Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)C(O)=O.C(O[C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)C(O)=O)(=O)C.[Cl:26][C:27]1[C:28]([CH3:34])=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[CH2:11]([Cl:26])[C:3]1[CH:4]=[CH:8][CH:9]=[CH:10][CH:2]=1.[CH2:25]([O:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[C:28]=1[CH3:34])[C:17]1[CH:18]=[CH:22][CH:23]=[CH:24][CH:16]=1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: Cc1c(O)cccc1Cl
Product: Cc1c(Cl)cccc1OCc1ccccc1
Product: ClCc1ccccc1

Procedure:
This object is achieved by a process for the preparation of 3-hydroxy-2-methylbenzoic acid and 3-acetoxy-2-methylbenzoic acid, which comprises reacting 3-chloro-2-methylphenol (3) ##STR3## with benzyl chloride to give 2-benzyloxy-6-chlorotoluene (4) ##STR4## subjecting this to a Grignard reaction with magnesium to give (3-benzyloxy-2-methylphenyl)magnesium chloride (5) ##STR5## reacting this with CO2 to give 3-benzyloxy-2-methylbenzoic acid (6) ##STR6## hydrogenating this or its alkali metal salts in the presence of a hydrogenation catalyst to give 3-hydroxy-2-methylbenzoic acid (2) and optionally acetylating this to give 3-acetoxy-2-methylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-3-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: O.O.Cl[Sn]Cl.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=2)=[N:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[N:16][N:17]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O.ClCCl>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=2)=[N:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[N:16][N:17]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4[N+](=O)[O-])o3)n2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4N)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
SnCl2.2H2O (151.6 mg, 0.6720 mmol) was added to a solution of 4-[5-amino-6-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (58 mg, 0.1344 mmol) in EtOAc (3 mL) and dichloromethane (1 mL) at room temperature and the resulting solution stirred overnight at room temperature. The reaction mixture was poured carefully onto saturated aqueous sodium hydrogen carbonate solution (5 mL) and the layers separated. The aqueous layer extracted further with dichloromethane (2×15 mL) and the combined organics dried over MgSO4 and concentrated in vacuo to leave a yellow solid. This was purified using by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were freeze dried to give the product as a yellow solid (17.2 mg, 34% yield); 1H NMR (400.0 MHz, DMSO) d 2.98 (m, 6H), 6.78 (t, 1H), 6.88 (br s, 1H), 7.34 (m, 1H), 7.55 (m, 2H), 7.79 (br s, 2H), 7.85 (m, 1H), 8.18 (m, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 402.26
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1([CH3:23])[NH:11][CH2:10][CH2:9][N:8]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N:8]4[CH2:9][CH2:10][NH:11][C:6]([CH3:5])([CH3:23])[CH2:7]4)=[CH:22][CH:21]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 10.5 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.691 mL, 1.38 mmol) was added dropwise to a stirred solution of ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (145 mg, 0.55 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (138 mg, 0.55 mmol) in toluene (5 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 20° C. for 24 h. This was diluted with acetone (25 ml) and an excess of damp solid sodium sulphite was added. The mixture was stirred for 1 h and the solid filtered off. The solid was washed with 10% MeOH/DCM and the combined organics evaporated to dryness. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (27.0 mg, 10.49%) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:19]=1[C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Reactant: O=Cc1cccnc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccnc2)nc2nc[nH]n12

Procedure:
Compound 6 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 3-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([C:9]2[C:10]([CH2:18]O)=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1.O.C(OCC)(=O)C>C1COCC1.Cl>[CH3:21][O:20][C:7]1[C:8]2[C:9]3[CH:17]=[C:13]4[O:14][CH2:15][O:16][C:12]4=[CH:11][C:10]=3[CH2:18][O:1][CH2:2][C:3]=2[CH:4]=[C:5]([O:24][CH3:25])[C:6]=1[O:22][CH3:23]
Reactant: COc1cc(CO)c(-c2cc3c(cc2CO)OCO3)c(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1cc3c(cc1COC2)OCO3
Yield: 65 %

Procedure:
A solution of (6-(6-(hydroxymethyl)-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxol-5-yl)methanol (170 mg, 0.48 mmol) in THF (2 mL), 2M HCl (2 mL) and concentrated hydrochloric acid (1 mL) was stirred under reflux for 3 hours. Water (15 mL) and ethyl acetate (15 mL) were added to the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography of the residue over silica gel (20 g), eluting with hexane-ethyl acetate (4:1), followed by crystallisation (ethyl acetate) yielded the title compound as large clear crystals (103 mg, 64%); m.p. 154-156° C.; Elemental Analysis Found: C, 65.3; H, 5.5 (C18H18O6 requires C, 65.45; H, 5.49%); NMR Spectrum δH (300 MHz, CDCl3) 7.21 (1H, s, 12-H), 6.98 (1H, s, 8-H), 6.96 (1H, s, 4-H), 6.75 (1H, s, 4-H), 6.04 (2H, d, J 4.8 Hz, 10-H2), 4.40 (2H, d, J 11.2 Hz, 5-H2), 4.04 (1H, d, J 10.8 Hz, 7-HA), 4.01 (1H, d, J 10.8 Hz, 7-HB), 3.96 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.71 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.3, 61.2, 61.5, 67.6, 67.8, 101.6, 109.0, 109.9, 110.2, 126.8, 129.5, 131.3, 131.7, 143.0, 147.3, 147.7, 150.8, 153.3; νmax/cm−1 (thin film) 2967, 2932, 2866, 1600, 1484, 1460, 1414, 1324, 1239, 1146, 1107, 1045; m/z (ES) 301 (MH+—CH2O, 100%); Rf (hexane-ethyl acetate 4:1) 0.28.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(O)(C)C.C(Cl)(Cl)Cl.CO>CO>[Br-:25].[CH2:1]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N+:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:23])[CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCBr
Reactant: CCCCCCCCCCCCNC(=O)CCN1CCN(C)CC1
Solvent: CC(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(=O)CCN1CC[N+](C)(CCCCCC)CC1
Product: [Br-]
Temperature: 40 °C

Procedure:
N-dodecyl-3-(4-methylpiperazin-1-yl)propanamide 30.0 g (0.088 moles), 1-bromohexane 14.6 g (0.088 moles), and 11.2 g of isopropyl alcohol are charged into a 3-neck 250-mL round bottom flask equipped with a thermocouple, and reflux condenser. The mixture is agitated using a magnetic stirring bar and heated to reflux overnight. Then, the reaction mass is cooled down to about 40° C. and diluted to 40% active solids with 56 g of methanol. Evidence of the chemical transformation is observed by TLC analysis using a 4:1 CHCl3/MeOH as mobile phase. The final product is a light brown solution at ambient temperature. 1H-NMR (300 MHz, CDCl3): δ 3.10 (m, 5H), 2.90 (m, 10H), 2.36 (m, 4H), 1.34 (bs, 2H), 0.80 (m, 26H), 0.44 (m, 6H). 13C-NMR (75 MHz, CDCl3): δ 170.94, 62.39, 59.24, 52.17, 48.35, 45.12, 38.39, 32.50, 30.75, 30.12, 28.52, 28.49, 28.38, 28.18, 28.18, 25.98, 24.85, 24.11, 21.50, 21.28, 20.74, 12.92, 12.74.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C(N)=O)cccc32)CC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C#N)cccc32)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of tert-butyl 4-[(7-carbamoyl-2,3-dihydro-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate in DCM (80 mg, 0.22 rnmol) was added Et3N (60 mg, 0.59 mmol). The solution was cooled to 0° C. and TFAA (60 mg, 0.29 mmol) was added dropwise under nitrogen. After 4 hours stirring at room temperature, the solvents were removed under vacuum to give the crude product tert-butyl 4-[(7-cyano-2,3-dihydro-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate (66 g, yield 87%) which was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]([CH:12]=[CH2:13])[N:4]=1.O=[O+][O-].[OH2:17].[OH-].[Li+].O.C1[CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([O:24][C:25](=[O:17])/[CH:13]=[CH:12]/[C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1)[CH3:22]
Reactant: C1CCOC1
Reactant: O
Reactant: C=Cc1ncc([N+](=O)[O-])c(OC)n1
Agent: O=[O+][O-]
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ncc([N+](=O)[O-])c(OC)n1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methoxy-5-nitro-2-vinylpyrimidine (260 mg) in methylene chloride (15 mL) was stirred with an ozone stream of bubbling at −50° C. for 1 hr. After the reaction mixture was warmed to −20° C., the ozone stream was stopped and dimethyl sulfide (1.06 mL) was added to the reaction mixture. The reaction mixture was gradually warmed up to room temperature with stirring for 30 min. The reaction mixture was concentrated under reduced pressure to obtain the corresponding crude aldehyde. To a solution of the crude aldehyde and triethyl phosphonoacetate (0.432 mL) in THF (5 mL) was added lithium hydroxide monohydrate (90.6 mg) at 0° C. After stirring for 1.5 hr at room temperature, water and ethyl acetate was added to the reaction mixture and an organic layer was separated. The obtained organic layer was sequentially washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane/ethyl acetate) to give the title compound (100 mg). The physical data of the title compound was described as below.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:9][CH:8]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O.O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:24]([C:9]2[CH:8]=[C:7]([Cl:6])[N:12]=[C:11]([F:13])[C:10]=2[O:14][CH2:15][O:16][CH3:17])[OH:25])[CH:26]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COCOc1ccc(Cl)nc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: -78 °C

