Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11](/[N:15]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=Cc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCC/N=C/c1c(F)cccc1F
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 25.4 g (179 mmol) 2,6-difluorobenzaldehyde, 19.5 ml (197 mmol) N-butylamine and 0.68 g (3.57 mmol) p-toluenesulfonic acid in 120 ml toluene was heated in a Dean-Stark apparatus at reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed sequentially with water (twice) and with saturated brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound 30.4 g (86%) as a brown oil which was used in the next step without further purification. MS (ISP): 198.3 ([M+H]+, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][NH:30][CH2:29][CH2:28]4)[N:21]=2)=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38].N12CCCN=C1CCCCC2>C(#N)C>[C:14]([C:13]1[CH:16]=[C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][N:30]([CH2:38][CH2:37][C:36]([O:40][CH2:41][CH3:42])=[O:39])[CH2:29][CH2:28]4)[N:21]=2)[CH:18]=[CH:19][C:12]=1[O:11][CH:9]([CH3:8])[CH3:10])#[N:15]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2
Reactant: C=CC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 2-[(1-methylethyl)oxy]-5-[3-(5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt (Example 11; 100 mg, 0.20 mmol), ethyl acrylate (31 mg, 33 μl, 0.31 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 187 mg, 185 μl, 1.23 mmol) in acetonitrile (3 ml) was stirred at room temperature for 3 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (10 ml); the solution was washed with water (5 ml), dried and evaporated. Purification of the residue by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane gave the title compound as a colourless oil (86 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:25])=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[N+:20]([O-:39])[C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(N(C)C)cc1C
Solvent: ClCCl
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1c[n+]([O-])c(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-N,N,4-trimethylpyridin-2-amine (43 mg, 0.10 mmol) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (27 mg, 0.11 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 2 hr. The reaction mixture was purified by flash chromatography on NH-silica gel eluting with a 0-20% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (30 mg, 0.0678 mmol, 68%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:22]#[N:23])=[CH:17][CH:18]=2)[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.N1C=CC=CC=1.[O:30]=[O+][O-]>C(Cl)Cl.CO>[C:22]([C:16]1[CH:15]=[C:14]2[C:19]([CH2:20][CH2:21][CH:12]([N:4]([CH2:1][CH:2]=[O:30])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:13]2)=[CH:18][CH:17]=1)#[N:23]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(CC=O)C1CCc2ccc(C#N)cc2C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl allyl(7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (320 mg, 1.0 mmol) in 1:1 CH2Cl2/MeOH (20 mL) containing pyridine (0.16 mL, 2.0 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (3 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give the title compound. MS m/z: 315 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.O1CC[CH2:19]OO1.C(O)C>C(N(CC)CC)C>[CH2:19]=[N:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: C1COOOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C

Procedure:
A mixture of 8.40 g. 9-amino-1,2,3,4-tetrahydroacridine and 4.71 g. Trioxan in 200 ml. ethanol in which 1 g. triethylamine had previously been dissolved was heated to reflux for 12 hours under vigorous stirring. The mixture was cooled to room temperature, then filtered. The filtrate was concentrated under reduced pressure and the dry residue was taken up in hot acetonitrile (25 ml.). The solution was filtered when hot and then cooled. The methylenic derivative started to crystallize as yellowish crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[NH:1][CH2:12][CH2:11][C:10]#[N:13]
Reactant: Cc1cc(C)cc(N)c1
Reactant: C=CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NCCC#N)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
3,5-Xylidine (5.0 g) and acrylonitrile (2.3 g) were dissolved in acetic acid (2 ml), and the mixture was stirred at 60° C. for 20 hr. Ethyl acetate (200 ml) was added to the reaction mixture and neutralized with saturated aqueous solution of sodium hydrogencarbonate. The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/10-1/3) to give 4.5 g of oily β-(3,5-dimethylanilino)propionitrile.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[S:9][C:5]=2[CH:4]=1.CO.[Li+].[OH-].O>C1COCC1>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 1 h

