Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[CH3:14][C:15](C)([O-:17])C.[K+]>C1(C)C=CC=CC=1>[CH:11]([O:10][C:1]1[O:9][CH2:14][C:15](=[O:17])[C:2]=1[C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
20 g of diisopropyl malonate were initially charged in 173 g of toluene. Subsequently, 12 g of potassium tert-butoxide were added in portions at room temperature. After 2 hours, the solvent was removed under reduced pressure and admixed again with 173 g of toluene. At 0° C., 6 g of chloroacetyl chloride were added dropwise and the reaction mixture was then stirred at room temperature. Subsequently, 50 g of ice and 100 ml of water were added and the mixture was stirred for 10 minutes. The organic phase was removed and dried over magnesium sulphate. After the solvent had been removed, a 1:1 mixture of isopropyl 2-isopropoxy-4,5-dihydro-4-oxofuran-3-carboxylate (45% yield) and diisopropyl malonate was obtained. The mixture could be used thus in the next stage. With the aid of column chromatography, the isopropyl 2-isopropoxy-4,5-dihydro-4-oxofuran-3-carboxylate was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23](CC4C=CC(OC)=CC=4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[C:12]([CH3:34])=[CH:11][N:10]=1.FC1C=CC(F)=CC=1C1N=C(NC2C=CN=C3C=NN(CC4C=CC(OC)=CC=4)C=23)C(C)=CN=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:34])=[CH:11][N:10]=1
Reactant: COc1ccc(Cn2cc3nccc(Nc4nc(-c5cc(F)ccc5F)ncc4C)c3n2)cc1
Agent: COc1ccc(Cn2ncc3nccc(Nc4nc(-c5cc(F)ccc5F)ncc4C)c32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(-c2cc(F)ccc2F)nc1Nc1ccnc2cn[nH]c12
Temperature: 70 °C

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyrimidin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(2,5-difluorophenyl)-5-methylpyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and trifluoroacetic acid (48.0 mL) were combined and heated at 70° C. for 3 hours. The reaction mixture was then concentrated to dryness, suspended in DCM (50 mL) and then poured into a stirred saturated solution of sodium bicarbonate (50 mL). The mixture was sonicated and the solids were filtered and dried under vacuum. The dried solid was subsequently washed with EtOAc and dried under vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 7.39 (t, J=6.32 Hz, 2H) 7.70 (br. s., 1H) 8.16 (br. s., 1H) 8.41 (br. s., 1H) 8.64 (d, J=5.31 Hz, 1H) 8.71 (s, 1H) 10.24 (br. s., 1H) 14.48 (br. s., 1H). MS [M+H] found, 339.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].N#N>>[O:15]1[CH2:16][CH2:17][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:13][CH2:14]1
Reactant: CCOP(OCC)OCC
Reactant: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Agent: N#N
Product: CCOP(=O)(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)OCC
Temperature: 100 °C
Yield: 71.3 %

