Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].[Br:42][CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[Br:42][CH2:43][C:44]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([NH:18][C:19]3[N:24]=[C:23]4[NH:25][N:26]=[C:27]([CH3:28])[C:22]4=[C:21]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=3)=[CH:7][C:8]=2[CH3:17])[CH2:12][CH2:13]1)=[O:45]
Reactant: O=C(Cl)CBr
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CBr)CC1

Procedure:
To a mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (50 mg, 0.087 mmol) in CH2Cl2 (3 mL) was added bromoacetyl chloride (10 uL, 0.095 mmol) dropwise at 0° C. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc/hexane (0-100%) to give the title compound (2-bromo-1-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)ethanone) as a light yellow solid. MS: m/z=698.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[C:16]([F:19])([F:18])[F:17])=[CH:11]\[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([F:17])([F:18])[F:19])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C(=C\C(=O)OC)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(C(CC(=O)OC)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of methyl E-3-(4-ethoxyphenyl)-4,4,4-trifluorobut-2-enoate (2.4 g, 8.8×10-3 moles) and 5% palladium on carbon (500 mg) in ethanol (50 cm3) was rapidly stirred under hydrogen (three atmospheres) for two hours. The catalyst was filtered off and the solvent removed to leave a colourless oil. Chromatographic purification allowed the isolation of the desired product (2.3 g, 96%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23]>>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][NH:21][C:22]([NH2:24])=[O:23])[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Reactant: NNC(N)=O
Agent: Cl
Product: CC(=NNC(N)=O)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 58) and 2.4 mmol of semicarbazide hydrochloride are treated as described in Example 138.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH3:15])=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:16].[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]2[C:7]([CH3:15])=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:16]
Reactant: COC(=O)c1ccc2sc(=O)n(C)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccc2sc(=O)n(C)c12
Yield: 83.7 %

Procedure:
A solution of 10.15 g (43 mmol) of methyl 3,4-dimethylbenzo-thiazol-2-one-5-carboxylate in 100 ml of tetrahydrofuran and 100 ml of water was admixed with 2.06 g (86 mmol) of lithium hydroxide. The solution was then heated at reflux for 2 hours. After cooling, the tetrahydrofuran was removed under reduced pressure, the remaining aqueous solution was acidified and the precipitated solid was filtered off with suction and dried. More product was obtained by extracting the mother liquor with ethyl acetate. This gave a total of 8 g (36 mmol, 83% yield) of 3,4-dimethylbenzothiazol-2-one-5-carboxylic acid of m.p. 235° C.-239° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([OH:17])=O)=[CH2:2].Cl.[N:19]1([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:22]1[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]3[C:31](=[O:34])[O:32][CH2:33][C:29]=3[CH:28]=2)[CH2:20][CH2:21]1)=[O:17])=[CH2:2]
Reactant: C=Cc1cc(-n2cnnn2)ccc1CC(=O)O
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid (43 mg, 0.19 mmol) in 10 mL of anhydrous DCM was added 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (53 mg, 0.19 mmol), EDC (56 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), TEA (115 mg, 1.14 mmol) and then stirred at ambient temperature overnight. Then DCM was added and then mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to afford 5-[2-(4-{[2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.75˜7.78 (m, 2H), 7.48˜7.51 (m, 1H), 7.26˜7.31 (m, 3H), 6.76˜6.84 (rn, 1H), 5.7 (d, J=17.2 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 2H), 3.6˜3.65 (m, 2H), 3.45˜3.48 (m, 2H), 2.86˜2.9 (m, 2H), 2.59˜2.64 (m, 2H), 2.41˜2.5 (m, 4H).
Reaction SMILES: P([O-])([O-])(O[CH:4]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[CH2:5]1)=O.[C:16]([NH:19][C@@H:20]1[C@@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][OH:30])[O:23][CH:21]1[OH:22])(=[O:18])[CH3:17].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.C(OP(O)(O)=O)[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O>>[C:16]([NH:19][C@@H:20]1[C@@H:26]([OH:27])[C@H:25]([O:28][C@@H:4]2[O:11][C@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@H:6]([OH:7])[CH2:5]2)[C@@H:24]([CH2:29][OH:30])[O:23][CH:21]1[OH:22])(=[O:18])[CH3:17]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=P([O-])([O-])OC1C[C@@H](O)[C@H](O)[C@@H](CO)O1
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@H]2C[C@@H](O)[C@@H](O)[C@@H](CO)O2)[C@@H]1O

