Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:26](=[O:27])[N:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH:21]([CH3:23])[O:20][CH:19]([CH3:24])[CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:33].C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]1([N:25]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:18][CH:19]([CH3:24])[O:20][CH:21]([CH3:23])[CH2:22]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:33])=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[C:26]2=[O:27])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O

Procedure:
6-Bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.062 g, 0.121 mmol), tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.068 mg, 0.188 mmol) were dissolved in toluene (2 mL) and slowly brought to reflux for 12 hours. Additional tetrakis(triphenylphosphine)palladium (0.010) was added and the reaction brought to reflux for 16 hours. The reaction mixture was cooled and purified by silica gel chromatography to 8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.055 g, 90.2%). 1H NMR δ (400 MHz, CDCl3) 8.72 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.83 (s, 1H), 7.29 (dd, J=2.9, 9.0 Hz, 1H), 5.89 (m, 1H), 4.51 (d, J=2.5 Hz, 1H), 4.17 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.83 (m, 2H), 3.37 (d, J=10.3 Hz, 2H), 2.44 (dd, J=10.5, 10.5, 2H), 2.41 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[NH2:9])[N:3]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([N:8]([CH3:10])/[N:9]=[C:14]2/[CH2:13][CH2:12][N:11]3[CH2:19][CH2:18][CH:15]/2[CH2:16][CH2:17]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(N)c1cccc(Br)n1
Reactant: O=C1CCN2CCC1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(/N=C1/CCN2CCC1CC2)c1cccc(Br)n1
Yield: 36.2 %

Procedure:
A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (4.50 g, 22.2 mmol), 1-azabicyclo[3.2.2]nonan-4-one (3.00 g, 22.2 mmol) and p-toluenesulphonic acid (844 mg, 4.40 mmol) in toluene (140 mL) was heated under reflux, with water removal (azeotrope), for 4 h. The mixture was concentrated and made basic using saturated aqueous NaHCO3. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (2.60 g, 36%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=8.0 Hz, 1H), 6.83 (d, J=7.0 Hz, 1H), 6.55 (d, J=8.5 Hz, 0.7H), 6.41 (d, J=8.5 Hz, 0.3 H), 3.20 (s, 3H), 3.17-2.94 (m, 7H), 2.80 (t, J=7.0 Hz, 0.6H), 2.73 (t, J=7.0 Hz, 1.4H), 1.89-1.85 (m, 3H), 1.74-1.60 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(O)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.08 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 80 ml of tetrahydrofuran is added dropwise at room temperature 14.2 ml of 3.0M phenylmagnesium bromide. The reaction mixture is stirred at room temperature overnight then diluted with aqueous ammonium chloride and extracted with chloroform. The organic layer is dried and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.535 g of the desired product as a solid. Cl MASS SPEC 323 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Yield: 55.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.44 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]2[OH:27])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Si:30]([CH3:37])([CH3:36])N1C=CN=C1>>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:13]2[O:27][Si:30]([CH3:37])([CH3:36])[CH3:29])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Reactant: C[Si](C)(C)n1ccnc1
Product: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O[Si](C)(C)C
Yield: 65.3 %

Procedure:
A solution of rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) (130 mg, 0.322 mmol) in 1-trimethylsilylimidazole (0.5 ml, 3.220 mmol) was stirred at room temperature for 16 h. The reaction was quenched with Na2PO4 0.1 M buffer (2 ml) and the mixture extracted with AcOEt (3×4 ml). The combined extracts were washed with saturated aqueous CuSO4 solution (1×8 ml) and brine (2×8 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:1) to give rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-trimethylsilyloxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (6) as a white solid (100 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:14])[CH3:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Yield: 55.2 %

Procedure:
A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (2.59 g, 10 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XCII) (2.05 g, 10 mmol, 1.3 eq), Na2CO3 (2.12 g, 20 mmol, 2 eq) and Pd(PPh3)4 (1.16 g, 1 mmol, 0.1 eq) in a mixed solvent of DME (30 mL) and H2O (10 mL) was heated to reflux under nitrogen overnight, the mixture was poured onto water (40 ml) and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, purification the resultant residue was purified by column chromatography (EtOAc:PE=1:4→100% EtOAc) to afford N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (1.42 g, 5.52 mmol, 55% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.92 (s, 3H), 7.46 (d, J=5.6 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.80 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 8.06 (dd, J=8 Hz, J=1.6 Hz, 1H), 8.73 (d, J=6 Hz, 2H), 9.96 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C(=O)C2=CC=CC=C12>C(O)C.O.NN>[NH2:5][CH2:6][CH2:7][P:8](=[O:15])([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14]
Reactant: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCN)OCC
Reaction time: 16 h

