Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:13]=[CH:12][C:5]2[CH2:6][C:7]([NH:9][C:10](=[O:11])[C:4]=2[CH2:3]1)=[O:8].[H-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O1CCCC1.CCCCCC>[Cl:17][C:18]([Cl:22])([Cl:21])[S:19][N:9]1[C:10](=[O:11])[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH:13]=[CH:12][C:5]=2[CH2:6][C:7]1=[O:8]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CC1(C)C=CC2=C(C1)C(=O)NC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)C=CC2=C(C1)C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To 4,4-dimethyl homophthalimide (5.6 g) in 200 ml dry tetrahydrofuran was added 1.73 g sodium hydride. The mixture was stirred for one hour, then 5.75 g (3.38 ml) trichloromethyl sulfenyl chloride was added dropwise. The mixture was refluxed overnight, stripped of solvent, slurried in hexane and decanted. The brown crystalline residue was purified by tlc and recrystallized in ethanol to yield 3.2 g of the brown crystalline product, m.p. 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].[Br:34]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])=[N:18][N:19]=[C:20]1[Br:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 2',5-dichloro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-bromosuccinimide to form the 2',5-dichloro-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:6]([CH:10]=1)[C:7]([N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])=[O:9]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)ccc1Oc1cccc(F)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To mixture of 5-bromo-2-(6-fluoropyridin-2-yloxy)benzoic acid (16 g, 51.3 mmol) and TBTU (16.46 g, 51.3 mmol) in 15 mL of DMF was added diethylamine (13.26 mL, 128 mmol). The resulting solution was allowed to stir at rt overnight. The reaction was quenched with saturated NaHCO3, extracted with a 2:1 mixture of EtOAc and hexanes (3×50 mL). The combined organics were washed with brine, and evaporated to dryness. Purification by silica gel chromatography (hexane to CH2Cl2 to CH2Cl2/EA=20:1 to 10:1 to 5:1) provided 5-bromo-N,N-diethyl-2-(6-fluoropyridin-2-yloxy)benzamide as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(F)cccc1Cl
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (293 mg, 2.0 mmol), 2-chloro-6-fluoro-benzoyl chloride (400 mg, 2.07 mmol) and triethylamine (300 μL, 218 mg, 2.15 mmol) in dioxane (6 mL) was heated at 50° C. for 4 hours. After cooling to ambient temperature, triethylamine (60 μL) and 2-chloro-6-fluorobenzoyl chloride (40 μL) were added. The resultant mixture was heated under reflux for a further 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM and the resultant solid was triturated in diethyl ether, filtered, and dried to give the desired compound as a white solid (380 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.46 (br s, 1H), 8.27-8.23 (m, 2H), 7.59 (td, J=8.3, 6.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.42-7.37 (m, 1H). LCMS (Method C): RT=3.34 min, m/z: 303 [M+H+].
Reaction SMILES: C[NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1C)(=[O:5])=[O:4].C([Li])CCC.C[Sn](Cl)(C)C.Cl>O1CCCC1>[C:6]1([S:3]([NH2:2])(=[O:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNS(=O)(=O)c1ccccc1C
Agent: C[Sn](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 108.1 %

