Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[Si:50]([O:57][CH:58]1[CH2:62][NH:61][C@@H:60]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[O:70][CH3:71])[CH2:59]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[Si:50]([O:57][CH:58]1[CH2:62][N:61]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C@@H:60]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[O:70][CH3:71])[CH2:59]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52]
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Reactant: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CC(O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.6 %

Procedure:
To a suspension of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.100 g, 0.483 mmol) and BOP reagent (0.320 g, 0.724 mmol) in DMF (1 mL) at 0° C. was added a solution of (R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (Preparation C, 0.167 g, 0.483 mmol) in CH2Cl2 (1 mL) and N,N-diisopropylethylamine (0.420 mL, 2.41 mmol) sequentially. The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 and brine. The brine phase was back-extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 0-50% EtOAc/Hexanes to afford (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers) (0.0487 g, 19.6% yield). LC/MS (ES+APCI) m/z=515.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:30])([CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[OH:29])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(C(=O)c2ccc(CC(C)(C)C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(C)(C)Cc1ccc(C(O)c2ccc(CC(C)(C)C(=O)OCC)cc2)cc1
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A solution of 3-{4-[4-(2-ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (4.40 g, 10.0 mmol) in methanol (80 mL) was cooled in an ice-water bath. Sodium borohydride (0.45 g, 13.7 mmol) was added and the mixture was stirred for 5 h. Water (150 mL) and dichloromethane (65 mL) were added and the layers were separated. The aqueous layer was washed with dichloromethane (2×65 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried over MgSO4, and concentrated under vacuum. The residue was subjected to column chromatography on silica using hexanes/ethyl acetate (9:1 and 6:1) as eluent to afford 3-(4-{[4-(2-ethoxycarbonyl-2-methylpropyl)-phenyl]-hydroxymethyl}-phenyl)-2,2-dimethylpropionic acid ethyl ester (3.63 g, 82%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.24 (d, 4H, J=8.0 Hz), 7.07 (d, 4H, J=8.0 Hz), 5.77 (s, 1H), 4.08 (q, 4H, J=7.1 Hz), 2.83 (s, 4H), 2.62 (s, 1H), 1.21 (t, 6H, J=7.1 Hz), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3=77.23 ppm): δ (ppm): 177.6, 142.2, 137.3, 130.3, 126.3, 75.9, 60.5, 46.0, 43.4, 25.1, 14.3. HRMS (LSIMS, nba): Calcd for C27H35O4 (M+H−H2O): 423.2535. found: 423.2520.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:45])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:35][CH:34]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:35][CH:34]=4)[N:25]=3)=[CH:21][CH:22]=2)=[O:45])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccccc5)cc4)cc4ccnn34)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccccc5)cc4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of {4-[4-(5-biphenyl-4-yl-pyrazolo[1,5-c]pyrimidin-7-ylamino)-phenylcarbamoyl]benzyl}-carbamic acid tert-butyl ester (compound A1)(0.14 g) and trifluoroacetic acid (TFA)(1 ml) in dichloromethane (5 ml) is stirred 3 h at ambient temperature. The reaction mixture is evaporated, coevaporated with toluene and dried at high vacuum. Colorless crystals (0.13 g) are obtained in quantitative yield and a transition temperature of 170° C. and a melting temperature at 230° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][N:52]([CH2:54][C:55]3[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=3)[CH:53]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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:57]1[CH:58]=[CH:59][CH:60]=[C:55]([CH2:54][N:52]2[CH:53]=[C:49]([C:16]3[C:10]4[C:11](=[N:12][CH:13]=[C:8]([C:6]5[CH:5]=[CH:4][C:3]([CH:28]6[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:30][CH2:29]6)=[CH:2][CH:7]=5)[CH:9]=4)[N:14]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])[CH:15]=3)[CH:50]=[N:51]2)[CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccnc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 71.