Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH2:15])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: NCCCc1ccccc1
Solvent: c1ccncc1
Product: Nc1nc2ccc(-c3ccnc(NCCCc4ccccc4)n3)cc2s1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (54.1 mg, 178 μmol) and 3-phenylpropylamine (25.2 μl, 178 μmol) were suspended in pyridine (0.80 mL) and sealed in a microwave vial and heated in the CEM microwave (CEM Corporation, Matthews, N.C.) at 120° C. and 300 watts with a 5 minute ramp time and 20-minute run time. The reaction was cooled to RT, concentrated, and the resulting crude material was purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford 6-(2-(3-phenylpropylamino) pyrimidin-4-yl)benzo[d]thiazol-2-amine. MS (ESI pos. ion) m/z: 362. Calculated exact mass for C20H19N5S: 361.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2Cl)cc1-c1c(Cl)cnn1C
Yield: 24 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-dichlorophenyl isocyanate in a similar manner as described in Example 1.53, providing 16.4 mg (24%) of Compound 77 (Note: Compound 77 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=427 (M+H37Cl, 72), 425 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.85 (s, 1H), 8.26 (dd, J1=12 Hz, J2=4 Hz, 1H) 7.90 (s, 1H), 7.59 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.38 (d, J=4 Hz, 1H), 7.36 (s, 1H), 7.36 (s, 1H), 7.24 (dd, J1=12 Hz, J2=4 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1
Reactant: NS(=O)(=O)c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Yield: 70.9 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.29 g, 0.96 mmol) in 2-butanone (10 mL) was added 5-chloro-2-hydroxy-benzenesulfonamide (0.20 g, 0.96 mmol), potassium carbonate (0.27 g, 1.92 mmol) and potassium iodide (0.16 g, 0.96 mmol). The reaction was refluxed for 4 hours, cooled diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.32 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C[C@H]1CCCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added (S)-2-methylpiperidine (166 mg, 1.7 mmol) and DIEA (217 mg, 1.7 mmol). The resulting solution was stirred at 70° C. for 3 h and then quenched by water (10 mL), the solids were collected by filtration to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:25])[C@H:13]([CH3:24])[NH:14][CH:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:30][CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:25])[C@H:13]([CH3:24])[NH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])([C:20]([O:22][CH3:23])=[O:21])[CH2:30][CH2:31][C:32](=[O:33])[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)CCC(=O)c1cccs1
Reactant: COC(=O)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC

Procedure:
A-mixture of N-(dimethoxycarbonylmethyl)-L-alanyl-L-proline t-butyl ester (2.0 g.), 3-dimethylamino-1-(2-thienyl)propan-1-one hydrochloride (1.8 g.), potassium carbonate (2.0 g.) and methanol (15 ml.) was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was stirred with dichloromethane, the mixture was filtered through a filter-aid and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 19:1 v/v mixture of dichloromethane and ethyl acetate as eluant. There was thus obtained as an oil N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[Br:11][C:12]1[CH:13]=[C:14]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH:15]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:11][C:12]1[CH:13]=[C:14]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH:15]=[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH:17]=1
Reactant: CC(C)(C#N)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccnc2[nH]ncc12
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
Product: CC(C)(C#N)c1cc(Br)cc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
A suspension of 4-iodo-1H-pyrazolo[3,4-b]pyridine (116 mg, 0.47 mmol), 2-(3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanenitrile (137 mg, 0.39 mmol), 2 M aqueous solution of sodium carbonate (0.79 ml, 1.58 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 23 mg, 0.02 mmol), in ethylene glycol dimethyl ether (4 ml) was heated under microwave irradiation at 150° C. for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (102.5 mg, 77% yield).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([N:20]3[CH2:28][C:27]4[C:22](=[C:23]([NH:29][CH2:30][C:31]5[CH:32]=[C:33]6[C:38](=[CH:39][CH:40]=5)[N:37]=[CH:36][CH:35]=[CH:34]6)[CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:41])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N:20]3[CH2:28][C:27]4[C:22](=[C:23]([NH:29][CH2:30][C:31]5[CH:32]=[C:33]6[C:38](=[CH:39][CH:40]=5)[N:37]=[CH:36][CH:35]=[CH:34]6)[CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:41])=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N3Cc4cccc(NCc5ccc6ncccc6c5)c4C3=O)ccc2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cc(N3Cc4cccc(NCc5ccc6ncccc6c5)c4C3=O)ccc21

