Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O>C(O)=O>[OH:16][CH:15]1[C:14]([CH3:17])([CH3:18])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10][CH:9]1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:21]
Reactant: CC1=CC(NCc2ccccc2)C(O)C(C)(C)CC1=O
Reactant: C=O
Solvent: O=CO
Product: CC1=CC(N(C)Cc2ccccc2)C(O)C(C)(C)CC1=O
Temperature: 90 °C
Yield: 39 %

Procedure:
The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 (5.86 g, 21.5 millimoles) was dissolved in formic acid (30 ml), formalin (30 ml) was added, and the mixture was heated at 90° C. for 3 hours. The reaction solution was concentrated and alkalified with a 1% aqueous sodium hydroxide solution. The aqueous solution was subjected to extraction with benzene, washed with water, and then dried over anhydrous potassium carbonate. The benzene solution was concentrated, and the resulting residue was subjected to silica gel column chromatography with hexane-ethyl acetate (9:1) as the eluent, to obtain 2.95 g of crude product which was then recrystallized from hexane to give 2.39 g (39%) of 5-hydroxy-4-(N-methylbenzylamino)-2,6,6-trimethyl-2-cyclohepten-1-one as colorless crystals. Melting point: 78.5°~80° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH2:17][OH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[CH2:17]([O:18][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
4-chloro-3-nitropyridine (30 g, 0.19 mol) was slowly added to a suspension of phenylmethanol (30 mL, 0.29 mol), K2CO3 (26.2 g, 0.19 mol and KOH (42.5 g, 0.76 mmol) in toluene (2 L) at 0° C. A catalytic amount of tris[2-(2-methoxyethoxyl)ethyl]amine was added to the reaction mixture, which was then stirred at room temperature for 2 hours. After filtration, the resulting filtrate was concentrated to give the crude product, which was crystallized from DCM/PE (1:5) to afford 4-(benzyloxy)-3-nitropyridine (27.3 g, yield: 62.7%). 1H-NMR (CDCl3, 400 MHz) δ 9.00 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 7.34˜7.43 (m, 5H), 7.03 (d, J=6.0 Hz, 1H), 5.29 (s, 2H). MS (M+H)+: 231.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC=C(N)C=1)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)=[O:26]>[Pd].C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)=[O:26]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Agent: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc(N)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4'-aminobenzophenone was prepared analogously to 3,4-dimethoxy-3'-aminobenzophenone using 3,4-dimethoxy-4'-nitrobenzophenone (1 g, 3.5 mmol) and 0.1 g of 10% palladium on carbon catalyst in 110 mL of ethyl acetate. The crude product was purified by flash column chromatography (silica gel, 12% ethyl acetate/methylene chloride) to afford 0.32 g (36%) of the product as a yellow solid: mp 189-191° C.; 1H NMR (CDCl3) δ 7.80-7.62 (m, 2H); 7.45-7.29 (m, 2H), 6.96-6.80 (m, 1H), 6.75-6.61 (m, 2H), 4.14 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H); 13C NMR (CDCl3) δ 194.2, 152.2, 150.5, 148.8, 132.6, 131.3, 128.0, 124.3, 113.6, 112.3, 109.7, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.95; H, 6.18; N, 5.13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[C:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α,α-Diphenyl-2-biphenylmethanol was prepared by the following procedure (Reaction Scheme 1). To a solution of 2-bromobiphenyl (5.00 g, 21.45 mmol) in freshly distilled THF (50 mL) at −78° C. was added n-BuLi (1.37 g, 21.45 mmol, 8.6 mL of 2.5 M solution in hexanes) dropwise via syringe. Approximately 5 minutes after complete addition, benzophenone (4.10 g, 22.52 mmol) was added in a single portion, after which time the ice bath was removed and the solution allowed to warm to room temperature. After 2 h, the reaction was quenched with the addition of NH4Cl and H2O (100 mL), and extracted with Et2O (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to dryness. Chromatography gave the product as a white solid (6.27 g, 87% yield).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34](=[O:41])[N:35]2[CH2:40][CH2:39]S[CH2:37][CH2:36]2)[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34]([N:35]2[CH2:40][CH2:39][S:3](=[O:5])(=[O:2])[CH2:37][CH2:36]2)=[O:41])[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=S([O-])OO
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCSCC1)CC1CCCCC1
Agent: [K+]
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCS(=O)(=O)CC1)CC1CCCCC1

