Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[NH4+:18].[Cl-]>CN(C=O)C>[CH3:9][CH:14]1[CH2:13][CH2:12][N:18]([CH2:4][CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1=O
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To an ice-cold solution of NaH (0.505 g, 12.6 mmol) in DMF (20 mL) 5-methyl-pyrrolidin-2-one (1.0 g, 10.1 mmol) in DMF (10.0 mL) was added slowly. This was stirred for 30 min at 0-25° C. 2-(3-Bromo-propyl)-isoindole-1,3-dione (2.47 g, 9.0 mmol) was added and the reaction was stirred at room temperature for 16 h. A solution of saturated NH4Cl (10.0 mL) was added and extracted with ethyl acetate. Organic layer was washed with LiCl solution and concentrated. The crude was purified on silica gel using CH2Cl2/MeOH (10%) as eluent to give 2-[3-(3-methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (1.2 g, 41%).
Reaction SMILES: [C:1]([C:4]1[NH:5][N:6]([CH2:10][CH2:11][C:12]#[N:13])[C:7](=[O:9])[CH:8]=1)(=O)[NH2:2].C(#N)C.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[NH:5][N:6]([CH2:10][CH2:11][C:12]#[N:13])[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: N#CCCn1[nH]c(C(N)=O)cc1=O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCCn1[nH]c(C#N)cc1=O
Temperature: 0 °C

Procedure:
13.5 g of 3-carbamoyl-1-(2-cyanoethyl)-5-pyrazolone and 120 ml of acetonitrile were put into a 200 ml 3-neck flask. A mixture solution of 27 ml of phosphorus oxychloride and 76 ml of N,N-dimethylformamide was added dropwise at a temperature below 15° C. After completion of the addition, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was concentrated and the crystals (white color) formed were collected by filtration. Yield: 7.8 g (64.2%), Melting Point: 162° to 164° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:34]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:34])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Yield: 76 %

Procedure:
6-chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (25 g, 45.5 mmol) was charged with 1,4-dioxane (200 ml) and selenium dioxide (15.13 g, 136 mmol) and heated to reflux overnight. The white slurry eventually dissolved to a dark yellow solution. TLC and LC/MS showed good conversion to product, with some SM left. The reaction was filtered through celite, washed with DCM and purified on silica gel, 10-50% EtOAc/hexanes to provide 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (15.7 g, 34.6 mmol, 76% yield).
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[Cl:17][C:18]1[C:19]([F:30])=[C:20]([C:24]([CH3:29])=[C:25]([F:28])[C:26]=1[F:27])C(O)=O>O1CCCC1.CN(C)C=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(O)C>[Cl:17][C:18]1[C:19]([F:30])=[C:20]([C:24]([CH3:29])=[C:25]([F:28])[C:26]=1[F:27])[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(Cl)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Magnesium (240 mg), ethanol (1 ml) and carbon tetrachloride (0.1 ml) were stirred at room temperature in a three necked flask to activate them. A solution of ethyl malonate (1.5 ml) in tetrahydrofuran (8 ml) was slowly added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (0.8 ml) and N,N-dimethylformamide (1 drop) were added to a solution of 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid (2 g) in methylene chloride (5 ml). The mixture was stirred at room temperature for 3.5 hours, and the solvent and reagents remaining in the reaction mixture were distilled off under reduced pressure. Toluene was added to the residue to conduct azeotropic distillation. The resultant residue was dissolved in tetrahydrofuran (5 ml), and the solution was slowly added dropwise at -40° C. to the reaction mixture obtained previously. After completion of the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The solvent in the reaction mixture was distilled off, and 12N hydrochloric acid (2 ml) was added to the resultant residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off under reduced pressure. Water (10 ml) and p-toluenesulfonic acid monohydrate (100 mg) were added to the resultant residue, and the mixture was stirred for 4.5 hours while heating under reflux. After the reaction mixture was allowed to cool, it was extracted with chloroform. An organic layer was washed with water dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to obtain the title compound (600 mg) as a pale yellow oil from a fraction eluted with a 1:10 mixture of ethyl acetate and hexane.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[N:66]1([CH2:72][CH2:73][NH2:74])[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH2:73][CH2:72][N:66]5[CH2:71][CH2:70][O:69][CH2:68][CH2:67]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCN1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCCN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.016 g (0.12 mmole) 2-morpholin-4-yl-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.036 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-morpholin-4-yl-ethyl)-benzamide (I-117) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C(#N)C>[CH3:27][C:15]([NH:14][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:26])[CH2:16][NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: CC(C)(N)CNc1ccc(C#N)cn1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CNc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.255 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 6-(2-amino-2-methyl-propylamino)-nicotinonitrile (0.1 g, 0.51 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a white solid. MS (DCI) m/z 351 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.03-2.5 (2H, m), 2.55 (2H, s), 2.1 (2H, s), 3.5 (1H, m), 3.82 (6H, s), 3.9-4.6 (2H, m), 4.7-4.82 (1H, m), 4.88-5.5 (1H, m), 7.3-7.5 (3H, m).
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[N:1]1[CH2:6][CH2:5][N:4]([C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:32])([F:16])[F:33])[O:22][N:21]=3)[CH:24]=2)=[O:27])[CH2:3][CH2:2]1
Reactant: c1ccc2[nH]c(N3CCNCC3)nc2c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nc3ccccc3[nH]2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from 2-(piperazin-1-yl)-1H-benzo[d]imidazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.19-8.17 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.76-7.72 (m, 2H), 7.21 (m, 2H), 6.94 (m, 2H), 3.80 (m, 2H), 3.63-3.52 (m, 6H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 441.4 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[F:13])([O-:3])=[O:2].O=S(Cl)Cl.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.O1CCCC1.ClCCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:10])=[CH:6][C:5]=1[F:13])([O-:3])=[O:2]
Reactant: Nc1nccs1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 65 °C
Yield: 35 %