Procedure:
A solution of N,2-dimethylbenzenesulfonamide (3.70 g, 20.0 mmol) in dry tetrahydrofuran (75 ml) was cooled to -78° with stirring under nitrogen. n-Butyllithium in hexanes (1.6 M, 28 ml, 44 mmol) was added dropwise over 1/2 hour. After 2 hours at -78°, a solution of trimethyltin chloride (4.42 g, 22.0 mmol) in dry tetrahydrofuran (20 ml) was added dropwise. The reaction mixture was allowed to warm to 0° over 1 hour, and then 5% HCl (50 ml) was added dropwise at a rate to maintain an internal temperature less than 10°. After concentrating the reaction mixture in vacuo, the product was extracted into methylene chloride (3×100 ml), washed with water (2×200 ml), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (SiO2, hexane/ethyl acetate, 8:2) gave N-methyl-2-[(trimethylstannyl)methyl)]benzenesulfonamide (3.4 g, 49%) as a white powder, m.p. 59° -60°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CC1(C)C(C)(C)OB([C:41]2[CH:49]=[CH:48][CH:47]=[C:46]3[C:42]=2[CH:43]=[N:44][NH:45]3)O1>C(Cl)Cl>[NH:45]1[C:46]2[C:42](=[C:41]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][S:29]([CH3:28])(=[O:31])=[O:30])([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:49]=[CH:48][CH:47]=2)[CH:43]=[N:44]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NS(C)(=O)=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (400 mg, 1.3 mmol) in CH2Cl2 (20 mL) was added Et3N (630 μL, 4.5 mmol) and methanesulfonyl chloride (200 μL, 2.6 mmol). The resulting mixture stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexane). A portion (0.1 mmol) of the resulting pure product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 398 after reverse phase HPLC purification (8 mg). MS (Q1) 473 (M)+
Reaction SMILES: [C:1]1([CH3:43])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=3)=[O:29])[C:11]2=[O:42])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:43])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[CH2:13][CH:12]([NH:27][C:28](=[O:29])[NH:30][C:31]3[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:37]([OH:39])=[O:38])[C:11]2=[O:42])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(CC=C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)=CCN1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 77.9 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (310 mg) was dissolved in methanol (16 ml), aqueous lithium hydroxide monohydrate (112 mg) solution (8 ml) and tetrahydrofuran (8 ml) were added, and the mixture was refluxed for 50 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and a mixed solvent of diisopropyl ether and n-hexane were added to the residue for trituration, collected by filtration, to thereby obtain 230 mg of the titled compound (Yield: 78.3%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (300 mg, 1.21 mmol) was added iodomethane (0.75 mL, 10 eq), K2CO3 (332 mg, 2.4 mmol) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 312 mg (98% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as an amber colored oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4].O=S(Cl)Cl.C(N)C1C=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2C=1.C[N:35](C=O)C>C(Cl)Cl>[O:29]1[C:30]([CH2:31][NH:35][CH2:10][C:9]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]([I:18])[NH:7][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:26][O:27][CH2:28]1
Reactant: CCCCN1C(CO)=C(c2ccccc2)NC1I
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCN1C(CNCC2=COCO2)=C(c2ccccc2)NC1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol (1.96 g) is dissolved in 20 mL of CH2Cl2. 5 equivalents of SOCl2 are added at 0° C. The solution is stirred at room temperature for 2 hours and then evaporated to dryness. The residue is dissolved in 20 mL of toluene and again evaporated to dryness in order to remove the remaining SOCl2. The crude product is dissolved in 5 mL DMF and added to an ice-cold solution of piperonyl amine (2 equivalents) in 10 mL DMF containing 2.0 equivalents K2CO3. The reaction mixture is stirred overnight at room temperature. The reaction is quenched with 20 mL water, extracted with ethyl acetate (3×30 mL), washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel chromatography gives [1,3]dioxol-5-ylmethyl-(1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-amine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:23])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-methyl-3-trifluoromethyl-benzoic acid (CAS RN 261952-01-6) after a reaction time of 90 hours. Grey solid (32%). MS (ESI): m/z=385.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Cl[S:27]([OH:30])(=O)=[O:28].[NH3:31].O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([S:27](=[O:30])(=[O:28])[NH2:31])=[CH:24][CH:25]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n1CCC2
Reactant: N
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(S(N)(=O)=O)cc2)c2n1CCC2
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
Methyl 2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate (0.87 g, 2.5 mmol) is dissolved in dichloroethane (10 ml) and the solution is cooled to 0-5° C. in an ice bath. A solution of chlorosulphonic acid (0.5 g, 5.7 mmol) in dichloroethane (5 ml) is slowly added dropwise (IT<10° C.), and the mixture is then stirred at RT for 12 h. A solution of NH3 in dichloroethane saturated in the cold is added, and the mixture is stirred at RT for a further 12 h. The mixture is then treated with water (20 ml), and the organic phase is separated in a separating funnel. Solid which is insoluble in water is filtered off from the aqueous phase with suction and dried in vacuo. The dried solid substance is crystallized from MeOH: 0.5 g (47%); a 2nd crystal fraction crystallized from the mother liquor in the cold: 23% (0.25 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-chlorobenzoyl chloride, there is obtained ethyl N-(p-chlorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 106°-107° C.;
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4cccnn4)cc3)c12
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cccnn3)cc2)c2c(N)nccn12
Yield: 31.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide (intermediate 33) and 2-butynoic acid, to afford the title compound (11 mg, 31.8%). Data: UPLC(C) Rt: 1.92 min; m/z 481.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: COC(=O)c1cccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1c(OC)cccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-3-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-3-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.18 (s, —CO2H); 7.10 (m, 3 arom. H); 5.97 (m, —CH═CH2); 5.28, 5.14 (2 d-like, CH═CH2); 4.43 (d-like, CH2—CH═CH2); 3.77 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.42 (C═O); 153.06; 146.24; 134.49; 127.66; 123.94; 121.07; 117.10; 115.57; 73.88; 55.93.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54]1[NH:58][N:57]=[C:56]([C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])[CH:55]=1>CN(C=O)C.O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:63](=[O:64])[CH2:62][NH:61][C:59]([C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[OH:47])[NH:58][N:57]=2)=[O:60])[CH2:24][CH2:25]1)=[O:19]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2O)[nH]n1
Reactant: O=C(c1cc(F)ccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1cc(-c2ccccc2O)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 68.5 %

