Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: CC(C)(O)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(C(=O)N2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (200 mg, 0.48 mmol), 2-piperidin-4-ylpropan-2-ol (78 mg, 0.55 mmol), HATU (205 mg, 0.54 mmol) and DIPEA (96 μL, 0.55 mmol) in DCM (5 mL) was allowed to stir at r.t. for 19 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-3%) then (Si-PCC, MeOH:EtOAc, 0-5%) affording 798 as a white solid (138 mg, 53%). LCMS (method G): RT 7.50 min, [M+H]+ 545.4. 1H NMR (CDCl3, 400 MHz): δ 7.97-7.96 (1 H, m), 7.68-7.67 (1 H, m), 7.28-7.20 (2 H, s), 4.91-4.82 (1 H, m), 4.68-4.65 (1 H, m), 4.40 (4 H, brd s), 3.97 (3 H, s), 3.86 (4 H, t, J=4.70 Hz), 3.18-3.10 (1 H, m), 2.84-2.83 (2 H, m), 1.94-1.92 (2 H, m), 1.64-1.62 (1 H, m), 1.44-1.43 (2 H, m), 1.35-1.34 (2 H, m), 1.24-1.22 (7 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]2[CH2:16][N:15]([C:17]([C@@H:19]3[CH2:23][C@H:22]([S:24][C:25]4[C@H:26]([CH3:49])[C@@H:27]5[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]5[C:29]=4[C:30]([O:32]CC4C=CC([N+]([O-])=O)=CC=4)=[O:31])[CH2:21][N:20]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:18])[CH2:14]2)=O)=CC=1)([O-])=O.[H][H]>O1CCCC1.O.[Pd]>[NH2:12][CH:13]1[CH2:14][N:15]([C:17]([C@@H:19]2[CH2:23][C@H:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([OH:32])=[O:31])[CH2:21][NH:20]2)=[O:18])[CH2:16]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N)C4)C3)[C@H](C)[C@H]12
Yield: 54.7 %

Procedure:
3630 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 121(1)] were dissolved in 190 ml of a 3:2 by volume mixture of tetrahydrofuran and water, and 5500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at 30° C. for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, the filtrate was washed with diethyl ether and the resulting aqueous solution was concentrated to 10 ml by evaporation under reduced pressure. The resulting solution was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, 250 ml, manufactured by Nacalai Tesque), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96, 6:94 by volume, in that order. The fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and freeze-dried, to obtain 901 mg of the title compound as a powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O.CCOC(C)=O>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:2]=[CH:3]2)#[N:11]
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Temperature: 80 °C

Procedure:
1H-indazole-5-carbonitrile (D1) (3.5 g, 24.45 mmol) was dissolved in N,N-dimethylformamide (60 ml). cesium carbonate (15.93 g, 48.9 mmol) and ethyl 3-bromopropanoate (4.68 ml, 36.7 mmol) were added. The mixture was heated at 80° C. for 4 hours. Diluted with EtOAc and washed with water (3×40 ml), dried over MgSO4 and evaporated. The mixture was purified by flash chromatography, eluting EtOAc/iso-Hexane 10-30% then 10-20% to give (3.682 g) for the first isomer (yellow oil) and (1.509 g) for the second isomer (pink solid). Analysis of the first isomer by 1H nmr indicated that is was the 1-isomer contaminated with the 2-isomer (ca. 20%) δH (d6-DMSO, 400 MHz) 1.05 (3H, t), 2.95 (2H, t), 3.97 (2H, q), 4.69 (2H, t), 7.74 (1H, dd), 7.92 (1H, dt), 8.28 (1H, d), 8.38 (1H, dd). MS (ES+): C13H13N3O2 requires 243; found (MH+) 244.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[CH2:19]([N:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([CH3:10])=[CH:9][C:4]=1[Br:3])[C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N(Cc2ccccc2)C(=O)C(C)C)c(Br)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
A mixture of powdered KOH (1.3 g, 23.13 mmol) in DMSO (25 mL) was stirred at 0° C. for 5 minutes. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (3.30 g, 11.56 mmol) was added cautiously followed immediately by the addition of benzylbromide (2.75 mL, 23.13 mmol) and the reaction stirred at room temperature for 48 hrs. Water was added and the mixture extracted with ethyl acetate. The organic extract was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 4.3 g of N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). 1H NMR (300 MHz; CDCl3): 1.02 (d, J=6.6 Hz, 3 H), 1.15 (d, J=6.6 Hz, 3 H), 2.16 (s, 3 H), 2.29 (m, 1 H), 3.43 (s, 3 H), 3.85 (d, J=14.1 Hz, 1 H), 5.75 (d, J=14.1 Hz, 1 H), 6.02 (s, 1 H), 7.18–7.27 (m, 5 H), 7.38 (s, 1 H).
