Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:28][CH3:29])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([O:28][CH3:29])=[C:5]([CH:10]2[O:27][CH2:25][C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: COc1c(C2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 100 °C

Procedure:
tert-Butyl (3S)-4-[2-(3-cyano-4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (2 g, 4.88 mmol) and cyanomethylenetri-n-butylphosphorane (2.122 g, 8.79 mmol) were dissolved in 15 mL benzene. The reaction mixture was degassed and heated to 100° C. for 16 hrs. LC-MS showed product peak at 2.07 (M+1=380). The reaction was cooled and evaporated to dryness. The residue was chromatographed through a 80 g Redi-sep column and eluted with 40% EtOAc/60% hexane mixture to yield cis-trans mixture of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:31]=O)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1.CC(O)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C([BH3-])#N>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:31][NH:40][CH:37]3[CH2:39][CH2:38]3)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1
Reactant: NC1CC1
Reactant: COc1ccc(-c2nc(C=O)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(-c2nc(CNC3CC3)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
3-(4-Methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine-1-carbaldehyde (0.075 g, 0.17 mmol), AcOH (0.048 mL, 0.84 mmol), and cyclopropanamine (0.026 mL, 0.37 mmol) were added in DCE (1.68 mL). The mixture was stirred at rt for 30 min. MP-Cyanoborohydride (0.23 g, 0.50 mmol, 2.15 mmol/g, Biotage™) was added in one portion. The mixture was stirred at 25° C. for 72 h. The mixture was purified directly by flash chromatography (40 g silica gel column, MeOH/DCM 0% to 10%) to give N-((3-(4-methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methyl)cyclopropanamine (0.050 g, 61%): LC/MS (Table 2, Method c) Rt=1.49 min; MS m/z: 488 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[NH:13][C:12](=[O:14])[CH2:11][N:10]3[N:15]=[CH:16][CH:17]=[C:9]23)[CH:5]=[CH:6][CH:7]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:3]=2)[NH:13][C:12](=[O:14])[CH2:11][N:10]2[N:15]=[CH:16][CH:17]=[C:9]12
Reactant: CC1(c2cccc(Cl)c2)NC(=O)Cn2nccc21
Reactant: OB(O)c1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(c2cccc(-c3cncnc3)c2)NC(=O)Cn2nccc21
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Palladium(II) acetate (0.017 g, 0.075 mmol) was added to a stirred suspension of rac-4-(3-chloro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.13 g, 0.50 mmol), pyrimidine-5-boronic acid (0.19 g, 1.49 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.061 g, 0.149 mmol) and potassium phosphate (0.21 g, 0.99 mmol) in toluene (5 mL) and EtOH (0.5 mL) at room temperature and under nitrogen. The mixture was stirred at 150° C. for 30 minutes under microwave irradiation. Then the mixture was filtered through diatomaceous earth and washed with AcOEt. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel; AcOEt). The desired fractions were collected and concentrated in vacuo to yield rac-4-methyl-4-(3-pyrimidin-5-yl-phenyl)-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.09 g, 59% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]([OH:20])[C:3]1=[O:21].N1C=CC=CC=1.[CH2:28]([CH:31]([CH2:35][CH2:36][CH3:37])[C:32](Cl)=[O:33])[CH2:29][CH3:30]>CN(C)C=O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]([O:20][C:32](=[O:33])[CH:31]([CH2:35][CH2:36][CH3:37])[CH2:28][CH2:29][CH3:30])[C:3]1=[O:21]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Reaction time: 4 h

