Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.87 (s, 1H), 8.45 (s, 1H), 7.56 (br. s., 1H), 7.38 (d, J=8.59 Hz, 1H), 7.26 (dd, J=2.15, 8.46 Hz, 2H), 4.58 (d, J=4.55 Hz, 1H), 4.52 (s, 2H), 3.91-4.01 (m, 4H), 3.46-3.54 (m, 1H), 3.17-3.27 (m, 2H), 3.08 (s, 3H), 1.94 (d, J=9.85 Hz, 2H), 1.76 (d, J=12.13 Hz, 2H), 1.53-1.65 (m, 2H), 1.23-1.36 (m, 2H), 1.18 (t, J=7.07 Hz, 6H). MS (ES+): m/z: 648.1830 [MH+]. HPLC: tR=1.44 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([N:19]1[CH2:33][C:22]2=[C:23]3[N:28]([N:29]=[C:21]2[CH2:20]1)[C:27]([CH3:30])=[C:26]([Cl:31])[C:25]([CH3:32])=[N:24]3)=[O:18])([F:9])[F:8])C>O1CCOCC1.CC(=O)OCC>[Cl:31][C:26]1[C:25]([CH3:32])=[N:24][C:23]2[N:28]([N:29]=[C:21]3[CH2:20][N:19]([C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][C:7]([F:8])([F:9])[CH2:6][OH:5])=[O:18])[CH2:33][C:22]3=2)[C:27]=1[CH3:30]
Reactant: CCOC(=O)C(F)(F)Oc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(F)(F)CO)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.8 %

Procedure:
Lithium borohydride (2.81 mg; 0.13 mmol; 1 eq.) was added to a solution of [2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-difluoro-acetic acid ethyl ester (60 mg; 0.13 mmol; 1 eq.) in 1,4-dioxane (1 mL) and the resulting mixture was stirred at room temperature for 1.5 hour. The solution was diluted with EA, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (30% to 75% EA in cyclohexane) followed by crystallization from ACN afforded the title compound (12 mg, 22%). HPLC (max plot) 98.4%, Rt 3.46 min. UPLC/MS: (MS+) 423.2 ([M+H]+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]O)=[N+:2]=[N-:3].CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][F:34])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCF
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
23-Azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (500 mg, 1.26 mmol) was dissolved in DCM (2 mL) and cooled to −10° C. DAST (482 μL, 3.78 mmol) was added in portions to the cooled solution and the resulting mixture was stirred at −10° C. for 30 minutes then allowed to warm to room temperature and stirred for additional 20 hours. The excess of DAST was quenched with methanol (5 mL) and the solvents were subsequently evaporated at the reduced pressure. The oily residue was dissolved in the water (3 mL) and the pH was adjusted to 5 using NaHCO3. The crude product was purified on semipreparative HPLC (System E) to yield 122 mg (24%) of 4 as a yellowish oil. 1H NMR (500 MHz, CDCl3): δ 3.39 (t, J=5.0 Hz, 2H), 3.65-3.68 (m, 26H), 3.75 (dt, J=4.2 Hz, 29.6 Hz, 2H), 4.56 (dt, J=4.0 Hz, 47.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3): δ 50.8, 70.1, 70.4, 70.5, 70.7-70.8, 70.9, 83.2 (d, J=169 Hz); 19F NMR (470.6 MHz, CDCl3): δ −225.9; MS ESI (m/z): [M+H]+ calcd. for C16H33FO7N3, 398.2. found 398.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[I:17](O)(=O)=O.II.S(=O)(=O)(O)O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O.C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: [O-][I+2]([O-])O
Reactant: COCCc1ccc(-c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COCCc1ccc(-c2ccc(I)cc2)cc1
Temperature: 83 °C
Yield: 231 %