Procedure:
A mixture of 4.67 g (0.015 mol) of diethyl phthalimidoethylphosphonate in 30 ml of ethanol and 1.2 ml of 100% hydrazine hydrate is kept at ambient temperature for ca. 16 hours then is refluxed for 2 hours. The mixture is cooled and filtered and the filtrate is concentrated to give diethyl (2-aminoethyl)phosphonate.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(NCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9-(tetrahydro-3-furanylmethyl)-9H-purine-2,6-diamine (209 mg) in methanol (21 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (3.93 ml) to give a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo. The resultant solid was taken up in water (50 ml) and filtered off to give a white solid. This solid was recrystallised from ethanol:water (1:1) and filtered to afford an off-white crystalline solid (105 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:30]([NH:37][CH2:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:25])([F:27])[F:26])[CH:18]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(CNCc4ccccc4)c3)cc21
Reaction time: 16 h
Yield: 59.9 %

Procedure:
1.2 g (2.9 mmol) of the compound of Example 70, 0.31 g (2.9 mmol) of benzylamine and 0.2 ml (2.9 mmol) of acetic acid were dissolved in 50 ml of ethanol and, at room temperature, 0.18 g (2.9 mmol) of sodium cyanoborohydride was added a little at a time. The mixture was stirred for 16 h and then concentrated under reduced pressure, and the organic phase was dried and finally concentrated again under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol=5:1) to yield 0.87 g (60%) of the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.65 g, 1.9 mmol) in acetonitrile (10 mL), was added acetyl chloride (0.13 mL, 1.8 mmol) and N,N-diisopropyl ethylamine (0.70 mL, 4.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a light yellow solid (104 mg, 16% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 3.93 min (99.0%); mp, 293-291° C.; 1HNMR (DMSO-d6)1.92 (s, 3H, CH3), 2.14-2.20 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.73-4.77 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.31-7.76 (m, 3H, Ar), 8.22 (t, J=6 Hz, 1H, CH2NH); 13C NMR (DMSO-d6) δ 20.78, 22.60, 23.26, 30.58, 41.49, 56.48, 117.65, 124.48, 125.42, 133.83, 141.06, 148.44, 154.75, 160.95, 169.32, 169.51, 172.58. LCMS MH=343; Anal Calcd For C17H18N4O4: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.46; H, 5.05; N, 16.24.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:25])=[O:26])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 96 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[[N-(tert-butoxycarbonyl)piperidin4-yl]methoxy]-5-methylphenyl ester (745 mg, 1.5 mmol), as prepared in the preceding step, was treated with 4 N HCl in 1,4-dioxane (20 mL) at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with NH3) to give the title compound as a colorless syrup (570 mg, 95%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (m, 1 H), 1.94 (m, 3 H), 2.23 (s, 3 H), 2.45 (m, 1 H), 2.71 (dt, 2 H, J=1.2, 12.3 Hz), 3.51 (m, 2 H), 3.76 (m, 2 H), 6.46 (t, 1 H, J=2.1 Hz), 6.53 (s, 1 H), 6.58 (s, 1 H), 7.40 (t, 1 H, J=6.5 Hz), 7.62 (m, 2 H), and 7.97 (dd, 1 H, J=1.4, 7.9 Hz). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H22NO4SCl: 396.1 (M+H), Found: 396.4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:19](=[O:20])[C:18]3[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=3)[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
To 8.0 g. (0.05 mole) of 3-amino-1-cyclohexylpyrrolidine in chloroform was added with stirring 12 g. (0.052 mole) of 3,5-dinitrobenzoylchloride. After stirring one hour, the solution was extracted with dilute sodium hydroxide, dried over sodium sulfate and concentrated. The residue was recrystallized from isooctane-ethyl acetate. The product weighed 5.1 g. (29%) and melted at 159°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N:20]([CH3:22])[CH3:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[N:23]([O-])=O.[Na+].[C:27]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>Cl.O.[OH-].[Na+].O>[CH3:21][N:20]([CH3:22])[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([N:9]=[N:8][C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:23][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]([OH:37])=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(N)cc2)c2ccccc12
