Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8]([C:15]([N:30]([CH3:32])[CH3:31])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21](OC)=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CC(N(C)C)=O>[CH2:8]([C:15]([N:30]([CH3:31])[CH3:32])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:6][CH2:5][CH2:4][CH2:3][OH:7])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(OC)c(OC)c1)N(C)C
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCO)c(OC)c1)N(C)C
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.40 mol of sodium hydride are suspended in 500 ml of dry dimethylacetamide and 72.3 ml (1.0 mol) of 1,3-propanediol are added dropwise at 0° C. Then 68.3 g (0.20 mol) of 2-benzyl-1-(3,4-dimethoxy-phenyl)-2-dimethylamino-butan-1-one in dimethylacetamide are added dropwise at 0° C. After the solution is stirred at 120° C. for 18 h, the solution is poured into water. The crude product is extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (40:60) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.69 (t, 3H), 1.83-1.92 (m, 1H), 2.04-2.16 (m, 3H), 2.38 (s, 6H), 2.40-2.55 (bs, 1H), 3.18-3.23 (m, 2H), 3.88 (s, 3H), 3.89 (t, 2H), 4.27 (t, 2H), 6.84 (d, 1H), 7.15-7.28 (m, 5H), 7.93 (d, 1H), 8.20 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][C:3]=1[CH3:24].C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:30]=[O:31])=[CH:4][C:3]=1[CH3:24]
Reactant: CCOC=O
Reactant: Cc1cc(C(=Cc2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=C(C=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyltetrazol-5-yl)ethene (3.58 g, 11.0 mmoles)) in dry tetrahydrofuran (20 mL) at -78° C. was treated with n-butyllithium (5.3 ml of 2.5M solution in hexane; 13.25 mmoles) and the mixture stirred at -78° C. for 0.5 hours. Ethyl formate (1.33 ml; 1.22 g, 16.5 mmoles) was added and the mixture was allowed to warm up to 23° C. over 1 hour, then quenched with 2N HCl (250 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 20% EtOAc-Hexane as eluent to afford 2.2 g (57%) of the title compound as a foam. MS (CI): m/e=355 for (M+H)+ ;
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH3:14])[N:7]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][C:48]=1[F:49])[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:48]([F:49])=[C:27]([NH:26][C:11]([C:9]5[N:8]([CH3:14])[N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=5)=[O:13])[CH:28]=4)=[N:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COCCOc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 50.2 %

Procedure:
Using 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (128 mg, yield 50%) was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Cl.Cl.[NH2:34][CH2:35][C@@H:36]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:37]([O:39][CH3:40])=[O:38]>ClCCl.CN(C)C=O>[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:34][CH2:35][C@@H:36]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:37]([O:39][CH3:40])=[O:38])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COC(=O)[C@@H](CN)N1CCCCC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
7.2 ml (51.5 mmol) of triethylamine and then 5.9 g (15.5 mmol) of 4-(2-methylquinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride are added to a solution of 3.34 g (12.9 mmol) of methyl (R)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride in 30 ml of dichloromethane and 30 ml of dimethylformamide cooled beforehand using an ice bath. The reaction medium is stirred at ambient temperature for 3 h 30, hydrolyzed, and then diluted with dichloromethane. The product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 4 g (62%) of methyl (R)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: ClCCCC(Cl)=[O:6].[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1(O)[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][C:19]2[CH:25]=[CH:26][C:27]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:28][C:18]1=2)=[O:15]>C(Cl)Cl>[CH3:24][C:21]1([CH3:23])[O:20][C:19]2[CH:25]=[CH:26][C:27]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:28][C:18]=2[C@@H:17]([N:16]2[CH2:11][CH2:12][CH2:13][C:14]2=[O:15])[C@@H:22]1[OH:6]
Reactant: CC1(C)CC(O)(NC(=O)CCCCl)c2cc(S(=O)(=O)c3ccccc3)ccc2O1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
A solution of 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol in ethanol is shaken under a pressure of 8 bar of NH3 at 50° in an autoclave for 8 hours. The mixture is cooled and then evaporated to dryness and recrystallized from ethyl acetate. 4-Amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol of melting point: 160°-163°C. is obtained and is immediately subjected to acylation with 4-chlorobutyryl chloride. For this purpose, the substance is dissolved together with the acid chloride in CH2Cl2 and stirred in a two-phase mixture with 2N sodium hydroxide solution at room temperature for 24 hours. The usual working up results in 4-(4-chlorobutyrylamino)-3,4-di-hydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol of melting point 155°-157° C. Cyclization to give the title compound is carried out by dissolving the substance in tetrahydrofuran, addition of a stoichiometric amount of 80% NaH suspension in oil and stirring the mixture at room temperature for 24 hours. The final product is identical to the product obtained by process b). Melting point: 200°-201° C. If 4-amino-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]pyran-3-ol is subjected to racemate resolution, it is possible to obtain from its (+) enantiomer the pure (+) enantiomer from Example 5a with the data indicated there.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH2:38][S:39][CH3:40])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[NH2:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH2:53][CH2:52]1.[OH-].[Na+]>CN(C=O)C>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH2:38][S:39][CH3:40])[C:34]([NH:50][CH:51]1[CH2:52][CH2:53][N:54]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH2:55][CH2:56]1)=[O:36])=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of HBTU (8.1 g, 21 mmol), (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanoic acid (5.3 g, 21 mmol) and DIEA (8.2 mL, 47 mmol) in DMF (50 mL) was stirred at ambient temperature for 30 minutes. Benzyl 4-aminopiperidine-1-carboxylate (5.0 g, 21 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The mixture was poured into 1N NaOH (500 mL) and the combined organic layers were extracted into EtOAc (500 mL). The combined organic layers were washed with 1N HCl (500 mL) and brine (500 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-benzyl 4-(2-(tert-butoxycarbonylamino)-4-(methylthio)butanamido)piperidine-1-carboxylate (10 g, 21 mmol, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[CH3:31])O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O.C(O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[CH3:31])[CH:3]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Yield: 63 %

