Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH:21]1([CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:27](=[O:28])[CH2:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:30][CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)CC2CCCC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CC1CCCC1)c1ccc(CBr)cc1
Temperature: 85 °C
Yield: 63.8 %

Procedure:
Add NBS (523 mg, 2.94 mmol) and AIBN (44 mg, 0.267 mmol) to a solution of 2-cyclopentyl-1-p-tolyl-ethanone (540 mg, 2.67 mmol) in carbon tetrachloride (80 mL) and heat overnight at 85° C. Add water and extract the aqueous phase with dichloromethane. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (98:2, 95:5) to obtain the desired intermediate as an oil (479 mg, 64%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>>[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1csc(-c2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
Chlorosulfonic acid (1.4 ml) was added to 2-(4-pyridyl)thiophene (500 mg) at 0° C. and the mixture was stirred for 5 days at room temperature. Ice-water was carefully added to this mixture at 0° C. to decompose excess reagent. This solution was poured into saturated aqueous NaHCO3 solution (ca. pH 7) and extracted with AcOEt (20 ml×3). The combined organic layer was washed with brine, and dried over MgSO4. After 4N HCl-AcOEt (10 ml) was added to the solution, the solvent was removed in vacuo to give 300 mg of 5-(4-pyridyl)-thiophenesulfonyl chloride as a white solid (yield 32.7%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)=[O:7].C(O[Mg][CH2:31][SiH:32]([CH3:34])[CH3:33])(C)C.[Cl-]>O1CCCC1>[OH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)[CH:31]([SiH:32]([CH3:33])[CH3:34])[O:7][CH:6]([CH3:8])[CH3:2]
Reactant: CC(C)O[Mg]C[SiH](C)C
Reactant: O=C(c1cccc(OCc2ccc3ccccc3c2)c1)c1nccs1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)OC([SiH](C)C)C(O)(c1cccc(OCc2ccc3ccccc3c2)c1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone (4.84 g; Note f. above) in tetrahydrofuran (5 ml) was added dropwise to a solution of isopropoxydimethylsilylmethylmagnesium chloride [prepared as described in J. Org. Chem., 1983, 48, 2120 from chloromethylisopropoxydimethylsilane (4.2 g) and magnesium powder (0.6 g) in tetrahydrofuran (7 ml)]. The mixture was stirred at ambient temperature for 1 hour, washed with saturated aqueous solution of ammonium chloride and then with a saturated aqueous solution of sodium chloride. The organic layer was separated, dried (Na2SO4) and evaporated to give 2-[1-hydroxy-2-isopropoxydimethylsilyl-1-(3-(naphth-2-ylmethoxy)phenyl)ethyl]thiazole as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[CH:15]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[O:21][C:20](=[O:31])[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:22]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[C:25]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]([OH:31])=[O:21])=[O:30]
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Reactant: CC(C)(S)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)c1ccccc1-c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (1.08 g, 7.62 mmol) in methylene chloride (20 mL) was added triethylamine (1.2 mL, 8.61 mmol) followed by dibenzo[c,e]oxepin-5,7-dione (1.68 g, 7.42 mmol). After stirring at room temperature for 1 h, cold 2 N HCl (50 mL) was added. After separation, the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine and dried under sodium sulfate. The solvent was removed and the resulting residue was triturated with hexane to give the title compound as white solid (2.44 g, 98.9%). mp 150-153° C.; 1H NMR (CDCl3, 300 MHz): δ1.03 (s, 3H), 1.12 (s, 3H), 1.36 (s, 1H), 3.15 (dd, J=13.7 and 5.7 Hz, 1H), 3.38 (dd, J=13.7 and 6.9 Hz, 1H), 6.92 (t, J=6.1 Hz, 1H), 7.09-7.17 (m 2H), 7.38-7.48 (m, 4H), 7.57-7.61 (m, 1H), 7.80-7.83 (m, 1H); 13C NMR (CDCl3, 75 MHz,): δ29.36, 29.75, 44.66, 53.01, 127.28, 127.96, 128.04, 129.38, 129.93, 130.06, 130.20, 131.19, 132.02, 134.69, 138.90, 140.11, 170.99, 171.24; LCMS (m/e): 330 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[Br:14]Br>CO>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11]2
Reactant: COc1cccc2ccc(C)nc12
Reactant: BrBr
Solvent: CO
Product: COc1ccc(Br)c2ccc(C)nc12
Temperature: 45 °C

Procedure:
A solution of 8-methoxy-2-methylquinoline (1.0 g) in methanol (30 ml) was treated at room temperature with bromine (0.31 ml). The mixture was heated at 45° C. for 2 hours and the reaction quenched with 5% aqueous sodium metabisulphite (50 ml). The solution was basified with 25% aqueous sodium hydroxide to pH13 and the product extracted with ethyl acetate (2×100 ml). The extracts were combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was dissolved in ethyl acetate and passed through a silica pad. The solution was evaporated in vacuo to yield the desired product as an off-white solid (0.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][CH2:19][NH:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:28]OCCl>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])=[CH:7][C:6]2[CH2:28][N:20]([NH:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18][CH2:17][C:5]=2[CH:4]=1
