Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12](O)=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>CO.ClCCl>[NH2:1][C:2]1[C:7]([CH:8]2[NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=3[O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: Nc1ncccc1C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2c1OC(c1cccnc1N)N2
Temperature: 50 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
A 2-aminopyridine-3-carbaldehyde (650 mg) was added to a stirred solution of methyl 3-amino-2-hydroxy-benzoate (890 mg) in methanol (10 ml) and dichloromethane (5 ml). The resulting solution was stirred at 50° C. for 10 hours. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-2,3-dihydro-1,3-benzoxazole-7-carboxylate (400 mg) as a pale yellow solid. Manganese(IV) oxide (4629 mg) was added to a solution of this yellow solid (400 mg) in dichloromethane (5 ml) and tetrahydrofuran (10 ml), the mixture was stirred at 25° C. for 15 hours. The mixture was filtered and the filtrate was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 30 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (345 mg) as a pale yellow solid. NMR Spectrum: (CDCl3) 4.06 (s, 3H), 6.79 (dd, 1H), 6.89 (bs, 2H), 7.43 (dd, 1H), 7.92 (dd, 1H), 8.00 (dd, 1H), 8.26 (dd, 1H), 8.44 (dd, 1H); Mass spectrum: M+H+ 270;
Reaction SMILES: C[O:2][C:3]([C:5]1([F:25])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=O.[NH3:26]>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:5]([F:25])([C:3]([NH2:26])=[O:2])[CH:6]=[C:7]3[N:11]([CH3:12])[CH2:10][N:9]=[C:8]3[CH:13]=2)=[C:17]([F:24])[CH:18]=1)[CH3:23]
Reactant: N
Reactant: CCc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1
Product: CCc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(N)=O)c(F)c1
Yield: 65 %

Procedure:
A solution of 6-(4-Ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (0.309 g) in ammonia-saturated isopropanol (10 mL) was heated in a sealed pressure tube at 80° C. for 80 h. The resultant reaction mixture was concentrated to dryness and recrystallized from ethanol to afford pure 6-(4-ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid amide (0.199 g, 65% yield): m.p. 249–251° C.; 1H NMR (400 MHz, acetone-d6) δ 8.45 (brs, 1 H), 8.18 (s, 1 H), 5.94 (s, 1 H), 5.59 (br s, 1 H), 6.95 (dd, J=12.5, 2.0 Hz, 1 H), 6.89 (br s, 1 H), 6.81 (br d, 1 H), 6.56 (td, J=8.6, 4.9 Hz, 1 H), 3.95 (s, 3 H), 2.54 (q, J=5.6 Hz, 2 H), 1.16 (t, J=5.6 Hz, 3 H). Anal. Calcd/Found for C15H16F2N4O: C, 61.64/61.26; H, 4.88/4.84; N, 16.96, 16.68; F, 11.50/11.85.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12]([O:14][C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]=[C:15]([CH:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]3[CH2:11][C:5]2([CH2:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH:9]3)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCCC12C=CC(C1)C(C(=O)O)C2C(O)=NC1CCCCC1
Temperature: 135 °C
Yield: 58.2 %

Procedure:
A mixture of 20 g of allylmethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride and 9.09 g of cyclohexylamine is heated at 135° C. for 3 hours, and the product is then distilled in vacuo. 16 g of a yellow, viscous oil distill over between 128° and 138° C. at 2.5 Pa, corresponding to a yield of 58.2%.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][CH3:28]>O>[CH2:25]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:26]=[CH:27][CH3:28]
Reactant: CC=CCBr
Reactant: CCCOC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CC=CCON=C(C)c1ccc(NC(=O)NCC(=O)OCCC)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-n-propoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-crotyloxyiminoethyl)phenyl]-N'-n-propoxycarbonylmethylurea.
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([I:14])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>Cl.ClCCl>[F:13][C:12]1[C:2]([NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[C:3]([CH:9]=[C:10]([I:14])[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1NC1CCC(O)CC1
Yield: 90 %

Procedure:
2,3-Difluoro-5-iodo-N,N-dimethyl-benzamide (2.36 g, 7.6 mmol) and trans-4-amino-cyclohexanol (3.5 g, 30 mmol) were stirred at 120° C. for 5 hrs. The resulting solid was dissolved in 1 N hydrochloric acid and dichloromethane. The aqueous layer was extracted with dichloromethane twice. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give 2.8 g (6.84 mmol, 91%) of 3-fluoro-2-(4-hydroxy-cyclohexylamino)-5-iodo-N,N-dimethyl-benzamide as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.45 (dd, J=12 Hz, J2=2 Hz, 1H), 7.15 (s, 1H), 4.57 (dd, J=10 Hz, J2=3 Hz, 1H), 4.50 (d, J=4.5 Hz, 1H), 3.33 (m, 1H), 3.02 (m, 1H), 2.94 (bs, 3H), 2.81 (bs, 3H), 1.74 (m, 4H), 1.04-1.24 (m, 4H); MS: m/z 407 [MH+]
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(F)cc3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 111 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.), sodium acetate (4.1 g.), water (αml.) and tetrahydrofuran (30 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.68 g.), m.p. 203° to 207° C. (dec.).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1>CO.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(N2CCNCC2)cc1
Yield: 56.5 %

