Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[CH:10]/[C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[CH3:26]>[OH-].[Na+]>[OH:1][C:2]1[C:3]([CH3:26])=[CH:4][C:5](/[CH:9]=[CH:10]/[C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)Cc1ccc(OCC(=O)/C=C/c2cc(C)c(O)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(/C=C/C(=O)COc2ccc(CC(=O)O)cc2)cc(C)c1O

Procedure:
Methyl (E)-4-[[4-(4-hydroxy-3,5-dimethylphenyl)-2-oxo-3-butenyl]oxy]-benzene acetate (1.73 g) (0.00488 mole) is dissolved in 150 ml 0.1 N NaOH and warmed on the steam bath. As soon as a temperature of 70° is reached the reaction mixture is removed from the bath and allowed to cool to 50°, at which point 1 N HCl (17 ml) is added slowly. The precipitated solid is filtered off, washed with H2O, and recrystallized from HOAc-H2O to yield yellow crystals, 1.22 g (73%), mp 151°-153.5° C. Anal. for C20H20O5 : Calc. C 70.58, H 5.92; Fd. C 70.48, H 5.72.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.O.[CH2:8]1C[O:11][CH2:10][CH2:9]1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:8])[CH:10]=[O:11])=[CH:2]1
Reactant: c1ccsc1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: CC(C=O)c1ccsc1
Yield: 30 %

Procedure:
A solution of methoxymethyldiphenyl phosphonium chloride (4 g, 11.9 mmol) in anhydrous ethanol (50 ml) was cooled to 0° C. and sodium ethoxide (0.8 g, 8.25 mmol) was added. After the mixture had warmed to room temperature, 1-thiophen-3-yl-ethanone (0.7 g, 5.9 mmol) was added and the reaction mixture was heated to 120° C. for 30 min in Microwave. The mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatograph using EtOAc:Hexane/20:80 as the eluent to give 0.5 g (54.5% yield) 3-((E or Z)-2-methoxy-1-methyl-vinyl)-thiophene. The solution of 3-((E or Z)-2-methoxy-1-methyl-vinyl)-thiophene in THF:HCl: H2O (10 ml total, 9:0.5:1) was heated to 150° C. for 30 min in microwave. After the mixture was concentrated the residue was partitioned between EtOAc and water. The combined organic layers were washed with sodium bicarbonate, water, brine, dried over sodium sulfate and concentrated to give the title compound as an oil 250 mg (30%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH3:19][N:20](C)C=O.Cl>O>[C:19]([C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)c2ccccc12
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)c3ccccc3c(=O)c2c1

Procedure:
A mixture of 5,6-dihydro-2-bromo-6,11-dioxodibenz[b,e]azepine (151 g), cuprous cyanide (49 g) and dimethylformamide (1.1 liters) was heated under refluxing for 8.5 hours. Then, the reaction mixture was cooled, and poured into a solution containing ferric chloride (200 g), conc. hydrochloric acid (50 ml) and water (500 ml) under stirring. The precipitated crystals were collected by filtration, washed with hydrochloric acid, and further washed thoroughly in water. Then, the crystals were dried at 60°-80° C. and dissolved in dimethylformamide (700 ml) with heating. The solution was filtered on heating, concentrated to 500 ml, and allowed to stand with the addition of dioxane (300 ml). The precipitated crystals were collected by filtration, washed with dioxane, then with n-hexane, and dried to obtain 5,6-dihydro-2-cyano-6,11-dioxodibenz[b,e]azepine (75 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Nc1ccccc1Br
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Brc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 23.3 %

