Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][CH:61]([O:64][CH2:65][C:66](O)=[O:67])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:69]([F:72])([F:71])[F:70])([O-:50])=[O:49]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:66](=[O:67])[CH2:65][O:64][CH:61]4[CH2:62][CH2:63][CH:58]([NH:57][C:54]5[CH:55]=[CH:56][C:51]([N+:48]([O-:50])=[O:49])=[C:52]([C:69]([F:71])([F:70])[F:72])[CH:53]=5)[CH2:59][CH2:60]4)[CH2:16][CH2:17]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: O=C(C1Cc2cc(F)ccc2O1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
In a 50 ml round-bottomed flask containing a solution of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone (76 mg, 0.30 mmol, 1.1 eq) in 30 ml of dichloromethane was added EDAC.HCl (76 mg, 0.40 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (56 mg, 0.55 mmol, 2.0 eq), and [4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid (100 mg, 0.28 mmol). The solution was stirred overnight at room temperature before diluting with 30 ml of water. The crude product was then extracted from the mixture using 3×30 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 72 mg of the desired amide as a yellow solid (44%); 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J=6.6 Hz, 1H), 6.95 (d, J=5.4, 1H), 6.83 (m, 2H), 6.66 (m, 2H), 5.43 (m, 1H), 4.25 (s, 1H), 3.75-3.95 (m, 4H), 3.27-3.80 (m, 8H), 2.12-2.22 (m, 4H), 1.50 (dd, J=7.8 Hz, 16.8 Hz, 2H), 1.31 (dd, J=7.8 Hz, 16.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)NCC2
Temperature: -20 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of 6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (3.4 g, 17.8 mmol) in H2SO4 (45 mL) at −20° C. was added HNO3 (1.58 mL, 21.3 mmol) dropwise. The mixture was allowed to stir for 3 h at −20° C. The mixture was poured into ice water and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure to give 6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (3.0 g, 71%). 1H NMR (CDCl3) δ 8.55 (1H), 6.88 (1H), 6.2 (1H), 4.0 (3H), 3.6 (2H), 3.05 (2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4]Cl)[CH3:3].CN(C)CCCCl.C([N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[CH:42][N:43]=[C:22]12)(=O)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:4][N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[CH:42][N:43]=[C:22]12)[CH3:3]
Reactant: CN(C)CCl
Reactant: O=C(c1ccccc1)n1c(=O)c2cnc3c(cnn3-c3ccccc3)c2n2ncnc12
Agent: CN(C)CCCCl
Product: CN(C)Cn1c(=O)c2cnc3c(cnn3-c3ccccc3)c2n2ncnc12

Procedure:
By substituting dimethylaminomethyl chloride for the 3-(dimethylamino)propyl chloride in the procedure of Example 2 and utilizing 8-phenyl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one product of Example 18 instead of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one, 4-dimethylaminomethyl-8-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H) -one is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=2.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[NH:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])=[CH:33][C:32]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[CH:31][CH:30]=2.[CH:49](OCC)(OCC)OCC>>[CH2:18]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH:26]=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[CH2:42]([C:32]1[CH:31]=[CH:30][C:29]2[N:28]=[CH:27][C:26]3[N:25]=[CH:49][N:36]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[C:35]=3[C:34]=2[CH:33]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Cc3ccccc3)ccc12
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(O)CNc1c(N)cnc2ccc(Cc3ccccc3)cc12
Product: CC(C)(O)Cn1cnc2cnc3cc(Cc4ccccc4)ccc3c21
Product: CC(C)(O)Cn1cnc2cnc3ccc(Cc4ccccc4)cc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For Examples 431 and 434, a modification of the method described in Part B of Examples 427–429 was used to treat 1-(3-amino-7-benzylquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(3-amino-6-benzylquinolin-4-ylamino)-2-methylpropan-2-ol with triethyl orthoformate, as indicated in the table below. The reaction was heated at reflux for one hour and then stirred overnight at ambient temperature. A precipitate formed, which was isolated by filtration to provide 1-(7-benzyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or 1-(8-benzyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:25]=[O:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-benzyloxyethyl)-1-bromobenzene (6.8 g) in tetrahydrofuran (80 mL) was added n-butyl lithium (2.6 mol/L n-hexane solution, 8.98 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,N-dimethylformamide (20 mL), and the mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2-benzyloxyethyl)benzaldehyde (5.6 g). This material was dissolved in methanol (80 mL). To the solution was added sodium borohydride (1.77 g) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue (solid) was treated with n-hexane, collected by filtration and dried under reduced pressure to give the title compound (5.41 g).
Reaction SMILES: O/N=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].CN.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2C=CC=CC=2N=N1.[O:58]1CCCC1>>[CH3:42][NH:38][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4][C:3]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:58])=[CH:21][CH:20]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: C1CCOC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (intermediate of example 272, step 2) was coupled with methylamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a white foam, MS (ESI+): m/z=373.1 [M+H]+.
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Br:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](/[N:2]=[CH:20]/[N:21]([CH3:23])[CH3:22])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Reactant: COC(OC)N(C)C
Agent: Br
Product: COC(=O)c1cc(Br)c2ccccc2c1/N=C/N(C)C
Temperature: 100 °C