Reactant: O=N[O-]
Reactant: Oc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(N=Nc2ccc(N=Nc3ccc(O)c4ccccc34)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
2.9 g of 1-(4-amino-phenylazo)-4-(dimethylamino)naphtalene were dissolved in a mixture of 2.5 ml of HCl 37% and 5 ml of water. The obtained solution was cooled to 0° C., followed by dropwise addition of 0.69 g of sodium nitrite in 3 ml of water, while keeping the reaction temperature below 4° C. After complete addition, stirring was continued for 45 min at about 4° C. and the obtained mixture was then added to an ice-cooled solution of 1.44 g of 1-naphtol in NaOH/water (1.1 g/11 ml, while keeping the reaction temperature below 5° C. After complete addition, the reaction mixture was further stirred for 1 h at about 5° C. and then poured into 100 ml of water. The resulting brownish precipitate was filtered off, washed with water (100 ml) and methanol (50 ml). Crystallisation in methanol gave 3.3 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:32][CH:31]=[CH:30]2.O.[C:53]([OH:57])(=[O:56])[CH:54]=O>>[C:48]([O:47][C:45]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][CH:54]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:16]([CH2:24][CH3:25])[CH:17]=3)[C:53]([OH:57])=[O:56])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Solvent: O
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 52 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 56B (175 mg, 0.52 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 57A (186 mg, 52%) as an oil. MS (ESI) m/z 710.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:40][C:41]1[CH:42]=[C:43]([N:48]2[C:52](=[O:53])[O:51][N:50]=[C:49]2[C:54]2[C:55]([NH:59]C(=O)C(F)(F)F)=[N:56][O:57][N:58]=2)[CH:44]=[CH:45][C:46]=1[F:47]>O1CCCC1>[Br:40][C:41]1[CH:42]=[C:43]([N:48]2[C:52](=[O:53])[O:51][N:50]=[C:49]2[C:54]2[C:55]([NH:59][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:56][O:57][N:58]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: COCCCO
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
A solution of 3-methoxypropan-1-ol [Fluka product #38457] (3.1 mL, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) in tetrahydrofuran (93 mL) at 0° C. was treated with diisopropyl azodicarboxylate (6.7 mL, 34 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (10 g, 23 mmol) in tetrahydrofuran (47 mL), and stirred at 25° C. for 72 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), treated with trifluoroacetic acid (20 mL) and water (20 mL), and heated at 50° C. for 6 h. The reaction mixture was concentrated, rediluted with ethyl acetate (200 mL) and washed with water (3×80 mL), saturated sodium bicarbonate (2×80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude residue. This material was purified on silica gel to give the desired product (6.4 g, 54%) as a white solid. LCMS for C14H14BrFN5O4 (M+H)+: m/z=414.0, 416.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:35]#[N:36])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:35]#[N:36])([CH3:37])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(CC(C#N)C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)(Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]-2-cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (prepared as detailed in Example 14, 1 eq.) in THF (0.1 M) was added, at −78° C., potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1 eq.). The resulting yellow suspension was stirred at −78° C. for 15 min and at −40° C. for 15 min. Iodomethane (1 eq.) was then added and the reaction mixture was slowly warmed to RT over 14 h. The reaction was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO2, 10:1→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: Cc1c(I)sc(C=O)c1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(I)sc(C2OCCO2)c1Br
Yield: 94.3 %

Procedure:
3-Bromo-5-iodo-4-methylthiophene-2-carbaldehyde (27 g, 82 mmol), ethylene glycol (5.9 mL, 110 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.6 mmol) were combined in benzene (200 mL) and the mixture was heated at reflux under Dean-Stark conditions for 8 h. At this time, the cooled solution was washed with 2.5 N aqueous NaOH (200 mL), water (4×200 mL) and brine (200 mL), dried (K2CO3) and concentrated in vacuo to give the title compound (29 g, 94%) as an orange oil.