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (200 mg, 0.304 mmol) was coupled with 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64) (104 mg, 0.364 mmol) using Pd(dppf)Cl2 (11 mg, 0.015 mol) and sodium carbonate (97 mg, 0.912 mmol) in acetonitrile/water (3/1 ml) to afford 150 mg (72.0% yield) of the titled compound after column purification using 3% methanol in DCM as eluent.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:12][C:11]1[C:2]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-n2ccnc2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.17 g, 10.0 mmol) was dissolved in ethyl acetate (55 mL) and imidazole (4.09 g, 60 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and treated with SnCl2-2H2O (13.5 g, 60.0 mmol). It was heated to 70° C. for 2 h, diluted with potassium carbonate (sat. aq.) and extracted with ethyl acetate (5×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude yellow solid, which was used in the next step without further purification. [M+H] calc'd for C10H10N4O2, 219; found, 219.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](F)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[OH-:14].[Na+].Cl>S1(=O)(=O)CCCC1>[F:11][C:6]1[N:5]([CH3:12])[N:4]=[C:3]([CH:2]([F:13])[F:1])[C:7]=1[C:8]([OH:14])=[O:9]
Reactant: [OH-]
Reactant: Cn1nc(C(F)F)c(C(=O)F)c1F
Agent: Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
67.5 g of a solution (10% molar) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl fluoride in tetrahydrothiophene-1,1-dioxide were added dropwise to 400 mL of an aqueous 1N NaOH solution. During the addition, the temperature was kept below 20° C. After 2 h of stirring at room temperature, the mixture was carefully acidified to pH 2 using concentrated hydrochloric acid. The white precipitate formed was filtered off, washed with water and dried. This gave 6 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])OCC)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][CH:24]([O:28][CH3:29])[CH2:25][NH:26][CH3:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:26]([CH2:25][CH:24]([O:28][CH3:29])[O:23][CH3:22])[CH3:27])=[O:19])=[CH:12][CH:13]=2)=[CH:20][CH:21]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1ccc(Oc2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(NC(=O)N(C)CC(OC)OC)cc2)cc1

Procedure:
Ethyl [4-(4-methoxyphenoxy)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4(4-methoxyphenoxy) phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](F)[CH:7]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Li+].[Cl-]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Oc1cccnc1
Reactant: Fc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2cccnc2)c1
Temperature: 200 °C
Yield: 93.7 %

Procedure:
A mixture of 3-bromo-5-fluoropyridine (1.5 g, 8.5 mmol, 1.0 eq), 3-hydroxypyridine (970 mg, 10.2 mmol, 1.20 eq), and potassium carbonate (1.8 g, 13 mmol, 1.5 eq) in DMF (30 mL) was heated at 200° C. for 30 minutes in the microwave. The reaction mixture was diluted with 3M LiCl and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to give 2.0 g (94%) of the title compound as a brown liquid: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.46-8.44 (m, 2H), 7.85 (t, J=2.2 Hz, 1H), 7.60 (ddd, J=8.4, 2.9, 1.2 Hz, 1H), 7.48 (dd, J=8.4, 4.6 Hz, 1H); ES-MS [M+1]+:251.