Procedure:
Into a 300 ml three-neck flask were added 4-(β-methyloxyethyl) biphenyl (34 g, 0.16 mol), acetic acid (112 ml), water (30 ml), iodic acid (6.8 g, 0.0384 mol), iodine (17.9 g, 0.0704 mol), carbon tetrachloride (13 ml) and conc. sulfuric acid (4.8 ml). The mixture was warmed by a mantle heater with stirring, and reaction was carried out under reflux at 83° C. for 3 hours. After completion of the reaction, the reaction liquid was cooled down to 70° C., and 10% sodium thiosulfate aqueous solution (10 ml) was added to cause excess iodine to disappear. The liquid was cooled down to room temperature, and the precipitated crystals were recrystallized from ethyl ethanol (300 ml) to obtain 4'-(β-methoxyethyl)-4-iodobiphenyl (V) (30 g) having a melting point of 97°~99.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:35]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(F)c2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.57 g) and benzophenone imine (1.15 ml) in toluene (40 ml) was added sodium tert-butoxide (691 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (280 mg) and tris(dibenzylideneacetone)dipalladium(0) (120 mg) were added and the reaction mixture was heated to 100° C. and stirred for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.215 g, quant.) as a yellow viscous oil. MS (ISP): 461.3 ([M+H]+), 405.4 ([M+H—C4H8]+), 361.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10]OS(C)(=O)=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][C:17]1([OH:21])[CH2:20][NH:19][CH2:18]1.C(N(CC)CC)C>CO.CO.C1COCC1>[CH3:16][C:17]1([OH:21])[CH2:20][N:19]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:18]1
Reactant: CC1(O)CNC1
Reactant: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(O)CN(Cc2ccc([N+](=O)[O-])cn2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 52 (0.5 g, 2.2 mmol) in MeOH (25 mL) was added Ambersep-900 OH resin (50 g) filtered to separate the resin and concentrated to obtain the free base. The free base was dissolved in MeOH-THF (10 mL, 1:1) and cooled to 0° C. 3-methyl-azetidin-3-ol (0.53 g, 4.3 mmol) and triethylamine (0.7 mL, 4.3 mmol) were added and the reaction mixture warmed to rt and stirred for 16 h. The reaction mixture was concentrated and the crude compound was purified by silica gel column chromatography (100-200 mesh), eluting with 3% MeOH/CHCl3 to give the desired compound (0.35 g, 48%, over two steps) as a pale yellow liquid. Rf: 0.3 (10% MeOH/DCM); (m/z): 224 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.27 (1H, d, J=2.4 Hz), 8.56 (1H, dd, J=8.8, 2.8 Hz), 7.64 (1H, d, J=8.8 Hz), 5.22 (1H, s), 3.85 (2H, s), 3.36-3.26 (2H, m), 3.02-3.00 (2H, m), 1.38 (3H, s).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:37])([F:36])[C:12]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:33]([N:32]([CH2:31][C:12]([OH:30])([CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([F:37])([F:36])[F:10])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:34][CH3:35]
Reactant: O=C(O)c1ccccc1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1>C(O)C.C[O-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:2][CH3:1])[CH:11]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(c1ccc(Cl)cc1)C(C(=O)C(C)(C)C)n1cncn1
Yield: 66.6 %

Procedure:
10 g (0.2 mol) of methylmercaptan were introduced into a solution of 0.5 g (9 millimol) of sodium methylate in 300 ml of ethanol. 47 g (0.16 mol) of 1-(4-chloro-phenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E isomer) were introduced into this solution. The initially clear solution soon changed to a thick crystal slurry. The crystals were filtered off, washed with diisopropyl ether and with ethanol, and dried. 36 g (66.6% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-1-methylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 145° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([OH:10])=O)=[CH:5][S:6][CH:7]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:53])[C:47]4[CH:48]=[N:49][NH:50][C:51]=4[CH:52]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:53][C:8]([C:4]4[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: COc1cscc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cscc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h

Procedure:
4-(Methyloxy)-3-thiophenecarboxylic acid (35 mg) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (84 mg) in DMF (250 μl) and DIPEA (69 μl). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg) in DMF (250 μl). The reaction mixture was left to stand at 22° C. for 18 h. The solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to an aminopropyl SPE cartridge (0.5 g) that had been preconditioned with methanol and then chloroform. The product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: CCN
Reactant: O=Cc1nccs1
Solvent: C1CCOC1
Product: CCNCc1nccs1

Procedure:
prepared by reaction of thiazole-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: O[CH:2]([N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9](O)[N:10]2[C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])[CH:4]=1.[C:25]([O-:28])(=O)[CH3:26].[Mg+2].[C:30]([O-])(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([CH:2]([N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:25](=[O:28])[CH3:26])[N:10]2[C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])[CH:4]=1)(=[O:32])[CH3:31]
Reactant: O=C1CCC(=O)N1C(O)c1cccc(C(O)N2C(=O)CCC2=O)c1
Reactant: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(c1cccc(C(C(C)=O)N2C(=O)CCC2=O)c1)N1C(=O)CCC1=O
Temperature: 100 °C
Yield: 16670.1 %

Procedure:
A mixture of 10 g 1,3-bis(hydroxysuccinimidomethyl)benzene, 20 mg magnesium acetate and 50 ml acetic anhydride was heated at 100° C. for 1 hour. The acetic anhydride and acetic acid were evaporated under reduced pressure, leaving 9 g (72%) of a light brown crystalline product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C@H:26]([O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[C:33]([OH:35])=O)[CH2:27][CH3:28].[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH3:53])[N:49]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C@H:26]([O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[C:33]([NH:47][C:48]1[CH:52]=[CH:51][N:50]([CH3:53])[N:49]=1)=[O:35])[CH2:27][CH3:28]
Reactant: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 16 h