Procedure:
A solution of 15 g of 1-methyl-7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Temazepam) and 5 g of absolute pyridine is cooled in 40 ml of freshly distilled dimethyl formamide to -5° and is mixed drop by drop with 10.5 g of dipropyl acetic acid chloride with the exclusion of atmospheric moisture. The mixture is stirred for an additional 4 hours at -5° and is allowed to stand over night at 0°, and then the mixture is poured on ice. The separated oil crystallizes while rubbed on with ethanol. By recrystallization from petroleum ether or isopropanol using activated charcoal, one will obtain the 1-methyl-7-chloro-3-dipropylacetoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one as a colorless powder with a melting point of 134°-136°.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)=[CH2:2].[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:2][CH:1]=[C:3]3[CH:7]=[CH:6][S:5][C:4]3=2)[C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Reactant: C=Cc1ccsc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccsc3c2C1=O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 3-vinylthiophene (10.0 g, 0.0908 mol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1- acetonitrile (18.3 g, 0.0953 mol) and chloroform is stirred at 50° C. for 20 hours and at room temperature for one week. The mixture is concentrated in vacuo to give a yellow oil residue, which is column chromatographed on silica gel using methylene chloride as an eluent to afford a yellow oil. The oil is taken up in dioxane and treated with dichlorodicyano-p-benzoquinone, (17.2 g, 0.0760 mol), stirred for 21 hours at 100° C., cooled to 25° C. and filtered (the filter cake is washed once with benzene). The filtrate is concentrated in vacuo to give an orange semisolid residue. The residue is washed through neutral alumina with methylene chloride:hexanes (1:1) and flash chromatographed on silica gel using hexane:ethyl acetate (4:1) as an eluent to afford the title product as a pale yellow solid, 4.21 g (15.6%), mp 99°-107° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=[CH2:29].C(N(CCCC)CCCC)CCC.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27](/[CH:28]=[CH:29]/[C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1OC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylacetamide 2.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 3,4-dimethoxystyrene 0.081 mL, tributylamine 0.13 mL, palladium acetate 3.0 mg and tri-tert-butylphosphine tetrafluoroborate 2.0 mg at room temperature, and it was stirred under nitrogen atmosphere at 120° C. for 2 hours. Palladium acetate 3.0 mg and tri-tert-butylphosphine tetrafluoroborate 2.0 mg were added to it, and it was stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-((E)-2-(3,4-dimethoxyphenyl)vinyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:6][CH2:5]1.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1>CO>[CH3:1][O:2][CH2:3][C@@H:4]([OH:6])[CH2:5][NH:14][CH2:13][C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: NCc1ccncc1
Reactant: COC[C@H]1CO1
Solvent: CO
Product: COC[C@@H](O)CNCc1ccncc1
Temperature: 120 °C
Yield: 17 %

Procedure:
(R)-(−)-Glycidyl methyl ether (88 mg, 1 mmol) and 4-picolylamine (108 mg, 1 mmol) in methanol (1 mL) were sealed in a reaction tube and heated at 120° C. for 30 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (17% yield).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH3:22])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1