Procedure:
Using the procedure of example 1, 2-bromoaniline (139 mg) was reacted with compound 1f (100 mg) to provide compound 28 (23 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=8.0 Hz, 1H), 8.30 (t, J=5.2 Hz, 1H), 8.25 (d, J=1.2 Hz, 1H), 8.24 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.26 (d, J=6.0 HZ, 1H), 7.15 (dd, J=7.8 Hz, 4.8 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H). MS (ESI) m/z: 366 (M+H)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[C@H:11]([CH2:36][CH3:37])[CH2:10]1)(C(C)(C)C)(C)C.Cl.CCOC(C)=O>C(O)C.C([C@H]1[C@@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)C[C@H](O)C1)C>[CH2:36]([CH:11]1[CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:13][CH:9]([OH:8])[CH2:10]1)[CH3:37]
Reactant: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC1CC(O)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reaction time: 1 h

Procedure:
A scalemic mixture enriched in 1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.55 g, 2.87 mmol) was suspended in ethanol (30 mL). Concentrated HCl (0.3 mL, 3.65 mmol) was added dropwise. After about 1 h., the suspension was sonicated until all solid went into solution. EtOAc (250 mL) was added and the organics were washed with saturated aqueous NaHCO3 (2×30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduce pressure. The residue was purified using silica gel chromatography eluting with 30-80% EtOAc in DCM to give a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (1.09 g, 90%): LC/MS (Table 1, Method b) Rt=1.99 min; MS m/z: 426 (M+H)+.
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH:11]([N:14]([CH2:18][CH2:19][CH:20]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>>[C:1]([CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH:11]([N:14]([CH2:18][CH2:19][CH:20]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[OH:34])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:15]([CH3:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: Cc1ccc(O)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
(-)-N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine hydrogen D(-)-tartrate was similarly prepared using D(-)-tartaric acid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:26][CH2:27][CH3:28])[C:4](=[O:25])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=4[F:24])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.C([O-])=O.[NH4+].CN(C=O)C>[Pd].O>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:7]2[NH:6][C:5]3[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[CH:2]=[N:10][C:9]=3[N:8]=2)[CH:12]=[N:13]1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(F)c4F)c3)[nH]c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccc(F)c4F)c3)[nH]c2c1=O
Temperature: 87.5 °C
Yield: 30 %

Procedure:
A mixture of 2-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.04 g, 0.09 mmol), ammonium formate (0.134 g, 1.97 mmol), Pd\C (10%) (0.02 g), DMF (2 ml) and H2O (0.5 ml) were heated at 85-90° C. for 15 hours. Reaction mixture was cooled to 20-25° C. and then it was filtered through celite bed washed with methanol (10 ml). The filtrate was concentrated under vacuum. To this residue water (1 ml) was added and acidified with citric acid up to pH (1-2). Solid precipitated was filtered off and washed sequentially with cold water, diethyl ether to obtain pure 8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.01 g, 28%) as a off white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:30])([CH3:29])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:29])([CH3:30])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:34][CH:33]=1
Reactant: CCN1CC(C)(C)c2ccc(N)cc2C1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CC(C)(C)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added to a stirred solution of 7-amino-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.18 mmol), 4-chlorobenzaldehyde (31 mg, 0.22 mmol) and acetic acid (11 μl, 0.18 mmol) in anhydrous dichloromethane (6 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by preparative tlc (20% ethyl acetate in petroleum ether) to afford the title compound as a colourless solid (20 mg, 32%). HPLC retention time 4.78 min. Mass spectrum (ES+) m/z 343 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([C:16]1([CH2:17][CH3:18])[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[O:1]1)[CH3:14]
Reactant: CCC(=O)CC
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)NC(=O)c2ccc([N+](=O)[O-])cc2O1