Procedure:
The compound was synthesized in a similar fashion to Example 6. An OXONE oxidation was employed title compound of Example 51 to furnish the sulfone. A procedure was used as described in McCarthy, J. R. et al. Org. Synth., CV9, 446. 1H NMR (CD3OD, 400 MHz) δ 0.73-0.79(m, 2H), 1.00-1.19(m, 7H), 1.10(d, J=6.8 Hz), 1.34-1.75(m, 6H), 2.34-2.37(m, 1H), 2.64-2.71(m, 2H), 2.94-3.08(m, 7H), 3.79-4.01(m, 5H), 6.53-6.56(m, 2H), 6.87-6.89(m, 2H). HPLC-MS calcd. for C25H36F3N3O5S (M+H+) 548.2. found 548.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([N:14]=[C:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.O1CCCC1.C(OCC)(=O)C>[CH2:7]([NH:14][C:15](=[O:16])[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(=O)O
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of β-alanine 5.0 g (56 mmol) in dichloromethane 56 ml and tetrahydrofuran 56 ml was added benzyl isocyanate 6.6 ml (53 mmol) at 0° C. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate 200 ml and washed with water 200 ml and brine 200 ml. The residual solution was concentrated to about 100 ml in vacuo. To the mixture was added 1N sodium hydroxide solution 60 ml at 0° C. The aqueous phase was acidified with 3N HCl aq. 20 ml and then extracted with ethyl acetate 100 ml twice. The extract was washed with brine 50 ml and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. To the residue was added ether:n-hexane=1:1 30 ml and the precipitate was corrected by filtration to obtain the title compound 7.05 g (59%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH2:29].[OH2:30].N>CN(C=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:12])(=[O:30])=[O:29])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:15])=[O:16])[CH3:2]
Reactant: CCc1nc2ccc(SC)nn2c1S(N)(=O)=O
Reactant: O
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nc2ccc(S(C)(=O)=O)nn2c1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Ethyl-6-methylthioimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.10 g, 4.04 mmol) was dissolved in DMF (10.0 ml) and stirred under ice-cooling, during which m-chloro-perbenzoic acid (abbreviated into mCPBA) (70%, 2.48 g, 10.1 mmol) was added thereto. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 3 hours, and then the reaction solution was poured into water (50.0 ml), and 25% ammonia water (1.0 ml) was added thereto. After the reaction solution was stirred for 5 minutes, the precipitated crystals were filtered and washed with water, to give the title compound as colorless crystals. The yield was 1.04 g (84.5%).
Reaction SMILES: C(N1CCC(C(Cl)=O)CC1)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:17]([CH:29]=1)[NH:18][C:19](=O)[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:30]([CH3:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:19]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]3)=[N:18][C:17]=2[CH:29]=1
Reactant: CCN1CCC(C(=O)Nc2cc(Cl)ccc2N(C)c2ccccc2)CC1
Agent: CCN1CCC(C(=O)Cl)CC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCC(C2=Nc3cc(Cl)ccc3N(C)c3ccccc32)CC1

