Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:30][O:29][C:27]1[CH:28]=[CH:23][C:24]([O:31][CH3:32])=[CH:25][C:26]=1[NH:11][C:7]1[N:8]=[CH:9][C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:5]2[N:6]=1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(OC)c(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)c1
Yield: 51.8 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 2-bromo-1,4-dimethoxybenzene (0.019 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-(2,5-dimethoxyphenyl)-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (0.020 g) as a yellow solid. 1H NMR (CDCl3): δ8.85 (s, 1H), 8.84-8.80 (m, 1H), 8.66 (s, 1H), 8.05 (d, J=3.0 Hz, 1H), 7.71-7.60 (m, 3H), 6.84 (d, J=8.8 Hz, 1H), 6.55 (dd, J=8.8, 3.0 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.63 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]([Mg]Cl)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Mg]Cl
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CC(C)C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 1,4-dioxaspiro[4.5]decan-8-one (3.00 g, 19.2 mmol, in THF (20 mL) cooled to −78° C. under argon was added a isopropylmagnesium chloride (10 mL, 20 mmol, 2 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]([N:19]=[C:20]=[O:21])=[O:18]>>[C:1]([C:5]1[CH:6]=[C:7]([N:8]2[CH2:16][C:17](=[O:18])[NH:19][C:20]2=[O:21])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C=NC(=O)CCl
Product: COc1c(I)cc(N2CC(=O)NC2=O)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol) and chloroacetyl isocyanate (0.256 mL, 3.00 mmol) were reacted in the same manner as Example 14 Part A to give crude product which was purified on an Isco 40 g silica cartridge eluting with methanol/dichloromethane (0% to 5%) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35]>>[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35]
Reactant: Cc1cc2cc(O)ccc2n1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc4c(c3)cc(C)n4C)ncnc2cc1OCCCN1CCOCC1
Yield: 73.4 %

Procedure:
Using an analogous procedure to that described in Example 120 OR 121 PER PP, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.48 mmol), (prepared as described for the starting material in Example 1), was reacted with 1,2-dimethyl-5-hydroxyindole (92 mg, 0.57 mol), (Tetrahedron 1994, 50, 13433), to give 4-(1,2-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (163 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@@H:39]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:51][C:50]=2[S:59]([C:62]([F:65])([F:64])[F:63])(=[O:61])=[O:60])[CH2:40][S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:33][CH2:32]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:58][S:55]([C:52]4[CH:53]=[CH:54][C:49]([NH:48][C@H:39]([CH2:38][CH2:37][N:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:40][S:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[C:50]([S:59]([C:62]([F:65])([F:63])[F:64])(=[O:61])=[O:60])[CH:51]=4)(=[O:56])=[O:57])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
(S)-4-(4-((4′-Chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 70, 137.4 mg, 0.33 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 190.3 mg, 0.34 mmol), DMAP (81.0 mg, 0.66 mmol), and EDC (134.5 mg, 0.70 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (6.5 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N aq. sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH in DCM). Clean fractions were combined, evaporated under vacuum, and dried overnight in a 40° C. vacuum oven to provide the title product as a substantially separated isomer (129.3 mg, yield: 41.5%).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: BrC1=Cc2ccccc2C1
Solvent: CCOCC
Product: C1=C(Cc2ccccc2)Cc2ccccc21
Temperature: 0 °C

Procedure:
A 500 mL 3 neck flask was charged with 2.5 g (13 mmol) of 2-bromo-indene, 50 mg of NiCl2(1,3-bis(diphenylphosphino)propane) (0.06 mmol) and 150 mL of diethyl ether. To this mixture was added dropwise 12.8 mL of 1.0 M benzyl magnesium chloride in ether (12.8 mmol). The reaction was heated to reflux overnight and then quenched by cooling to 0° C. and adding 150 mL of 1.0 M aqueous hydrochloric acid. The organic layer was separated and washed twice with 50 mL of ether. The organic extracts were combined, dried over magnesium sulfate, filtered and the volatiles removed in vacuo to leave a dark oil. The sample was dissolved in a small amount of hexanes and purified by flash column chromatography using silica and hexanes as the elutent. Yield: 1.75 g, 66 percent
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].O>C(O)C.[Fe]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)NCCc1cccc(N)c1
Yield: 95.9 %

