Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:25][C:26](=[O:35])[C@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]([C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[NH:25][C:26](=[O:35])[C@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CC(C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@H]2CCCN2)cc1
Yield: 16.9 %

Procedure:
(R)-tert-Butyl 2-((R)-(4-isobutoxyphenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (34.1 mg, 0.071 mmol) in hydrogen chloride (2M in diethyl ether) (355 mL, 0.710 mmol) was stirred at room temperature for 6 h then the solution was concentrated in vacuo. The residue was purified by HPLC (20%→100% acetonitrile/water with 0.1% TFA) to afford after preparing the free base, (S)-N-((R)-(4-isobutoxyphenyl)((R)-pyrrolidin-2-yl)methyl)-2-phenylpropanamide (4.6 mg, 0.012 mmol, 16.69% yield over two steps). 1H NMR (400 MHz, CDCl3) δ 7.40 (br s, 1H), 7.26-7.35 (m, 5H), 6.98 (d, J=8.56 Hz, 2H), 6.74 (d, J=8.81 Hz, 2H), 4.93 (t, J=7.18 Hz, 1H), 3.77 (q, J=7.05 Hz, 1H), 3.64-3.67 (m, 1H), 3.62 (d, J=6.55 Hz, 2H), 2.97-3.06 (m, 2H), 2.87-2.96 (m, 1 H), 1.96-2.09 (m, 1H), 1.67-1.83 (m, 3H), 1.53-1.57 (m, 1H), 1.50 (d, J=7.05 Hz, 3H), 0.97 (d, J=6.80 Hz, 6H); LRMS (ESI) m/e 381.30 [(M+H)+, calcd for C24H33N2O2 381.25].
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:52]=[CH:51][CH:50]=[C:49]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[C:27]=1[C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([CH3:36])[C@H:31]1[CH2:37][N:38]1C(=O)C2C(=CC=CC=2)C1=O)=[O:29]>>[NH2:38][CH2:37][C@@H:31]1[C@H:32]([CH3:36])[CH2:33][CH2:34][CH2:35][N:30]1[C:28]([C:27]1[C:49]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[CH:50][CH:51]=[CH:52][C:26]=1[F:25])=[O:29]
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(((2S,3R)-1-(2-fluoro-6-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 329 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:16]([NH:23][CH2:24][C:25]#[CH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([NH:23][CH2:24][C:25]#[C:26][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C#CCNCc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCNCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of dimethyl 5-bromodicarboxylate (from Example 3) and 1.25 g of N-benzylpropargylamine are dissolved in methylene chloride in a flask flushed with argon, and 3.4 ml of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 25 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 36 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation, 1.25 g of a dark oil which is hydrogenated without purification (Example 18) remain.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]=[C:2]1[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2[C:7]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2c(Oc3ccccc3)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c(=O)sc2cccc(Oc3ccccc3)c21
Yield: 73.9 %

Procedure:
A mixture of 2-oxo-4-phenoxybenzothiazoline (2.0 g), ethyl bromoacetate (1.7 g), potassium carbonate (1.4 g) in acetone (30 ml) was refluxed for an hour with stirring. After the resultant mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue, which was recrystallized from a mixture of ethanol and n-hexane to give crystalline ethyl 2-oxo-4-phenoxy-3-benzothiazolineacetate (2.0 g).
