Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.CS([Cl:27])(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Cl:27])=[CH:17][CH:16]=1
Reactant: CC(C)Cn1nnc2c(Br)c(-c3ccc(CO)cc3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CCl)cc3)ccc21
Reaction time: 2 h

Procedure:
To a solution of {4-[4-bromo-1-(2-methylpropyl)-1H-benzotriazol-5-yl]phenyl}methanol (234 mg, 0.650 mmol) in dichloromethane (5 ml) at 0° C. was treated with methanesulfonyl chloride (0.056 ml, 0.715 mmol), followed by the dropwise addition of triethylamine (0.181 ml, 1.299 mmol). After 2 hours, the mixture was purified via silica gel chromatography (acetone/dichloromethane gradient), providing the titled compound as white solid. LRMS m/z (M+H) 377.9 and 379.9 found, 378.03 and 380.03 required.
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N1CCCN(C2C=C(CC)C3C(C=2)=[S+][C:59]2[C:54](=C(C)C=[CH:57][CH:58]=2)[N:53]=3)CC1)(OC(C)(C)C)=O.C(N1CCCN(C2C=C(CC)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(OC(C)(C)C)=O.N1CCCC1>CO>[I-:1].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([N:53]4[CH2:54][CH2:59][CH2:58][CH2:57]4)[CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: C1CCNC1
Solvent: CO
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12

Procedure:
a solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-phenothiazin-5-ium triiodide (100 mg, 0.12 mmol) in methanol (10 mL) and pyrrolidine (71 mg, 1.0 mmol) was stirred for 4 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([C:25]([F:28])([F:27])[F:26])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([C:25]([F:27])([F:26])[F:28])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A mixture of 310 mg (0.77 mmol) of 3-[4-(hydroxymethyl)phenyl]-5-(4-phenyl-5-trifluoromethyl-2-thienyl)-1,2,4-oxadiazole (from Step E), 527 mg (1.5 mmol) of 4-methylmorpholine N-oxide and 500 mg of 4 A molecular sieves in 15 mL of CH3CN was treated with 12 mg (0.034 mmol) of tetrapropylammonium perruthenate and the resulting mixture was stirred ar rt for 2 h. The solids were filtered and the filtrated was concentrated. Chromatography on a Biotage 40 S cartridge using 9:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 205 mg (66%) of the title compound: 1H NMR (500 MHz) δ 7.48 (app s, 5H), 7.93 (app s, 1H), 8.03 (d, J=8.5, 2H), 8.33 (d, J=8.5, 2H), 10.1 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]2[NH:9][CH:12]=[CH:13][C:3]=12
Reactant: C=C[Mg]Br
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ncc(Br)c2cc[nH]c12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
5-Bromo-2-methyl-3-nitropyridine (217 mg, 1 mmol) was dissolved in THF (10 mL) and the solution was cooled to −50° C. under argon. Vinylmagnesium bromide (3 mL, 1M in THF) was added immediately in one portion, resulting in a bright orange solution. The orange solution was stirred at −40° C. for 30 min and the reaction was quenched by the addition of NH4Cl (10 mL of saturated. aqueous solution). The mixture was diluted with water and extracted with EtOAc (2×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude material was purified by chromatography on silica (Si—PPC) using EtOAc in cyclohexane (20-80%) as eluent to give the product as a pale yellow crystalline solid (63 mg, 30%). 1H NMR (CDCl3) 8.23 (s, 1H), 7.41-7.45 (m, 1H), 6.62-6.65 (m, 1H), 2.73 (s, 3H)
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].CO[C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:15]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][O:6][C:14]([CH:16]1[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH2:25][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:23])[CH2:20][CH2:21]1)=[O:15])[CH2:2][CH3:3]
Reactant: CCCCCC(CO)CCC
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(CCC)COC(=O)C1CCC(C(=O)OCC(CCC)CCCCC)CC1
Temperature: 185 °C

Procedure:
2-Propylheptyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 81.8%, trans 18.2%, SK NJC, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(2-propylheptyl)cyclohexane-1,4-dicarboxylate (cis 81%, trans 19%) was obtained with a purity of 99.3% in the same manner as in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[CH:4]=[C:5]([C:8]([NH:10][NH:11][C:12](=[O:28])[C:13]([CH3:27])([O:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH3:14])=[O:9])[NH:6][CH:7]=1.CNN.C(O)C>CN(C)C=O>[NH2:16][O:15][C:13]([CH3:27])([CH3:14])[C:12]([NH:11][NH:10][C:8]([C:5]1[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:29])[CH:4]=1)=[O:9])=[O:28]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1
Agent: CNN
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(ON)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1