Procedure:
4-Nitro-3-fluoro benzoic acid (535 mmol) was dissolved in toluene (500 mL) and tetrahydrofuran (THF) (75 mL). SOCl2 (930 mmol) was added and the mixture was heated at 65° C. for 5 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue was re-dissolved in 1,2-dichloroethane. This solution was added dropwise to a suspension of 2-aminothiazole (480 mmol) and DIPEA (370 mmol) in 1,2-dichloroethane (1 L) with mechanical stirring, while the temperature was kept at 45° C. Upon complete addition the reaction mixture was heated at 60° C. for 1.5 h, then allowed to cool to room temperature and stirred over night. The reaction mixture was filtered, the solids were washed with 1,2-dichloroethane and dried in vacuo to give 4-nitro-3-fluoro-N-thiazol-2-yl-benzamide.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:30][C:31]([N:4]1[C@H:3]([CH2:2][OH:1])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reaction time: 3 h
Yield: 86 %

Procedure:
2.02 g of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 24 ml of methanol, and 1.5 ml of triethylamine and 1.8 ml of benzyloxycarbonyl chloride are added dropwise to the mixture. The mixture is stirred at 5°-10° C. for 3 hours, and the mixture is evaporated to remove the solvent. The residue is dissolved in ethyl acetate. The solution is washed with water, a 0.5M citric acid solution and water, dried and then evaporated to remove the solvent. 2.90 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are obtained as colorless oil. Yield: 86%
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.[CH:20](=O)[CH3:21]>CO>[CH2:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH3:21]
Reactant: CC=O
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g of ethyl 4-aminocinnamate in 100 ml of methanol, 0.1 ml of acetaldehyde, 1.256 g of sodium cyanoborohydride and 2.15 ml of hydrochloric acid 23% were added. The solution was stirred at room temperature for one day, then the solvent evaporated in vacuum and the crude residue purified by flash chromatography (n-exane/ethyl acetate 9/1) to yield 2.1 g of intermediate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+:17]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:8]2[CH:7]=[N:17][CH:13]=[CH:14][C:10]=2[O:11][CH3:12])=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1cc(Br)c(-c2ccco2)nc1N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Yield: 56 %

Procedure:
A solution of 2-amino-5-bromo-6-(2-furyl)nicotinonitrile (1.80 g, 6.82 mmol), 2-methoxy-5-(1,1,1-tributylstannyl)pyridine (5.20 g, 13.1 mmol) and dichlorobis(triphenylphosphine) palladium (II) (480 mg, 0.634 mmol) in N,N-dimethylformamide (18 ml) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=8:1, 4:1), and then suspended in diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (1.12 g, 56%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1.[CH2:25]([CH:33]([CH2:36]O)[CH2:34][OH:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:7]([CH:8]2[O:35][CH2:34][CH:33]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:36][O:9]2)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)c(F)n2)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(C3OCC(CCCCCCCC)CO3)c(F)n2)cc1
Yield: 41.9 %