Procedure:
The aforementioned compound 1, (500 mg, 1.56 mmol) and triethyl phosphite (1.07 mL, 6.24 mmol) was mixed and heated to 100° C. for 1 hr. The reaction mixture was subjected to N2 flow over weekend to remove the excess ethyl phosphite. The resulting yellow oil was purified on a 12 g silica gel column to yield a colorless oil (420 mg, 71% yield). 1H NMR (CD2Cl2) δ ppm: 7.72 (d, J=8.4 Hz, 2H), 7.54 (dd, J1=8.4 Hz, J2=2.4 Hz, 2H), 4.1-4.0 (m, 4H), 3.77-3.72 (m, 4H), 3.25 (d, J=22.4 Hz, 2H), 3.02-2.96 (m, 4H), 1.27 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([O:21][CH3:22])[CH2:19][N:18](C(OCC2C=CC=CC=2)=O)[CH2:17]1.CCN(C(C)C)C(C)C.I[Si](C)(C)C>CN(C=O)C.CCOCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([O:21][CH3:22])[CH2:19][NH:18][CH2:17]3)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: C[Si](C)(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 114.1 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 0.27 g, 0.99 mmol) in DMF (1 mL) was added (±)-cis-benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate (Intermediate 12, 0.3 g, 1.18 mmol) and DIPEA (0.37 mL, 2.1 mmol). The mixture was heated at 80° C. overnight. The mixture was then poured into water, stirred for 1 h, and filtered. The solid was rinsed with water, dried under vacuum. The solid was dissolved in acetonitrile (5 mL) and iodotrimethylsilane (0.590 g, 2.95 mmol) was added at 0° C., then the mixture was stirred at rt for 3 h, diluted with ether and stirred at rt for 1 h. The solids were filtered and rinsed with ether and dried to afford the hydroiodide salt of 6-bromo-4-((cis-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.4 g, 84% yield) as brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.07 (s, 1H), 4.97-4.88 (m, 2H), 4.56 (br. s., 1H), 4.16-4.09 (m, 1H), 3.67 (dd, J=11.4, 7.7 Hz, 1H), 3.53-3.50 (m, 3H), 3.50-3.45 (m, 1H), 3.40-3.34 (m, 1H), 3.11 (dd, J=11.6, 8.5 Hz, 1H); MS (ES+) m/z: 353.1, 354.0 (M+H); LC retention time: 2.01 min (analytical HPLC Method J).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:22]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C.[OH2:40]>O1CCOCC1.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:25]([O-:27])(=[O:26])[C:24]1[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O-:32])=[O:40]
Reactant: O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([O-])c1ccccc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.9 g of florfenicol, 3.6 g of phthalic anhydride and 7.2 ml of triethyl amine in 36 ml of dioxane were taken in a 100 ml round bottom flask equipped with a magnetic stir bar and a drying tube. The reaction mixture was stirred at room temperature for 6 hours. After 6 hours, the contents were poured into 300 ml of cold water. The resulting gummy solid was dissolved in dichloromethane and washed thoroughly with saturated bicarbonate several times followed by water. The organic layer was dried over anhydrous sodium sulfate and concentrated over roto-evaporator. The semisolid obtained was recrystallized in a mixture of ethylacetate and hexane to obtain a solid product of 4.2 grams.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].C(=O)(O)[O-:20].[Na+].OOS([O-])=O.[K+]>O.CC(C)=O>[OH:20][C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 130.9 %

Procedure:
3-Nitro-5-methoxycarbonylphenylboronic acid (225 mg, 1.0 mmol) was added to a vigorously stirred solution of sodium hydroxide (59 mg, 1.5 mmol) in water (15 mL), followed by sodium bicarbonate (681 mg, 8.1 mmol) and acetone (1 mL). Oxone® (543 mg, 0.88 mmol) was added slowly, keeping the temperature below 8° C. The reaction mixture was stirred 5 min and quenched with sodium bisulfite (600 mg). The reaction mixture was diluted with ethyl acetate and carefully acidified with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×) and the combined organic layers were washed with water and brine and concentrated in vacuo to give 93A (258 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 3.95 (s, 3H) 7.74-7.78 (m, 1H) 7.78-7.83 (m, 1 H) 8.23-8.28 (m, 1H); LC/MS 198 (M+H).
Reaction SMILES: [Br-:1].[Li+].[C:3](=[O:11])([O:7][CH:8](Cl)[CH3:9])[O:4][CH2:5][CH3:6]>CN(C)C=O>[C:3](=[O:11])([O:7][CH:8]([Br:1])[CH3:9])[O:4][CH2:5][CH3:6]
Reactant: [Br-]
Reactant: CCOC(=O)OC(C)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Lithium bromide (17.4 g, 0.2 m) was dissolved in dimethy formamide (150 ml) and the mixture cooled to ambient temperature. Ethyl alpha-chloroethyl carbonate (30.5 g, 0.2 m) was added and the mixture stirred at ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate vacuum distilled to afford after careful re-fractionation, ethyl alpha-bromoethyl carbonate in 76% yield based upon recovered ethyl alphachloroethyl carbonate.
Reaction SMILES: Br[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1Br.Cl[Si:16](C)([CH3:18])[CH3:17]>C1COCC1>[CH3:17][Si:16]1([CH3:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)Cl
Reactant: BrC1C=CC=CC1(Br)c1ccccc1
Solvent: C1CCOC1
Product: C[Si]1(C)c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
1,2-Dibromobiphenyl (10 g, 1 eq, 0.032 mol) was placed in a flask, and THF (150 ml) was added thereto. Then, n-buthyllithium (24.1 ml, 1.2 eq, 0.038 mol) was gradually added at −78° C., the reaction mixture was stirred for 30 minutes, and chlorotrimethylsilane (4.1 g, 1.2 eq, 0.038 mol) was added thereto. The resultant solution was stirred for four hours and distilled water was added thereto, followed by stirring for about 10 minutes. The reaction solution was extracted with hexane, dried to remove the solvent and purified by column chromatography to give 5,5-dimethyl-5H-dibenzo[b,d]silole (5.17 g, yield=77%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[CH:23][NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:29](=O)([O-])[O-:30].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[C:23]([CH:29]=[O:30])[NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
By means of a syringe 0.6 ml (6.5 mmol) of phosphorous oxychloride was added to a solution of 0.7 g (2.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 8 ml of dimethylformamide which was cooled to 0°. The mixture was stirred at 0° for 1 hr, poured into 50 ml of saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red amorphous solid. Purification by column chromatography (silica gel, 20 g; 4% ether in methylene chloride, eluent) gave an off-white solid. Recrystallization from a mixture of methylene chloride and ethyl acetate gave off-white crystals, mp 274°-276°.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[CH:32]>C(O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:32][C:31]#[CH:30])[CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CCCC(c2ccc(C(C)(C)CCCCCC)cc2O)C1