Procedure:
0.670 g (1.675 mmol) of 1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl)carbonyl]-2-[2-methyl-2-(phthalimidooxy)propionyl]hydrazine was dissolved in 1.5 ml of dimethylformamide and treated with 0.077 g (1.675 mmol) of methylhydrazine. After stirring for 21/2 hours at room temperature about 2 ml of ethanol were added. The crystals obtained were filtered off and discarded. The filtrate was evaporated under strongly reduced pressure and the product was crystallized from ethanol. 1-[2-(aminooxy)-2-methylpropionyl]-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl)carbonyl]hydrazine was obtained as white crystals melting at 234° (dec.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.S(=O)(=O)(O)[OH:28]>>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]([NH2:25])=[O:28])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Reactant: O=S(=O)(O)O
Product: Cc1nc(N)sc1-c1ccnc(C2(C(N)=O)CCC2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of {5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 19.2) (640 mg, 1.73 mmol) and concentrated sulfuric acid is stirred for 40 min at 0° C., allowed to warm to rt, stirred for 1 h, quenched by addition of a saturated solution of NaHCO3 (50 mL) and extracted with DCM (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 99:0:1→93:6:1) to afford 35 mg of the title compound as a yellow solid: ESI-MS: 289.1 [M+H]+; TLC: Rf=0.32 (DCM/MeOH, 9:1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=2)[NH:25][N:24]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N:12]1[CH:11]=[CH:10][C:9]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=3)[NH:25][N:24]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc2[nH]nc(Br)c2c1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.965 g, 4.70 mmol), PdCl2(dppf)-CH2Cl2 (0.256 g, 0.314 mmol), sodium carbonate (3.14 mL, 6.27 mmol) and methyl 3-bromo-1H-indazole-5-carboxylate (0.8 g, 3.14 mmol) were taken up in 1,4-dioxane (15 mL). The flask was evacuated and back-filled with N2 (×3) before stirring at 100° C. for 24 hours. Room temperature was attained, the reaction mixture was diluted with MeOH, filtered through Celite and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave methyl 3-pyridin-4-yl-1H-indazole-5-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[C:9]=2[C:10]=1[CH2:11][CH3:12].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20]N2CCOCC2)[CH2:16][CH2:15]1>>[CH3:12][CH2:11][C:10]1[C:9]2[C:8]([CH:7]([CH2:20][N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH2:6][CH2:5][C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: C1CN(CN2CCOCC2)CCO1
Reactant: CCc1c(C)[nH]c2c1C(=O)CCC2
Product: CCc1c(C)[nH]c2c1C(=O)C(CN1CCOCC1)CC2

Procedure:
For the sake of convenience and without putting any limitations thereof, the methods of manufacture of molindone have been separated into several independent steps, each independent step being disclosed herein in a multiplicity of non-limiting and independent embodiments. These independent steps comprise steps 1-3 and optional steps 4 and 5, wherein in the 1st step 2,3-pentadione is reacted with hydroxylamine hydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); and in the 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts with bismorpholinomethane to produce molindone (SUMO-3). In the 4th step molindone is converted into a molindone salt; and in the 5th step the molindone salt is purified/recrystallized, and various polymorphic forms of the molindone salt are prepared.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][N:15]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2nc(Br)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN(CCCN(C)C(=O)c1ccc2nc(Br)sc2c1)C(=O)OC(C)(C)C
Yield: 77.1 %

Procedure:
The compound (100 mg, 0.387 mmol) obtained in Example 93a, tert-butyl methyl[3-(methylamino)propyl]carbamate (78 mg, 0.387 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.464 mmol) were used to give the title compound (132 mg; yield, 77%) as a yellow oily substance according to the method described in Example 89b.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1>O1CCOCC1>[CH:4]1[C:3]([CH:2]=[O:1])=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: OCc1ccc(CO)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(C=O)cc1
Reaction time: 0 h
Yield: 63 %

Procedure:
Using a similar method to Example 1, a mixture of 200 parts of 4-(hydroxymethyl)-benzyl alcohol and 400 parts of dioxane with 290 parts of air is passed per hour over the catalyst at 600° C. and 1.1 bar. The residence time is 0.05 second and the throughput is 0.3 tonne/m2.h. 124 parts of terephthaldialdehyde (in the form of a 22 percent strength by weight solution) are obtained per hour, corresponding to a yield of 63% of theory. The conversion is 92 percent and the space-time yield is 6 grams of terephthaldialdehyde per cm3 of catalyst volume per hour.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:21]([CH:25]=2)[C:22]([OH:24])=O)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:21]([CH:25]=2)[C:22]([NH:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[O:24])(=[O:16])=[O:15])[CH2:12][CH2:13]1
Reactant: Nc1cccnc1
Reactant: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.03 ml, 0.31 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-[(4-methyl-1-piperazinyl)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 72; 120 mg, 0.31 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated to give crude acyl chloride. A solution of this acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (28.9 mg, 0.31 mmol) and diisopropylethylamine (0.05 ml, 0.31 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as an orange oil. The crude product was crystallized from methanol to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH3:24])[O:21][C:20]=2[CH3:25])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH3:24])[O:21][C:20]=2[CH3:25])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(C)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of cyclohexyl(2,5-dimethylfuran-3-yl)methanol (521 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (456 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.2 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.2 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-[cyclohexyl(2,5-dimethylfuran-3-yl)methoxy]benzoate as an oil. The obtained methyl 4-[cyclohexyl(2,5-dimethylfuran-3-yl)methoxy]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give the title compound (501 mg, 61%) as a white crystal.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([O:22]CC)=[O:21].[Mg].BrC1C=CC=CC=1OC.COC1C=CC=CC=1[Mg]Br.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>C1COCC1.C1COCC1.CCOCC>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccccc1Br
Agent: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 0.25 h

