Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[CH:5]1([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO.Cl>C1COCC1>[NH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc(OC2CCCCC2)cn1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex (20.3 mL, 40.6 mmol, 2M solution in THF) to a solution of 5-cyclohexyloxy-pyridine-2-carbonitrile (0.82 g, 4.06 mmol) in THF (800 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Cool the mixture in an ice-bath, add methanol (15 mL) and concentrated HCl (2 mL). Stir for 2 h, and concentrate in vacuo. Dissolve the residue in saturated aqueous K2CO3. Extract with DCM and wash the organic phase with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo to obtain the title compound (0.3 g, 36%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1.N>C(O)(=O)C.C(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1
Reactant: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Agent: Br
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)c2cccnc2)ccc1O
Reaction time: 3 h

Procedure:
ca) 50 ml of 33 percent hydrobromic acid in acetic acid are added dropwise within 15 minutes at 10° to 20 g of 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride. After stirring at 20° for 3 hours, the reaction mixture is poured into a mixture of 100 ml of conc. aqueous ammonia and ice. The pH is adjusted to 6 by adding acetic acid. The methylene chloride phase is separated; the aqueous phase is extracted twice more with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone of m.p. 150°-151°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37]Cl)=[CH:31][CH:30]=1.Cl>O1CCCC1.CCCCCC>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH:23]([CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[C:24]([OH:26])=[O:25])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCCCl)cc1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(CCCC(CCc2ccc(OC)cc2)C(=O)O)cc1
Temperature: 0 °C

Procedure:
A solution of diisopropylamine (15 g, 0.148 mol) in dry tetrahydrofuran (100 ml) at -78° C. was treated dropwise with a solution of butyl lithium in hexane (100 ml of a 1.6M solution 0.16 mol) under an atmosphere of dry argon. The solution was allowed to warm up to 0° C. over 2 hours, cooled back to -78° C. and treated with a solution of 4-(4-methoxyphenyl)butyric acid (14.1 g, 0.0726 mol) in dry tetrahydrofuran (50 ml). The solution was allowed to warm up to -20° C., cooled back to -78° C. and treated dropwise over 2 hours with 3-(4-methoxyphenyl)propyl chloride (13.5 g, 0.0731 mol). The solution was allowed to warm up to room temperature, poured into excess 2N hydrochloric acid and extracted with chloroform. The combined extracts were dried (MgSO4) and the solvent was evaporated off under reduced pressure to give the crude product, which was further purified by column chromatography (silica gel, 50% chloroform in hexane) to give 5-(4-methoxyphenyl)-2-[2-(4-methoxyphenyl)ethyl]pentanoic acid as a colourless crystalline solid, m.p. 91°-94° C. (from toluene).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([N:20]=C=NC2CCCCC2)CCCCC1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[N:29]1([NH:20][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCC(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CCC(=O)c1ccccc1)NN1CCOCC1
Yield: 74.3 %

Procedure:
A solution is prepared containing 17.8 grams (0.1 mole) β-benzoyl-propionic acid in 500 ml of anhydrous tetrahydrofuran. There are then added 20.7 grams (0.1 mole) dicyclohexylcarbodiimide and 9.8 grams (0.2 mole) morpholine. The reactants are reacted at reflux for 30 hrs. The reaction mixture is allowed to cool. The cooled mixture is filtered and the filtrate is concentrated to about one-fifth its initial volume. After vacuum drying, there are obtained 19.5 grams of crystalline N-morpholinyl-β-benzoyl-propionamide having a melting point of 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:35][CH2:34][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 104.1 %

Procedure:
A solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (Preparation 1) (30.9 g, 0.11 mol) in isopropyl alcohol (600 ml) was treated with N-ethyl-N-isopropyl-2-propanamine (47.5 ml, 0.27 mol) and 2,2-diphenylethylamine (24.8 g, 0.13 mol) and the resulting mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was azeotroped from ethyl acetate. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:hexane (40:60 by volume) gradually changing to ethyl acetate:hexane (60:40 by volume) to afford the title compound as a foam (49.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][CH:20]=O)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([N+]1C2C=CC=CC=2OC=1Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N+:19]#[C-:20])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCC(Cn1cncn1)(NC=O)c1ccc(Cl)cc1
Agent: CC[n+]1c(Cl)oc2ccccc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(CCCC)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 0.40 g (1.3 mmols) of N-[2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexyl]formamide in 5 mL of methylene chloride under nitrogen was added 0.45 mL (3.26 mmols) of triethylamine. To this mixture was added a slurry of 0.439 g (1.63 mmols) of 3-ethyl-2-chlorobenzoxazolium tetrafluoroborate, which was weighed out under a nitrogen atmosphere, in 5 mL of methylene chloride. The reaction mixture was then allowed to stir at room temperature for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed once with 10% hydrochloric acid, brine, and dried over magnesium sulfate. Removal of solvents gave a crude oil which was purified by column chromatography (Merck 60 silica gel, ethyl acetate/hexane) to give 0.20 g (52%) of a clear, colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1