Procedure:
To ethyl 6-(trifluoromethyl)-1-benzothiophene-2-carboxylate dissolved in THF and MeOH was added a solution of LiOH in H2O (1.5 equiv). The reaction media became cloudy so H2O, MeOH and THF were added until a clear solution ensued (Final composition of media=2 THF:1 MeOH:1 H2O) (0.2 M). After 1 h, analysis showed consumption of all the starting material. A large proportion of the volatiles were removed under reduced pressure. The remaining solution was treated with 1N HCl. The precipitate was filtered off and dissolved in a mixture of THF, MeOH and EtOAc. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a solid. The latter was ground with a mortar and pestle and let dry overnight under high vacuum.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](=[O:15])[NH:22][CH:19]1[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC1CC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NC1CC1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A mixture of carbobenzyloxy-L-proline (994 mg, 3.99 mmol), cyclopropylamine (0.41 mL, 5.9 mmol), HOBt (807 mg, 6 mmol), EDC (1.12 g, 5.9 mmol) and TEA (1.1 mL) in DMF (11 mL) was stirred at room temperature for 48 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was column chromatographed to give 985 mg (81%) of (S)-2-cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:11]2[CH:12]([C:7]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(C2(c3cccc(C)c3)C=CC(=O)CC2)c1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (12 drops) is added to a solution of 4,4-bis-(3-tolyl)cyclohexenone (16.7 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (18.7 cc) in dry dichloromethane (150 cc). The reaction mixture is brought to reflux and then stirred for 3 hours allowing the temperature to return to 25° C. and for a further 10 minutes after addition of potassium carbonate (12 g). After filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 25 cc fractions. Fractions 14 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis-(3-tolyl)-4-perhydroisoindolone (13.9 g) in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])[CH3:2].[NH2:12][C:13]([NH2:15])=[S:14].[NH4+].[OH-]>ClCCl>[CH2:1]([O:3][C:4]([C:5]1[S:14][C:13]([NH2:15])=[N:12][C:6]=1[CH:7]([CH3:9])[CH3:8])=[O:11])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N)nc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (10 g, 63.2 mmol) in dichloromethane (150 mL) at 0° C. is added SO2Cl2 (5.64 mL, 69.5 mmol). The reaction mixture is stirred at ambient temperature for 1 hour. The reaction mixture is extracted with water (30 mL). To the aqueous layer is added 1,4-dioxane (60 mL) followed by thiourea (8.8 g, 63.2 mmol). The mixture is stirred at 80° C. overnight and cooled to room temperature. The reaction mixture is adjusted to pH 12 with conc. NH4OH and filtered. The filter cake is washed with water to give the title compound (12.4 g, 92%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9]N[C@H](C(O)=O)C)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:18]([N:20](CC)CC)[CH3:19].[CH2:25]([NH2:28])[CH2:26][NH2:27]>CO.CCOCC>[ClH:1].[ClH:1].[ClH:1].[NH2:27][CH2:26][CH2:25][NH:28][CH2:19][C@@H:18]([NH2:20])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:17][CH:16]=1
Reactant: NCCN
Reactant: CCN(CC)CC
Reactant: C[C@H](NCc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCCNC[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The (S)—N1-(2-aminoethyl)-3-(4-nitrophenyl)propane-1,2-diamine trihydrochloride salt was synthesized following the procedures of Brechbiel and Meares (Brechbiel, M. W. et al. Inorg. Chem. 1986, 25, 2772; Meares, C. F. Bioconjugate Chem. 2000, 11, 292.). The HCl salt of the methyl ester of para-nitrobenzylalanine (p-NO2Bn-Ala-OMe, HCl salt, 13.03 g, 50 mmoles, 1 eq.) was dissolved in methanol (30 mL) and triethylamine (10.5 mL, 75 mmoles, 1.5 eq.) was added. The reaction mixture was stirred for 15 minutes at RT and ether (225 mL) was added. The reaction mixture was cooled to 0° C. with an ice-bath and the precipitate was filtered off and rinsed with ether (20 mL). The filtrate was concentrated to an orange oil which was re-dissolved in methanol (10 mL) and the solution of free amine was added at RT to ethylenediamine (100 mL, 1500 mmoles, 30 eq.) via a syringe pump over 4 h under argon. The mixture was stirred for 11 h and the ethylenediamine and the methanol were evaporated under high vacuum to give the desired crude amide (13.16 g, 104%) as a brown oil which was used directly in the next step without any further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[CH2:18](I)[CH3:19]>>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:18][CH3:19])[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Reactant: CCI
Product: CCc1cc2c(=O)c(C(=O)O)cn(CC)c2s1

Procedure:
In a manner similar to that described in Example 13, ethyl 2-ethyl-4-hydroxythieno(2,3-b)pyridine-5-carboxylate is reacted with ethyl iodine to obtain 2,7-diethyl-4,7-dihydro-4-oxothieno-(2,3-b)pyridine-5-carboxylic acid. Recrystallization from methanol gives colorless prisms melting at 197°-198° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])I1C2C=CC=CC=2C(=O)O1.[CH3:15][O:16][C:17](=[O:24])[C@:18]([CH2:22][OH:23])([CH3:21])[CH:19]=[CH2:20]>[2H]C(Cl)(Cl)Cl.ClCCl.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Zn+2].[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>[CH3:15][O:16][C:17](=[O:24])[C@@:18]([CH3:21])([CH2:22][O:23][C:2]([F:14])([F:13])[F:1])[CH:19]=[CH2:20]
Reactant: C=C[C@](C)(CO)C(=O)OC
Reactant: O=C1OI(C(F)(F)F)c2ccccc21
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [2H]C(Cl)(Cl)Cl
Agent: [Zn+2]
Solvent: ClCCl
Product: C=C[C@](C)(COC(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 23.1 %