Procedure:
2-Deoxyglucose 6-phosphate (2, 60 mg, 190 μmol), N-acetylglucosamine (6, 71 mg, 321 μmol), UDP (2 mg, 5 μmol), PEP (44 mg, 210 μmol), glucose 1, 6-diphosphate (0.1 mg) and bovine serum albumin (BSA, 5 mg) are dissolved in 10 ml of deoxygenated buffer. The enzymes are subsequently added:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C([O-])=O.[CH2:22]([O:24][C:25]([CH2:27][O:28][C:29]1[C:33]2[S:34][C:35]3[CH:36]=[C:37]([NH3+:41])[CH:38]=[CH:39][C:40]=3[C:32]=2[S:31][C:30]=1[C:42]([O:44][CH3:45])=[O:43])=[O:26])[CH3:23].[CH:46](=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH3:45][O:44][C:42]([C:30]1[S:31][C:32]2[C:40]3[CH:39]=[CH:38][C:37]([NH:41][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:36][C:35]=3[S:34][C:33]=2[C:29]=1[O:28][CH2:27][C:25]([O:24][CH2:22][CH3:23])=[O:26])=[O:43]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc([NH3+])ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Sodium triacetoxyborohydride (90 mg, 0.42 mmol, 2.5 equiv) was added to a mixture of 1-ethoxycarbonylmethoxy-2-methoxycarbonyl-3,8-dithia-cyclopenta[a]inden-6-yl-ammonium trifluoroacetate (82 mg, 0.17 mmol), benzaldehyde (21 mg, 0.2 mmol, 1.2 equiv), and acetic acid (5wl) in DCE (4 ml). The reaction mixture was stirred at RT for 16 hr then DCM (20 ml) was added. The mixture was washed with sat. NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. Purification by column chromatography yielded 61 mg (81%) of 6-benzylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][O:10][CH:18]2[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCc3ccc(Br)cc32)cc1

Procedure:
20.1 g (100 mM) of 2-(4-bromophenyl)-ethanol and 15.1 g (100 mM) of 4-nitrobenzaldehyde were dissolved in 300 ml of anhydrous benzene, then 13.6 g (100 mM) of anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the stirred mixture for 4 hours. Then the process described under Examples 1-7, Step a) was applied. The crude product was recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.O1CCCC1.C([Mg]Cl)(C)C.CCCCCC.C([Li])CCC.[S:37]([N:47]1[CH:51]=[C:50]([CH:52]=[O:53])[N:49]=[CH:48]1)([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[Cl-].[NH4+]>O1CCCC1.CC(C)=O>[OH:53][CH:52]([C:50]1[N:49]=[CH:48][N:47]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:51]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C=O)c2)cc1
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CNC(=O)c1ccc2cc(C(O)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Temperature: -30 °C
Yield: 51.5 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (10.0 g, 37.9 mmol) was added to tetrahydrofuran (250 mL), and to the obtained solution was added dropwise 2.0 mol/L isopropylmagnesium chloride tetrahydrofuran solution (18.9 mL) at room temperature. The obtained reaction mixture was cooled to −30° C., 1.65 mol/L n-butyllithium hexane solution (37.9 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1 hr or more. To the obtained reaction mixture was added dropwise a solution of 1-tosyl-4-formyl-1H-imidazole (14.2 g, 56.8 mmol) in tetrahydrofuran (200 mL) at −20° C., and the mixture was stirred at the same temperature for 2 hr. The obtained reaction mixture was warmed over 2 hr to 0° C., 20 w/v % aqueous ammonium chloride solution (150 mL) was added dropwise thereto. The separated organic layer was concentrated to the volume of about 130 mL under reduced pressure to give a residue. To the obtained residue was added tetrahydrofuran (200 mL), and the mixture was concentrated to the volume of about 130 mL under reduced pressure to give a residue. To the obtained residue was added acetone (200 mL), and the mixture was concentrated to the volume of about 200 mL under reduced pressure. These operations were repeated three times to give a residue. To the obtained residue was added acetone to adjust the volume to about 260 mL. The obtained solution was stirred at room temperature for 2 hr or more. The obtained crystals were collected by filtration, and washed with acetone (100 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give 6-(hydroxy(1-tosyl-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (8.5 g, 19.5 mmol). yield 52%.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[C:31](C#N)=[CH:30][C:29]([N+:34]([O-:36])=[O:35])=[C:28]([NH2:37])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:34]([O-:36])=[O:35])=[C:28]([NH2:37])[N:27]=2)[N:11]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)nc1Cl
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(CCNc1ccc([N+](=O)[O-])c(N)n1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-amino-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24](=[O:29])[CH2:23]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)ccc2N1
Temperature: 90 °C