Reactant: COc1cc(CCCNNc2ccncc2)ccc1O[Si](C)(C)C(C)(C)C
Reactant: COCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CN(Nc1ccncc1)CCC2
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of N-[3-(3-methoxy-4,6-butyldimethylsilyloxyphenyl)propylidene]-N'-pyridin-4-yl-hydrazine (5.81 g) in tetrahydrofuran (150 ml) was added lithium aluminum hydride in small portions at ambient temperature. The reaction mixture was stirred for 1.5 hrs at ambient temperature, sodium sulfate decahydrate was added. Ethyl acetate was added, and the mixture was filtered over celite. The filtrate was concentrated in vacuo to afford 5.81 g (75%) of N-[3-(3-methoxy-4-t-butyldimethylsilyloxyphenyl)propyl]-N'-pyridin-4-yl hydrazine. To a solution of N-[3-(3-methoxy-4-t-butyldimethylsilyloxyphenyl)propyl]-N'-pyridin-4-yl hydrazine in glacial acetic acid (50 ml) was added chloromethyl methyl ether (1.42 g). The reaction mixture was stirred overnight, then partitioned between 10% aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml). The organic extract was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. This residue was chromatographed over silica gel, eluting with dichloromethane/methanol (9:1). The appropriate fractions were collected and evaporated to afford 3.61 g (60%) of product, mp 149-150° C.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])O.[Na+]>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CC1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (2,2-difluorocyclopropyl)methanol (20.0 g) and triethylamine (32.2 mL) in THF (300 mL) was added 4-nitrobenzenesulfonyl chloride (41.0 g) at 0° C., and the mixture was stirred for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (47.2 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=34)[CH:3]=[N:2]2)[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24]
Reactant: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (0.811 g, 2.58 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-N-isopropylbenzamide (0.625 g, 2.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (190 μL, 1.3 mmol) in acetonitrile (8 mL, 200 mmol) was heated at 50° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was diluted with dichloromethylene, neutralized with 0.5 N HCl aqueous solution to about pH 7. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (1.40 g, 84.3%), which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=570.3.
Reaction SMILES: [CH:1]1([N:6]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][CH2:9][C@@H:8]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:19][C@@H:8]1[CH2:9][CH:10]=[CH:11][C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 2-[(3R,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (100 mg) in MeOH (4 ml), was added hydrazine hydrate (27 mg) at RT under N2. The mixture was allowed to stir overnight at RT. The reaction was evaporated and the residue was taken up in DCM and washed with water. The organics were dried (Na2SO4), filtered and evacuated to afford the title compound (65 mg, 96% crude yield) yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.38-2.31 (m, 1H), 3.46-3.56 (m, 1H), 4.91 (d, 1H, J=8 Hz), 5.24-5.34 (m, 1H), 5.88-5.96 (m, 1H), 6.25-6.33 (m, 1H), 7.21-7.36 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[CH3:10][N:11]=[C:12]=[O:13].O>CN(C=O)C.[Cu]Cl>[CH3:10][NH:11][C:12](=[O:13])[O:9][CH2:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: CN=C=O
Reactant: OCc1nccc(Cl)n1
Agent: Cl[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)OCc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4-Chloropyrimidin-2-yl)methanol (Example 548, Step 1) (0.304 g, 2.10 mmol) and copper(I) chloride (0.208 g, 2.10 mmol) were taken up in DMF (10 mL) and stirred at room temperature for 5 minutes. Methyl isocyanate (0.120 g, 2.10 mmol) was added and stirring at room temperature continued for 3 hours. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (12-100% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Cl)cc3)nc21

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 626 mg (3.77 mmol) of 4-chlorophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 150 mg (26%) of the diastereomer which elutes more rapidly, M.p.: 125° C., and 90 mg (16%) of the diastereomer which elutes more slowly, M.p.: 101° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)[CH:2]=C.C(Cl)Cl.[BH4-].[Na+].C[OH:20]>>[N:9]1[C:10]2[C:5](=[C:4]([CH2:1][CH2:2][OH:20])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: C=CCc1cccc2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