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[C:13]=2[O:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:40].B(Br)(Br)Br>C(OCC)(=O)C.C(OCC)C.CO.ClCCl.O>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:27][CH:26]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]3)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Dissolve the product of Example 17 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (1 mL, 2.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add 1M BBr3 in dichloromethane (0.1 mL, 1.1 mmol) and stir for 1 hour. Add water (1.0 mL) and dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting 6-(3-fluoro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol in dichloromethane-(0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (1 mL, 2.0 mmol). Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) at 65° C. for 48 hours to give 19 mg of the title compound (26%): mass spectrum (ion spray): m/z=536.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C1(C)C(C)=CC=CC=1>[CH2:18]([N:22]=[C:7]([OH:8])[C:6]1[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[C:10]([OH:9])=[O:11])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: CCCCN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Temperature: 105 °C

Procedure:
23.81 g (0.1 mole) of 3,5-dinitrophthalic anhydride are dissolved under reflux in 150 ml of xylene. The mixture is cooled to 105° C. and 7.31 g (0.1 mol) of n-butylamine in 10 ml of xylene are added dropwise, with vigorous stirring. On warming slowly to the reflux temperature, the amic acid which has precipitated out is converted to the soluble product, partly with vigorous foaming. After refluxing for 30 minutes under a water separator, the mixture is cooled and filtered and the mother liquor is evaporated. After recrystallisation from methylene chloride/diethyl ether/n-pentane, 27.53 g (94% of theory) of 3,5-dinitrophthalic acid N-n-butylimide, with a melting point of 40°-42° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][S:8][C:9]([CH3:40])([CH3:39])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][N:36]=[C:37]=[S:38])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][S:22][C:20]([CH3:32])([CH3:21])[C:19]([NH:18][CH2:17][CH2:16][N:15]([CH2:34][CH2:35][NH:36][C:37]([NH:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=2)=[S:38])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]([CH3:40])([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:42][CH:41]=2)[CH3:39])=[O:33])=[CH:29][CH:28]=1
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN=C=S)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Reactant: COc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)CCNC(=S)Nc2ccc(OC)cc2)cc1
Yield: 87.7 %

Procedure:
A solution of the isothiocyanate 25 (18.9 mg, 0.02986 mmol), triethylamine (7.26 mg, 0.07175 mmol), anisidine (6.9 mg, 0.05602 mmol), and CHCl3 (15 mL) was refluxed for 3 hours and the solvent was removed in vacuo. Flash chromatography of this crude product using 100% EtOAc gave the anisidine derivative 26 as a clear oil (19.8 mg, 87.6% yield). 1H NMR (in CDCl3): δ8.17 (brs,lH,NH--CS--NH--Ar), 7.28 (d,j=8.8 Hz,2H,H2 &H6 --Ar--N), 7.15 (d,j=8.6 Hz,4H,2H3 &H5 --Ar--OCH3), 7.06 (brs,lH,NH--CS--NH--Ar), 7.06 (t,j=5.7 Hz,2H,2NH--CO), 6.90 (d,j=8.9 Hz,2H,H3 &H5 --Ar--N), 6.82 (d,j=8.6 Hz,4H,2H2 &H6 --Ar--OCH3), 3.79 (s,3H,CH3O--Ar--N), 3.77 (s,6H,2CH3O--Ar--CH2), 3.67 (s,4H,2S--CH2 -Ar), 3.61 (q,j=5.3 Hz,2H,N--CH2CH2 --NHCS), 3.14 (q,j=6.2 Hz,4H,2N-CH 2CH2 --NHCO), 2.69 (t,j=5.6 Hz,2H,N--CH2CH2 --NHCS), 2.52 (t,j=6.3Hz,4H 2N--CH2CH2 --NH--CO), 1.51 (br s,12H,4CH3 --C--S) ppm. 13C NMR (in CDCl3): δ181.9 (s,N--CS--N), 175.2 (s,2NH--CO), 158.8 (s,3C1 --Ar--OCH3), 130.0 (s,C1 --Ar--N), 130.0 (d,2C2 &C6 --Ar--OCH3), 129.2 (s,2C4 --Ar--OCH3), 127.0 (d,C2 &C6 --Ar--N), 114.5 (d,C3 &C5 --Ar--N), 114.2 (d,2C3 &C5 --Ar--OCH3), 55.4 (q,3CH3O), 54.4 (t,2N-CH 2CH2 --NHCO), 52.9 (t,N--CH2CH2 --NHCS), 50.1 (s,2S--C--CH3), 42.8 (t,N--CH2CH2 --NHCS), 38.3 (t,2N--CH2CH2 --NHCO), 34.2 (t,2S--CH2 --Ar), 28.3 (q,4CH3 --C--S) ppm. MS (m/z,FAB): 756(4.2, M+). IR (CDCl3): 3320, 2960, 1720, 1655, 1510, 1290, 1245, 1030 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:23]([C:22]1[CH:26]=[CH:27][C:19]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[C:20]([N+:28]([O-:30])=[O:29])[CH:21]=1)(=[O:24])[NH2:25]