Procedure:
Ethyl 2-chloro-4-(4-fluorophenyl)-5-oxazolebutanoate (3.11 g), 2-methylimidazole (2.46 g), potassium carbonate (4.15 g) and N,N-dimethylformamide (25 ml) was stirred at 120-130° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate was obtained as an oil (3.47 g, 57%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Conversion to the hydrochloride and the subsequent recrystallization from hexane-ethyl acetate gave pale yellow prisms. Melting point 140-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:28][C:29]1[N:36]=[C:35](F)[C:34]([F:38])=[CH:33][C:30]=1[C:31]#[N:32]>C1COCC1>[C:31]([C:30]1[CH:33]=[C:34]([F:38])[C:35]([NH:1][C:2]2[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[N:5]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=2)=[N:36][C:29]=1[F:28])#[N:32]
Reactant: CC(C)Oc1cc(N)n(C(=O)OC(C)(C)C)n1
Reactant: N#Cc1cc(F)c(F)nc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n(C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of tert-butyl 5-amino-3-isopropoxy-1H-pyrazole-1-carboxylate (Method 78, 4.0 g, 16.4 mmol) in THF (45 ml) was cooled to −78° C. A 1.0M THF solution of LiHMDS (2.61 g, 15.6 mmol) was added dropwise and the reaction was stirred at −78° C. for 30 minutes. A −78° C. solution of 2,5,6-trifluoronicotinonitrile (1.3 g, 8.2 mmol) in THF (20 ml) was added dropwise via cannula to the above anion solution. Upon completion of the addition, the resulting reaction was allowed to stir for 10 minutes at −78° C., and was then quenched with water (100 ml). The reaction was allowed to warm to room temperature, extracted with DCM (3×100 ml), dried (Na2SO4), filtered, and then concentrated to give the title compound (95% conversion by LCMS) which was used without further purification. MS: Calcd.: 379. Found: [M+H]+ 380.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H52Cl2N5O3 [(M+H)+] 732.3442, observed 732.3440.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[N:31][CH:32]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[N:31][CH:32]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3)ncc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3)ncc2C(F)(F)F)CC1
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 4-(5-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A10) (134 mg, 0.216 mmol), 10% Pd/C (100 mg) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL) and filtered through Celite. The filtrate was evaporated in vacuo and the resulting residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A11 as a colourless oil (117 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.6 Hz, 1H), 8.57 (s, 1H), 8.15 (dd, J=8.5, 2.7 Hz, 1H), 7.45 (s, 1H), 7.34-7.27 (m, 3H), 7.24-7.15 (m, 2H), 4.26 (s, 2H), 3.60 (s, 3H), 3.22-3.07 (m, 4H), 2.92-2.76 (m, 3H), 1.92 (d, J=11.4 Hz, 2H), 1.79-1.65 (m, 4H), 1.48 (s, 9H), 1.22-1.18 (m, 2H). LCMS-A: rt 5.971 min; m/z 626 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(Cl)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-chloro-6-methoxypyridin-3-amine and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.71 (s, 1H); 8.78 (dd, J=7.8, 2.2 Hz, 1H); 8.33 (dd, J=4.7, 2.0 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 8.19 (d, J=2.3 Hz, 1H); 7.17-7.29 (m, 4H); 6.82-6.96 (m, 5H); 4.81 (d, J=6.5 Hz, 4H); 3.91 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.55-2.58 (m, 3H). m/z (ESI, +ve ion) 584.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6](=[O:8])(=[O:7])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13].C(C(CCCC)C([O-])=O)C.[Na+:26].[Na]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:15])[S:6](=[O:7])(=[O:8])[CH:5]2[CH2:9][C:10](=[O:11])[N:4]2[CH:3]1[C:12]([O-:14])=[O:13].[Na+:26]
Reactant: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC1(C)C(C(=O)[O-])N2C(=O)CC2S1(=O)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 32.75 g. (0.14 mole) of penicillanic acid 1,1-dioxide in 450 ml. of ethyl acetate was added a solution of 25.7 g. of sodium 2-ethylhexanoate (0.155 mole) in 200 ml. of ethyl acetate. The resulting solution was stirred for 1 hour and then an additional 10% excess of sodium 2-ethylhexanoate in a small volume of ethyl acetate was added. Product immediately began to precipitate. Stirring was continued for 30 minutes and then the precipitate was removed by filtration. It was washed sequentially with ethyl acetate, with 1:1 ethyl acetate-ether and with ether. The solid was then dried over phosphorus pentoxide, at ca. 0.1 mm of Hg for 16 hours at 25° C., giving 36.8 g. of the title sodium salt, contaminated with a small amount of ethyl acetate. The ethyl acetate content was reduced by heating to 100° C. for 3 hours under vacuum. The IR spectrum of this final product (KBr disc) showed absorptions at 1786 and 1608 cm-1. The NMR spectrum (D2O) showed absorptions at 1.48 (s, 3H), 1.62 (s, 3H), 3.35 (d of d's, 1H, J1 =16 Hz, J2 =2 Hz), 3.70 (d of d's, 1H, J1 =16 Hz, J2 =4 Hz), 4.25 (s, 1H) and 5.03 (d of d's, 1H, J1 =4 Hz, J2 =2 Hz) ppm.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[N+:11]([O-])([O-])=[O:12].[Na+].C(=O)([O-])[O-].[K+].[K+]>Cl.O>[N:11]([N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]2[CH2:1]1)=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: C1CCN2CCNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=NN1CCN2CCCCC2C1
Reaction time: 3 h

Procedure:
Octahydropyrido-[1,2-a]-pyrazine (5 g) was dissolved in hydrochloric acid (5 N, 16 ml) and sodium nitrate (2.7 g) in water (10 ml) added dropwise at 0°. The solution was then heated at 60° for 30 minutes and stood at room temperature for 3 hours. It was basified, saturated with potassium carbonate and extracted with ether. The ethereal extract was dried and evaporated to give N-nitroso-octahydropyrido-[1,2-a]-pyrazine as an oil.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1)(=O)=O.[I-:24].[Na+]>>[I:24][CH2:5][CH:6]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1
Reactant: [I-]
Reactant: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Product: COc1cccc2c1OC(CI)C2

Procedure:
This compound was obtained according to the process described in Example 4, stage C, from 7-methoxy-2,3-dihydro-2-benzofuranylmethyl tosylate and sodium iodide.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][OH:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: OCc1cccc(Cl)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(Cl)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-chlorobenzyl alcohol (115 mg; 0.789 mmol), example 85 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>C1COCC1>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a stirred suspension of 1 (2 tert-butylphenyl)piperazine dihydrochloride (29 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.3 mmol) in THF (1.0 mL) was added acetyl chloride (23 mg, 0.3 mmol) at rt. After stirring for 2 h at room temperature, saturated sodium hydrogen carbonate solution (1.5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 mL). The organic layer was separated by phase separation filter kit and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in DMSO (1 mL) and the solution was purified by preparative HPLC. The eluted fraction was evaporated by air blowing at 60° C. to give a title compound (20.5 mg, 79%). LC/MS (ESI+) m/z 261 [M+H], purity 100%.