Procedure:
A mixture of 0.900 g. (2.97 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]piperidine, 481 mg. (3.49 mmoles) of anhydrous potassium carbonate and 353 mg. (2.97 mmoles) of 1-bromo-2-propyne in 20 ml. of ethanol is heated at reflux for 22 hours. The reaction mixture is then evaporated and dissolved in 100 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed with two 150 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 100 g. silica gel eluted with 2% methanol-dichloromethane. The product is crystallized from pentane (117 mg., 11.5%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:28])[CH:19]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCCCCCC.CCOCC>[NH2:15][C:10]1[C:9]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:28])[CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CCCCCCC
Product: COC(=O)c1ccc(-c2cccnc2N)cc1C
Temperature: 108 °C
Yield: 62.1 %

Procedure:
To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(7.37 g, 33.5 mmol) in 500 mL round bottom flask were added methyl 4-bromo-2-methylbenzoate (6.390 g, 27.9 mmol), PdCl2(dppf)-DCM (2.041 g, 2.79 mmol), DME (209 mL) and 2 M Na2CO3 solution (69.7 mL). The reaction mixture was bubbled through N2 for 20 min and heated in an oil bath at 108° C. for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH)/heptane to provide crude product around 8 g which contained fair amount of B2(PIN)2 from previous experiment. Ether was added to dissolve the crude mixture, and then heptane was added to crush out the desired product. Solid was filtered out to provide 4.2 g of desired product with high purity in 62.1% yield. LCMS (m/z): 243.5 (MH+), 0.56 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([O:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of cis 3-((benzyloxy)methyl)-1-cyclobutanol (2.50 g, 0.0130 mol) in pyridine (50 mL) was cooled to 0° C. Methanesulfonyl chloride (1.21 mL, 1.79 g, 0.0126 mol) was added dropwise, keeping the temperature below 2° C. The mixture was stirred for four hours, and then poured into ice water (100 mL) and extracted with ethyl ether (2×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate (2.73 g, 0.0101 mol) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[K+:25]>C(O)C>[K+:25].[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)[O-])c1
Reaction time: 1 h