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](Cl)=[N:7][C:6]1=[NH:13])(=O)C.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:13])[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: C1CCNCC1
Reactant: CC(=O)On1c(N)cc(Cl)nc1=N
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Yield: 86 %

Procedure:
2.02 g (10 mmoles) of 1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added to 8 ml of piperidine at room temperature while stirring. The mixture is stirred at room temperature for 2 hours, then piperidine is evaporated under reduced pressure. The residue is taken up in a mixture containing 20 ml of ethanol and 10 ml of 1N aqueous sodium hydroxide solution and refluxed for 30 minutes, then evaporated under reduced pressure. The residue is taken up in 20 ml of water, the crystals are filtered, washed with water and dried to give 1.74 g (86% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([CH2:18]O)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(Cl)Cl.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([OH:20])[CH:16]([CH2:18][N:24]=[N+:25]=[N-:26])[CH2:17]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(CO)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(CN=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Ms-Cl (0.38 mL, 2.6 eq) was added to a solution of 3-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of stereoisomers, prepared according to WO9303026, 410 mg, 1.89 mmol) in pyridine (3.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then DCM was added and the mixture was washed with sat. aq. NaHCO3, dried over MgSO4, concentrated under reduced pressure and dried at HV. The crude mesylate was dissolved in DMF (18 mL), treated with NaN3 (1.23 g, 10 eq) and stirred at 95° C. for 1.5 h. After cooling to rt the mixture was concentrated to dryness and dissolved in DCM. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and the residue was purified by CC (DCM to DCM/MeOH 95:5) to afford the title intermediate as a yellow oil (390 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH2:17][C:18](=O)[CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.C([O:37]C(NC1C=CC(OC)=CC=1C)=O)(C)(C)C.CON(C)C(C1CC1)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]([CH:18]1[CH2:20][CH2:19]1)=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: CON(C)C(=O)C1CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C2CC2)c1
Temperature: -55 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
1-[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl]-2-butanone. A solution of 1.3M sec-butyl lithium/cyclohexane (100 mL, 0.13 mol) was added slowly to 15.17 g (0.065 mol) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline in 230 mL of THF while keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -20° C. and then the bath was replaced. After the temperature had cooled to -55° C., 8.4 g (0.065 mol) of N-methoxy-N-methylcyclopropylcarboxamide in 20 mL of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 2 hours. It was then poured into 500 mL of water. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The residue was crystallized from hexane to give 15.22 g (77% yield) of [2-(tert-butoxycarbonylamino)-5-methoxyphenyl]cyclopropyl ketone, melting at 96°-97° C.,
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH3:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(Cl)(Cl)Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([CH:16]=1)[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:5][CH:4]=1)=[O:20]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)O)cc1

Procedure:
N-phenethyl-5-chloro-2-methoxybenzamide (10 g.) dissolved in 25 ml. of chloroform was cooled to -10° and 19 g. of chlorosulfonic acid was added dropwise, maintaining the temperature at -10° to 0°. After the addition was complete the mixture was allowed to rise to room temperature and it was poured onto cracked ice. The crude sulfonic acid was filtered and 7.3 g. (57%) was obtained. A sample recrystallized for analysis from alcohol-acetonitrile melted at 188°-189°. Anal. Calcd. for C16H16ClNO5S: C, 51.94; H, 4.36; Cl, 9.58; N, 3.79; S, 8.67. Found: C, 50.10; H, 4.27; Cl, 9.93; N, 4.04; S, 8.84.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[H-].[Na+].[CH3:28]I>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[N:4]=[C:5]([N:13]([CH3:28])[C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1nc(C#N)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (235 mg, 0.694 mmol) in DMF (6 mL) was added NaH (27.8 mg, 0.694 mmol) and methyl iodide (0.052 mL, 0.833 mmol) at 0° C. The reaction mixture was allowed to warm to RT with stirring over a 2 hour period and was subsequently diluted with EtOAc and washed with aqueous NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Toluene (2×5 mL) was added and removed in vacuo to give the title compound as a crude residue.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.5 g of docosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.2 g of diethyl 2-acetamido-2-docosylmalonate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH2:22](I)[CH3:23]>>[CH2:22]([O:21][C:19]1[O:20][C:16]([C:13]2[O:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][O:4][CH3:3])[C:15]=3[CH:14]=2)=[N:17][N:18]=1)[CH3:23]