Procedure:
Zinc bis(trifluoromethylsulfonyl)imide (750 mg, 1.2 mmol) and (1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (758 mg, 2.4 mmol) were added to a stirred solution of (R)-2-hydroxymethyl-2-methyl-but-3-enoic acid methyl ester (288 mg, 2.0 mmol) in dry deuterochloroform (4 mL) under nitrogen. The reaction mixture was stirred at room temperature under nitrogen in a sealed flask for 5 days. The resulting suspension was diluted with dichloromethane and the supernatant was separated and evaporated. Dichloromethane (5 mL) was added to the residue and the supernatant solution was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid methyl ester (98 mg) as a clear oil which was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([OH:34])=[C:16]2[C:31](=[O:32])[N:20]3[C@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12].N[C@H](C)CCN[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44].[C:47](O)(=O)[CH3:48].[Cl:51]CCl>>[ClH:51].[ClH:51].[NH2:20][C@H:21]([CH3:30])[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([OH:34])=[C:16]2[C:31](=[O:32])[N:20]3[C@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([O:34][CH2:45][C:43]2[CH:42]=[CH:41][CH:48]=[CH:47][CH:44]=2)=[C:16]2[C:31](=[O:32])[N:20]3[C@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12]
Reactant: CC(=O)O
Reactant: ClCCl
Agent: CC(C)CCN1CC[C@@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@H]12
Agent: CC(C)CCNCC[C@@H](C)N
Product: CC(C)CCN1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@H]12
Product: Cl
Yield: 90 %

Procedure:
[(3R)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride was prepared in a similar manner as described in example Z-32. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.87 (d, J=5.2 Hz, 6H), 1.32 (m, 3H), 1.61 (m, 3H), 2.10-2.20 (m, 2H), 2.90-3.04 (m, 4H), 3.45 (m, 1H), 8.23 (br, <1H), 8.96 (br, <1H). b) (4R,12aR)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2, 16a (40 mg, 0.085 mmol) and free [(3R)-3-aminobutyl](3-methylbutyl)amine (46 mg, 0.35 mmol) were reacted in dichloromethane (2 mid) with acetic acid to give (4R,12aR)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (44 mg, 90%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (11 mg, 30%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 0.84 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 1.24-1.36 (m, 5H), 1.47-1.53 (m, 2H), 2.02-2.11 (m, 1H), 2.36-2.43 (m, 1H), 2.54-2.61 (m, 1H), 2.77-2.92 (m, 2H), 4.16-4.26 (m, 2H), 4.44 (m, 1H), 4.62-4.64 (m, 2H), 4.95-5.02 (m, 1H), 6.75-6.81 (m, 2H), 7.31-7.37 (m, 1H), 8.27 (s, 1H), 10.43 (m, 1H), 12.54 (s, 1H); ES+ MS: 489 (M+1),
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:3][CH:2]=1.[Na+:13].[CH3:14][C:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.C(N(CC)CC)C>C(O)C>[CH3:14][C:15]1[C:19](=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9]([O-:12])(=[O:11])=[O:10])[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.[Na+:13]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1=NN(c2ccccc2)C(=O)C1=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
2.1 g of sodium benzaldehyde-2-sulfonate, 1.75 g of 3-methyl-1-phenyl-2-pyrazolin-5-one and 1 g of triethylamine in 20 mL of ethanol were allowed to reflux 5 hours. After cooling to room temperature, the precipitate was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)benzoic acid (Preparation 30, 3.76 g, 14.02 mmol) and ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (3.89 g, 16.83 mmol) in 2-methyltetrahydrofuran (150 mL) was added DIPEA (7.33 mL, 42 mmol) and the reaction was heated to 95° C. T3P (50% solution in EtOAc, 16.53 mL, 28 mmol) was added and the reaction was stirred at 95° C. for 18 hours. The reaction was cooled and partitioned between saturated aqueous sodium carbonate solution (200 mL) and EtOAc (200 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with TBME to afford the title compound (5.72 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.O>CN(C)C(=O)C.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>[ClH:1].[CH2:21]([N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH2:31][O:30][CH3:29])=[CH:33][CH:34]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1)[CH3:22]
Reactant: COCc1ccc(B(O)O)cc1
Reactant: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccc(COC)cc3)CC2)c1C
Product: Cl
Yield: 61.8 %

Procedure:
Combine 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.300 g, 0.935 mmol), potassium carbonate (0.310 g, 2.24 mmol), 4-methoxymethylphenylboronic acid (0.186 g, 1.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in N,N-dimethylacetamide (1.9 mL). Add water (940 μL), and reflux reaction for 6 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate), to give the free base of the title compound (256 mg, 67%). Dissolve the free base (0.254 g, 0.624 mmol) in acetonitrile (748 μL) and add aq. 1 N HCl solution (748 μL, 0.748 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (273 mg, 99%). MS (ES): m/z=407 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC1(C)CC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0509.