Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Na].C([N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]=2[CH:12]=[CH:11]1)C1C=CC=CC=1>CCOCC>[CH:20]1([O:19][C:18]2[C:13]3[CH:12]=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(Cn2ccc3c(OC4CCCCC4)ncnc32)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: c1nc(OC2CCCCC2)c2cc[nH]c2n1
Temperature: -78 °C
Yield: 9.4 %

Procedure:
To liquid ammonia (6.0 mL) at −78° C. was added 33 mg (1.43 mmol) sodium metal and the resulting dark blue solution stirred at −78° C. 10 min. A solution of 75 mg (0.244 mmol) of the product from Method M in 3.0 mL of ether was added dropwise over a 5 min period. The resulting solution stirred at −78° C. for 1 h followed by quenching upon addition of 500 mg of solid ammonium chloride. After evaporation at room temperature, the residual solid was triturated with 25 mL of ethylacetate containing 1 mL of acetic acid for 1 h. Filtration and concetration in vacuo afforded crude material which was purified by preparative thin layer chromatography (silica-gel; 2:1 ethyl acetate/hexanes) to produce 5 mg of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 1.27-1.35 (m, 6H), 1.62-1.67 (m, 4H), 5.30-5.36 (m, 1H), 6.55 (d, 1H, J=3.2 Hz), 7.11 (d, 1H, J=3.2 Hz), 8.37 (br s 1H). LRMS: 218.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:18]([C:19]#[N:20])=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[NH:16][N:15]=1>C(O)(=O)C>[CH3:10][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:15]2[N:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:18]([C:19]#[N:20])=[C:14]2[N:13]=1
Reactant: CC(=O)CC(=O)c1ccncc1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccncc2)n2nc(N3CCN(Cc4ccccc4)CC3)c(C#N)c2n1

Procedure:
A mixture of 4.8 g (0.03 moles) of 1-(4-pyridyl)-1,3-butanedione [J. Chem. Soc. (1950) p 1680], 8.4 g (0.03 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 100 ml of glacial acetic acid was stirred at reflux for 18 hours.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:15]1.C(O)(C(F)(F)F)=O>>[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]3[C:7]4[NH:6][C:5]5[C:12](=[CH:13][C:2]([F:1])=[CH:3][CH:4]=5)[C:8]=4[CH2:9][CH2:10][NH:11]3)=[CH:17][C:16]=2[O:15]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c3c(c2c1)CCNC3c1ccc2c(c1)OCO2
Yield: 84.7 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL, 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals. MP: 172° C.
Reaction SMILES: [O:1]([C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:22](=[O:23])[C@H:21]3[CH2:24][CH2:25][CH2:26][C@H:20]3[NH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:33][CH2:34][C:35]([N:19]1[C@@H:20]2[CH2:26][CH2:25][CH2:24][C@@H:21]2[C:22](=[O:23])[N:16]([CH2:15][C:14]2[CH:31]=[CH:32][C:11]([NH:10][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:12][CH:13]=2)[C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]1=2)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(phenoxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.61 g, 3.8 mmol) in DMF (20 mL) was added chloroacetyl chloride (0.36 mL, 4.5 mmol) and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with 3 portions of chloroform. The pooled organic layer was washed with 2 portions of water and, then, with saturated aqueous NaCl solution. This solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from chloroform-diethyl ether to provide 0.90 g (yield 47%) of the compound. m.p. 207-210° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15](=O)[NH:14][C:13]=23)[CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[CH:16]=[CH:17][N:12]2[N:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=3)=[C:13]2[N:14]=1
Reactant: O=c1ccn2ncc(-c3cccc(C(F)(F)F)c3)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cnn3ccc(Cl)nc23)c1
Temperature: 107 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A mixture of 3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (2.07 g, 7.41 mmol) and POCl3 (6.91 ml, 74.1 mmol) was heated to 107° C. The heating was continued for 16 hours. The reaction mixture was cooled to RT and the POCl3 removed in vacuo to give a waxy solid. The solid was triturated multiple times with Et2O and the Et2O layers were combined and rotovaced. The resulting residue was taken up in DCM and washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 5-chloro-3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine (1.47 g, 67% yield) as a brown solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:39](N1C=CN=C1)([N:41]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C.O>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:41][CH3:39])=[O:34])(=[O:29])=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A mixture of 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid. (159 mg, 0.30 mmol) and 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) in DMF (2 ml) was stirred at 50° C.(bath) for 10 min. Triethylamine (0.21 ml, 1.50 mmol) and methylamine hydrochloride (61 mg, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Water (15 ml) was added and stirred at 0° C. for 30 min. The precipitate was filtered, washed with water, and dried to give a crude product which was recrystalized from ethyl acetate-MeOH to afford the required compound as a light brown solid, 85 mg, 52% yield; mp 249-251° C. NMR was consistent with the structure. Calcd. For C30H29N3O5S:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Cl:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)ccc12
Product: Fc1ccc2c(Cl)ncnc2c1

Procedure:
7-Fluoro-3H-quinazolin-4-one (8.2 g, 50 mmol) is heated at reflux in thionyl chloride (80 mL). Concentration affords the expected 4-Chloro-7-fluoro-quinazoline (9.1 g, ˜quant).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccccn1
Agent: Br
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccn1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 3 of Example 12, and 2-(bromomethyl)pyridine hydrobromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>85° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.95 (m, 6 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.66 (d, J=9.0 Hz, 2 H), 6.75 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.50 (s, 1 H), 8.90 (brs, 1 H); MS (ES) m/z: 269.0 ((M+2H)2+, 100%); 537.6 (MH+, 10%); HRMS Calcd. for C29H37N4O4S (MH+): 537.2536. Found: 537.2500.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:14]I.S([O-])(O)=O>O.CCCCCC.C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1F
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
2-Fluoroaniline (54 g, 486 mmol) was added to a vigorously stirred solution of sodium bicarbonate (41 g, 486 mmol) in water (250 mL). The suspension was warmed to 60° C. on an oil bath and iodine (123 g, 486 mmol) was added portion-wise. After complete addition, the dark mixture was stirred for an additional 3 h at 60° C. After cooling to rt, methylene chloride (300 mL) was added followed by saturated hydrogensulfite solution (300 mL). The biphasic system was vigorously stirred for an additional 10 min. The mixture was poured into a 2 L separatory funnel and the organic layer was released. The aqueous was further extracted with methylene chloride (3×200 mL) and the combined organics were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to give a black crystalline solid. Hexane (300 mL) was added and the mixture was heated to reflux. The hexane was decanted from a black, insoluble syrup. The product crystallized from the hexane on cooling as fine yellow needles. 65 g (274 mmol) was isolated as a fine yellow solid. Yield: 56%; mp 53° C.; 1H NMR (400 MHz, CDCl3) δ 8.1 (t, J=8 Hz, 1H), 7.4 (d, J=6 Hz, 1H), 7.2 (d, J=6 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCCC2)CCC1
Reactant: Clc1ccc(I)cc1
Product: NC(c1ccc(Cl)cc1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=265.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 1-chloro-4-iodobenzene.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1)[CH3:33]
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)Cc1cc(C(=O)Nc2nc(-c3ccco3)c(-c3ccncc3)s2)ccn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Compound 107 (150 mg, 0.387 mmol) was dissolved in N,N,N′-trimethylethylenediamine (1 mL), followed by stirring at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) and then crystallized from diisopropyl ether to afford the entitled Compound 109 (70 mg, 40. %) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:41]=[C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.89-1.00 (m, 6H), 1.58 (dt, J=13.39, 6.63 Hz, 1H), 1.78 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.01-2.13 (m, 1H), 3.82 (t, J=7.83 Hz, 1H), 7.05-7.13 (m, 1H), 7.32 (dd, J=10.03, 1.47 Hz, 1H), 7.36-7.47 (m, 2H), 7.52-7.61 (m, 2H), 7.66-7.76 (m, 5H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: Cc1csc2c(NC(C)C)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(C)C)c2scc(C)c2n1
Yield: 77.5 %