Procedure:
A suspension of the compound obtained in (1) described above (5 g), 3-pentanone (6.6 g) and p-toluenesulfonic acid monohydrate (1.6 g) in toluene (70 mL) was heated under reflux overnight. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was recrystallized from ethyl acetate/dichloromethane (1:1) to give the titled compound (5 g) as a colorless powder.
Reaction SMILES: [H-].[Na+:2].Cl[C:4]1[C:5]([C:12]([O:14]C)=O)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1.[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([C:17]1[S:16][C:4]2[CH:9]=[N:8][C:7]([S:10][CH3:11])=[N:6][C:5]=2[C:12]=1[O-:14])=[O:19].[Na+:2]
Reactant: COC(=O)CS
Reactant: COC(=O)c1nc(SC)ncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(SC)nc2c1[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
1.2 g of sodium hydride (60% in oil) are added slowly to a mixture of 6.0 g of methyl 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2 and 3.0 g of methyl sulfanylacetate in 60 ml of DMF. After 15 min at ambient temperature, the mixture is heated at 60° C. for 3 h, and then cooled to ambient temperature overnight. The resulting suspension is filtered and the solid is washed with ethyl acetate and dried under vacuum so as to obtain 3.6 g of sodium 6-(methoxycarbonyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-7-olate 3 in the form of a beige solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH3:18][C:13]1[C:12]2[C:17](=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc2c(C)cccc2c1-c1ccc(O)cc1
Yield: 45.3 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-7-methyl-2-pentyl-2H-indazole (0.014 g, 0.045 mmol), boron tribromide (0.050 mL, 1.0 mmol) and 0.2 mL of cyclohexene to give the product (0.006 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)n1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
(6-Bromopyridin-2-yl)methanol (5.0 g, 26.6 mmol), DMAP (0.65 g, 5.3 mmol), tert-butyl(chloro)dimethylsilane (4.8 g, 31.9 mmol) and imidazole (2.3 g, 34.0 mmol) was mixed in DCM (100 mL) and stirred at room temperature over night. The reaction mixture was washed with water (3×100 mL), dried over a phase separator and concentrated in vacuo to give the product as an oil. Yield: 8.3 g (103%) 1H NMR (400 MHz, CDCl3) δ 7.55 (t, 1H, J=7.87 Hz), 7.46 (d, 1H, J=7.87 Hz), 7.32 (d, 1H, J=7.87 Hz), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH2:11])=[CH:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH:11][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:27])=[CH:7][C:6]=2[CH:12]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCc1cc2cc(Cl)ccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCc1cc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of (5-chloro-1-benzofuran-2-yl)methanamine (420 mg, crude) in dichloromethane (50 ml) was added triethylamine (315 mg, 3.12 mmol). Then ethyl 2-chloro-2-oxoacetate (378 mg, 2.77 mmol) was added dropwise and the contents were stirred for 30 minutes at 0° C. The resulting solution was quenched with water (100 ml) and extracted with dichloromethane (3×70 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in petroleum ether to afford ethyl [[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate as an off-white solid (600 mg). (ES, m/z): [M+H]+ 282.0; 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.64 (s, 1H), 4.68 (d, J=4.2 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[O:11])[CH2:6]1>>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:7]3[CH2:8][CH2:9][C@@H:5]([O:4][CH2:2][CH3:3])[CH2:6]3)=[O:11])[S:20][C:19]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CCI
Product: CCO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from iodoethane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 311.2/313.2 (MH+); HPLC Rf: 4.697 min.; HPLC purity: 98%.
Reaction SMILES: C1C2C=CC3C(=CC=CC=3)C=2C=CC=1[B:15]([OH:17])[OH:16].Br[C:19]1[C:32]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[C:19]1([B:15]([OH:17])[OH:16])[C:32]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc2c(ccc3ccccc32)c1
Reactant: Brc1cccc2c1ccc1ccccc12
Product: OB(O)c1cccc2c1ccc1ccccc12