Procedure:
The title compound was prepared by treatment of 4,4-dimethyl-7-{1-oxo-7-[(quinolin-6-ylmethyl)-amino]-1,3-dihydro-isoindol-2-yl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 3) with TFA in CH2Cl2. MS (m/z)=449.0 (M+H)+ Calc'd for C29H28N4O: 448.5.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (as prepared above) (1.8 g, 4.51 mmol) was taken up in CH2Cl2 (10 ml). N-bromosuccinimide (0.80 g, 4.51 mmol) was added and the mixture stirred at room temperature for two hours. The CH2Cl2 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.30 g, 14%, first crop)
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[CH3:20][C:21]1[O:22][C:23]([CH3:26])=[CH:24][CH:25]=1>C1(C)C=CC=CC=1>[CH3:20][C:21]12[O:22][C:23]([CH3:26])([CH:24]=[CH:25]1)[CH:6]1[CH:5]2[C:4](=[O:7])[N:3]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:19])[F:18])[CH:9]=2)[C:2]1=[O:1]
Reactant: Cc1ccc(C)o1
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC12C=CC(C)(O1)C1C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C12
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A slurry of 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethyl-benzonitrile (30 g, 113 mmol) and 2,5-dimethylfuran (70 mL) was stirred at 60° C. for 0.5 h. After toluene (40 mL) was added, the reaction mixture was stirred at 60° C. for 3 h. The mixture was then cooled in ice bath. The solid was collected by filtration and washed with cold toluene (30 mL) to give Preparation 1 as an off white solid (36.8 g, 102 mmol, 90% yield).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=O)=[CH:12][CH:11]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a three-neck round-bottomed flask equipped with a magnetic stir bar, reflux condenser, rubber septum, and two nitrogen inlets, was added zinc powder (13.0 g, 199 mmol) followed by anhydrous THF (200 mL). To the stirred suspension was slowly added TiCl4 (11.0 mL, 19.0 g, 100.0 mmol) via syringe (caution: vigorous fuming). The reaction mixture was heated at reflux for 2 h. To the refluxing reaction mixture was added a solution of cycloheptanone (9.0 mL, 8.56 g, 76.3 mmol) and (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (6.91 g, 24.9 mmol) in THF (200 mL) slowly via syringe. The reaction mixture was heated at reflux under a nitrogen atmosphere with stirring for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. The three neck round-bottomed flask was equipped with an addition funnel and water (150 mL) was slowly added to the reaction mixture followed by 10% aqueous K2CO3 (150 mL). The reaction mixture was filtered through a pad of Celite. The pad washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an orange oil. The crude product was partially purified by flush chromatography on silica gel with hexanes:EtOAc (100:0 to 95:5) to give a solid. The solid was triturated with hexanes and filtered to give 6.3 g (71%) of compound (9) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 8 H), 2.20 (m, 4 H), 6.66 (d, J=8.5 Hz, 2 H), 6.89 (d, J=8.4 Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H), 9.30 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]=1[CH:11](OCC)OCC)=O)C.O.[NH2:26][NH2:27].Cl>C(O)(=O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:10]3=[CH:11][N:26]=[N:27][C:4]([OH:3])=[C:6]3[CH:7]=[N:8]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C(OCC)OCC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Oc1nncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-diethoxymethyl-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.70 g, 16.9 mmol) in acetic acid (100 mL) is added hydrazine monohydrate (5.0 mL, 6.1 mmol) and 12 N aqueous hydrochloric acid (200 μL). The reaction mixture is warmed at reflux. After 2 hours, the mixture is cooled to room temperature and diluted with water. The solid is collected by filtration, washed with water and air dried to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)n1

Procedure:
Example 66 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.34 (m, 2H), 7.01–6.97 (m, 2H), 6.88 (d, 1H, J=7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz), 2.94 (d, 2H, J=14.0 Hz), 2.54–2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz), 1.99–1.60 (m, 14H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 495.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](O)=[O:8])=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])[CH:16]=[N:15][C:14]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C@H:54]1[C:59]([F:61])([F:60])[CH2:58][CH2:57][CH2:56][C@H:55]1[NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:65]([O:64][C:63](=[O:69])[NH:62][C@@H:55]1[CH2:56][CH2:57][CH2:58][C:59]([F:61])([F:60])[C@@H:54]1[NH:53][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:20][CH3:21])[O:22][CH3:23])[CH:16]=[N:15][C:14]=23)[CH:4]=1)=[O:8])([CH3:66])([CH3:68])[CH3:67]
Reactant: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)O)sc3C)cnn2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](NC(=O)OC(C)(C)C)CCCC4(F)F)sc3C)cnn2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Methyl-4-[6-(trimethoxymethyl)pyrazolo [1,5-a]pyrimidin-3-yl]thiophene-2-carboxylic acid (41.0 mg, 0.113 mmol) and BOP (59.9 mg, 0.135 mmol) were dissolved in DMF (752 μL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (31.1 mg, 0.124 mmol) and diisopropylethyl amine (59.1 μL, 0.338 mmol) and the reaction stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and purified by column chromatography (0-60% EtOAc/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C27H35F2N5O6S) [M+H]+, 596.2; found 596.1.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:5])#[N:2].[CH3:16][C:17]([CH3:24])=[CH:18][C:19](OCC)=[O:20].CC(C)([O-])C.[K+].Cl>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:6]2[C:19](=[O:20])[CH2:18][C:17]([CH3:24])([CH3:16])[CH:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=C(C)C
Reactant: N#CCC(=O)NCCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CC1(C)CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 2-cyano-N-[2-(4-fluorophenyl)-ethyl]-acetamide (2.0 g, 19.4 mmol), ethyl 3-methylbut-2-enoate with a solution of potassium tert-butoxide in 80° C. After 16 hours, the mixture was cooled to room temperature and acidified with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to provide a brown solid. Recrystallization from 95% ethanol provided a tan solid (2.37 g, 85%). 1H NMR (300 MHz, dmso-d6) δ7.24 (m, 2H), 7.11 (t, J=9 Hz, 2H), 4.70 (s, 2H), 3.88 (m, 2H), 2.8-2.6 (m, 4H), 1.16 (s, 3H), 0.98 (s, 3H). Mass spec (ES−) m/z 287.2 (M−H−, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:14]2[C:16](=[O:28])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[NH:12][CH2:13][CH:14]([C:16](=[O:28])[NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:15]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2NCC(C(=O)Nc3cccc4ccccc34)C21
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
A solution of 53 (490 mg, 0.95 mmol) in 1:1 MeOH/EtOAc (4 mL) was treated with Pd/C (5% wet, ca. 100 mg) and placed under H2 (50 psi) using a Parr apparatus. After 1.5 h, the reaction mixture was filtered through syringe filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford crude 54 (360 mg) which was used without further purification. Mass spectrum, m/z [382.2] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>CC(C)=O>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][CH:34]([CH2:33][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCC3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (0.557 g, 1.48 mmol) and K2CO3 (0.306 g, 2.22 mmol) in acetone (4 mL) was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.431 g, 1.55 mmol). The reaction was heated at reflux. After 4 h, the reaction was concentrated and purified by column chromatography using Hex:EtOAc as eluents to afford the title compound (0.765 g) as a white solid. MS (EI) m/z 574 [M+H]+.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N-:20]([C:23]#[N:24])[C:21]#[N:22].[Na+]>C(O)CCC>[C:21]([NH:20][C:23](=[NH:24])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:23]([NH:20][C:21]#[N:22])=[NH:24])#[N:22]
Reactant: CCCCCCCCCCCCNCCCN
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCCCCCCCN(CCCNC(=N)NC#N)C(=N)NC#N

Procedure:
3-Dodecylaminopropylamine dihydrochloride (15 g.) sodium dicyanamide (9.47 g.) and butanol (250 ml.) were heated under reflux for 4 hours. The mixture was allowed to cool, and filtered, and the solvent was evaporated under reduced pressure. The residue was suspended in toluene and evaporated to small volume under reduced pressure to yield a pale oil, which was purified by chromatography on silica gel, using a gradient elution of isopropanol/methylene dichloride starting at 1:9, and then eluting the required product using a ratio of 1:4. The product 1-(3-cyano-guanidino)-3-(3-cyano-1-dodecylguanidino)propane was obtained as a solid m.p. 126°-129°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[S:15][CH2:16][CH3:17])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([S:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: CCOC(=O)C=C(N)SCC
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(SCC)C(C(=O)OCC)C1c1ccncc1
Yield: 47 %

Procedure:
Upon boiling a solution of 5.3 g of pyridine-4-aldehyde and 17.5 g of 3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for 5 hours, 2-amino-4-(4-pyridyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 156° C is obtained. Yield: 47% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9](O)=[O:10].[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:10]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for intermediate 1,3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl-4-carboxylic acid (intermediate 10) was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 447.1 (MH+).