Procedure:
To a flask containing 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (68 mg, 0.2 mmol, as prepared in Example 4, step (a)), 4,4,5,5-tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane (61 mg, 0.27 mmol, as prepared in the previous step) and Pd(PPh3)4 (14 mg, 6 mol %) was charged toluene (3 mL), ethanol (3 mL) and 2M Na2CO3 (4 mL). The resultant mixture was heated at 80° C. for 2 h and then poured into EtOAc (25 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel preparative thin layer chromatography (EtOAc) afforded 40 mg (63%) of the title compound as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H19N3O2S, 318.1 (M+H). found 318.2.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C=Nc1ccccc1Br
Product: Cc1ccc(NC(=O)Nc2ccccc2Br)c(O)c1

Procedure:
The urea was prepared from 2-hydroxy 4-methyl aniline(0.274 g, 2 mmol) and 2-bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39%). EI-MS m/z 319(M-H)-
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(#N)C>[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CBr)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-([4-bromoacetylphenyl]methyl)-4-methylphenylsulphonamide (470 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction to a small volume crystallisation occurred. These crystals, on filtration and washing with dichloromethane gave the title compound, 130 mg, as a solid: m.p. 215°-219° C. dec; NMR (d6DMSO) δ 8.14(3H,m), 7.91(2H,d), 7.69(2H,d), 7.38(4H,d), 6.82(2H,d), 4.03(2H,d), 3.89(2H,s), 3.32(4H,t), 2.62(4H,t), 2.39(3H,s); m/e 465(M+H)+ ; calculated for C25H28N4O3S: C, 64.6; N, 6.1; N, 12.1. found C, 64.7; H, 6.2; N, 12.0%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](B(O)O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:25])[NH:15][C@@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][OH:18])=[CH:10][CH:9]=1.Br[C:30]1[CH:31]=[CH:32][C:33](=[O:36])[NH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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].C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][C@@H:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][OH:18])=[O:25])=[CH:10][CH:9]=2)=[N:6][C:5]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][CH:35]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(B(O)O)nc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)cc1
Reactant: O=c1ccc(Br)c[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1ncc(-c2ccc(=O)[nH]c2)nc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)cc1
Temperature: 120 °C
Yield: 6.9 %

