH:8][C:7]([CH2:20][OH:21])=[CH:6][N:5]2[C:25]=1[CH3:26]
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cc(CO)cn2c(C)c(C)nc12
Yield: 66.5 %

Procedure:
To a stirred solution of ethyl 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (1.2 g, 3.4 mmol) in tetrahydrofuran (30 ml) was added LiALH4 (0.7 g, 18.5 mmol) during 20 min. at 5° C. 0.7 ml of water was added dropwise, followed by 0.7 ml of 15% sodium hydroxide and then 2.1 ml of water. The solids were removed by filtration and washed thoroughly with methylene chloride:methanol (1:1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. Treating the residue with diethyl ether and filtration gave 0.7 g (67%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][N:6]([CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:7]2.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][N:6]2[CH2:7][CH:8]3[CH:3]([N:2]([CH3:1])[C:24](=[O:25])[O:26][CH2:27][CH3:28])[CH:4]([CH2:10][CH2:9]3)[CH2:5]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CCOC(=O)Cl
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
A mixture of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Preparation G; 74.6 mg, 0.25 mmol) and ethyl chloroformate (29.8 mg, 0.27 mmol) in DMF (2.5 mL) was stirred at rt for 24 h. Mass spectroscopic analysis showed that the amine starting material had not been totally consumed, and so additional ethyl chloroformate (50 μL) was added. The mixture was stirred overnight, after which time it was concentrated in vacuo. The resulting residue was dissolved in a mixture of DCM (0.5 mL) and MeCN (2 mL). K2CO3 (100 mg, 0.7 mmol) was added and the mixture stirred for 4 h. Filtration of the mixture and evaporation of the filtrate gave a residue that was dissolved in CHCl3 (1 mL). The solution was filtered through an ion-exchange solid-phase extraction plug (CBA, 2 g). The source flask was washed with additional CHCl3 (0.75 mL), which was then added to the extraction plug, and eluted as fraction 1. The plug was then eluted with CHCl3:MeOH:TEA (8:1:1; 4×2 mL) to give further fractions that were found not to contain any product. Fraction 1 was then added to a silica plug, which was eluted with CHCl3:MeCN (4:1; 3×2.5 mL). Evaporation of the fractions collected gave 79.6 mg (85.9%) of the title compound.
Reaction SMILES: [OH-].[Na+].[OH-].[K+].[C:5]([N:12]1[CH:16]=[CH:15]N=C1)([N:7]1[CH:11]=[CH:10]N=C1)=O.O1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:16]1([N:12]=[C:5]=[N:7][CH:11]2[CH2:10][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Ethyl cyanoacetate is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at from 0° to 25° C. to give the alkylated nitrile (40). The nitrile is then treated with (n-Bu)3SnN3 in dioxane at reflux for 24 hours to give after acidic hydrolysis the tetrazole (41) which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (42) and (43). The regioisomers are separated by flash chromatography and each ester is reduced by DIBAL-H in CH2Cl2 or toluene at -78° C. to give the corresponding alcohols (44) and (45). The alcohols are treated with methanesulfonyl chloride in CH2Cl2 using triethylamine as a base at 0° C. to give the corresponding mesylates which are then treated with KCN in dimethylformamide or dimethyl sulfoxide at 100° C. to give the corresponding nitriles (46) and (47). These are then hydrolyzed to the corresponding acids (48) and (49) by treatment with ethanolic NaOH (or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give the amides (50) and (51).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([CH:26]3[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([CH:26]3[CH2:27][NH:28][CH2:29]3)=[O:25])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)C1CNC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)azetidine-1-carboxylate (Example 46; 17 mg, 0.033 mmol), was added 0.5 mL 50% TFA solution in DCM and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product (TFA salt) as a fine beige powder (12 mg, 88% yield). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)([OH:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclohexylmagnesium cloride, 0.127 mol (63.6 ml of a solution 2M in ether), was added to a solution of 28.7 g (0.111 mol) of 2-oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 350 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (27.0 g) was purified by chromatography on silica gel eluting with chloroform/methanol 10:1. The yield was 18.7 g (49.2%) of a pure product, mixture of diastereomers: I-16a and I-16b.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:20]=2)=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(C(F)(F)F)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:10]([NH:12][NH2:13])=[O:11]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10]2[O:11][C:1](=[O:2])[NH:13][N:12]=2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(-c2n[nH]c(=O)o2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 equivalents of a 20% phosgene solution in toluene were added dropwise to the solution of 850 mg of 3-methoxy-4-nitrobenzoic hydrazide (m.p.: 158.2° C., prepared from methyl 3-methoxy-4-nitrobenzoate and hydrazine hydrate in isopropanol at 80° C.) in 25 ml of dioxane and the mixture was stirred at room temperature for 1 hour. After concentrating, the residue was recrystallized from isopropanol, filtered off with suction and dried under reduced pressure.