Procedure:
In a sealed tube were heated 290 mg (1.2 mmol) of 2-chloro-4-isopropylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 244 mg (yield: 77.7%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(F)ccc1F
Yield: 73.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,5-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 74%) as crystals.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O>O1CCCC1.C(OCC)C.C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)CC(OCc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC(OCc1ccc(-c2ccc(N3CCNCC3)cc2)cc1)C(=O)NCC#N
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A solution of tert-butyl 4-{4′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)methyl][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate (115 mg, 0.21 mmoles) in tetrahydrofuran (3.5 mL) was treated with methanesulfonic acid (30 μL, 0.4 mmoles). The same amount of acid was added 5 times at 1.5 hour intervals and stirred overnight. Acid addition was resumed and two more portions (30 μL, 0.4 mmoles) were added, with a 1.5 hour interval. The reaction was diluted with diethyl ether, ethylacetate, sat. aq. sodium bicarbonate. The phases were separated and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product was chromatographed (1% sat. aq. ammonium hydroxyde, 9% methanol, 90% dichloromethane) to obtain 77 mg N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methoxy}pentanamide, a yellowish solid.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH3:32][NH:33][C:34]([C:36]1[C:37](=[O:63])[C:38]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:39]([CH3:52])[N:40]([CH:42]([C:45]2[CH:50]=[CH:49][C:48](Br)=[CH:47][CH:46]=2)[CH2:43][CH3:44])[CH:41]=1)=[O:35]>>[CH3:32][NH:33][C:34]([C:36]1[C:37](=[O:63])[C:38]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:39]([CH3:52])[N:40]([CH:42]([C:45]2[CH:50]=[CH:49][C:48]([C:1]#[N:2])=[CH:47][CH:46]=2)[CH2:43][CH3:44])[CH:41]=1)=[O:35]
Reactant: CCC(c1ccc(Br)cc1)n1cc(C(=O)NC)c(=O)c(-c2ccnc(C(F)(F)F)c2)c1C
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCC(c1ccc(C#N)cc1)n1cc(C(=O)NC)c(=O)c(-c2ccnc(C(F)(F)F)c2)c1C

Procedure:
Example 36 is prepared as described for Example 15, substituting preparation 15b with preparation 36b. ESI mass spectrum: [M+H]+=455; Retention time HPLC: 0.85 min (Z011_S03).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=O)(C)(C)C.C(O[K])(C)(C)C.[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(N(C)C)=O>[NH2:8][C:9]1([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10]1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A suspension of 7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (10.0 g, 41.6 mmol) in dimethylacetamide (100 mL) was cooled with ice, and t-butoxy potassium (4.67 g, 1.0 eq.) and benzyl chloride (5.27 mL, 1.1 eq.) were added thereto. The reaction mixture was returned to room temperature, followed by stirring for 2 hours. Thereafter, water was added to the mixture, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield 5-benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane as a crude product. The crude product was dissolved in toluene (100 mL), and methanesulfonic acid (2.97 mL) was added to the solution, followed by stirring under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the cooled mixture for extraction, and the formed organic layer was removed. Aqueous sodium hydroxide solution (5N) was added to the remaining aqueous layer so as to alkalify the layer, followed by extraction with toluene. The solvent of the extract was evaporated under reduced pressure, to thereby yield the title product as a pale brown solid (8.63 g, yield: 90.1%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:33][CH:34]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)cc3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 63 mg (0.269 mmol) of 2-bromo-1-(4-chlorophenyl)ethanone were reacted according to the General Method 3. Yield: 15 mg (12% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:15])=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:19]([CH3:22])[CH2:20]O>CN(C)C=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:15])=[N:9][N:10]([CH:19]([CH3:22])[CH3:20])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]nc(Br)c2ccc([N+](=O)[O-])cc12
Reactant: CC(Br)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200.5 %

Procedure:
7-Nitro-4-bromo-2H-phthalazin-1-one (84 g, 0.31 mol) was dissolved in dimethylformamide (DMF) (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at room temperature for 30 minutes then 2-bromo-propanol (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours whereupon LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g 0.15 mol) and the reaction stirred for a further 24 hours. The DMF was removed under vacuum and the resulting crude material purified by successive column chromatography (elution: 92% heptane to 8% ethyl acetate) to give the title compound (38.8 g, 40% yield) as a light yellow solid.