Procedure:
The general procedures of Example 1 are repeated. From 2-amino-4-chloro-N-methyldiphenylamine and 1-ethylisonipecotoyl chloride, 5'-chloro-1-ethyl-2'-(N-methylanilino)-isonipecotanilide is prepared. This intermediate is cyclized by heating with a mixture of phosphorus oxychloride and phosphorus pentoxide and, after isolation and purification by the methods described in Examples 1 and 2, 8-chloro-11-(1-ethyl-4-piperidyl)-5-methyl-5H-dibenzo[b,e][1,4]diazepine is obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.[C:53](OC(=O)C)(=[O:55])[CH3:54].[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:53]([N:40]1[CH2:41][CH2:42][N:37]([C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])[CH2:38][CH2:39]1)(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A solution of 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (20 mg, 32 μmol) and N,N-diisopropylethylamine (27 μL, 0.16 mmol) in tetrahydrofuran (0.5 mL) was treated with acetic anhydride (15 μL, 0.16 mmol) and stirred at 20° C. for 16 h. The reaction mixture was treated with 2 M sodium hydroxide (0.16 mL, 0.32 mmol) and stirred at 20° C. for 16 h to remove the undesired acetamide. The reaction mixture was purified by preparative LCMS to give the desired product (10 mg, 47%) as a solid. LCMS for C24H26ClN6O (M+H)+: m/z=449.0.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 3-benzyl-5-bromo-1,2-dimethyl-1H-indole (1.453 g, 4.624 mmol) was reacted with aqueous 2M K2CO3 (4.6 ml), 4-methoxyphenylboronic acid (0.843 g, 5.549 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.076 g, 0.092 mmol) in dioxane (46 ml) to give the product (0.419 g, 1.227 mmol, 27%) as a solid, mp 139-141° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.67 (s, 3H), 3.76 (s, 3H), 4.06 (s, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.08-7.12 (m, 1H), 7.19-7.24 (m, 4H), 7.29 (dd, J=1.8, 8.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.9 Hz, 2H), 7.55 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Cc1ccc2c(c1)C(C)NCC2
Product: Cc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Yield: 58 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[S:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[S:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=3[CH3:32])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2cc(B3OC(C)(C)C(C)(C)O3)sc12
Reactant: Cc1cc(O)ccc1Br
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3C)sc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophene-7-carboxylic acid ethyl ester (1.04 mmoles; 345.00 mg) in anhydrous DMF (2.5 mL) is added, under nitrogen atmosphere, via syringe pump (3 mL/2 h) to a suspension at 80° C. of 4-bromo-3-methylphenol (1.04 mmoles; 194.23 mg), Cesium carbonate (2.08 mmoles; 683.53 mg), Pd(OAc)2 (103.84 μmoles; 23.55 mg), 1,1′-bis(diphenylphosphino)ferrocene (311 μmoles; 176 mg) in anhydrous DMF (1.6 mL). The mixture is stirred at 80° C. for 1 h and allowed to reach room temperature. The reaction is poured into a mixture of ethyl acetate and HCl (1M), filtered through Celite® and washed with ethyl acetate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 mL). The organic layers are combined, washed with water, dried (Na2SO4), filtered and concentrated. The residue is chromatographed (10-40% EtOAc in hexanes) to obtain the title compound (143 mg, 44%) as a white solid. LC-ES/MS m/e 311 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:35][CH2:36][CH:37]([O:40][C:41]5[N:42]=[CH:43][CH:44]=[CH:45][N:46]=5)[CH2:38][CH2:39]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: c1cnc(OC2CCNCC2)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(Oc5ncccn5)CC4)c3)n2)n1
Yield: 54.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(piperidin-4-yloxy)-pyrimidine [CAS-no. 499240-48-1](0.367 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.140 g, 54%) as a white foam. MS (ISP) 632.3 [(M+H)+]; mp 134° C. (dec.).
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[N:25][C:24]([C:27](OCC)=[O:28])=[CH:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[NH3:39]>>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[N:25][C:24]([C:27]([NH2:39])=[O:28])=[CH:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2cn1
Reactant: N
Product: NC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-a]pyrazine-6-carboxylate [Int-5] (70 mg, 0.14 mmol, 1.0 eq) in 2.0 mL ammonia (7M solution in methanol, ˜100 eq) was heated to 130° C. for 5 h in a single mode microwave oven. The volatile components were removed by the use of a rotary evaporator. The crude amide detected by UPLC was directly forwarded to the deprotection step. Therefore, the raw material was dissolved in 1.3 mL DCM/methanol (5/3) and 0.61 mL of 4 M hydrogenchloride in dioxane were added. The solution was stirred overnight at room temperature. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine and dried with sodium sulphate. The solvent was using a rotary evaporator and the crude material was purified via MPLC (Biotage Isolera, 25 g Snap-cartridge; eluent: hexane/ethyl acetate (1/1)→ethyl acetate) to deliver 20 mg (40%) of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])[C:10]2=[N:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:30]1([NH:35][C:36]2[N:38]=[C:5]([C:7]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:15]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])[C:10]4=[N:9][C:8]=3[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:4]=[CH:3][N:37]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN(C)C=Nc1cccn2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=Nc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a solution of N′-[3-[(2E)-3-(dimethylamino)-2-propenoyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide (130 mg, 0.34 mmol) in N,N-dimethylformamide was added N-cyclopentylguanidine hydrochloride (168 mg, 1.02 mmol), followed by anhydrous potassium carbonate (140 mg, 1.02 mmol). The resulting solution was heated at 100° C. for 16 hours. Upon cooling to room temperature, ethyl acetate and water were added. The phases were separated and the organics were washed with brine. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to give N′-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide (80 mg, 53%) as a solid. 1H NMR (CDCl3): δ 9.09 (broad s, 1H), 8.60 (s, 1H), 8.04 (d, 1H), 7.63 (q, 2H), 7.04 (t, 2H), 6.78 (m, 2H), 6.36 (d, 1H), 5.14 (d, 1H), 4.31 (m, 1H), 3.10 (s, 3H), 3.05 (s, 3H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); MS m/z 444 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:34]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=2[S:32][CH:31]=1>CN(C)C=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[S:32][CH:31]=[C:30]([CH2:29][N:17]3[C:9]4=[N:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][C:11](=[O:13])[N:10]4[CH2:14][CH2:15][C@H:16]3[C:18]([F:20])([F:21])[F:19])[C:34]=2[CH:35]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1csc2ccc(Cl)cc12

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 95 mg of 3-(bromomethyl)-5-chloro-1-benzothiophene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 72 mg of (8S)-9-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[OH:28][C:29]1[CH:46]=[CH:45][C:44]2[C@:43]3([CH:47]=O)[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[CH2:38][C@H:37]([OH:49])[CH2:36]4)[CH2:33][CH2:32][C:31]=2[CH:30]=1.CS(C)=O.O>C(OCC)(=O)C>[CH:47]([C@:43]12[CH2:42][CH2:41][C@@:39]3([CH3:40])[C@@H:35]([CH2:36][C@@H:37]([OH:49])[CH2:38]3)[C@@H:34]1[CH2:33][CH2:32][C:31]1[CH:30]=[C:29]([OH:28])[CH:46]=[CH:45][C:44]2=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCC=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12

Procedure:
8.68 g (20 mmol) of pentyltriphenyl-phosphonium bromide+sodium amide (1 g contains 2.3 mmol of pentyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 ml DMSO are introduced into a reaction flask that was rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at 60° C. After the reaction is completed, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing of the organic phase with water and concentration by evaporation until a dry state is reached.