Procedure:
A solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (see Example 1, 3.20 g, 8.86 mmol) in N,N-dimethylformamide dimethylacetal (3.56 mL, 26.6 mmol) was heated at 100° C. for 2 h. Additional N,N-dimethylformamide dimethylacetal (1.19 mL, 8.9 mmol) was added and the solution was heated at 100° C. for an additional 3 h. The reaction was cooled to rt, concentrated, and dried to provide crude methyl 4-bromo-1-{[(1E)-(dimethylamino)methylene]amino}-2-naphthoate that gave a mass ion (ES+) of 337.1 (81Br) for [M+1-1]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH:14](C=O)=O>>[CH2:14]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: O=CC=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Product: c1ccc2c3c([nH]c2c1)CNCC3

Procedure:
A stirred solution of 13 g (0.0756 mol) 1,2,3,4-tetrahydro-β-carboline, produced of tryptamine hydrochloride and glyoxal acid, as described by Ho and Walker (1988), and 2.6 g of Pd/C (10%) in 600 ml cumene were refluxed under nitrogen atmosphere for 90 minutes. After adding 100 ml ethanol the heated solution was filtered and the carbon was extracted with 3×30 ml heated ethanol. The combined liquid fractions were concentrated and the remainder crystallized from toluene for obtaining 10.5 g (82%) of norharman. The methylation in position 9 was carried out as described in literature (Ho B T, McIsaac W M, Walker K E, Estevez V, J Pharm Sci 57: 269, 1968), but with an improved processing: 1 g (5.95 mmol) of norharman was dissolved in 10 ml dry DMF under nitrogen atmosphere. Then 0.36 g (14.9 mmol) sodium hydride was added as a 60% dispersion in petroleum at 0° C. After the mixture cooled down to room temperature it was cooled down to −10° C. and 0.84 g (5.95 mmol) methyl iodide were added. After continued stirring for 12 hours, the mixture was again cooled down to room temperature. All volatile components were removed under reduced pressure. Then 100 ml of water were added and the mixture was extracted with 3×50 ml CHCl3. The combined organic fractions were washed with 5×20 ml water and concentrated for drying. The remainder was transferred into 100 ml of 2N hydrochloric acid. To isolate the educt of the desired methylated product an ion pair extraction of the HCl salt was carried out in CHCl3 and in a liquid/liquid extractor for 2 days. After removing the solvent 0.7 g (64%) of yellow crystals of 9-methyl-β-carboliniumhydrochloride were obtained.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: Cl
Reactant: CCOC(=O)C(CC1CC1)c1cc(OCC2CC2)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) followed by brine (50 mL), was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1.1 g) as a yellow oil.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)O)[CH3:5]>>[ClH:1].[CH3:17][O:16][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:7]([CH2:6][N:4]([CH3:5])[CH3:3])[CH2:15]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CC(CN(C)C)C2(O)c1cccnc1
Agent: Cl
Product: COc1ccc2c(c1)CC(CN(C)C)=C2c1cccnc1
Reaction time: 8 h

Procedure:
About 9 ml of 37% hydrochloric acid were added at room temperature to 0.837 g of 2-dimethylaminomethyl-5-methoxy-1-pyridin-3-yl-indan-1-ol hydrochloride (mixture of the diastereoisomers); the mixture was stirred overnight and then concentrated in vacuo at 70° C. The residue was taken up twice in dichloromethane and concentrated again. The oily brown residue was taken up in 40 ml of acetone and stirred, whereupon a crystalline solid formed. After further stirring for 2.5 days, filtration with suction was carried out with the exclusion of air, followed by washing twice with diethyl ether and drying under an oil-pump vacuum. 0.603 g of (6-methoxy-3-pyridin-3-yl-1H-inden-2-ylmethyl)-dimethyl-amine hydrochloride was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH:13]=2)=[CH:8][CH:7]=1.C1C=C[NH+]=CC=1.[Br:30][Br-]Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[Br:30])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(C2=CCCCc3ccccc32)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(C2=C(Br)CCCc3ccccc32)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of the olefin (2b) (5.44 g, 17.9 mmol) in CH2Cl2 (300 mL) at 0° C. was added pyridinium bromide perbromide (90%, 7.0 g, 19.6 mmol) in portions over 0.5 h. After stirring 1 h the solution was washed with water, sat. NaHSO3, water and was dried (MgSO4). The solvent was removed under reduced pressure to give the bromide (2c) as an oil (6.85 g, 100%): 1H NMR (CDCl3) δ 7.69 (d, J=16.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.20 (m, 5H), 6.80 (d, J=7.3 Hz, 1H), 6.43 (d, J=16.1 Hz, 1H), 3.81 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.30 (m, 2H); APcI m/z: 424 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[C@H:23]1[O:25][CH2:24]1>CC(C)=O>[CH2:22]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[OH:15])[C@@H:23]1[O:25][CH2:24]1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1cccc(OCc2ccccc2)c1C[C@H]1CO1