Reaction SMILES: [C:1]1([S:7]([CH:10]([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](I)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC([O-])(C)C.[K+]>CN(C=O)C>[C:1]1([S:7]([C:10]([F:12])([F:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)C(F)F
Reactant: CCCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCC(F)(F)S(=O)(=O)c1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Typical Procedure for Nucleophilic Substitution Reactions of Difluoromethyl Phenyl Sulfone with Alkyl Iodides. Under an argon atmosphere, into a Schlenk flask containing difluoromethyl phenyl sulfone (192 mg, 1 mmol) and n-heptyl iodide (904 mg, 4 mmol) in DMF (4 mL) at −50° C., was added dropwise via a syringe t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction mixture was stirred at −50° C. for 1 h, and the completion of the reaction was monitored by 19F NMR. The reaction was then quenched by adding 1N HCl aqueous solution (5 mL) at −50° C., followed by warming to room temperature. A saturated NaCl aqueous solution (10 mL) was added, and the mixture was extracted with Et2O (15 mL×3). The combined organic phase was dried over MgSO4, filtered, and the solvent was removed in a rotary evaporator. The residue was further purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1,1-difluorooctyl phenyl sulfone (4a) (230 mg, 79% yield) as a colorless oily liquid. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J=6.9 Hz, 3 H); 1.28 (m, 8 H); 1.64 (m, 2 H); 2.33 (m, 2H); 7.60 (t, J=8.3 Hz, 2H); 7.73 (t, J=7.3 Hz, 1H); 7.99 (d, J=7.9 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9; 20.7 (t, J=3.4 Hz); 22.4; 28.7; 29.0; 29.1; 31.4; 124.6 (t, J=286 Hz); 129.1; 130.6; 132.7; 135.1. 19F NMR (470 MHz, CDCl3): δ −104.2 (t, J=19 Hz). GC-MS (EI, m/z): 291 (M++1); 142; 77. HRMS (EI): m/z calcd for C14H21F2O2S (M++H) 291.1230, found 291.1222.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][O:24]C3C=CC(OC)=CC=3)[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][OH:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CN(C(=O)OC(C)(C)C)CCCO2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCOC(CO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl (2RS)-2-(3,4-dichlorophenyl)-2-[(4-methoxyphenoxy)methyl]-1,4-oxazepane-4-carboxylate (3.18 g) in acetonitrile (80 ml) and water (20 mL) was added ceric ammonium nitrate (10.8 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cnccc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=Cc1cnccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to Preparation 65 starting from 3,4-dichlorophenol and 4-chloronicotinaldehyde (prepared according to D. Albanese, M. Penso, M. Zenoni, Synthesis 1999, 1294–1296); δH (CDCl3, 400 MHz) 6.71 (1H, d), 7.04 (1H, dd), 7.27 (1H, m), 7.55 (1H, d), 8.02 (1H, s), 8.60 (1H, dd), 10.54 (1H, s); MS rn/z268 (MH+).
Reaction SMILES: [CH2:1]([C@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:24]([Mg]Br)=[CH2:25].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH:24]=[CH2:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=C[Mg]Br
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(C[C@H]2OC(C)(C)O[C@@H]2CCCCCCC)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)benzaldehyde (N) (15.5 mg, 0.048 mmol) in THF (1.2 mL) at 0° C. was added vinylmagnesium bromide (55 μL, 1M in THF) dropwise. After 30 minutes, saturated aqueous NH4Cl was added at 0° C., and the mixture was extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered and concentrated to yield the title compound (12.1 mg, 0.035 mmol, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.36-7.22 (4H, m), 6.10-5.99 (1H, m), 5.34 (1H, d, J=17.1 Hz), 5.20-5.17 (2H, m), 3.88-3.81 (1H, m), 3.71-3.65 (1H, m), 2.95-2.84 (2H, m), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.88 (3H, t, J=4.8 Hz); LRMS (APCI+) calcd for C22H35O3 [M−H]: 345.2; found 345.4.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[CH2:26]([CH:25]([NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)[CH2:28][CH3:29])[CH3:27]
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: CCC(N)CC
Product: CCC(CC)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12
Temperature: 120 °C
Yield: 41.9 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-aminopentane (86 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 3.66 min. (purity 96%). LC/MS, M+(ESI): 392.9, M−(ESI): 391.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][O:20][CH3:21])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 3-chlorophenol (50 g, 390.62 mmol, 1.00 equiv) in DCM (500 mL) was added DIEA (554 g, 4.29 mol, 11.00 equiv), followed by chloro(methoxy)methane (380 g, 10.00 equiv) at 20° C. The resulting mixture was allowed to react, with stirring, for 4 h at 20° C. The reaction mixture was then quenched with water. The separated organic phase was washed with water (2×), dried over Na2SO4 and then concentrated under vacuum to give 1-chloro-3-(methoxymethoxy)benzene as a white oil.
