Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCCCC>CC(=O)CC>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: CCCOc1ccc(CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 52.9 %

Procedure:
A solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Preparation 16, 0.60 g, 0.0016 mol) in 2-butanone (10 ml) was added dropwise to a stirred solution of morpholine (0.42 g, 0.0048 mol) in 2-butanone (40 ml) at 0° C. The solution was then heated under reflux for 16 hours, cooled and evaporated under vacuum. The residue was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (12 g), using an elution gradient of methanol in dichloromethane (0-2% methanol), to give an oil which solidified on trituration with hexane. Crystallisation from ethyl acetate-hexane gave the title compound as a colourless solid (0.36 g, 53%), m.p. 106°-107° C. Found C,64.76; H,7.34; N,16.36. C23H31N5O3 requires C,64.92; H,7.34; N,16.46%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([NH2:21])=O)=[CH:6]3.C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:22])[C:5]([C:19]#[N:21])=[CH:6]3
Reactant: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A mixture of 11 (2.92 g, 9.44 mmol) and triethylamine (6.6 mL, 47 mmol) in CH2Cl2 (20 ml) was cooled to 0° C. and POCl3 (4.35 g, 28 mmol) was added drop wise with stirring. The mixture was stirred an additional 5 h at 0° C. During that time, the reaction mixture turned dark-brown. Upon completion of the reaction, the solvent was removed by evaporation. 70 mL of water were added and the mixture stirred at room temperature for 1 h. The precipitate that formed was collected by filtration and washed with water. The solid was dried under vacuum to yield 12 as a brown solid (2.6 g, 94%). This compound was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:21][CH:20]=1.O>CCOCC>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:24][CH:23]=2)=[O:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a suspension of 83 (135 mg, 0.59 mmol) in ether (10 mL) was added HCl (1.17 mL, 1.00 M, 1.17 mmol) in ether. The mixture was stirred for 3 h and the solvent was removed under vacuo. A suspension of this HCl salt in NMP (3 mL) was added N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (209 mg, 0.70 mmol). The mixture was stirred at 150° C. for 3 h. After cooling to room temperature, H2O was added. The resulting product precipitate and the solid was filtered, washed with H2O and MeOH, and dried under vacuum to provide 378 (210 mg, 73% yield) as pale solid.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37]>CN(C=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH2:26][NH:27][C:36](=[O:37])[O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Reactant: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)OCC(C)C)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (37 mg, 0.10 mmol) in DMF (2.0 mL) is added 4-methylmorpholine (44 μL, 0.40 mmol) followed by isobutyl chloroformate (21 mg, 0.15 mmol). After stirring at room temperature for 12 hours, the mixture is evaporated in vacuo and the resulting oil purified on reverse phase HPLC to obtain a white solid, 26 mg, 54%, LC/MS ESI m/z (M+H)+=470.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
120.00 g (0.33 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) of triethylamine were stirred in 1200 ml of toluene at 60° C. for 2 days. The precipitated solid was filtered off with suction and recrystallized from acetone/n-hexane. 102.10 g (71%) of the title compound having a melting point of 243-245° C. were obtained.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])[CH2:5][C@@H:4]([OH:22])[CH2:3]1.N1C=CN=C1.[C:28]([Si:34](Cl)([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])([CH3:30])[CH3:29].[CH2:38]([Si:40](Cl)([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39]>CCCCCC.ClCCl>[CH3:35][Si:34]([CH3:36])([C:28]([CH3:30])([CH3:29])[CH:31]([CH3:33])[CH3:32])[O:22][C@H:4]1[CH2:3][C@H:2]([O:1][Si:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:38][CH3:39])[C@@:19]2([CH3:20])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])[CH2:5]1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@]12C(=CC=C3[C@@H]1CC[C@]1(C)C(=O)CC[C@@H]31)C[C@@H](O)C[C@@H]2O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC[Si](CC)(CC)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C(C)C)CC2=CC=C3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A 3-L three-necked flask equipped with a mechanical stirrer, addition funnel, and Ar-inlet tube was charged with 60.1 g (199 mmol) of (1α,3β)-1,3-dihydroxyandrosta-5,7-dien-17-one, 40.7 g (598 mmol) of imidazole, and 400 mL of dichloromethane. After cooling with an ice-water bath for 5 min., 50.7 mL (257 mmol) of thexyldimethylsilyl chloride was added over 12 min. The cold bath was removed, and the mixture was stirred at room temperature for 5 hr. After cooling again with an ice-water bath. 36.8 mL (219 mmol) of triethylsilyl chloride was added over 10 min. After stirring at room temperature overnight, 220 mL of hexane was added. After 15 min, the precipitate was removed by filtration and washed with 2×120 mL of hexane. The combined filtrate and washes were concentrated, and the residual hexane was removed by co-evaporation with 120 mL of methanol, and the suspension was stirred for 2 hr in order to obtain a powdery material. After the suspension was stored in a refrigerator overnight, the precipitate was filtered and washed with 2×160 mL of 95% methanol. Drying under high vacuum afforded 96.8 g of (1α,3β)-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]-1-[(triethylsilyl)oxy]androsta-5,7-dien-17-one as a beige solid.