Procedure:
A mixture of 3-benzyloxyphenol (900 mg, 4.5 mMol) and potassium carbonate (1.87 g, 13.5 mMol) in acetone (45 ml) was heated under reflux for 15 mins. (S)-Glycidyl-3-nitrobenzenesulphonate (1.0 g, 4.5 mMol) was added and the reaction mixture was heated under reflux for 23 hours. After cooling the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [CH2:1]([P:8]([CH2:11][CH:12]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O>[CH2:1]([P:8]([CH2:11][CH:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:25]([OH:27])=[O:26])([OH:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)Cc1ccccc1)C(=O)O
Yield: 56.6 %

Procedure:
Benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (0.5 g, 1.0 mmol) in 20 Ml of water containing 120 mg of 10% Pd/C was hydrogenated at 40 psi for 6 hours. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.17 g (57%) of 2-[(benzylhydroxyphosphinyl)methyl]-pentanedioic acid (4, R=CH2Ph) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][CH:4]([OH:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[F:26][C:2]([F:25])([F:1])[CH2:3][CH:4]([OH:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22]([CH3:23])=[O:35])[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Yield: 89.6 %

Procedure:
4,4,4-Trifluoro-1-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (1.5 g) in CHCl3 (200 mL) at 0° C. was stirred for 3 h with MCPBA (0.962 g) at 0° C., then quenched with 10% aqueous sodium thiosulfate. The organic layer was separated, washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified on a column with 100% DCM to 15% MeOH/DCM (product eluting at 5% MeOH) to yield 4,4,4-trifluoro-1-[1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (˜1.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.OC[C@H]1CCCN1C(OC(C)(C)C)=O.[F:39][C:40]1[CH:41]=[C:42]([CH:59]=[CH:60][CH:61]=1)[O:43][C:44]1[CH:49]=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]4[CH:59]=[CH:60][CH:61]=[C:40]([F:39])[CH:41]=4)=[CH:49][CH:48]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and extracted with dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:14][C:13]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9].[NH3:23]>C(O)C>[NH2:23][C:2]1[N:3]=[C:4]2[S:14][C:13]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=c1c([N+](=O)[O-])c(Cl)nc2sc(CCC3CCCCC3)nn12
Reactant: N
Solvent: CCO
Product: Nc1nc2sc(CCC3CCCCC3)nn2c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
In 100 ml of ethanol was suspended 9.59 g of 7-chloro-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 7 ml of concentrated aqueous ammonia was added thereto at room temperature while stirring. The stirring was continued for 5.5 hours. The precipitate formed was collected by filtration and washed successively with ethanol and diethyl ether to obtain 7.05 g of 7-amino-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14](O)=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(O)(=O)/C=C/[C:24](O)=[O:25].[NH2:29][CH2:30][CH2:31][C:32]#[N:33]>>[C:32]([CH2:31][CH2:30][NH:29][C:24]([CH2:14][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:25])#[N:33]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: N#CCCN
Reactant: O=C(O)/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2ccccc2CC(=O)NCCC#N)cc1
Yield: 80085.5 %

Procedure:
4'-Methylbiphenyl-2-carboxylic acid (50.0 g, 0.24 mmol) was converted into the corresponding acid chloride as described in Example 89, Part B using thionyl chloride. This acid chloride was subsequently reacted with 3-aminopropionitrile fumarate (30.25 g, 0.24 mmol) under Schotten-Baumann reaction conditions described in Example 209, Part B to yield 53.50 g of white powder after recrystallization from methylcylcohexane/butylchloride; m.p. 102.0-103.5° C. NMR (200 MHz, CDCl3): δ 7.68 (d, 1H, J=7Hz); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H, J=7,7Hz); 2.39 (t, 2H, J=7Hz). Anal. calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.42; H, 6.40; N, 10.68.