Procedure:
DIPA (0.750 mL, 5.35 mmol) was dissolved in dry THF (20 mL) under nitrogen and cooled in a dry ice bath to −78° C. Butyllithium solution (2.5 M in hexanes, 2.0 mL, 5.00 mmol) was added and the solution was stirred for a few minutes. A solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (0.864 g, 4.51 mmol) in dry THF (10 mL) was added slowly and the resulting solution stirred for 40 minutes. A solution of 5-bromo-2-fluorobenzaldehyde (1.02 g, 5.05 mmol) in dry THF (1 mL) was added dropwise. After 10 minutes saturated ammonium chloride (10 mL), water (100 mL) and EtOAc (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:24][C:25]([NH:27][CH3:28])=[O:26].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CNC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.07 g, 0.22 mmol) and 2-chloro-N-methylacetamide (0.023 g, 0.22 mmol) in dry DMF (3 mL) in a sealable tube was added triethylamine (0.1 mL, 0.72 mmol) and NaI (0.01 g). The tube was sealed and heated for four hours at 80° C., then cooled and quenched by addition of water. The reaction mixture was extracted EtOAc, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (EtOAc:MeOH 99:1 to 97:3) gave 0.044 g of 2-{[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-amino}-N-methyl-acetamide as a foam. MS (M+H)=393.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)NCC[C@@H](C)N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 55.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-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 (26 mg, 56%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (21 mg, 90%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H), 4.48 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Cl)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C=O)C.C1COCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH2:29][N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[O:31])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1
Reactant: C1CNCCN1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CCl)cc3)nc(=O)c1-2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CN4CCNCC4)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Part B: To a stirred solution of 300 mg (0.55 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 6 mL of 1:1 DMF-THF was added 1 g of piperazine. The solution was stirred overnight at ambient temperature and poured into water. The mixture was extracted twice with EtOAc, and the combined organic extracts were washed (brine), dried (MgSO4), and concentrated under reduced pressure to afford 230 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass spec.(ESI+): 588((M+H)+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1.C([Cl:36])(=O)C>CCOC(C)=O.CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[NH:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCNC2=O
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: O=C1NCC[C@]12CC[C@H](c1ccc(OCc3ccccc3F)cc1)N2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D26, 29.3 g) in AcOEt (325 mL) and MeOH (108 mL) at 0° C., was added acetyl chloride (28.5 mL). The resulting solution was stirred at 0° C. for 15 minutes then at ambient temperature for 16 hours. Solvent was evaporated (bath temperature: first ambient and then 38° C.) and the residue solid was triturated with Et2O (3×244 mL). Finally the solid was collected by filtration and dried under high vacuum at 35° C. overnight to afford the title compound (23 g, Y=92%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:9]([CH2:25][C:26]2[CH:30]=[C:29]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][N:27]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Reaction time: 0.25 h

Procedure:
500 mg (2.0 mmol) of 2-(4-Chlorophenyl)-3H-imidazole-4-carboxylic acid ethyl ester was dissolved in 5 ml of DMF and 2.6 g (8 mmol) of cesium carbonate were added at RT. After stirring for 15 min, 445 mg (1.6 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 16 h. The reaction solution was filtered and the product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid. Yield: 480 mg; MS (LCMS-ES+): m/e=448.
Reaction SMILES: [OH:1][CH:2]([P:11](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].C/C(/[O-])=C/C(C)=O.C(OO)(C)(C)C>ClC1C=CC=CC=1>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[C:2]([P:11](=[O:24])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:1]
Reactant: O=P(c1ccccc1)(c1ccccc1)C(O)c1c(Cl)cccc1Cl
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 64 %

Procedure:
To 15 g (0.04 mol) of α-hydroxy-(2,6-dichorobenzyl)-diphenyl phosphine oxide and 0.4 g (1.5 mmol) of vanadyl(IV) bis-acetylacetonate in 100 g of chlorobenzene there were added 12.9 g (0.1 mol) 70 wt % strength aqueous tert-butylhydroperoxide, and the mixture was kept at 70° C. for 5 h. The product was isolated by crystallization. Yield: 64%, mp 156°-158° C.