Procedure:
DIPEA (100 mg, 0.13 mL, 0.7 mmol) was added to a stirred solution of (2-Bromo-5-fluoro-phenyl)-piperazin-1-yl-methanone; hydrochloride salt (prepared by the method as described above)(68 mg, 0.21 mmol) in DMF (4 mL). HOBT (31 mg, 0.23 mmol) and EDCI (91 mg, 0.47 mmol) were then added at room temperature. After 2 minutes, {[5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (50 mg, 0.19 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 68.5 mg (68.5% yield) 5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.24%. 1H NMR (DMSO-d6): δ 13.4-13.2 (bs, 1H), 10.4-10.2 (bs, 1H), 8.2-8.0 (bs, 1H), 7.8-7.64 (m, 2H), 7.46-7.34 (bs, 1H), 7.34-7.2 (t, 2H), 7.02-6.84 (m, 4H), 4.26-4.1 (bd, 2H), 3.76-3.46 (bt, 6H), 3.24-3.1 (bd, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([F:25])=[C:15]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[F:25][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[N:3][C:4]3=[N:10][CH:9]=2)=[CH:16][C:15]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(Cl)ccn23)ccc1F
Reactant: OB(O)c1ccsc1
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(-c4ccsc4)ccn23)ccc1F
Yield: 77.6 %

Procedure:
5′-(7-Chloroimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (50 mg, 0.143 mmol) and 3-thiopheneboronic acid (346 mg, 0.287 mmol) were reacted using the procedure in Example 23 to give 2′-fluoro-5′-[7-(thien-3-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile (44 mg, 77%) as a yellow powder: δH (400 MHz, CDCl3) 7.31 (1H, d, J 7), 7.39-7.45 (2H, m), 7.55 (1H, dt, J 9 and 1), 7.61-7.67 (3, m), 7.71 (1H, dt, J 8 and 1), 7.84-7.90 (3H, m), 8.11 (1H, s), 8.82 (1H, d, J 7); m/z (ES+) 397 (M++H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[CH:20]=[CH:19][CH:18]=[C:17]([F:22])[C:16]=5[C:15]5=[N:23][CH2:24][CH2:25][N:14]5[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[O-2].[Ni+3].[Ni+3].C1C=CC=CC=1>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[CH:20]=[CH:19][CH:18]=[C:17]([F:22])[C:16]=5[C:15]5=[N:23][CH:24]=[CH:25][N:14]5[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc2c1C1=NCCN1c1c(-c3nc(C4CC4)no3)ncn1-2
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: Fc1cccc2c1c1nccn1c1c(-c3nc(C4CC4)no3)ncn21

Procedure:
A mixture of 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-12-fluoro-2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline (2.0 g, 5.9 mmol), nickel peroxide (10 g), and benzene (125 ml) was heated at reflux for 3.5 hours, cooled slightly, and filtered. The filtrate was evaporated to give the title compound as light yellow crystals, m.p. 266°-268° C. (Compound 38).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]([NH2:8])=[S:7].[CH:9]([C:21](OCC)=[O:22])([C:16](OCC)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[OH:22][C:21]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([OH:17])[N:8]=[C:6]([SH:7])[N:5]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(O)nc(S)nc1O
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of sodium ethoxide [prepared from sodium metal (1.6 g) and ethanol] was added thiourea (5.28 g) and triethyl 1,1,2-ethane tricarboxylate (17 g). The mixture was heated under reflux for 8 hours. The solution was cooled to room temperature and the solid collected by filtration, washed with a little ether. The solid was dissolved in water (100 ml) and the pH adjusted to 6-7 by the addition of hydrochloric acid. No solid was precipitated therefore the solution was lyophilised to give a pink solid (8.1 g)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([C:10]3([F:13])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]([C:10]2([F:13])[CH2:12][CH2:11]2)([OH:8])[CH2:9][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: FC1(C2(Cc3ccc(Cl)cc3)CO2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)C1(F)CC1
Yield: 47.4 %

Procedure:
A solution of 3.3 g (15.7 mmol) of 2-(4-chlorobenzyl)-2-(1-fluorocyclopropyl)-oxirane in 10 ml of dimethylformamide is added dropwise to a mixture of 3.3 g (47.1 mmol) of 1,2,4-triazole end 0.35 g (3.14 mmol) of potassium tert.-butylate in 20 ml of dimethylformamide at a temperature of 80° C., while stirring. When the addition has ended, the reaction mixture is stirred for 13 hours at 80° C. The solvent is then stripped off under reduced pressure, and the remaining residue is taken up with water. The aqueous phase is extracted four times with methylene chloride. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The remaining residue is chromatographed over silica over silica gel using cyclohxane:ethylacetate=2:1 as the mobile phase. Evaporation of the eluate gives 2.2 g (47% of theory) of 1-(4-chlorophenyl)-2-(1-fluorocyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol in form of a solid substance.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1)=O)C.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:9]2[CH:10]=[C:11]([C:14](=[O:17])[NH:15][CH3:16])[C:12](=[O:13])[N:7]([CH2:6][C:4](=[O:3])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:8]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)NC)c1=O
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1C
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)NCc2ccccn2)c1=O
Yield: 44.5 %

Procedure:
In xylene, 2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one and 2-(aminomethyl)pyridine were refluxed at 150° C. for 7 hours. Post-treatments were conducted as in Example 47-(2), whereby the title compound was obtained in a yield of 44.5%.