Procedure:
This compound was prepared by the hydrogenation of 7.7 g (0.025 mol) of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]acetamide in 100 mL of methanol using palladium on carbon as the catalyst. The solution was filtered and the filtrate concentrated under reduced pressure to give an oil which crystallized. The solid was dissolved in a minimum amount of a methylene chloride/10% methanol solution and passed through a 100 g Florisil column. The desired fractions were concentrated to an oil under reduced pressure which crystallized to give 3.1 g (56%) of crude product. A 0.5 g portion was recrystallized from methanol/petroleum ether to give a cream colored solid, mp 191°-193° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[({[2-(trifluoromethyl)phenyl]methyl}amino)-carbonyl]-1-piperidinecarboxylate and CH2Cl2 (180 ml) at 0° C., a premixed solution of CH2Cl2 and TFA (180 ml) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. The solvents were removed under reduced pressure to afford 11.9 g of the title compound. MS (ES+): m/e 287.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:6][N:5]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.4 %

Procedure:
To a suspension of 10.7 g of (2S, 4R)-4-hydroxy-1-(2-nitrobenzoyl) proline methyl ester and 5.7 g of imidazole in 100 ml of N,N-dimethylformamide, there was added 6.6 g of tert-butyldimethylsilyl chloride at room temperature in a nitrogen gas atmosphere and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate three times, water washing of the organic phase, drying and concentration thereof under reduced pressure. The resulting residue was subjected to silica gel column chromatography, then eluted with a 1/1 ethyl acetate/hexane mixed solvent, followed by recrystallization from ethyl acetate-hexane to give 10.6 g (yield 71.6%) of (2S, 4R)-4-(tert-butyldimethylsilyloxy)-1-(2-nitrobenzoyl) proline methyl ester as colorless needles.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C(N(CC)C(C)C)(C)C.[CH2:32]([O:34][C:35](=[O:41])[CH2:36][CH2:37][N:38]=[C:39]=[O:40])[CH3:33]>C(Cl)Cl>[CH3:20]/[C:10](/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])=[CH:11]\[CH2:12][S:13][CH2:14][C@@H:15]([C:16]([OH:18])=[O:17])[NH:19][C:39](=[O:40])[NH:38][CH2:37][CH2:36][C:35](=[O:41])[O:34][CH2:32][CH3:33]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CCOC(=O)CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). Ethyl-3-isocyanato-propionate (143, 1 mmol) was added to the reaction mixture. The reaction solution was stirred at room temperature overnight and the solvent was removed by rotary evaporation. The remaining residue was dissolved in ethyl acetate (100 mL) and washed with 1 N HCl solution (50 mL×2). The ethyl acetate solution was dried over Na2SO4 and concentrated to a crude reaction mixture. The resulting mixture was purified by HPLC (200 mg, 43%) to yield Compound D. 1H-NMR (500 MHz, MeOH-d4): δ 1.28 (t, J=7.5 Hz, 3H), 1.62 (s, 3H), 1.63 (s, 3H), 1.69 (s, 3H), 1.70 (s, 3H), 1.98 (m, 2H), 2.06 (m, 6H), 2.52 (t, J=6.5, 2H), 2.79 (dd, J=7.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 13.5 Hz, 1H), 3.17 (dd, J=7.5, 13.5 Hz, 1H), 3.28 (dd, J=8.5, 13.5 Hz, 1H), 3.41 (t, J=6.5 Hz, 3H), 4.16 (q, J=7.5 Hz, 2H), 4.50 (dd, J=4.5, 6.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 14.6, 16.1, 16.2, 17.8, 26.0, 27.4, 27.8, 30.5, 34.4, 35.9, 36.7, 40.8, 40.9, 54.0, 61.7, 121.7, 125.1, 125.5, 132.1, 136.3, 140.5, 160.2, 173.8, 175.0; ES-MS: mass calcd for Chemical Formula: C24H40N2O5S 468.7. Found (M+Na) m/z 491.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].[OH-].[Na+].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C>CCOC(C)=O>[NH2:22][C:21]1[N:10]([C:4]2[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])[N:11]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnn(-c2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
(2,6-Dichlorophenyl)hydrazine hydrochloride (5 g, 23.42 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (40 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in methanol (50 mL) under nitrogen at −5° C. 2-(Ethoxymethylene)malononitrile (2.86 g, 23.42 mmol) added portion-wise over 5 mins and the mixture stiffed at 0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (5.60 g, 94%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.47 (2H, s), 7.43-7.47 (1H, m), 7.51-7.53 (2H, m), 7.73 (1H, s); m/z (ES+) (M+H)+=253; HPLC tR=1.62 min. Alternatively the product was obtained by concentrating the reaction mixture to half volume and allowing the product to crystallise.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].[CH2:14](Cl)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:6]2[N:7]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:8]=1)#[N:2]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1[nH]c2ncc(C#N)cc2c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(C#N)cc-2c1C
Yield: 23.5 %