Procedure:
2.20 g (6.68 mmol) of 2-fluoro-3-formyl-6-(4-octyloxyphenyl)pyridine, 1.26 g (6.68 mmol) of 2-octylpropane-1,3-diol, 0.02g (0.10mmol) of p-toluenesulfonic acid and 3.00 g of sodium sulfate are stirred in 100 ml of toluene at room temperature for 68 hours. 0.14 ml (1.00 mmol) of triethylamine is then added, sodium sulfate is filtered off, the filtrate is concentrated, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.40 g of 2-fluoro-3-(5-octyl-1,3-dioxane-2-yl)-6-(4-octyloxyphenyl)pyridine. ##STR63##
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.C1(P(=[CH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[CH:28]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(C(=O)O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=C1CC(C(=O)O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 3-oxocyclobutanecarboxylic acid (0.303 g, 2.66 mmol), tert-butyl triphenylphosphoranylidenacetate (1 g, 2.66 mmol) and toluene (5 mL) was stirred overnight at 90° C. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 70→100% ethyl acetate/hexane) to give 3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (0.500 g, 2.356 mmol, 89%) as pale-yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=[O:2].P([O-])(O)(O)=[O:32].[Na+].OO.Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+].Cl>C(#N)C.O>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([NH:22][C:5]1[C:4]([CH3:30])=[C:3]([C:1]([OH:32])=[O:2])[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]=1[CH3:21])=[O:29]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: O=S([O-])O
Agent: OO
Solvent: O
Solvent: CC#N
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(=O)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 2 h
Yield: 269.1 %

Procedure:
To a mixed solution of N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.23 mmol) obtained in Example 20, sodium dihydrogenphosphate (40 mg), and hydrogen peroxide (0.125 mL) in acetonitrile (5 mL)-water (2 mL) was added at room temperature a solution of sodium chlorite (190 mg, 1.69 mmol) in water (2 mL) and the resulting mixture was stirred at the same temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfite solution, added 1 N hydrochloric acid to make the mixture acidic, and the mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 380 mg (yield: 73%) of the title compound. Melting point: 194-195° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]
Reactant: Fc1cccc(CCl)c1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
A mixture of 3-fluorobenzyl chloride (0.71 g; 4.91 mmol), 3-hydroxybenzaldehyde (0.6 g; 4.91 mmol) and Cs2CO3 (1.6 g; 4.91 mmol) in anhydrous DMF (5 ml) was stirred for 4 h at ˜60° C. under N2, cooled to room temperature and poured onto H2O (15 ml). The precipitate formed was filtered off, washed with H2O and dried in vacuo to give the title compound (0.9 g; 80%), as creamy solid. 1H-NMR (CDCl3) 5.11 (s, 2H); 7.13-7.25 (m, 3H+CDCl3); 7.3-7.36 (m, 1H); 7.44-7.48 (m, 3H); 9.96 (5, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCOC1>O>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:22]=1[O:21][CH3:20])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc2cc(SCc3ccccc3)ccc12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: C1COCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(SCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinoline (3.101 g, 10.85 mmol)-(2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (2.86 g, 13.02 mmol), Pd(AmPhos)2Cl2 (0.384 g, 0.543 mmol), potassium phosphate (6.91 g, 32.6 mmol), 1,3-dioxane (27.1 ml), and water (9.04 ml). The vial was flushed with Ar (g), fitted with a reflux condenser, and placed in a 100° C. heating bath for 45 min. The mixture was cooled to room temperature, then diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (120-g, 10 to 40% EtOAc/Heptane) to give 6-(benzylthio)-1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline (4.47 g, 10.51 mmol, 97% yield) as a light-yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.58 (d, J=5.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.26 (m, 8H), 4.31 (s, 2H), 3.76 (s, 3H); m/z (ESI) 426.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.CCCCC=CCCCCC.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:25])[N:33]=1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: CCCCC=CCCCCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a solution containing 0.62 g of the sulfonamide prepared in Example 3 contained in 10 ml of p-dioxane was added 0.6 g of phenyl(4.6-dimethoxy pyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1,5-diazbicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 100 ml of water. The clear solution was acidified with concentrated hydrochloric acid (red to litmus paper), to give a viscous oil. The oil was triturated by decanting off the aqueous solvent and stirring the oil residue in about 5 ml of acetonitrile. After filtering the suspension, the solid residue was washed with 1×5 ml of warm ethyl acetate to give 0.26 g of the subject compound; m.p. 174°-177° C.