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.Cl[Si](C)(C)C.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[NH2:6][C:7]1[S:8][C:9]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:10][N:11]=1
Reactant: CC(C)=O
Reactant: Nc1nccs1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(N)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Add n-Butyl lithium (1.6 M solution in hexane, 24 mL, 38 mmol, 2.0 eq.) in a dropwise manner at −78° C. under nitrogen to the solution of 2-amino thiazole (1.90 g, 18.97 mmol, 1.0 eq.) in anhydrous THF (80 mL). Add chlorotrimethyl silane (4.8 mL, 38 mmol, 2.0 eq.) to the mixture slowly at −78° C. Let the reaction mixture warm up to 0° C. slowly and stir the mixture at 0° C. for 10 minutes. Cool the solution to −78° C. and add n-Butyl lithium (1.6 M solution in hexane, 12 mL, 19 mmol, 1.0 eq.) in a dropwise manner. Add acetone (1.4 mL, 19 mmol, 1.0 eq.) last. Stir the reaction mixture at −78° C. for 10 minutes, then at room temperature for 30 minutes. Quench with ammonium chloride (sat. 10 mL) at −78° C. Then warm up to room temperature. Add ethyl acetate (200 mL). Wash the organic layer with aqueous saturated sodium chloride (3×30 mL), water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% methanol in dichloromethane→10% methanol in dichloromethane) to afford product (1.38 g, 46%). MS(ES), m/z 159 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O-:23].[Na+].CO>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([O:23][CH3:22])[N:3]=1
Reactant: COc1ccc(-c2cc(Cl)nc(S(C)(=O)=O)n2)cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(Cl)cc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidine [5.05 g, 0.0154 mol, Intermediate (49)] in ethylene glycol dimethyl ether (100 mL) is chilled to 0° C. and added 25 wt % sodium methoxide in MeOH (1.32 mL, 0.0231 mol). After 15 minutes the reaction is allowed to warm to ambient temperature and stirred overnight. The mixture is concentrated to afford 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methoxy-pyrimidine [4.3 g, 100%, Intermediate (50)]
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[C:5]([OH:8])=[CH:6][CH:7]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[C:3]=1[CH3:22]
Reactant: Cc1c(Cl)ccc(O)c1C(=O)c1cnn(-c2ccccc2)c1
Reactant: CCOC(=O)CBr
Product: Cc1c(Cl)ccc(OCC(=O)O)c1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from (3-chloro-6-hydroxy-2-methyl-phenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.34 min, m/z 370.6 [M+1]+; 1H NMR (CDCl3): δ 2.44 (s, 3H), 4.77 (s, 2H), 6.92 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.59 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.52 (s, 1H), 10.39 (br s, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Cl)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(3-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (62 mg, 44%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.70 (s, 2H), 8.53 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.26-7.50 (M, 8H), 7.10 (m, 2H), 5.69 (d, J=6.0 Hz, 1H), 4.70 (d, J=5.1 Hz, 2H), 3.67 (s, 3H), 3.46 (s, 3H). MS (ESI) m/z=533 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[S:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[S:31]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:35]4[S:29][C:30](=[S:31])[NH:32][C:33]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 30 mg, 0.1 mmol) in EtOH (1 mL) was added piperidine (13 μL, 0.1 mmol), and rhodanine (13 mg, 0.1 mmol). The reaction was stirred at 80° C. for 2 hours. The solid formed was isolated by filtration, washed with water then ethanol. The recovered solid was further purified by washing with 20% methanol/dichloromethan to provide 15 mg of 5-((7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one (35%). LCMS (M+1=413)
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].Br[CH2:11][C:12]#[CH:13].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:9][CH2:8][C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To a suspension of sodium hydride (1.570 g, 39.2 mmol) in DMF (46 ml) stirred under argon at 0° C. a solution of 2-furanylmethanol (3.5 g, 35.7 mmol) in DMF (4 ml) was added dropwise over 20 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. 3-bromo-1-propyne (4.24 g, 35.7 mmol) 80% in toluene was dropped in 10 minutes at 0° C., then the mixture was left stirring at room temperature overnight. Water was added and then the mixture was extracted with ethyl ether 3 times. The organic phase was dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage SP1 instrument), eluting with a gradient cyclohexane/ethyl acetate 95/5 to 85/15. Evaporation afforded the title compound (1.63 g, 35% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(Cl)Cl>[C:11]1([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccnc2scc(-c3ccccc3)c12