Reaction SMILES: [C:1]([C:3]1([CH2:8][CH2:9][CH3:10])[CH2:7][CH:6]=[CH:5][CH2:4]1)#[N:2].[CH2:11]([Mg]Br)[CH3:12].[BH4-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:2][CH:1]([C:3]1([CH2:8][CH2:9][CH3:10])[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH2:11][CH3:12]
Reactant: CC[Mg]Br
Reactant: CCCC1(C#N)CC=CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCC1(C(N)CC)CC=CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 134.4 %

Procedure:
1-cyano-1-propylcyclopent-3-ene (62, 2.3 g, 16.9 mmol) was dissolved in toluene (15 mL) and ethyl magnesium bromide (11.2 mL, 33.7 mmol, 3M in ether) added. After stirring for 30 minutes at 90° C., the reaction mixture was cooled and added dropwise to ice cold methanol (66 mL), followed by sodium borohydride (638 mg, 17 mmol). The mixture was warmed to room temperature and stirred overnight. The white suspension was treated with sodium hydroxide solution (aqueous, 1M), filtered through celite and then extracted with dichloromethane/isopropanol (3:1). The filtrate was washed with dichloromethane. The organic phase was washed with brine, dried over sodium sulphate and evaporated to give 3.8 g of a yellow oil. This was taken up in dichloromethane and extracted twice with hydrochloric acid (2M). The aqueous layer was made basic with sodium hydroxide solution (6M) and extracted with dichloromethane. Evaporation gave 1.38 g of desired product as a yellow oil which was used without further purification.
Reaction SMILES: CS(Cl)(=O)=O.C(N(CC)CC)C.O[C:14]([C:17]1[CH:21]=[C:20]([C:22]2[CH:38]=[CH:37][C:25]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][CH:23]=2)[N:19]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:18]=1)([CH3:16])[CH3:15].CN(C)C=O>ClCCl>[C:14]([C:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=2)[N:19]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:18]=1)([CH3:16])=[CH2:15]
Reactant: COc1ccc(-n2nc(C(C)(C)O)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (367 mg) and triethylamine (649 mg) were added successively to a solution of tert-butyl 2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 6 (1.0 g) and N,N-dimethylformamide (91.5 mg) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 2 hrs. Additional methanesulfonyl chloride and triethylamine were added until all starting material was consumed with stirring at the same temperature.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([O:14]COC)[C:4](=[O:18])[C:3]=1[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27].Br[Si](C)(C)C.O>ClCCl>[OH:14][N:5]1[C:6]2([CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]2)[C:2]([OH:1])=[C:3]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])[C:4]1=[O:18]
Reactant: COCON1C(=O)C(c2c(C)cc(C)cc2C)=C(O)C12CCN(OC)CC2
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methoxymethoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.6 obtained in analogy to preparation example 11, step 5) (500 mg, 1.33 mmol) in dichloromethane (10 ml) under argon atmosphere at 0° C. was added 3 {acute over (Å)} molecular sieves (0.5 g), followed by bromotrimethylsilane (1.72 ml, 2.03 g, 13.28 mmol) dropewise and the reaction mixture was stirred at 0° C. for one hour and at room temperature for 48 hours. The mixture was poured on cold water, the water layer saturated with sodium chloride and thoroughly extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 40 mg of 1,4-dihydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2ii.4) as a white solid, mp 152-154° C.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH:22]1[CH:27]([OH:28])[CH2:26][CH2:25][CH2:24][O:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[C:1]([NH:20][CH2:21][CH:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][O:23]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCOC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCOC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 51.9 %

Procedure:
A solution of a sulfur trioxide-pyridine complex (23.7 g, 149 mmol) in dimethyl sulfoxide (150 mL) was added to a solution of 2-(tritylamino)methyl-3,4,5,6-tetrahydro-2H-pyran-3-ol (18.54 g, 49.6 mmol) and triethylamine (45 mL, 323 mmol) in dimethyl sulfoxide (150 mL) in a nitrogen atmosphere at room temperature. The mixture was stirred at the same temperature for 10 hours. The reaction solution was poured into ice water (1 L), followed by extraction with ethyl acetate (2×1 L). Then, the organic layers were combined and washed with water (2×1 L) and brine (1 L). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90→20:80) to give 9.56 g (52%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1F