Procedure:
To a solution of (S)-5-amino-6-(4-(2-hydroxy-1-phenylethylcarbamoyl)phenyl)pyrazin-2-ylboronic acid (55 mg, 0.145 mmol), 5-bromopyridin-2(1H)-one (38.0 mg, 0.218 mmol), and PdCl2(dppf)-CH2Cl2 (11.88 mg, 0.015 mmol) in DME (1091 μL) was added 2M Na2CO3 (364 μL). The reaction mixture was heated at microwave synthesizer (120° C., 10 min). The reaction mixture was worked up with EtOAc. The organic layer was washed with sat NaHCO3, water and brine, dried over Na2SO4, filtered off, concentrated in vacuo. The crude product was purified by prep HPLC yielding 4.3 mg of (S)-4-(3-amino-6-(6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)-N-(2-hydroxy-1-phenylethyl)benzamide as a TFA salt. LCMS (m/z): 428.2 (MH+), 0.55 min; 1H NMR (400 MHz, DMSO-d6) 3.60-3.75 (m, 2H) 5.03-5.12 (m, 1H) 6.40 (d, J=9.39 Hz, 1H) 7.22 (d, J=7.43 Hz, 1H) 7.30 (t, J=7.63 Hz, 2H) 7.34-7.40 (m, 2H) 7.83 (d, J=8.22 Hz, 2H) 7.94 (br. s., 1H) 8.01 (d, J=8.61 Hz, 2H) 8.06 (dd, J=9.39, 2.74 Hz, 1H) 8.41 (s, 1H) 8.74 (d, J=8.22 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:21][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[C:19]#[N:20])[CH2:11][CH:6]2[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC.Cl>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][CH:3]2[CH2:21][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[C:19]#[N:20])[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:44][CH:43]=1
Reactant: N#Cc1cc(F)ccc1N1CCN2CC(CO)CCC2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1N1CCN2CC(COc3ccc(F)cc3)CCC2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A solution of 0.51 g (1.8 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.555 g (2.12 mmol) of triphenylphosphine, and 0.296 g (2.64 mmol) of 4-fluorophenol in 8 mL of dry THF was treated with 0.368 g (2.12 mmol) of diethyl azodicarboxylate and stirred at ambient temperature for 24 h. The mixture was diluted with ether, and 1M HCl was added until a gummy residue formed. The layers were separated and the aqueous layer was washed with ether (3×). The aqueous layer was combined with the gummy residue and dissolved in a mixture of ethyl acetate and 10% ammonium hydroxide, the layers were separated and the aqueous layer was extracted with more ethyl acetate (2×). The organic layers were evaporated, the residue dissolved in chloroform, washed with 1M NaOH (3×), dried (magnesium sulfate), filtered and evaporated. The product was dissolved in absolute ethanol, filtered and evaporated to give 0.21 g of the title compound. mp (.HCl) 235–240° C. HRMS calcd for C22H23F2N3O: 383.1809, found: 383.1796.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:28]1C=NC=CC=1C>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:28])=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: Cc1ccncc1Br
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) and 3-Bromo-4-methylpyridine in accordance with the general method of example 20 to yield the final compound as a orange solid, MS (ISP): m/e=394.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:9][C:10]=1[CH3:11])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH2:32][CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CS(C)=O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)=[N:7][C:6]=1[O:22][CH2:32][CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A solution of 0.62 g (2.0 mmol) of 4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methyl ester in 10 ml of DMSO was treated at RT with 1.947 g (6.0 mmol) of cesium carbonate and 0.066 g (0.4 mmol) of potassium iodide. 0.38 ml=0.514 g (2.4 mmol) of (2-bromo-ethoxymethyl)-benzene was added drop by drop and the reaction mixture was stirred for 16 hours at RT. It was then poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1:0 to 1:1) to give 0.73 g (82%) of the title compound as light yellow oil. MS: 446.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18]([OH:21])([CH3:20])[CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)(C)C>[OH:21][C:18]([C:5]1[N:4]=[C:3]([C:22]([NH2:24])=[O:23])[C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]3)=[CH:38][CH:37]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c(C(C)(C)O)nc3C(N)=O)cc2)CC1
Temperature: 80 °C
Reaction time: 120 h
Yield: 21.1 %

Procedure:
A mixture of 3-chloro-6-(2-hydroxypropan-2-yl)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (1 g), 4-(4-methylpiperazin-1-yl)aniline (542 mg), tris(dibenzylideneacetone)dipalladium (0) (130 mg), dicyclohexyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (135 mg), potassium carbonate (1.29 g), and tert-butanol (5 mL) was stirred at 80° C. for 5 days. The reaction mixture was left to be cooled and then diluted with chloroform, and the insoluble matter was separated by filtration. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=100:0:0-300:10:1) to obtain 6-(2-hydroxypropan-2-yl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (303 mg) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[CH:4]1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[O:35][CH2:36][CH3:37].O>C(Cl)Cl.CCOCC>[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][CH3:37])=[O:38])[CH2:22][C:21]2=[O:26])=[CH:4]1
Reactant: CCOC(=O)Cl
Reactant: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2cn(C)c3nc(OCc4ccccn4)ccc23)C(=O)C1
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
To a solution of 1-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one, hydrochloride (0.10 g, 0.267 mmol) and triethylamine (160 μL, 1.148 mmol) in DCM (1.5 mL) is added dropwise ethyl carbonochloridate (35 μL, 0.366 mmol) at room temperature and the reaction mixture is stirred for 1.5 h. The reaction is poured into water and extracted with DCM. After separation, the organic layer is dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on silica gel (10 g Isolute cartridge), eluting with EtOAc, to afford a very dense pale yellow oil, which solidified upon addition of Et2O. The material is triturated in Et2O, filtered off and washed twice with Et2O, to afford the title compound (0.066 g, 0.161 mmol) as a colorless solid. MS (m/z) 410 (M+1).