Procedure:
The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D, 6.0 g, 19.4 mmol) was dissolved in abs ethanol (20 ml) by warming gently followed by addition of KOH (1.21 g) at 0° C. temperature. The reaction mixture was stirred for one hour, concentrated in vacuo and lyophilized to give the title compound as white solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](O)(=O)C>Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:2]2[CH2:3][CH2:4][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1]2)=[CH:13][CH:14]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccc(C2CCc3ccccc3O2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The crude flavanone was dissolved in a mixture of acetic acid (200 ml.) and concentrated hydrochloric acid (45 ml.), warmed to 50° C., and added to wet zinc amalgam (prepared from 60 g. zinc powder and 6 g. mercuric acetate). The mixture was swirled for 15 mins., allowed to stand for 30 mins., then heated on the steam bath for 15 mins. The residual zinc was filtered off and the filtrate diluted with water. The crude product was extracted into toluene and the extract washed with water and saturated sodium bicarbonate solution. Evaporation gave a residue which was chromatographed on alkaline, alumina, eluting with toluene. The first fraction obtained on evaporation of the solvent was recrystallised from ethanol to yield 4'-methylflavan (1.4 g.). m.p. 94° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[N:16]>C1COCC1>[OH:21][CH:20]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9])[C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(C=O)c1
Reactant: OCc1cnccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccncc2CO)c1
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methanol (20 mg, 0.11 mmol) in THF (1 mL) at −78° C. was added dropwise 2.5M n-butyllithium (0.22 mL). After 15 min, a solution of 3-cyanobenzaldehyde (69 mg) in THF (0.5 mL) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4yl)-methyl]-benzonitrile as a white solid.
Reaction SMILES: CO.O.[CH3:4][C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[S:23][CH:24]=[CH:25][C:7]=2[C:6]=1[CH2:26][C:27]([O:29]C)=[O:28].[OH-].[K+]>CC(O)=O>[CH3:4][C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C:8]2[S:23][CH:24]=[CH:25][C:7]=2[C:6]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)c2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(CC(=O)O)c2ccsc2n1S(=O)(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
Methanol (0.5 mL) and water (0.5 mL) were added to the crude methyl 2-(5-methyl-6-(4-(methylsulfonyl)phenylsulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetate, followed by the addition of KOH (47.5 mg, 0.846 mmol). The mixture was stirred at ambient temperature for 1 h before adding the AcOH (0.66 mL). The reaction mixture was dried under reduced pressure (Genevac®) and the residue purified by HPLC (Table 1, Method g) to afford the title compound (0.017 g, 14.6%): LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z 412 (M−H)−; 1H NMR (DMSO) δ 8.19-8.08 (m, 4H), 7.23 (d, 1H, J=5.28 Hz), 6.96 (d, 1H, J=5.28 Hz), 3.41 (s, 2H), 3.29 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)s1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl ((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (400 mg, 0.89 mmol) in THF (60 mL) was added 10% Pd(OH)2C (3 g). The mixture was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was filtered and concentrated to afford tert-butyl ((5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate as a yellow solid, which was directly used in the next step. ESI-MS (EI+, m/z): 356.1 [M+H]+.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16](Cl)=[C:15]3[C:10]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[N:13]([CH3:19])[C:14]3=[O:18])=[N:9]2)=[CH:3][CH:2]=1.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[K])(C)(C)C>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]>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]([NH:31][C@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[C:15]3[C:10]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[N:13]([CH3:19])[C:14]3=[O:18])=[N:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4ccccc4)cc3)nc21
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(N[C@H]3CCNC3)n(Cc3ccc(-c4ccccc4)cc3)nc21
Temperature: 130 °C

Procedure:
2-(biphenyl-4-ylmethyl)-3-chloro-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.056 mmol) is dissolved in anhydrous and degassed THF, and then (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (64 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.026 mmol) and Xantphos (16 mg, 0.026 mmol) are added, followed by tBuOK (7.5 mg, 0.067 mmol). The reaction mixture is heated in microwave at 130° C. for 2.5 h. After cooling, solvent is removed. The residue is diluted with ethyl acetate (50 mL), and then washed with sodium carbonate aqueous solution three times. Solvent is removed under reduced pressure, the residue is treated with 50% TFA in CH2Cl2 (v/v) at room temperature for 6 hours. Evaporation to remove TFA and solvent, and the residue is purified by a semi-preparative HPLC to give pure product. MS (ESI) m/z 473.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:26])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([Cl:26])=[O:23])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-c2ccc(OCCCCCC(=O)O)cc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(OCCCCCC(=O)Cl)cc2)cc1

Procedure:
A solution comprising 16.3 g (52.7 mmol) of 6-(4'-cyanobiphenyl-4-oxy)caproic acid, 7.5 g (63.3 mmol) of thionyl chloride and 3 drops of dimethylformamide in 160 ml of toluene was heated at the boil for 1.5 hours. The readily volatile constituents were removed under reduced pressure at 80° C. and the residue was dried under reduced pressure at room temperature.