Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([C:17](=[O:19])[CH3:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[CH:20](OCC)=[O:21]>Cl>[OH:21][CH:20]1[CH2:18][C:17](=[O:19])[C:4]2[C:3](=[CH:12][C:11]3[C:10]([CH3:13])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:16])([CH3:15])[C:6]=3[CH:5]=2)[O:2]1
Reactant: CCOC=O
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na]
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OC(O)CC3=O
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A 200-mL round bottom flask was flame dried under nitrogen and charged with sodium metal (3.2 g, 140 mmol). A solution of 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethanone (15 g, 61.0 mmol) in ethyl formate (350 mL) was added dropwise over 1 h. The resulting yellow solution was stirred at 35° C. for 4 h. The mixture was cooled to 25° C. solution, diluted with 1N HCl (20 mL) and extracted with ether. The extracts were washed with water, brine, and dried over MgSO4. The extracts were concentrated under vacuum to give 2-hydroxy-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-one: 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H, ArH), 6.9 (s, 1H, ArH), 5,85 (t, 1H, CH), 3.32 (br s, 1H, OH), 2.9 (dd, 2H, CH2), 1.67 (s, 4H, 2CH2), 1.27 (s, 12H, 4CH3).
Reaction SMILES: Br.Br[CH:3]([C:5]1[O:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].[NH:23]1[C:27]2=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]2[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([CH:3]([C:5]3[O:6][C:7](=[O:22])[C:8]4[C:13]([C:14]=3[C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH3:4])[N:24]=[CH:25][C:26]=12
Reactant: Cc1ccc(-c2c(C(C)Br)oc(=O)c3ccccc23)cn1
Reactant: Nc1ncnc2[nH]ncc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(C)n3ncc4c(N)ncnc43)oc(=O)c3ccccc23)cn1
Yield: 14.9 %

Procedure:
3-(1-Bromoethyl)-4-(6-methylpyridin-3-yl)-1H-isochromen-1-one hydrobromide (intermediate C10, 120 mg, 0.282 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (76 mg, 0.565 mmol), and K2CO3 (117 mg, 0.847 mmol) were stirred in DMF (1.5 ml) at 50° C. for 2.5 hrs. The reaction mixture was diluted with 1M HClaqueous (2 ml) and purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound as colourless solid (16.7 mg, 15%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 2'mg of t-butyl 4-(2-ethoxy-2-oxoethyl)-tetrahydropyridine-1(2H)-carboxylate in 15 ml of tetrahydrofuran, 100 mg of lithiumaluminum hydride was added under cooling with ice, followed by 20 minutes' stirring at the same temperature. To the reaction liquid sodium sulfate decahydrate was added, stirred for 30 minutes and filtered with Celite. Distilling the solvent off under reduced pressure, 207 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([CH:15]=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C)C=O.O>[Br:29][C:15]1[C:16]2[C:21]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:9]3[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Brc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
9-(4-Bromophenyl)anthracene (6.3 g, 19 mmole) was dissolved in anhydrous dimethylformamide (DMF) (100 ml). To the resultant solution, a solution (15 ml) of NBS (3.7 g, 21 mmole, 1.1 eq) in anhydrous DMF was added and the obtained mixture was stirred at the room temperature for 7 hours and left standing for one night. After the reaction mixture was diluted with water (30 ml), the formed solid was separated by filtration and washed with methanol and a yellow solid (6.0 g, 77%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[H][H]>CCO.Cl.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: [H][H]
Reactant: C=CCC(C(=O)O)c1ccc(C)c(-c2ccccn2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC(C(=O)O)c1ccc(C)c(-c2ccccn2)c1
Yield: 59.6 %

Procedure:
4-Methyl-3-(2-pyridyl)phenyl-pent-4-enoic acid (0.5 g, 1.87 mmol) was dissolved in EtOH (15 ml) and 6N HCl (0.15 ml). 10% Palladium on carbon (0.08 g) was added and the reaction mixture was stirred under a balloon of hydrogen gas overnight. Then, additional 10% palladium on carbon (0.09 g) and 6N HCl (0.2 ml) were added and the reaction was stirred under a balloon of hydrogen gas for an additional 6 h. The reaction mixture was then filtered through a pad of Celite, azeotroped with toluene (40 ml) and was suspended in water (3 ml). Aqueous sodium hydroxide (1 M) was then added dropwise until the pH was adjusted to 7. The aqueous layer was then extracted with chloroform 2 times and the combined organics were dried with magnesium sulfate, concentrated in vacuo, and triturated with hexanes/Et2O to yield a white solid (0.3 g, 60%): MS ES(+) 270.1 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O:13]1[CH:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>>[ClH:1].[OH:13][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(O)cc1
Agent: Cl
Product: Oc1ccc(OCCNCC(O)COc2ccccc2)cc1
Yield: 15.6 %