Procedure:
N-Acetyl-N-(3-nitrophenethyl)amine (2.1 g, Production Example 28b) was dissolved in ethanol (40 ml). To the mixture were added an iron powder (2.25 g), ammonium acetate (4.3 g) and water (20 ml), followed by heating under reflux for 1.5 hours. Solid was filtered off and washed with ethanol, and then the filtrate was partially evaporated. The residue was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.723 g, 96%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[CH3:14]C(C[AlH]CC(C)C)C>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COC(=O)c1nc(C2CC2)oc1Br
Reactant: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C2CC2)oc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 5-bromo-2-cyclopropyloxazole-4-carboxylate (120 g, 487.80 mmol, 1.00 equiv.) in tetrahydrofuran (1200 mL). This was followed by the addition of DIBAL-H (1200 mL, 4.00 equiv., 25%) dropwise with stirring at −78° C. over 15 minutes. The resulting solution was stirred for 2 hours at −78˜−10° C., then quenched by the addition of 2000 mL of 2N HCl. The resulting solution was extracted with 3×3000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from EAOAc:PE in the ratio of 1:20. This resulted in 70 g (66% yield) of ethyl 5-bromo-2-cyclopropyloxazole-4-carboxylate as a white solid. LC-MS (ES, m/z): 218 [M+H]+. H1NMR (400 MHz, CDCl3) δ: 4.459 (2H, s), 2.011˜2.065 (1H, m), 1.628 (1H, br), 1.020˜1.106 (4H, m).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>ClCCl>[CH3:34][O:33][C:31]1[CH:30]=[C:27]([CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:26]=[C:25]([O:24][CH3:23])[CH:32]=1
Reactant: OCCO
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: COc1cc(OC)cc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
4.2 ml of ethylene glycol, 4.1 ml of trimethyl orthoformate and 5 mg of p-toluenesulfonic acid are added to a solution of 5 g of 3,5 dimethoxy benzaldehyde in 100 ml of dichloromethane. It is allowed to stir for 20 more hours at 25° C. Then, it is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 5.67 g of product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:25][C:26]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1)c1ccccc1
Yield: 91.1 %

Procedure:
Following the procedure in Example 7, Step C, 5-bromo-3-(4-fluorophenoxy)pyridin-2-amine (800 mg, 2.83 mmol) and benzoyl isothiocyanate (0.457 mL, 3.39 mmol) afforded 1-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg, 91.2% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[C:27]([C:28](Cl)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=1>>[CH3:22][C:23]1[C:27]([C:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1noc(C)c1C(=O)Cl
Product: Cc1noc(C)c1C(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 40 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3,5-dimethylisoxazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.=274-275° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.08 (d, 1H), 7.73 (m, 2H), 7.54 (t, 1H), 3.42 (t, 2H), 2.99 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H), 2.21 (m, 2H), 1.90 (brm 2H), 1.58 (s, 2H); LCMS: 425 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:7])=[C:4]([N+:29]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[NH2:29][C:4]1[CH:3]=[C:2]([F:1])[CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])[CH2:15][CH2:16]1)=[O:7]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 8.7 parts of 4-fluoro-N-{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-nitrobenzamide and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of methanol and 2-propanol. The product is filtered off and dried, yielding 4.5 parts of 2-amino-N-{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-4-fluorobenzamide; mp. 229.3° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].CCCCCC.C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[Br:33][CH2:34][CH2:35][CH2:36]Br>O1CCCC1>[Br:33][CH2:34][CH2:35][CH2:36][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: BrCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: BrCCCC#CCOC1CCCCO1
Temperature: -10 °C
Yield: 47.9 %

Procedure:
Under argon flow, 13.46 g of 3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne was dissolved in 135 ml of anhydrous tetrahydrofuran, and 60 ml of 1.6 N n-butyllithium hexane solution was added dropwise over 20 minutes with stirring at −10° C. of inner temperature. The mixture was stirred for 1 hour at the same temperature. After stirring for additional 1 hour at room temperature, the inner temperature was changed to −3° C., and 16.7 ml of hexamethylphosphoric triamide (HMPA) was added to the mixture. Then 58.14 g of 1,3-dibromopropane was added in a portion at −10° C. of inner temperature, and the mixture was stirred for 12 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 12.0 g of the objective compound as colorless oil.
Reaction SMILES: O=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC=CC=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].O=P(Cl)(Cl)Cl>O>[O:21]=[C:17]1[CH2:18][CH2:19][CH2:20][N:16]1/[C:2](=[CH:7]\[CH3:8])/[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C1CCCN1
Reactant: CCC(=O)C(=O)OC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: C/C=C(/C(=O)OC)N1CCCC1=O
Yield: 35.1 %