Procedure:
HATU (1.19 g, 3.13 mmol) was added to 3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (750 mg, 2.5 mmol) and 3-amino-1 methylpyrazole (291 mg, 3 mmol) in DMF (5 mL) followed by addition of DIPEA (0.807 mL, 6.25 mmol) and the reaction was stirred for 16 hours. The reaction mixture was added to ethyl acetate (30 mL), washed with water (10 mL), 2N citric acid (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL), then dried (MgSO4), filtered and evaporated to a gummy residue. The residue was taken up in 50% ether in ethylacetate (50 mL), washed with 2N hydrochloric acid (10 mL), water (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL) then dried (MgSO4), filtered and evaporated to a foam (900 mg) which was used without further purification in the next step. 1H NMR δ (CDCl3): 0.96 (t, 3H), 1.28 (d, 3H), 1.51-1.80 (m, 2H), 3.78 (s, 1H), 4.31 (q, 1H), 5.06 (s, 2H), 6.68 (t, 1H), 6.82 (d, 1H), 7.00 (s, 1H), 7.06 (s, 1H), 7.29 (s, 3H), 7.31-7.47 (m, 5H), 8.63 (s, 1H); m/z 380 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])[CH:5]=[CH:6][CH:7]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1cccc(F)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: N#Cc1cccc(C=Cc2cccc(F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 111–112° C. (iPrOH), MS: m/e=224 (M+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:17].C([Li])CCC.[CH:23](N1CCCCC1)=[O:24].Cl>C1COCC1.CCCCCC.O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH:23]=[O:24])[O:9][CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6]2
Reactant: CCCCCC1COc2cc(Br)c(F)cc2C1
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1COc2cc(C=O)c(F)cc2C1
Reaction time: 1 h

Procedure:
15.5 g (51.5 mmol) of 7-bromo-6-fluoro-3-pentylchroman are dissolved in 85 ml of THF, and 35 ml (55.7 mmol) of a 15 percent solution of n-butyllithium in n-hexane are slowly added at −70° C. After 1 h, 6.3 ml (56.7 mmol) of N-formylpiperidine in 15 ml of THF are added dropwise, and the mixture is stirred for 1 h. The batch is subsequently allowed to thaw, added to water, acidified using dil. hydrochloric acid and extracted three times with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate, the solvent is removed in vacuo, and the residue is recrystallised from heptane at −25° C., giving 6-fluoro-3-pentylchroman-7-carbaldehyde as colourless crystals (Rf=0.4; 1-chlorobutane).
Reaction SMILES: C(C1SC2C(C(=O)N2C(=C(O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:124][CH2:123][O:122][CH2:121][CH2:120]2)[CH3:118])[C:101]([O:103][CH:104]([C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Br:126]Br>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:120][CH2:121][O:122][CH2:123][CH2:124]2)[CH2:118][Br:126])[C:101]([O:103][CH:104]([C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
Reactant: BrBr
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Agent: CC(O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (4.84 g) in tetrahydroufran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3 hours at room temperature, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70% IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4 Hz)1H, 5.66 dd(9:4)1H, 6.77d(9 Hz)1H, 6.90s1H, 7.35 ml 5H.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19]3)(=[O:15])=[O:14])[CH2:9][CH2:8]1.[B:32](OC)([O:35]C)[O:33]C>CCCCC.C1COCC1>[C:28]([O:27][C:25]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([S:13]([N:10]3[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]3)(=[O:15])=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[B:32]([OH:35])[OH:33])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of tert-butyllithium (1.7 M, 6.20 mL, 10.5 mmol, 2.00 equiv) in pentane was added to a solution of tert-butyl 5-[(4-methylpiperazin-1-yl) sulfonyl]-1H-indole-1-carboxylate (1-9, 2.00 g, 5.27 mmol, 1 equiv) in THF (150 mL) at −78° C. The resulting orange-colored reaction mixture was stirred at −78° C. for 1.5 hours before trimethyl borate (1.50 mL, 13.2 mmol, 2.50 equiv) was added. The mixture was warmed to 0° C. where it was stirred for 20 minutes, then partitioned between aqueous half-saturated ammonium chloride solution (200 mL) and EtOAc (2×200 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-(tert-butoxycarbonyl)-5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-ylboronic acid (1-10) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H, J=8.8 Hz), 8.02 (d, 1H, J=1.6 Hz), 7.71 (d, 7.71 (dd, 1H, J=8.6, 1.8 Hz), 7.49 (s, 1H), 3.05 (br m, 4H), 2.48 (br m, 4H), 2.25 (s, 3H), 1.75 (s, 9H).