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: c1ccc(-c2csc3nccc(NCc4ccccn4)c23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-3-phenyl-thieno[2,3-b]pyridine (47 mg, 0.19 mmol) and 2-aminomethyl pyridine (0.5 ml, 4.85 mmol) were placed in a 10 ml glass tube. The vessel was sealed with a septum and placed in the microwave cavity. Using microwave irradiation the temperature was ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 90 minutes. After cooling to room temperature, the temperature was ramped to 200° C. and held at this temperature for 30 min. After cooling, the reaction mixture was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give (3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine. Yield=14 mg, 23%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH2:19]([NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([F:40])[CH:26]=1)=[O:23])[CH3:20]>>[CH2:19]([NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)=[C:27]([F:40])[CH:26]=1)=[O:23])[CH3:20]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)c(F)c1
Yield: 4 %

Procedure:
Method as described for example 147 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) as starting materials. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic fit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at low pH to afford a yellow solid (8.4 mg, 0.02 mmol, 4%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC)=O)=NC(OC)=O>O1CCCC1>[CH2:1]([C:35]1[CH:34]=[CH:33][CH:32]=[C:28]2[C:29]([NH:30][C:26](=[O:36])[C:27]=12)=[O:31])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCO
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCc1cccc2c1C(=O)NC2=O
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To solution (60 ml) of 5-(N-tert.butyloxycarbonyl, N-ethylamino)-1-pentanol (4.7 g) in anhydrous tetrahydrofuran were added triphenylphosphine (7.8 g) and phthalimide (4.4 g). To the solution was added dropwise dimethyl azodicarboxylate (5.2 g) with stirring under ice cooling. After stirring was made for one hour, the solvent was distilled off under reduced pressure. The residue was extracted with n-hexane-ethyl acetate (2:1). Solution extracted was washed with water and the solvent was distilled off to obtain N-[5-(N-tert.butyloxycarbonyl, N-ethylamino)] pentylphthalimide (4.2 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)=[O:18])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:12]2[CH:16]=[C:15]([C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]3[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:18])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(C1=CCCCC1)c1cc(-c2ccccc2)no1
Reactant: C1CCNC1
Product: O=C(c1cc(-c2ccccc2)no1)C1CCCCC1N1CCCC1

Procedure:
Pyrrolidine (5 ml) was added to 0.98 g (3.9 mmol) of 3-phenyl-5-(1-cyclohexenoyl)isoxazole prepared above in the procedure (1). The resultant mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. To the concentrate was added diethyl ether and then 10% hydrochloric acid, whereby the reaction product was extracted in a water layer. The water layer was collected, alkalinized with a 10% aqueous solution of sodium hydroxide, and then extracted with dichloromethane. The solvent was distilled off, so that 3-phenyl- 5-{2-(1-pyrrolidinyl)cyclohexanoyl}isoxazole was obtained as yellow crystals.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:62]([NH:72][C:73](=[O:91])[CH2:74][N:75]2[C:83]3[C:82]([F:85])([F:84])[CH2:81][CH2:80][C:79]([F:87])([F:86])[C:78]=3[C:77]([CH:88]([F:90])[F:89])=[N:76]2)[CH2:63][C:64]2[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[N:54][CH:55]=1>>[F:90][CH:88]([F:89])[C:77]1[C:78]2[C:79]([F:87])([F:86])[CH2:80][CH2:81][C:82]([F:84])([F:85])[C:83]=2[N:75]([CH2:74][C:73]([NH:72][C@H:62]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][N:59]([CH3:60])[CH3:61])[N:52]=2)[CH2:63][C:64]2[CH:65]=[C:66]([F:71])[CH:67]=[C:68]([F:70])[CH:69]=2)=[O:91])[N:76]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: CN(C)CCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: CN(C)CCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (16B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 16A. 1H NMR (400 MHz, —CD3OD) δ 8.75 (d, J=7.4 Hz, 1H), 8.13 (s, 1H), 7.38 (m, 2H), 7.21 (dd, J=10.8, 8.4 Hz, 1H), 6.98-6.63 (m, 2H), 6.42 (m, 2H), 5.23 (d, J=7.6 Hz, 1H), 5.02 (q, J=16.8 Hz, 2H), 3.88 (m, 2H), 3.45 (t, J=5.5 Hz, 2H), 3.15-2.93 (m, 8H), 2.52 (m, 4H). MS (m/z) 743.60 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:16]([NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccnc(Cl)c1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 257 mg. (2 mmol) of 2-chloro-4-aminopyridine dissolved in ten ml. of dry acetone, 238 mg. (2 mmol) of phenyl isocyanate is added and the mixture is stirred at room temperature for 8 hrs. The solvent is evaporated under a reduced pressure, the residue is chromatographed over alumina, and the column is developed with chloroform. Eluates containing the objective substance are collected, and the solvent is evaporated under a reduced pressure. The residue is recrystallized from acetone-ether mixture and 364 mg. of N-(2-chloro-4-pyridyl)-N'-phenylurea is obtained. Yield, 73.5%, mp 173°-174° C.