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To dry magnesium turnings (81 mg, 3.4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([O-])=O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1ccc(Oc2cccc(N)c2)cc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Iron powder (5.03 g; 56 mmol), water (5 mL) and hydrochloric acid (0.1 mL; 36 mmol) are added consecutively to a solution of methyl 2-[4-(3-nitrophenoxy)phenyl]acetate (1.3 g; 4.5 mmol) in ethanol (20 mL). After stirring at 95° C. for four hours, the solid is filtered while still hot and the filtrate is stripped of solvent in vacuo to yield methyl 2-[4-(3-aminophenoxy)phenyl]acetate as an oil. Yield: 1.1 g (95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=O)[CH3:9])=[CH:3][CH:2]=1.[CH3:11][C:12](=[CH2:16])[C:13]([NH2:15])=[O:14].[K].CC(C)([O-])C>O1CCOCC1>[CH3:11][CH:12]1[CH2:16][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:8]([CH3:9])[NH:15][C:13]1=[O:14]
Reactant: CC(=O)Cc1ccncc1
Reactant: C=C(C)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: C1COCCO1
Product: CC1=C(c2ccncc2)CC(C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.5 %

Procedure:
A mixture containing 35 g of 1-(4-pyridinyl)-2-propanone, 25 g of α-methylacrylamide, 30 g of potassium-tert.-butoxide and 250 ml of p-dioxane was stirred at ambient temperature for 40 minutes during which time an exothermic reaction occurred. The reaction mixture was then heated on a steam bath for 90 minutes and stripped to dryness on a rotary evaporator. To the residue was added 200 ml of water and the aqueous mixture was acidified with acetic acid. The product was extracted with chloroform (two 300 ml portions) and the combined extracts stripped to dryness in vacuo. The gummy solid was dissolved in 200 ml of isopropyl alcohol, the hot solution treated with decolorizing charcoal and filtered, and the filtrate diluted with 300 ml of n-hexane. The crystalline precipitate was collected and dried in an oven at 80° C. to yield 25.4 g of 3,4-dihydro-3,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 148°-150° C. A second crop of 4.3 g, m.p. 147-150, was obtained from the mother liquor. The nmr spectrum of the product was consistent with the assigned structure.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:6]1[O:7][C:8](=[O:21])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[N:18][NH:19][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:5].[Cl:22][C:23]1[C:24]2[S:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1>CC(O)(C)C>[ClH:22].[NH:18]1[CH:17]=[C:16]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:21])[O:7][C:6]=2[CH:4]([NH:3][C:23]2[C:24]3[S:31][CH:30]=[CH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:5])[CH:20]=[N:19]1
Reactant: Clc1ncnc2ccsc12
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Yield: 29.8 %

Procedure:
3-(1-aminoethyl)-4-(1H-pyrazol-4-yl)-1H-isochromen-1-one dihydrochloride (Intermediate E4, 62 mg, 0.189 mmol), 4-chlorothieno[3,2-d]pyrimidine (45.1 mg, 0.264 mmol), TEA (0.092 ml, 0.661 mmol) were reacted in t-BuOH (1.1 ml) at 85° C. for 2 hrs and 90° C. for 4 hrs. The reaction was quenched by the addition of 1M HClaqueous (2 ml) and purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give the title compound (24 mg, 29.8%) as yellowish solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Brc1ccncc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccncc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-bromopyridine.
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([CH3:11])([OH:10])[CH:6]=[C:7]([CH3:9])[CH3:8])=[CH2:3].[OH-].[K+].C(O)(=O)C>CN(C)C=O>[CH3:11][C:5]([CH2:6][C:7]([CH3:9])=[CH2:8])([CH2:4][C:2]#[CH:3])[OH:10]
Reactant: C=C(Cl)CC(C)(O)C=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCC(C)(O)CC(=C)C

Procedure:
10.00 Grams of the 2-chloro-4,6-dimethyl-1,5-heptadien-4-ol obtained above were dissolved in 94 g of N,N-dimethylformamide, and 9.65 g of potassium hydroxide in a flake form were added. The resultant mixture was stirred at room temperature for 4 hours and neutralized with a 20% acetic acid aqueous solution, and the resultant mixture was subjected to extraction with toluene. The toluene phase was washed with water and then dried over magnesium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 6.32 g of methyl 2-methylallylpropargylcarbinol; nD25 =1.496, FI-MS m/e 138 (M+) (Propargyl compound/allene compound=100.0/0.0).