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 1 h
Yield: 253.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 140° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 80 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixture poured into 1 L of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the solid which formed on stirring was collected. The Celite pad was washed well with methylene chloride, the methylene chloride removed and the residue was combined with the solid obtained from basification of the aqueous phase. The combined material was dissolved in refluxing ethanol (175 mL), and treated hot with 125 mL of water. The brown solid obtaing on cooling was additionally recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) yielded the aniline as a white solid (5.45 g, 25%); mp 128°-130° C. 1H--NMR (250 MHz, d6 --DMSO): 6.32 (s, 2H, NH2) 6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic) 7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: C(C1C(N)=CC=CC=1B(O)O)(OC(C)(C)C)=O.[Cl-].CC1C=C(C)C=C(C)C=1[N+]1C=CN(C2C(C)=CC(C)=CC=2C)C=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(=O)[NH:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[C:65]([NH:67][N:68]=[C:69]([C:71]2[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][CH:72]=2)[CH3:70])[N:64]=[C:63]([CH3:78])[N:62]=1)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:78][C:63]1[N:62]=[C:61]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[NH2:54])[CH:66]=[C:65]([NH:67][N:68]=[C:69]([C:71]2[CH:72]=[CH:73][C:74]([CH3:77])=[CH:75][CH:76]=2)[CH3:70])[N:64]=1
Reactant: CC(=NNc1cc(-c2ccccc2NC(=O)OC(C)(C)C)nc(C)n1)c1ccc(C)cc1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)c1c(N)cccc1B(O)O
Agent: Cc1cc(C)c(-n2cc[n+](-c3c(C)cc(C)cc3C)c2)c(C)c1
Solvent: C1COCCO1
Product: CC(=NNc1cc(-c2ccccc2N)nc(C)n1)c1ccc(C)cc1

Procedure:
The title compound was prepared from (1)-1-(4-methylphenyl)ethanone (6-chloro-2-methylpyrimidin-4-yl)hydrazone (130 mg, 0.47 mmol), (2-BOC-aminophenyl)boronic acid (560 mg, 2.37 mmol), 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (23 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol) and cesium carbonate (925 mg, 2.8 mmol) in 1,4-dioxane (4 mL) by a procedure similar to Example 9, Step 3 yielding 16 mg (10%) of a white solid. HPLC Purity: 95%. (Reaction also yielded 106 mg (52%) of [2-(2-Methyl-6-{N′-[1-p-tolyl-ethylidene]-hydrazino}-pyrimidin-4-yl)-phenyl]-carbamic acid tert-butyl ester).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][C:15]([O:17][C:18](C)(C)[CH3:19])=[O:16]>C(O)C>[NH2:12][CH:13]([C:22]#[C:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)CC(N)C#C[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC(N)C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
The p-toluenesulfonic acid salt of (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate is prepared by treating p-toluenesulfonic acid with (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, the product of step 2, in the presence of MTBE/heptane. The resulting reaction mixture is then heated to 55°-60° C. for one hour, cooled, filtered and dried to give (±) 1,1,-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt. The (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate mono p-toluenesulfonic acid salt is treated with ethanol in the presence an organic acid or an inorganic acid at reflux temperature. The reaction mixture is then cooled to ambient temperature, concentrated and treated with methyl t-butyl ether and a suitable aqueous base to give ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate. Suitable inorganic acid agents are exemplified by sulfuric acid and hydrochloric acid and suitable organic acid agents are exemplified by camphorsulfonic acid and p-toluenesulfonic acid with p-toluenesulfonic acid being preferred. Suitable aqueous bases are exemplified by sodium bicarbonate, sodium carbonate, sodium hydroxide with sodium bicarbonate being preferred. Other alkanol solvents such as methanol, isopropanol, butanol and pentanol would also be suitable for the practice of this invention. However, it is to be understood that the use of a different alkanol solvent would give a different ester i.e. use of methanol for ethanol would give the corresponding methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18](O)C)[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.FC1C=C(C)C=C(F)C=1.C([Li])CCC>>[F:17][C:6]1[CH:5]=[C:4]([CH3:18])[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Product: Cc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 1,3-difluoro-5-methylbenzene, and reducing the number of equivalents of butyl lithium to 1.05 provided the title compound.