Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[ClH:7].[ClH:7].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CNCCN1
Product: Cl
Product: Fc1ccc(CN2CCNCC2)cc1
Yield: 67 %

Procedure:
A mixture of 4-fluorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-fluorobenzyl) piperazine dihydrochloride (67%), mp, 282-284° C. The N1-(4-fluorobenzyl)-N4-phenacyl piperazine dihydrochloride could be preparated according to the general preparation 2, which was reduced with KHCO3 (0.65 g, 6.5 mmol) and KBH4 (0.59 g, 10.4 mmol) in methanol (40 ml) according to the general preparation 3 to obtain 0.72 g of the title compound as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=S)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Ni]>[Si:1]([O:8][C@H:9]1[C@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Yield: 74 %

Procedure:
3-(R)-Tert-butyldimethylsilyloxy-4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (7.96 g, 17.74 mmol) was dissolved in anhydrous ethanol (490 ml), and the solution was mixed with Raney nickel (25 ml) and heated under reflux for 40 minutes. After removing the catalyst by celite filtration (ethanol washing), the resulting filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in chloroform (400 ml), washed with 10% ammonia water (300 ml), water (300 ml) and saturated brine (300 ml) in that order and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=6:1, to thereby obtain 5.48 g (74%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](OC)(=[O:18])[C:14]([O:16]C)=[O:15].CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1>C1COCC1.O>[F:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COC(=O)C(=O)OC
Reactant: COc1ccc(C(C)=O)cc1F
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)CC(=O)C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.5 %

Procedure:
To a solution of 3-fluoro-4-methoxyacetophenone (2.59 g, 15.4 mmol) and dimethyl oxalate (2.0 g, 16.9 mmol) in THF (25 ml) was portionwise added a 1.7 M solution of potassium tert-amylate in toluene (25 ml, 42.5 mmol). The mixture was stirred at room temperature for 14 hours. Water (1.0 ml) and more THF (25 ml) were added, and stirring at room temperature was continued for 30 hours. Water (250 ml) was added, and the mixture was washed with a mixture of heptane and toluene. The aqueous phase was filtered, acidified with concentrated hydrochloric acid (6.0 ml), and filtered. After drying, 3.09 g (84%) of 4-(3-fluoro-4-methoxyphenyl)-4,2-dioxobutyric acid was obtained. A mixture of this acid (1.99 g, 8.29 mmol), ethanol (75 ml), and hydrazine hydrate (0.80 ml, 2 equiv.) was refluxed for 18 hours. Water (250 ml) and concentrated hydrochloric acid (4.0 ml) were added, and the mixture was filtered. After drying under reduced pressure 1.76 g (90%) of 5-(3-fluoro-4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid acid was obtained as a solid. This acid was used to prepare the title amide using General Procedure (D).
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:35](#[N:39])[CH2:36][C:37]#[N:38]>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:36]([C:35]#[N:39])[C:37]#[N:38])=[O:32])=[CH:33][CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCC#N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
Diethylcyanophosphonate (5 mmol) and triethylamine (15 mmol) are added to a solution of 4-benzyloxybenzoic acid (18, 5 mmol) and malononitrile (4.8 mmol) in DMF (10 mL) stirred at 0° C. After the addition is complete, stirring is continued as the solution is allowed to warm to ambient temperature. Progress of the reaction is followed by tic and when complete, the reaction solution is concentrated under reduced pressure. The residue is taken up in EtOAc and washed with cold 1N HCl and then with aq. NaHCO3. The alkaline bicarbonate wash is acidified with 6N HCl and the mixture is extracted with EtOAc. The combined EtOAc extract solutions are dried (Na2SO4), filtered and concentrated under reduced pressure, giving the desired 4-benzyloxybenzoylmalononitrile 19. The product is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11]OC(C)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][Cl:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCl)cc1
Temperature: -65 °C

Procedure:
To a suitable reaction vessel there was added 6.07 g (0.044 mol) of 4-nitroaniline dissolved in 300 ml of methylene chloride. The solution was cooled with vigorous stirring to -65° C, giving a suspension of the nitro compound. A solution of 5.75 g (0.055 mol) of t-butyl hypochlorite in 10 ml of methylene chloride was added to form the 4-nitro-N-chloraniline and subsequently after 3 hr, 7.4 g (0.071 mol) of methylthio-2-propanone in 10 mol of methylene chloride was added, while stirring was continued for 10 hr. to form the azasulfonium chloride salt. The triethylamine, 4.4 g (0.044 mol), dissolved in 10 ml of methylene chloride was added and the solution was warmed to room temperature to form the 2-methyl-3-methylthio-5-nitroindole. A 50-ml portion of water was added and after separation, the organic layer was extracted thoroughly with a 2N aqueous hydrochloric acid. Drying over anhydrous magnesium sulfate and filtration of the organic solution was followed by evaporation, leaving a solid residue that was stirred for several hr with 30 ml of benzene. The remaining precipitate was collected by filtration giving 2.92 g (0.013 mol, 30%) of 2-methyl-3-methylthio-5-nitroindole, mp 197.5°-198.5° (recr. from 95% ethanol); ir (KBr) 3250 cm-1 (NH); pmr (acetone-d6) 1.40 (1H, br, s, NH), 1.02 (1H, d, J=2.0Hz,4-aryl H), 2.02 (1H, dd, J=8.0 and 2.0 Hz, 6-aryl H), 2.57 (1H, d J=9.0 Hz, 7-aryl H) and 7.42 and 7.73 (3H, s, SCH3 and CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:35]1[CH2:36][CH2:37][N:32]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)[O:21][C:20]=34)[CH:23]=2)=[O:26])[CH2:33][CH2:34]1
Reactant: CN1CCOCC1
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)N5CCOCC5)c4)c3o2)cc(OC)c1OC
Yield: 70 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and 4-methylmorpholin (0.182 mmol) the product is prepared analogously to “A43” and obtained as colorless solid in a yield of 70%. HPLC (method A): Rt 2.59 min (purity 98.1%); LCMS (ESI+) (method E): Rt 1.76 min, M+H+ 475.2 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.58 (d, J=5.1, 1H), 8.29 (t, J=1.5, 1H), 8.19 (d, J=8.0, 1H), 7.76 (s, 1H), 7.74-7.65 (m, 2H), 7.58 (d, J=7.6, 1H), 7.33 (s, 2H), 3.91 (d, J=11.4, 6H), 3.74 (s, 3H), 3.69-3.37 (m, 8H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1CCCC1=O>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: Sc1ccccc1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Solvent: CN1CCCC1=O
Product: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Temperature: 140 °C

Procedure:
The title compound was prepared as follows: To a solution of 250 mg of [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml 1-methyl-2-pyrrolidinone was added 1.2 ml of benzenethiol. The solution was heated at 130 to 150° C. in a sealed tube for 16 h. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 91 mg of a tan solid; MS (−) m/z 353.07 (M−1)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[NH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C(O)CO>[ClH:1].[N:13]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5](=[O:12])[NH:4][N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: O=c1[nH]nc(Cl)c2c1CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: Cl
Product: O=c1[nH]nc(N2CCNCC2)c2c1CCCC2
Temperature: 200 °C
Reaction time: 7 h