Reactant: CCI
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Agent: [H-]
Agent: [Na+]
Product: CCOc1nnc(-c2cc3c(OCOC)cccc3o2)o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 117 using sodium hydride (0.37 g), 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (2.0 g) and ethyl iodide (0.73 ml), the title compound (1.9 g) was obtained as pale-yellow crystals.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:23])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH3:26][C:27]1[O:28][C:29]([C:35]2[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=2)=[C:30]([C:32](Cl)=[O:33])[N:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:23])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[CH3:20])[O:13][CH:14]=1)[C:32]([C:30]1[N:31]=[C:27]([CH3:26])[O:28][C:29]=1[C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)=[O:33])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Reactant: CC(F)(F)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2oc(C)nc2C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)(F)F)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5,5-difluoro-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (74 mg, 0.24 mL) in THF (2.0 mL) was added to a suspension of NaH (26 mg, 0.60 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride in THF (1.5 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil. TLC: rf (7:3 hept-EA)=0.18. LC-MS-conditions 02: tR=1.17 min, [M+H]+=504.17.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Z-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (2.0 g, 0.0051 mol) (prepared as described in Method A) was dissolved in ethanol (8 ml) and 12N sodium hydroxide solution (1.3 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 1.8 ml) was added with cooling, followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to give the title compound (0.70 g, 34%), m.p. 206°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8](Br)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8]([N:69]3[CH2:70][CH2:71][N:66]([CH3:65])[CH2:67][CH2:68]3)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(OC)c2cc(F)cc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)c2cc(F)cc(N3CCN(C)CC3)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
Into a 250 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 2.1 g (6.68 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic acid methyl ester (Reference Example 29a) (122 mg, 0.134 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 499 mg (0.802 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 80 mL of dry toluene. To the stirred suspension is then added 736 mg, 815 μL, (7.35 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 3.05 g (9.35 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 36 hr. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of celite, with toluene washing to remove solid by products. Purification by flash chromatography using a gradient of 5 to 20% methanol in methylene chloride as eluent yielded 2.0 g, (90%) of the desired product. Mass Spec.: calc. for [C17H20FN3O3+H]+ Theor. m/z=334; Obs.=334
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 45.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiprazine were reacted to yield the title compound as a slightly-brown crystalline powder (yield: 45.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[NH2:13][C:14]1[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=1[NH2:20].C(N(CC)CC)C.[OH-].[Na+].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]1[NH:13][C:14]2[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCOc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1-c1nc2c([nH]1)c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (12.0 g, 65 mmol) in dimethylformamide (10 mL) was added dropwise to a stirred solution of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione (10.4 g, 61 mmol) and triethylamine (9.8 mL, 65 mmol) in dimethylformamide (250 mL). The resulting mixture was stirred for 20 hours at room temperature, then evaporated under reduced pressure. Aqueous sodium hydroxide solution (1N, 98 mL, 98 mmol) was added and the mixture heated under reflux for 6 hours. The resulting solution was acidified with 1N hydrochloric acid and the precipitate collected and dried by suction to give 8-(2-ethoxyphenyl)-3-ethyl-3,7-dihydropurine-2,6-dione as a beige solid (7.0 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCCCCC>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:12])[CH3:11]
Reactant: ClCCCCI
Reactant: CC(=O)Nc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)N(CCCCCl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 g (54.1 mmol) of N-(4-cyanophenyl)acetamide are dissolved in 100 ml of THF. The mixture is cooled to 0° C. before the dropwise addition of 51 ml of a 1.6 N solution in hexane of nBuLi (1.5 eq.). The solution is left for one hour to return to ambient temperature and is then cooled to 0° C. before the dropwise addition of 9.9 ml of 1-chloro-4-iodobutane (81 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then hydrolysed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. Purification by chromatography on silica (eluant: petroleum ether/ethyl acetate: 1/1) yields a yellow oil containing the expected product.