Procedure:
A 100 ml flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with methyl 2-oxobutanoate (7.5 g, 73 mmol), toluene (50 ml, 7 vol) and 2-pyrrolidinone (8.4 ml, 111 mmol, 1.5 equiv) followed by dropwise addition of POCl3 (1.6 ml, 20 mmol, 0.27 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Stask trap for 8 hours. After cooling down the solution was washed with 10% aq KHSO4 (2×3 vol). The aqueous phase was saturated with NaCl and back extracted with toluene (1×6 vol). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford crude material (7.5 g) as an orange mobile oil. The crude oil was distilled (92-94° C., 0.1 mm Hg) and gave pure product (4.7 g, 60%) as a colourless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH:15]=[CH2:16].Cl>CN(C=O)C>[CH2:14]([NH:17][C:18]([N:10]1[C:11]([CH3:13])=[CH:12][C:8]([OH:7])=[N:9]1)=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCN=C=O
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNC(=O)n1nc(O)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.1 %

Procedure:
Potassium carbonate (3.52 g, 25.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (5.00 g, 51.0 mmol) in DMF (80 ml). Then, allylisocyanate (4.51 ml, 51.0 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate (50 ml×2). An organic layer was washed with water (50 ml×3), dried over anhydrous magnesium sulfate and then filtered to remove a desiccant, and the solvent was distilled off from a filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a white solid of N-allyl-3-hydroxy-5-methylpyrazole-1-carboxamide (4.72 g, yield: 51.1%). mp: 80-83° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.55 (d, J=0.8 Hz, 3H), 3.97 (dddt, J=1.6, 1.6, 5.8 and 5.8 Hz, 2H), 5.19 (ddt, J=1.6, 2.7 and 10.3 Hz, 1H), 5.28 (ddt, J=1.6, 2.7 and 17.2 Hz, 1H), 5.63 (d, J=0.8 Hz, 1H), 5.90 (ddt, J=5.8, 10.3 and 17.2 Hz, 1H), 6.70 (m, 1H). (Hydroxy proton was not assigned.)
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH3:32][NH:33][CH3:34]>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:33]([CH3:34])[CH3:32]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C23H23N5O3, 417.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH3:11])[N:4]=1.N12CCN(CC1)CC2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:11])[C:32]([NH:31][S:28]([C:22]2[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])(=[O:29])=[O:30])=[O:33])[N:4]=1
Reactant: CNc1nc(C)cc(OC)n1
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
To 0.8 g of 4-methoxy-6-methyl-2-methylaminopyrimidine in 25 ml of dry acetonitrile containing a few crystals of 1,4-diazabicyclo[2.2.2]octane was added 1.3 g of 2,6-dichlorobenzenesulfonyl isocyanate. The mixture was stirred at ambient temperature for 16 hours and the resultant solution was evaporated leaving a white solid. Trituration with 1-chlorobutane followed by filtration afforded 0.5 g of N-[N-(4-methoxy-6-methylpyrimidine-2-yl)-N-methylaminocarbonyl]-2,6-dichlorobenzenesulfonamide melting at 170°-171°. Infrared absorption peaks were observed at 1700 cm-1, 1600 cm-1, and 1570 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:38]([O:37][C:35](=[O:36])[O:14][C:13]1[C:12]2([CH2:15][CH2:16][N:17]([O:20][CH3:21])[CH2:18][CH2:19]2)[N:11]([O:22][CH2:23][O:24][CH3:25])[C:10](=[O:26])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:39]
Reactant: COCON1C(=O)C(c2cc(C)ccc2C)=C(O)C12CCN(OC)CC2
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)N(OCOC)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (9.0 g, 24.83 mmol), triethylamine (6.9 ml, 5.0 g, 49.66 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) in tetrahydrofuran (250 ml) at 0° C. was added a solution of ethyl chloroformate (3.09 ml, 3.5 g, 32.28 mmol) in tetrahydrofuran (20 ml) dropwise. The suspension was stirred at 0° C. for one hour, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 9.63 g of carbonic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxy-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound P1ii.2) as a white solid, mp 109-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)cc1OCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
Methyl 4-methoxysalicylate (7.91 g, 43.4 mmol), 2-(4-tert-butoxycarbonylpiperazin-1-yl)ethanol (10.0 g, 43.4 mmol), and triphenylphosphine (PPh3) (11.3 g, 43.4 mmol) in THF (190 ml) were cooled to 0° C. under N2. DIAD (8.54 ml, 43.4 mmol) was added dropwise, and the reaction allowed to warm to room temperature. After stirring for 18 h, the THF was removed in vacuo, the residue taken up in dichloromethane, and washed with water, dried, and the solvent removed in vacuo to give a yellow oil. After the oil was dissolved in diethyl ether and the solution allowed to stand for 18 h, the triphenylphosphine oxide was filtered, the solvent removed in vacuo, and the crude product purified on silica gel using preparative HPLC and a gradient of hexane and EtOAc to give 11.0 g (64.3%) of a pale yellow oil.