Procedure:
A solution of 5-(4-methylphenyl)-2H-tetrazole (W. G. Finnegan, R. A. Henry, R. Lofquist J. Am. Chem. Soc. 1958, 80, 3908.) (19.9 g, 0.12 mol), t-butanol (19.5 g, 0.26 mol) and concentrated sulfuric acid (5.84 g, 0.06 mol) in trifluoroacetic acid (122 mL) was stirred at room temperature (3 h) and then diluted with ethyl acetate (250 mL). The mixture was washed sequentially with water (2×50 mL), 10% aqueous sodium hydroxide until washings were basic, water (2×30 mL), and then dried over sodium sulfate (Na2SO4) and filtered. Following removal of the solvents in vacuo, the resultant oil was purified by HPLC on silica gel eluting with 20:1 mixture of hexanes-ethyl acetate to provide 17.5 g of 5-(4-methylphenyl)-2-(1,1-dimethylethyl)-2H-tetrazole as a clear oil, bp. 120°-122° C. (0.3 mm Hg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43]C(=O)C)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>CO>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
650 mg of compound (3) was dissolved in 46 ml of methanol and stirred together with 13.9 ml of 0.1 N aqueous NaOH at room temperature for 2 hours. The reaction solution mixed with 24 ml of water and stirred at 4° C. for 2 hours. The reaction solution was filtered, and the recovered precipitate was washed with water and dried to give 464 mg of compound (4) as a colorless powder.
Reaction SMILES: Cl.[Na].[C:3]([C:11]1[N:12]([CH2:16][CH2:17][CH:18]2[C:23](=[O:24])[O:22][C:21](C)(C)[O:20][C:19]2=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]O>>[C:3]([C:11]1[N:12]([CH2:16][CH2:17][CH:18]([C:23]([O:22][CH3:21])=[O:24])[C:19]([O:20][CH3:28])=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CO
Reactant: CC1(C)OC(=O)C(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Agent: Cl
Agent: [Na]
Product: COC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Yield: 42 %