Procedure:
To a suspension of 4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one (150 mg; CAS Registry No. 89981-21-5; the compound described in Yakugaku Zassi., 82, 302-303 (1962)) in ethylene glycol (1.6 mL) was added piperazine (420 mg) and the mixture was stirred at 200° C. for 7 hours. After cooling to room temperature, the reaction mixture was poured in a cold saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=20:1→10:1) to give free form of the title compound (64 mg). To a solution of the obtained free form in methanol (2.0 mL) was added 4N hydrogen chloride-ethyl acetate solution (1 mL). The mixture was stirred at room temperature and concentrated. The residue was recrystallized from a mixed solution of methanol and ethyl acetate to give the compound of the present invention (21 mg) having the following physical data.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]=12.ClC1C2N=CN=CC=2NN=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: Clc1n[nH]c2cncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 16 mL reaction vial was placed sodium hydride (7.8 mg, 60% in oil, 0.195 mmol) and 0.5 mL of THF. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 0.0487 mmol) was added to the suspension and the mixture was stirred 20 min under N2 at room temperature, followed by the slow addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (10 mg, 0.0325 mmol). After stirring overnight under N2 at room temperature, all of the starting chloropyrazolopyrimidine had been converted as indicated by LCMS. The reaction mixture was then concentrated under vacuum and purified by flash column chromatography using 50% EtOAc/Hex as eluent. 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.85 (m, 2H), 2.09 (m, 2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.86 (m, 2H), 5.60 (m, 1H), 8.09 (d, 2H), 8.26 (s, 1H), 8.61 (d, 2H), 8.66 (s, 1H). LCMS: calculated for C22H27N5S 473.17, observed 474.4 (MH+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)C#N)cc1
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
2-(4-bromophenyl)-2-methylpropanenitrile (1 g, 4.46 mmol) is dissolved in anhydrous THF (75 ml) the solution is cooled down to −100° C. with a diethyl ether-liquid nitrogen bath, n-butyl lithium 2M in c-hexane (4.0 ml, 8.0 mmol) is added and this reaction mixture stirred for 10 min., then N-methoxy-N-methyl acetamide (1.6 g, 15.6 mmol) is added and the reaction is then left to slowly warm-up to room temperature. After work-up (washing with acidic brine) and concentration the crude mixture is purified on silica gel using a 0 to 50% ethyl acetate in hexane gradient, to give the desired compound (660 mg, 78%) as a clear oil.
Reaction SMILES: ClCCl.[CH3:4][O:5][N:6]([CH3:14])[C:7]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)=[O:8].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:4][O:5][N:6]([CH3:14])[C:7]([C:9]1[CH:13]=[N:12][N:11]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=1)=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CON(C)C(=O)c1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A dichloromethane solution (3 mL) of N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (142.7 mg, 2.68 mmol) was mixed with 2-(trimethysilyl)ethoxymethyl chloride (0.47 mL, 2.68 mmol) and N,N-diisopropylethylamine (0.94 mL, 5.36 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate washed with saturated aqueous sodium chloride and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the desired product (325.8 mg, 85% yield).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of 200 mg (0.56 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide (prepared as described in Preparation 5) and 4 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene; the solvent was then removed by distillation under reduced pressure. This operation was repeated three times in total. After drying the final residue in vacuo for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 150 mg (1.68 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension. After this, 0.1 ml (0.67 mmole) of 95% diethyl cyanophosphonate and 0.23 ml (1.68 mmole) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 15 hours. At the end of this time, the reaction solvent was stripped from the mixture by distillation under reduced pressure and the residue was mixed with water. The precipitate which deposited was collected by filtration and washed with water. It was then dissolved in methylene chloride and the resulting solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 260 mg of the title compound as a pale yellow powder, melting at 158°-160° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:12]([O:20][CH2:21][CH2:22]I)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:12]([O:20][CH2:21][CH2:22][N:11]1[C:4]2[C:3]([S:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[CH:9]=[N:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:12]([O:20][CH2:21][CH2:22][N:10]1[CH:9]=[C:5]2[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]2=[N:11]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCCI)c1ccccc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2cn(CCOC(=O)c3ccccc3)nc12
Product: CSc1ncnc2cnn(CCOC(=O)c3ccccc3)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (300 mg) and 2-iodoethyl benzoate (548 mg) in N,N-dimethylformamide (10 mL) was added potassium carbonate (374 mg), and the mixture was stirred at 60° C. for 1 hr. After the completion of the reaction, water was added to the reaction mixture. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give 2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl benzoate (266 mg) and 2-[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate (191 mg) both as pale-yellow solids.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (24.6 mg, 0.090 mmol) in CH2Cl2 (2 mL) was added 4-fluorophenyl isocyanate (0.12 μL, 0.107 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 125 as a colorless solid (27.0 mg, 73%). LCMS m/z (%)=412 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (bs, 1H), 8.58 (bs, 1H), 7.48-7.41 (m, 4H), 7.36 (d, J=2.70 Hz, 1H), 7.14-7.06 (m, 3H), 6.23 (d, J=1.82 Hz, 1H), 3.97 (t, J=6.34 Hz, 2H), 3.65 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25]
Reactant: COc1ccc2c(c1)c(CCNC(C)=O)cn2S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of the compound obtained in Step A are dissolved in 100 ml of dichloromethane. The reaction mixture is then cooled in an ice-bath, and 3.81 ml of boron tribromide are added dropwise. After stirring at room temperature for two hours, the reaction mixture is poured into 500 ml of water and ice. The precipitate that forms is filtered off, washed with water and oven-dried at 50° C.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31][CH3:32])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31][CH3:32])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenoxy]acetate (64 mg, 0.14 mmol, 1.0 eq) in THF (3 mL) was added an aqueous solution of LiOH (2M aqueous solution, 2 mL, 4 mmol). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo give the title compound as a white solid (32 mg, 53%).