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3[N+](=O)[O-])c(Cl)cc21
Temperature: 90 °C

Procedure:
To a stirred solution of ethyl 6-chloro-7-hydroxychroman-4-carboxylate (6.40 g, 24.9 mmol) and 4-chloro-3-nitrobenzamide in N,N′-dimethylformamide (75 mL) at ambient temperature was added potassium carbonate (8.61 g, 62.3 mmol). An argon balloon with purge valve was attached, and the stirred mixture was evacuated and purged 5 times with argon. The mixture was stirred in an oil bath at 90° C. under argon. After 15 hours the reaction mixture was cooled to ambient temperature, then poured into a reparatory funnel containing water (1000 mL) and the extracted with ether (2×1000 mL). The organic layers were combined and dried over sodium sulfate, then evaporated to give 10.5 g of brown semi-solid. The crude material was purified by silica gel column chromatography, eluting with 99/1 chloroform/methanol followed by 98/2 chloroform/methanol to provide the desired product (7.74 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][C:3]=1[CH3:19].[H-].C([Al+]CC(C)C)C(C)C.O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[CH3:19]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2oncc2CCCO)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionate (1.20 g) in tetrahydrofuran (40 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 9.5 ml) at 0° C., and the mixture was stirred at room temperature for 3 hr. Water was carefully added to the reaction mixture, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) were recrystallized from ethyl acetate-hexane to give a colorless needle of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propan-1-ol (780 mg, yield 72%). melting point: 50–51° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[C:6]([NH:14][CH:15]([CH3:19])[CH:16]([CH3:18])[CH3:17])[N:5]2[N:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[C:4]2[N:3]=1.[CH2:26](OC(OCC)CCl)[CH3:27]>C(O)C>[Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[C:6]([NH:14][CH:15]([CH3:19])[CH:16]([CH3:18])[CH3:17])[N:5]2[N:20]=[CH:21][C:22]([C:23]3[O:24][CH:26]=[CH:27][N:25]=3)=[C:4]2[N:3]=1
Reactant: CCOC(CCl)OCC
Reactant: Cc1ccsc1-c1c(Cl)nc2c(C(N)=O)cnn2c1NC(C)C(C)C
Solvent: CCO
Product: Cc1ccsc1-c1c(Cl)nc2c(-c3ncco3)cnn2c1NC(C)C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
0.95 g (2.5 mmol) of 5-chloro-7-(1,2-dimethylpropylamino)-6-(3-methylthiophen-2-yl)pyrazolo-[1,5-α]pyrimidine-3-carboxamide was dissolved in 25 ml of ethanol, and 1.0 g (6.5 mmol) of chloroacetaldehyde diethyl acetal was added. The mixture was stirred for 3 hours at 120° C. and 15 bar in a microwave oven (200 W). The reaction mixture was then concentrated under reduced pressure, and the residue that remained was chromatographed on silica gel using a mixture of cyclohexane:ethyl acetate=1:1. This gave 0.3 g of [5-chloro-6-(3-methylthiophen-2-yl)-3-oxazol-2-yl-pyrazolo[1,5-α]pyrimidin-7-yl](1,2-dimethylpropyl)amine (logPs=4.3; content according to HPLC: 98%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:12])[CH2:4][CH2:3]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCN(CCCC(=O)c2ccc(Cl)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-p-chlorophenyl-4-oxobutyl)piperidine may be reacted with benzenesulphonyl chloride to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:41]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 50% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z=582.0.