Procedure:
To a 0° C. solution of methanol (10 mL) which had been saturated with gaseous hydrogen chloride was added a solution of the sodium salt of 2-benzoyl-1-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethyl]pyrrole (1.41 g, 3.9 mmol) in methanol (10 mL). The mixture was stirred for sixteen hours at room temperature and was then concentrated under reduced pressure. The residue was purified by chromato-graphy on silica eluting with hexane/ethyl acetate (70:30) to yield 530 mg (42%) of 2-benzoyl-1-[3,3-di(methoxycarbonyl)propyl]pyrrole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5](C(Cl)=O)=[CH:4][C:3]=1[Cl:11].C[Si](C=[N+]=[N-])(C)C.[ClH:19].CCO[C:23]([CH3:25])=[O:24]>C(#N)C.C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:23](=[O:24])[CH2:25][Cl:19])=[CH:4][C:3]=1[Cl:11]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(Br)c(Cl)c1
Reactant: Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of 4-bromo-3-chlorobenzoyl chloride (11 g, CAS 21900-32-3) in acetonitrile (50 ml) and THF (50 ml) at 0-5° C. was added dropwise (trimethylsilyl)diazomethane (26.0 ml, 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the reaction was complete. Hydrochloric acid (7.22 ml, 37% aq.) was then added dropwise at 0-5° C. over 10 minutes and the reaction mixture was then stirred at room temperature for a further 20 minutes. The reaction mixture was poured into EtOAc and extracted sequentially with aq. Na2CO3 solution, water and saturated brine. The organic layer was then dried over Na2SO4 and concentrated in vacuo to afford 1-(4-bromo-3-chlorophenyl)-2-chloroethanone (11.0 g, 95%) as a light brown solid which was used in the next step without further purification. MS (EI): 221 ([{81Br37Cl}M-CH2Cl]+), 219 ([{79Br37Cl/81Br35Cl}M-CH2Cl]+), 217 ([{79Br35Cl}M-CH2Cl]+), 193 ([{81Br37Cl}M-CH2Cl—CO]+), 191 ([{79Br37Cl/81Br35Cl}M-CH2Cl—CO]+), 189 ([{79Br35Cl}M-CH2Cl—CO]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[CH:25]1([NH:28][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[CH3:17])[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: CN1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Reactant: NC1CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A solution of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-7-methylpyrazolo[1,5-b]pyridazine (i.e. the product of Step B) (30.0 mg, 0.087 mmol) and cyclopropylamine (0.31 mL, 4.36 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated under microwave irradiation at 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-80% ethyl acetate in hexanes as eluant to give 27 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2COC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(C2COC2)C1
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 455A (0.7 g) in dichloromethane (2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 4 hours and concentrated. The concentrate was loaded onto an ion exchange column (Bond Elut Plexa column from Varian) which had been previously washed with 1:1 methanol/CH2Cl2. The trifluoroacetic acid was washed through with 1:1 methanol/CH2Cl2. The column was then eluted with 7 N NH3 in methanol to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:27][N:8]([C:6]1[C:5]([CH3:28])=[CH:4][N:3]=[C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[N:7]=1)[CH:9]1[CH2:26][CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a suspension of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (211 mg, 0.52 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (160.3 mg, 1.20 mmol) in butan-1-ol (5 mL) was added DIPEA (201.63 mg, 1.56 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a white solid (176.87 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[CH:14][N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, 3-methoxy-benzaldehyde (16.0 g, 118.518 mmol) in ethanol (160 mL) was reacted with nitro methane (7.0 mL, 118.518 mmol) and 10N NaOH (4.7 g, 118.518 mmol). The resulting mixture was stirred at 0° C. for 4 hours to afford 10.5 g of the product (49% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:20])=[C:14]([C:16]([O:18]C)=[O:17])[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:2].O.O.[OH-].[Li+]>C1COCC1.CO>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:20])=[C:14]([C:16]([OH:18])=[O:17])[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:23]
Reactant: CCN(CC)C(=O)Cn1cnc2sc(C(=O)OC)c(C)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)O)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of methyl 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (3.3 g, 10 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.26 g, 30 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.6 g of 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([CH:8]=1)[O:9][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(Cc2ccc(OC)cc2O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cc2ccc(OC)cc2Oc2ccc(C=O)cc2)cc1
Yield: 74.2 %

Procedure:
The title compound was synthesized by referring to Synthesis, 1991,(1), 63. To a solution of 5-methoxy-2-(4-methoxybenzyl)phenol (1.9 g) in N,N-dimethylacetamide (6 ml) was added 4-fluorobenzaldehyde (960 mg) and potassium carbonate (1.3 g), and the solution was refluxed for 1 hour and 10 minutes. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.0 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].N.[C:17](OC(=O)C)(=O)[CH3:18]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:13]=[C:17]([CH3:18])[O:15][N:14]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Agent: N
Solvent: O
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)no1

Procedure:
Compound of example 4 (5.5 g, 24 mmol) was refluxed in acetic anhydride (10 mL) at a temperature in the range of 115-120° C. for 2 hours. The black colored reaction mixture was cooled, diluted with water, basified with ammonia solution, and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product obtained was purified over silica gel using ethyl acetate/petroleum ether (25%-50%) as eluent and the semipurified fractions were further purified using methanol/chloroform (0.5% -1%) as eluent. Pure fractions were concentrated and crystallized using chloroform/petroleum ether, to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([Cl:19])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Combine (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid (6.55 g, 26.7 mmol), dichloromethane (10 mL), and dimethylformamide (2 drops). Add a solution of oxalyl chloride (16 mL, 2 M, 32 mmol) in dichloromethane. After 2 hours, evaporate in vacuo to give (S)-2-(3,4-dichlorophenyl)pent-4-enoyl chloride. Combine with toluene (20 mL) and slowly add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (4 mL, 40%) while maintaining the temperature of the reaction mixture at less than 10° C. When the addition is complete add toluene (40 mL). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, extract the organic layer with a saturated aqueous sodium bicarbonate solution, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane, 20% ethyl acetate/hexane, and 30% ethyl acetate/hexane to give (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid, N-methyl amide: Rf=0.50 (silica gel, 50% ethyl acetate/hexane).