5-Allyl-quinoline (3.12 g, 18.4 mmol) was dissolved in 40 mL methanol and 40 mL methylene chloride and cooled to −78° C. Ozone was bubbled in until a green solution was seen. Sodium borohydride (1.4 g, 36.8 mmol) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water. A saturated solution of KHPO4 was added and the mixture extracted with methylene chloride. The organic extracts were dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed with ethyl acetate to yield 1.6 g (50%) of 2-quinolin-5-yl-ethanol as a yellow solid. MS (APCI) m/z 174.1 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>C(OCC)C.C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:14]([OH:19])[OH:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1ccccc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 1,2-diiodobenzene (0.102 g, 3.08 mmol) in 60 mL of a mixture of THF and diethylether (Et2O) (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 1.54 mL, 3.08 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (1.74 g 2.12 mL, 9.24 mmol) was added. The solution was warmed to room temperature overnight; then 40 mL of HCl (10%) was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times). Drying over Na2SO4, evaporation and purification by flash chromatography gave 0.62 g of the pure product (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(C(=O)O)ccc1N1CCCC1
Solvent: CO
Product: COC(=O)c1ccc(N2CCCC2)c(N)c1

Procedure:
3-Amino-4-(1-pyrrolidinyl)benzoic acid.hemioxalate (5.0 g) is suspended in methanol (40 ml) and thereto is added p-toluenesulfonic acid (2.5 g), and the mixture is refluxed for 3 hours. Mathanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off to give methyl 3-amino-4-(1-pyrrolidinyl)benzoate (3.4 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([OH:25])=[C:19]2[CH:18]=[N:17]1)(=[O:9])=[O:8].[H-].[Na+].O[C@@H:29]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31]>C1COCC1>[CH:42]([O:41][CH2:40][C@H:29]([O:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7]([CH3:6])(=[O:9])=[O:8])[N:17]=[CH:18][C:19]=12)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31])([CH3:44])[CH3:43]
Reactant: CS(=O)(=O)c1ccccc1-n1ncc2c(O)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2S(C)(=O)=O)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
Phosphorus oxychloride (1.864 ml, 20.00 mmol) was added to 1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate N1) (0.290 g, 1 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was evaporated. The residue was dissolved in DCM (30 mL). MP-Carbonate was added and the mixture stirred for 30 minutes then evaporated. The residue was dissolved in THF (5 mL). Sodium hydride (55.9 mg, 1.40 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (238 mg, 1.00 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes and then the THF solution prepared above was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated, diluted with water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (25 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluent to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (242 mg, 47.5%, 81% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (6H, dd), 2.24 (3H, s), 3.38 (3H, s), 3.72-3.80 (1H, m), 3.96-4.05 (2H, m), 5.87-5.91 (1H, m), 7.58 (1H, dd), 7.77 (1H, dd), 7.86-7.92 (2H, m), 7.94-7.99 (1H, m), 8.16-8.21 (2H, m), 8.53 (1H, s), 8.60 (1H, s), 10.82 (1H, s); m/z (ESI+) (M+H)+=511; HPLC tR=2.07 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)(=[O:4])=[O:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
A mixture of 4.1 g. 3-methylsulphonyl-1,2,4-triazole, 4.75 g. diallylcarbamoyl chloride, 20 ml. dry tetrahydrofuran and 5.5 ml. dry triethylamine was refluxed under anhydrous conditions for 1 hour. The reaction mixture was filtered and the filtrate was distilled to dryness under reduced pressure. The solid residue was recrystallized from a mixture of toluene and petroleum ether (b.p. 40° - 60° C.) to give 1-diallylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 52° - 54° C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[BH4-].[Na+].O>C(O)C>[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A solution of 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde (0.62 g, 1.7 mmol), prepared as in Example 8 or 9, and sodium borohydride in 30 mL of absolute ethanol was stirred at room temperature for 1 hour. The mixture poured into 150 mL of water and the mixture was extracted withethyl acetate. The ethyl acetate layer was dried over magnesium sulfate andthen concentrated. The residue was dissolved in approximately 10 mL of absolute diethyl ether and the solution was cooled in an ice bath giving aprecipitate. The precipitate was isolated by filtration and drying gave 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-methanol (0.37 g, 1.0 mmol), m.p. 119°-120° C.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([OH:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:28]([O:27][C:25]([C:24]1[O:22][C:16]2[CH:15]=[C:14]([O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:21]=[CH:20][C:17]=2[CH:18]=1)=[O:26])[CH3:29]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 125 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a N,N-dimethylformamide (200 mL) solution of 4-benzyloxy-2-hydroxybenzaldehyde (18.6 g, 81.4 mmol) were added ethyl bromoacetate (9.94 mL, 89.6 mmol) and potassium carbonate (22.6 g, 163 mmol) at room temperature, which was stirred at 125° C. for 3 hours. To the reaction mixture was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered followed by concentrating the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=7:3) to obtain the title compound (18.4 g, 76%) as a white solid.