Procedure:
Synthesis was performed in the same manner as in the synthesis of phenanthrene-2-boronic acid except that 1-bromophenanthrene was used instead of 2-iodophenanthrene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([N:13]([CH2:14][CH3:15])[CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CCNC
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CCN(C)S(C)(=O)=Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and methylethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=291, 293 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([S:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1>CN(C)C=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:21]1[C:17]([CH2:16][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:18][N:19]=[C:20]1[S:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To dry dimethylformamide (10 mL) under argon was added sodium hydride (0.14 g, 5.83 mmol) followed by diethyl malonate (0.92 g, 5.75 mmol) in dimethylformamide (2 mL) at 0° C. The mixture was stirred at ambient temperature for one hour. A solution of 5-chloromethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole hydrochloride (1.0 g, 2.84 mmol) in dimethylformamide (4 mL) was added over 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours, then partitioned between water and methylene chloride. The organic layer was washed with water, dried, and concentrated. The crude product was flash chromatographed over silica gel with 1:1 hexane/ethyl acetate to give 0.62 g (49.7%) of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol- 5-yl]methylmalonate as a pale yellow syrup.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]1([CH2:16][C:17](P(=O)(OCC)OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][C:17]([N:1]2[CH2:9][CH2:8][N:7]([C:17](=[O:18])[CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][N:4]([C:17](=[O:18])[CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:3][CH2:2]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CNCCNCCN1
Reactant: CCOP(=O)(OCC)C(=O)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCN(C(=O)Cc2ccccc2)CCN(C(=O)Cc2ccccc2)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), diethyl phenylacetylphosphonate [PhCH2COP(O)(OEt)2].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[S:14][C:13]([NH:16][C:20]([CH:17]4[CH2:19][CH2:18]4)=[O:21])=[N:12][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2[nH]nc(-c3ccc(O)cc3)c2s1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2[nH]nc(-c3ccc(O)cc3)c2s1)C1CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a vial charged with 3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (60 mg, 0.259 mmol), PS-DMAP (Argonaut resin, 1.05 g, 6 equiv.), and a stirring bar were added THF (2.5 mL) and cyclopropane-carbonyl chloride (118 μL, 1.29 mmol). The reaction mixture was stirred at 70° C. for 15 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.26 g, 20 equiv.) at 50° C. for 48 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification on silica gel with 0-8% MeOH in CH2Cl2 as eluent provided 32 mg (41% yield) of cyclopropanecarboxylic acid [3-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-amide as a white solid. 1H-NMR (d6-DMSO) δ: 13.3 (broad s, 1H), 12.6 (broad s, 1H), 9.80 (broad s, 1H), 7.52 (d, 2H), 6.88 (d, 1H), 1.98 (m, 1H), 0.93 (m, 4H); HPLC/MS m/z: 301.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl([O-])(=O)(=O)=O.[Li+].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@@:29]1([CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[C@@H:31]([CH3:32])[O:30]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C@H:31]([CH3:32])[C@:29]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])([OH:30])[CH2:33][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Clc1ccc(NC2CCNCC2)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCC(Nc2ccc(Cl)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 31 %

Procedure:
To a solution of the N-(4-chlorophenyl)piperidine-4-amine (400.0 mg, 1.9 mmol) obtained in step 2 in acetonitrile were added lithium perchlorate (134.1 mg, 1.3 mmol) and 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (158.9 mg, 0.6 mmol), followed by irradiating microwaves onto the solution at 150° C. for 30 min. After removal of the solvent, the reaction mixture was diluted in ethyl acetate and washed with distilled water and saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Isolation and purification of the concentrate through silica gel chromatography afforded the title compound (yield 31%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1>C(OC)(C)(C)C>[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
Benzyl alcohol (37.5 g, 0.347 mol) and sodium hydroxide (2.96 g, 0.074 mol) were mixed and heated, and sodium hydroxide was dissolved. After cooling, 2-amino-6-chloropurine (6.00 g, 0.035 mol) was added, and the reaction was completed by heating and stirring at 80-90° C. for 5 hr. Methyl tert-butyl ether (120 ml) was added to the reaction mixture, and the mixture was extracted twice with 1% aqueous sodium hydroxide solution (70 ml). The obtained aqueous alkali layers were combined, washed with toluene, and after removing toluene, neutralized with 35% hydrochloric acid to pH 6-8. The precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2-amino-6-benzyloxypurine (7.60 g, 0.032 mol, yield 92%) as crude crystals.