Procedure:
Under N2 a mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine V (2.0 g, 9.08 mmol), 5-(2-chloroethyl)oxindole (0.95 g, 10 mmol), Na2CO3 (1.06 g, 10 mmol) and KI (1.0 g, 6.0 mmol) in 45 ml dry DMF was heated at 90° C. for 72 hours. The reaction mixture was then poured over 150 ml ice/water, stirred, and filtered to give 3.04 g of brown solids. Chromatography on silica gel (230-400 mesh), eluting with 95% EtOAc: 5% triethylamine provided clean product, 0.645 g (19%), light brown solid, m.p. 199°-204° C. Analysis for C22H22FN3O2 ·0.5H2O: C 68.03, H 5.97, N 10.82. Found: C 67.94, H 5.57, N 10.81; MS(%): 379 (1, p+), 253 (4), 234 (32), 233 (100). NMR (300 MHz, CDCl3, delta), 2.0-2.4 (m, 6H), 2.65 (m, 2H), 2.8 (m, 2H), 3.1-3.2 (m,3H), 3.5 (s, 2H), 6.75 (d, 1H), 7.1 (m, 3H), 7.2 (s, 1H), 7.7 (m, H), 8.25 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[C:14]([O:18][C:19](=[O:22])[CH2:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(O)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (33.87 g) and glycine tert-butyl ester hydrochloride (55.98 g) in ethanol (400 ml) was added triethylamine (77.6 ml), and the mixture was stirred at room temperature for 15 hours and then at 50° C. for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether and collected by filtration to give the title compound (38.419 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@H]3O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1R,2R)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37-8.30 (m, 2H), 8.21-8.16 (m, 1H), 7.97 (m, 1H), 7.68-7.62 (m, 1H), 7.60-7.54 (m, 1H), 7.40-7.32 (m, 3H), 3.26-3.18 (m, 1H), 2.87-2.79 (m, 1H), 1.94-1.77 (m, 2H), 1.67-1.50 (m, 2H), 1.26-1.09 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.[C:36](=[O:38])=[O:37]>C1COCC1.O>[F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]
Reactant: O=C=O
Reactant: Fc1cccc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
4-Fluoro-2,2-diphenyl-benzo[1,3]dioxole (5.8 g, 20 mmol) were dissolved in THF (40 ml). The reaction was cooled to −78° C. under argon. TMEDA (2.9 ml, 20 mmol) was added followed by n-butyl lithium (12.5 ml, 1.6 N in hexane) dropwise. The reaction was stirred at −78° C. for 2 hours. Carbon dioxide (20 g) was added at that temperature. The reaction was allowed to warm to 0° C. and poured into water (80 ml). The reaction was extracted twice with ethyl acetate. The aqueous layer was neutralized with 1N aqueous HCl solution, extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue suspended in n-hexane, stirred for 10 minutes and the product was filtered off to yield the acid as a white solid (4.0 g, 60%). m.p.: 189-191° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][N:8]([C@@H:16]([CH3:37])[C:17](=[O:36])[NH:18][C@H:19]1[C:25]2([CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[O:24][C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[NH:21][C:20]1=[O:35])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1C(=O)N([Br:45])C(=O)C1>CN(C=O)C.[NH4+].[Cl-]>[Br:45][C:32]1[CH:33]=[CH:34][C:22]2[NH:21][C:20](=[O:35])[C@@H:19]([NH:18][C:17](=[O:36])[C@@H:16]([N:8]([CH3:7])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[CH3:37])[C:25]3([CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[O:24][C:23]=2[CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(Br)cc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 127 %

Procedure:
Cs2CO3 (331 mg, 1.01 mmol, Eq: 2.2) was added was added to a solution of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-yl)carbamate (200 mg, 461 μmol, Eq: 1.00) and DMF (10 mL) and the mixture was cooled to 0° C. and a solution of NBS (82.1 mg, 461 μmol, Eq: 1.00) in 2 mL DMF was added dropwise over 5 min. and the mixture warmed to RT. After 10 h the mixture was diluted with sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with H2O, concentrated and the residue was purified by preparative TLC to give tert-butyl (S)-1-((S)-8-bromo-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (300 mg, 98%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1ccc(OCc2cccc(CC(=O)O)c2)cc1

Procedure:
[3-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid was prepared using general procedure 4 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=363.
Reaction SMILES: [CH2:1]([S:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1N)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+]>OS(O)(=O)=O.O>[CH:14]1[C:15]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][S:8](=[O:9])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccccc1S(=O)Cc1ccccc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=S1Cc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
To a stirred suspension of benzyl-(2-aminophenyl)-sulfoxide (1.9 g; 0.008 mol) in 30 ml of 11% H2SO4 was added a solution of sodium nitrite (0.78 g; 0.011 mol) in 20 ml of water at about 0° C. After 1 hour at 0° C. to the yellow solution was quickly added a solution of cupric nitrate trihydrate (34.2 g; 0.140 mol) in 75 ml of water and cuprous oxide (1.33 g; 0.009 mol). The solution was allowed to warm to room temperature and stirred for further 5 hours. The solid was filtered and treated with hot ethyl acetate. The solution was dried over sodium sulfate concentrated and the residue was crystallized from ethyl acetate/pentane (1:4) to give 6H-dibenzo[b,d]thiopyran-5-oxide (1.25 g; yield 71%); m.p. 97°-100° C. By proceeding analogously the following compounds were obtained:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:26]([CH3:30])[CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:29][CH2:28][CH2:27][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=1)[CH3:30])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCO)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cccc(OCc3ccccc3)c2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (9.8 g., 51 mM) is added to a solution of 3-(3-benzyloxyphenyl)-1-butanol (12.8 g., 50 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexane.