Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:18]1([C:2]2[CH:3]=[C:4]3[CH2:10][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
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: COCCOC
Solvent: CCO
Product: c1ccc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)cc1
Yield: 68.5 %

Procedure:
Under a nitrogen atmosphere, 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (118 mg, 0.4 mmol), phenylboronic acid (54 mg, 0.443 mmol), and tetrakis(triphenylphosphine)palladium(0) (11 mg, 2.3 mol %) were stirred in a solution of 1,2-dimethoxyethane (3 mL) and ethanol (0.75 mL) containing 2M aqueous sodium carbonate (0.65 mL, 1.3 mmol). The mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in chloroform (15 mL), and the extract was washed with saturated aqueous sodium carbonate (5 mL). The aqueous layer was extracted with chloroform (2×15 mL), and the organic layers were combined, dried (MgSO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (95:5 to 9:1), provided the title compound (80 mg, 0.274 mmol, 68%) as a tan solid: electrospray MS 293 ([MH]+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[OH-].[Na+].[N:11](OC)=[O:12]>CO>[OH:12][N:11]=[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]#[N:8]
Reactant: N#CCc1ccsc1
Reactant: CON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=NO)c1ccsc1
Temperature: 2.5 °C
Reaction time: 4.5 h
Yield: 39.2 %

Procedure:
In general analogy to the process described under 3.1, 59 g (0.48 mol) of thiophene-3-acetonitril are placed in a sulfonation flask and are charged with 19.2 g (0.48 mol) of sodium hydroxide, dissolved in 200 ml of methanol. 0.48 mol of gaseous methyl nitrite is introduced, with stirring, into this solution at 0-5° C. over 4.5 hours. The ice bath is then removed and the brown solution is stirred overnight at room temperature. The methanol is distilled off on a rotary evaporator and the resulting orange residue is charged with water and ethyl acetate. The aqueous phase is separated, washed twice with ethyl acetate and acidified with conc. HCl. The aqueous phase is extracted twice with ethyl acetate, the extracts are washed with water and dried over magnesium sulfate. After fitration, the solvent is distilled off and a brown solid is obtained which is then recrystallised from toluene, giving 28.6 g (39% of theory) of α-hydroxyiminothiophene-3-acetonitrile as a beige solid having a melting point of 96-106° C. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([S:12][C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.O>[CH:7]1([S:12]([C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Sodium periodate (333 mg) was added to a solution of (5R)-3-[6-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (230 mg) in ethanol (12 ml) and water (4 ml). The mixture was stirred at room temperature under nitrogen for 3 h. and the ethanol evaporated in vacuo. The aqueous phase was diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% ethyl acetate-cyclohexane, to give the title compound (201 mg). LCMS RT=3.54 min.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])[OH:6])=[N+]=[N-].[CH3:19][S:20](O)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:6][CH:5]([CH2:4][NH2:1])[C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CN=[N+]=[N-]
Product: COc1ccc(S(N)(=O)=O)cc1C(CN)OS(C)(=O)=O

Procedure:
Starting from (+)-α-azidomethyl-2-methoxy-5-sulphamoylbenzenemethanol, hydrogenated under the conditions described in step 6 of Example 2 and then treated with 1 equivalent of methanesulphonic acid, (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol methanesulphonate was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (1.31 g, 4.12 mmol) in DMF (40 ml) was added N-iodosuccinimide (1.39 g, 6.17 mmol) and TFA (2.4 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 1.71 g (93%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a brown solid.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]=1[C:52](=O)[CH3:53].[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]=1[C:52]1[CH:53]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=4[N:19]=3)[CH:14]=2)[N:9]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Oc5ccc(Cl)cc5)cc4Cl)ccc3c1)n2C1CCCCC1
Yield: 49 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 49% yield). MS: 608.17 (M+H+); HPLC Procedure B, retention time=8.44 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 4-bromoveratrole (20 g) in acetic acid (50 ml) was added 2M nitric acid (48 ml). It was stirred at room temperature for 30 min and then the reaction solution was poured into water. The resultant solid was filtered, washed with water and dried in vacuum.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][CH:54]=1)[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:57][CH:58]=1)[CH3:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 73% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:22]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:36])[NH:23][S@@](C(C)(C)C)=O)=[C:19]([CH3:21])[N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:23][CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:18]1[S:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:12][CH2:11]2)=[O:14])=[N:20][C:19]=1[CH3:21]
Reactant: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N[S@](=O)C(C)(C)C)c1ccccc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A), (1.47 g, 2.69 mmol) in MeOH (13 mL) was added 4 M HCl in dioxane (4 mL, 16 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated. The crude product was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (×2) and brine, then dried over MgSO4 and concentrated. The crude product was adsorbed onto silica gel and purified by column chromatography (70-100% EtOAc/hexanes) to provide N-(5-(amino(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (Isomer A), as an orange solid (540 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=7.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.27 (m, 1H), 6.94 (s, 1H), 6.85 (m, 2H), 6.00 (s, 2H), 5.56 (s, 1H), 2.19 (s, 3H), 1.40 (m, 2H), 1.10 (m, 2H); HPLC ret. time 2.65 min, 10-99% CH3CN, 5 min run; ESI-MS 442.5 m/z (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:11]1[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12]1=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.67 h
Yield: 98 %

Procedure:
To a solution (65 mL) of 7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-4-one (3.12 g, 12.97 mmol) in dimethylformamide in an ice bath was gradually added sodium hydride (55%, dispersion in a mineral oil, 538 mg, 12.33 mmol) in 5 minutes, and the mixture was stirred at the same temperature for 40 minutes. Benzyl bromide (1.851 mL, 15.56 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted by adding ethyl acetate (300 mL), and the solution was washed with water (100 mL×2) and saturated aqueous solution of sodium chloride (100 mL). After drying the solution with anhydrous sodium sulfate and removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate, 9:1→4:1→2:1) to obtain 4.20 g (12.71 mmol, 98%) of the target compound as a colorless transparent gummy solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1-c1ccccc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-phenylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C[O-].[Na+].[CH2:13](N)[CH2:14][NH2:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:15][CH2:14][CH2:13][N:9]=2)[CH:3]=1
Reactant: NCCN
Reactant: N#Cc1cc(Cl)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccnc(C2=NCCN2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-chloropyridine-2-carbonitrile (20.0 g, 121 nmuol, prepared as described by Sakamoto et al. Chem. Pharm. Bull. 1985, 33, 565-71) in MeOH (240 mL), was added sodium methoxide (0.655 g, 12.1 mmol). The reaction mixture was allowed to stir at rt under an atmosphere of argon for 2 h. Ethylene diamine (40.0 mL, 597 imol) was added and the mixture was allowed to stir at 50° C. for 20 h. The reaction mixture was allowed to cool to rt and then concentrated. The residue was dissolved in a mixture of water and DCM. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine as a light brown solid (21.9 g, >99%). LCMS: (FA) ES+ 182.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(C(F)(F)F)cc3)c2c1

Procedure:
The title compound, light brown solid (88 mg, 59%), MS (ISP) m/z=424.2 [(M+H)+], mp 156° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C@:27]([C:44]([OH:46])=[O:45])([OH:43])[C@:28]([C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([OH:32])[C:29]([OH:31])=[O:30])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CC(=O)CC>[C:33]([C@:28]([C:29]([OH:31])=[O:30])([OH:32])[C@:27]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:43])[C:44]([OH:46])=[O:45])(=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCC(C)=O
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1.0 g, 38.5 mmol) and butanone. Add a solution of (R,R)-di-p-anisoyltartaric acid (1.6 g, 38.0 mmol) in butanone (80 mL). Heat to reflux. After 15 minutes, cool to ambient temperature and then cool further in an salt-ice bath. Filter the solid that forms and rinse with butanone. Recrystallize the solid from water/methanol to give (S)-(-)-2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (R,R)-di-p-anisoyltartaric acid salt: mp; 201°-204° C. (dec). [α]2D0 =-18.9° (c=0.60, dimethylsulfoxide). X-ray diffraction analysis of a single crystal confirms the (S)-configuration. Analysis on HPLC, on an analytical sample of the free amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cm column eluting with pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0 mL/minute indicates an enantiomeric excess of 96%, (96% ee), retention time of the (S)-isomer 11.2 minutes, retention time of the (R)-isomer 14.5 minutes.
Reaction SMILES: N(C([O-])=O)=NC([O-])=O.[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([OH:33])[C:23]([Br:34])=[CH:22][CH:21]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O[CH2:36][C@H:37]1[CH2:40][CH2:39][N:38]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([C:23]([Br:34])=[CH:22][CH:21]=1)[O:33][CH2:36][C@H:37]1[CH2:40][CH2:39][N:38]1[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(Br)c1O
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(Br)c1OC[C@H]1CCN1C(=O)OC(C)(C)C
Yield: 99.4 %

Procedure:
Disopropyl azodicarboxylate (0.717 g) was added to a solution of tert-butyl 6-benzyloxycarbonylamino-3-bromo-2-hydroxybenzoate (Intermediate 48, 1.25 g), tert-butyl (R)-2-hydroxymethylazetidine-1-carboxylate (0.665 g) and triphenylphosphine (0.93 g) in anhydrous THF (20 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give tert-butyl (R)-2-(3-benzyloxycarbonylamino-6-bromo-2-tert-butoxycarbonylphenoxymethyl)-azetidine-1-carboxylate (1.74 g) as a colourless gum.
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(O)C>[CH3:9][C:2]1[N:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Product: COC(=O)c1nc2ccc([N+](=O)[O-])cn2c1C
Yield: 23.1 %

Procedure:
An ethanol suspension (400 mL) of methyl 3-bromo-2-oxobutyrate (46.6 g) and 2-amino-5-nitropyridine (33.3 g) was stirred at 90° C. for 24 hours. The precipitated solid was taken out through filtration, and the obtained solid was suspended in ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution, and purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain methyl 3-methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate (13.0 g) as a yellow crystal.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:27]([CH3:41])[CH2:28][CH2:29][N:30]1C(=O)C2C(=CC=CC=2)C1=O>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:19][CH2:20][N:21]([CH:27]([CH3:41])[CH2:28][CH2:29][NH2:30])[CH2:22][CH2:23]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3ccccc3O2)CC1
Yield: 69.2 %

Procedure:
Using general procedure B with the above amine (115 mg, 0.330 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (143 mg, 0.660 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (96 mg, 69% over 2 steps) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.BrCCN1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)[C:41]([C:56]2C=C(Cl)C=C[C:57]=2OC(F)F)=N1.C1(CN)C=CC=CC=1>>[CH2:28]([NH:27][CH2:26][CH2:25][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1)[C:29]1[CH:57]=[CH:56][CH:41]=[CH:42][CH:43]=1
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: NCc1ccccc1
Product: O=C(Nc1cn(CCNCc2ccccc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and phenylmethanamine. LCMS (Method 20) [M+H]+=538.2, RT=2.70 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.84 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.67 (dd, 1H, J=1.6, 4.4 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.64-7.59 (m, 2H), 7.46-7.42 (m, 1H), 7.32-7.19 (m, 6H), 7.06 (t, 1H, J=73.2 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.73 (s, 2H), 2.93 (t, 2H, J=6.4 Hz).