Procedure:
A mixture of p-(2-aminoethoxy)phenol hydrochloride (1.89 g) triethylamine (1.01 g) and 1,2-epoxy-3-phenoxypropane (1.5 g) was heated under reflux for 24 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic layer was separated, dried (MgSO4), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen chloride was passed through the solution until no further solid precipitated. The precipitate was collected and recrystallised from methanol and ethyl acetate to give p-(2-[2-hydroxy-3-phenoxypropylamino]-ethoxy)phenol hydrochloride (0.53 g), mp, 171°-72° C.; microanalysis: found C,60.3; H,6.7; N,4.0; Cl, 10.6%; required for C17H22NClO4 : C,60.1; H,6.5; N,4.1; Cl,10.5%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[CH:10]=[CH:9]1.[C:21]1(I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:21]1([C:9]2[CH2:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1ccccc1
Reactant: C1=Cc2ccc3ccccc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C1=C(c2ccccc2)Cc2c1ccc1ccccc21
Temperature: 25 °C
Yield: 49.5 %

Procedure:
20 ml of triethylamine, 3.32 g (20 mmole) of benzindene, 4.08 g (20 mmole) of phenyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 2.4 g (50%) of the mixture of two isomers.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N:1]1([CH2:14][CH2:15][C:16]([NH:24][CH2:21][CH2:22][CH3:23])=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCCN
Reactant: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Product: CCCNC(=O)CCn1cnc2cnc3ccccc3c21

Procedure:
Ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate (3.75 g, 13.9 mmol, prepared as described in Part A of Example 20) was treated with n-propylamine (11.4 mL, 139 mmol) according to the method described in Part B of Example 20 to provide 3.9 g of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:20]
Reactant: CC(C)Br
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
30.3 g of bis(p-hydroxyphenyl)sulfone, 18.5 g of isopropylbromide, and 22.2 g of potassium carbonate as acid-binding agent were added to 200 ml of dimethylformamide, then stirred for 4 hours at about 120° C. and dimethylformamide was distilled off under reduced pressure. When this was accomplished, chloroform was added to the residue to extract crude 4-hydroxy-4'-isopropoxydiphenylsulfone. Then this crude compound was refined by using a silica gel column chromatography and 15.7 g of 4-hydroxy-4'-isopropoxydiphenylsulfone was obtained in white microfine crystals with a melting point of 129.0°~131.0° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.C1([SiH3])C=CC=CC=1.C([OH:46])(C)C.C(Cl)Cl>[Co]>[OH:46][C:2]([CH3:1])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([B:19]3[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23]3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)N1
Reactant: CC(C)O
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of (S)-4-(2-methylallyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (260 mg, 0.55 mmol) in 2:1 i-propanol/CH2Cl2 (10 mL) was added cobalt catalyst A (7 mg, 2% mol) and phenylsilane (1 mL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction completed. The mixture was quenched with 1% aq HCl, concentrated and purified by chromatography on a 12 g-silica gel cartridge, eluted with a 50˜100% EtOAc in hexanes gradient, to afford (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (163 mg, 60%). LC-MS Method 1 tR==2.13 min., m/z 492(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].[I:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](I)[CH:20]=1.[C@H]1(N)CCCC[C@@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:19]1[CH:18]=[N:17][CH:16]=[C:15]([I:14])[CH:20]=1)[C:5]2([CH3:13])[CH3:12]
Reactant: Ic1cncc(I)c1
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(I)c1
Temperature: 110 °C
Yield: 62.1 %

Procedure:
A mixture of 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12) (390 mg, 2 mmol), 3,5-diiodo-pyridine (662 mg, 2 mmol), CuI (38 mg, 0.2 mmol), (1S,2S)-cyclohexane-1,2-diamine (45 mg, 0.4 mmol) and K3PO4 (888 mg, 4 mmol) were dissolved in dioxane (10 mL). The reaction mixture was heated at 110° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (25 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (495 mg, 62%) as a white solid. MS: 399.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10](OCC)=[O:11])[N:5]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:3]=1.O.[NH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]([NH:25][NH2:26])=[O:11])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 1.1 g of (6-chloro-4-p-chlorobenzylamino-2pyrimidinylthio)acetic acid, ethyl ester 0.18 g of hydrazine hydrate (98%) and 0.3 g of sodium carbonate in 15 ml. of ethanol was heated under reflux for 3 hr. The reaction mixture was filtered and the filtrate diluted with water until a precipitate appeared. The solid was washed with aqueous (10%) sodium carbonate then recrystallized from ethanol to a mp. of 178-182°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[NH2:33][CH2:34][CH2:35][C:36]1[C:37]([N:45]([CH3:47])[CH3:46])=[N:38][C:39]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][CH:41]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:33][CH2:34][CH2:35][C:36]3[C:37]([N:45]([CH3:46])[CH3:47])=[N:38][C:39]([CH:42]4[CH2:43][CH2:44]4)=[CH:40][CH:41]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CN(C)c1nc(C2CC2)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4N(C)C)cc3)c(Cl)cc21
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 200 mg, 0.531 mmol) was diluted with dichloromethane (2 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (292 μL, 0.584 mmol) and dimethylformamide (1 drop). After stirring for 15 minutes, 3-(2-aminoethyl)-6-cyclopropyl-N,N-dimethylpyridin-2-amine (109 mg, 0.531 mmol) and diisopropyl ethylamine (277 μL, 1.59 mmol) were added. After stirring for 2 hours, the reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (77 mg, 0.137 mmol, 25.7% yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@H:20]2[C@@H:24]3[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@@H:23]3[C@@H:22]([C:30](O)=[O:31])[O:21]2)=[C:13]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:12]=1.C(Cl)(=O)C(C)(C)C.[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH2:52])=[O:50]>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH:52][C:30]([C@@H:22]1[C@@H:23]2[C@@H:24]([O:25][C:26]([CH3:28])([CH3:29])[O:27]2)[C@H:20]([N:17]2[CH:16]=[N:15][C:14]3[C:18]2=[N:19][C:11]([Cl:10])=[N:12][C:13]=3[NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[O:21]1)=[O:31])=[O:50]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NNC(=O)C(C)(C)C)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Diisopropylethylamine (0.487 ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (350 mg) in dry tetrahydrofuran (8 ml) at 0° C. under nitrogen. After 5 min pivaloyl chloride (0.098 ml) was added and the mixture was stirred at 0° C. for 2.5 h. 2,2-Dimethyl-propionic acid hydrazide was added in tetrahydrofuran (2 ml) at 0°, and stirring was continued at 0-22° C. overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (2×30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was azeotroped with dichloromethane (10 ml) to give the title compound as a cream solid (357 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][C:4]=1[CH:16]=[CH2:17].C12BC(CCC1)CCC2.[OH:27]O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][C:4]=1[CH2:16][CH2:17][OH:27]
Reactant: OO
Reactant: C=Cc1ccc(OCOCCOC)cc1OC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(CCO)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
3.9 g (16.4 mmol) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-1-vinyl-benzene diluted in 30 ml of tetrahydrofuran is added dropwise to a solution at room temperature of 4 g (16.4 mmol) of the dimer of 9-borabicyclo[3.3.1]nonane diluted in 10 ml of tetrahydrofuran. After stirring at room temperature for 20 hours, the above reaction mixture is cooled to 0° C. and 10 ml of water is added dropwise. The reaction mixture is stirred at room temperature for 1 hour and then cooled again to 0° C. and 10 ml of hydrogen peroxide is added. After stirring for 2 hours at room temperature, the reaction mixture is treated by adding 3 ml of an aqueous solution of sodium hydroxide of concentration 3M and stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 60/40 to give 3.3 g (78%) of 2-[2-methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol in the form of a light yellow oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:23][CH3:24])[C:11]=2[N:10]=[C:9]1[O:25][CH2:26][CH3:27])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:26]([O:25][C:9]1[NH:8][C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:23][CH3:24])[C:11]=2[N:10]=1)[CH3:27]
Reactant: CCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOc1nc2c([nH]1)c(=O)n(CCCO)c(=O)n2CC
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (0.12 g, 0.323 mmol) was dissolved in ethanol (20 mL) and degassed and refilled with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added and the mixture was again degassed and refilled with nitrogen three times. The reaction was stirred at 80° C. overnight. Then the mixture was cooled, filtered and the filter cake was washed with methanol. The filtrate was concentrated to give 8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg, 77.1% yield) as white solid. LCMS retention time 0.413 min; LCMS MH+ 283.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(C)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1C
Reaction time: 3 h
Yield: 81 %

Procedure:
To an ambient temperature suspension of 4-Methoxy-2-methyl-benzoic acid (1.0 g, 6.02 mmol) in MeOH (10 mL) is added thionyl chloride (1.10 mL, 15.04 mmol) dropwise. The reaction mixture is heated to reflux. After 3 h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated to yield the title compound (877 mg, 81%) 1H NMR (400 MHz, CDCl3) δ 7.95-7.91 (m, 1H), 6.77-6.72 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: CS(N)(=O)=O.[CH3:6][NH:7][S:8]([NH2:11])(=[O:10])=[O:9].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:39][C:40]1[C:41]([O:50][CH2:51][C:52]2([C:62]#[N:63])[CH:59]3[CH2:60][CH:55]4[CH2:56][CH:57]([CH2:61][CH:53]2[CH2:54]4)[CH2:58]3)=[CH:42][C:43]([F:49])=[C:44]([CH:48]=1)[C:45]([OH:47])=O>>[Cl:39][C:40]1[C:41]([O:50][CH2:51][C:52]2([C:62]#[N:63])[CH:59]3[CH2:58][CH:57]4[CH2:56][CH:55]([CH2:54][CH:53]2[CH2:61]4)[CH2:60]3)=[CH:42][C:43]([F:49])=[C:44]([CH:48]=1)[C:45]([NH:11][S:8](=[O:10])(=[O:9])[NH:7][CH3:6])=[O:47]
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Reactant: CNS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CNS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with methyl sulfamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following trituration with diethyl ether (10 mL) as a colorless powder (0.073 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.73-7.66 (m, 2H), 7.34 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 2.53 (d, J=4.6 Hz, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z 454.1, 456.1 (M−1).