Procedure:
A mixture of 5-cyano-2,3-dimethyl-pyrrolo [2,3-b]pyridine (77 mg, 0.5 mmol ) and phenacyl chloride (650 mg, 4.2 mmol ) in 12 ml CH3CN was refluxed for 62 h. The mixture was basified with a saturated Na2CO3 solution and extracted with CH2Cl2. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed (silica, CH2Cl2 /diethyl ether;7/3) yielding 34 mg (26%) pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCS(=O)(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-D-02, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (40 mg) and ethanesulfonyl chloride (0.70 ml) instead of mesyl chloride, a crude product of bis-(4-methoxy-benzyl)-[5-(7-ethanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained. Using this crude product (10 mg), the PMB groups were removed according to the above Deprotection method 2, to obtain 5-(7-ethanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine as a colorless powder (4 mg, 65%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][C:11]1[N:12]=[C:13]([C:22](OCC)=[O:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCO>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:22]([C:13]1[S:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH3:10])[N:12]=1)=[O:23])[CH2:3]2
Reactant: CCOC(=O)c1nc(C)c(-c2ccccc2)s1
Reactant: N[C@H]1CN2CCC1CC2
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@H]2CN3CCC2CC3)sc1-c1ccccc1
Reaction time: 48 h
Yield: 55 %

Procedure:
The freebase of (R)-3-aminoquinuclidine (1.0 g, 5.02 mmol, 2.26 eq) dissolved in THF (5 mL) is added to a solution of the product from Step 89c (0.55 g, 2.22 mmol, 1 eq) in 10 mL EtOH. The mixture is heated under reflux. After 48 h, the mixture is cooled and concentrated in vacuo. The residue is purified by silica gel chromatography using a Biotage Flash 40S column (90:9:1 CHCl3/MeOH/NH4OH) to provide N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-methyl-5-phenyl-1,3-thiazole-2-carboxamide (0.40 g, 55%) as a yellow oil. The p-toluenesulfonic acid salt of the product is made and recrystallized from IPA/ether to give the product as light yellow solid. MS (ESI) for C18H21N3OS m/z 328.2 (M+H)+.
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:15])[CH2:13][NH2:14])[CH:9]=[CH:10][CH:11]=1.[CH2:16]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][C:26]#[N:27])=[CH:22][CH:21]=1)[C:17]([CH3:19])=O.O>C1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH:12]([OH:15])[CH2:13][NH:14][CH:17]([CH3:19])[CH2:16][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][C:26]#[N:27])=[CH:22][CH:21]=1
Reactant: CC(=O)Cc1ccc(OCC#N)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: O=C(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCC#N)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(3-chlorophenyl)-2-hydroxyethylamine carbonate (3.35 g) and 4-acetonylphenoxyacetonitrile in benzene was heated under reflux for 1 h with azeotropic removal of water using a Dean and Stark head. The solution was cooled, and the solvent removed in vacuo. The residue was dissolved in methanol and treated with sodium cyanoborohydride (1.25 g) and stirred for 5 h at ambient temperature. The solvent was then evaporated under reduced pressure, the residue dissolved in ethyl acetate, washed with water (2×50 ml), brine (1×50 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography on silica using methanol:chloroform 2:98 as eluent to give 4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl] phenoxyacetonitrile, (4.0 g).
Reaction SMILES: Br[C:2]1[C:3]([N:40]2[CH2:45][CH2:44][S:43][CH2:42][CH2:41]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[CH:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:39])[C:7]=1[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Sn]([C:59]#[N:60])(CCCC)(CCCC)CCCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]1[N:6]2[N:25]=[CH:26][C:27]([CH:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:39])=[C:5]2[N:4]=[C:3]([N:40]2[CH2:45][CH2:44][S:43][CH2:42][CH2:41]2)[C:2]=1[C:59]#[N:60]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCSCC2)nc2c(C3C(=O)Nc4ccccc4C3=O)cnn12
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-thiomorpholinodioxo-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (35 mg, 0.051 mmoL), Bu3SnCN (32.3 mg, 0.10 mmoL), Pd[P(t-Bu)3]2 (5.2 mg, 0.010 mmoL) in Dioxane (3 mL) was heated at 100° C. overnight. The mixture was cooled to room temperature and the solvent was evaporated. Purification by column chromatography afforded 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-5-thiomorpholinodioxo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS tR=2.76 Min (5 min run, UV254nm). Mass calculated for, M+ 678.28, observed LC/MS m/z 679.20 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([O:23][C:22]2[CH:32]=[CH:33][C:19]([F:18])=[CH:20][CH:21]=2)[N:29]=1)=[O:13]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: OCc1cccc(Oc2ccc(F)cc2)n1
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccc(F)cc2)n1)c1ccc2ccccc2c1

Procedure:
The acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid is reacted with [6-(4-fluorophenoxy)-2-pyridyl]methanol using the procedure of Example 1 to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3methylbutanoate.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:14]3)=[O:17])[CH2:21]1
Reactant: CN(C)C1CCCNC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, Intermediate 1a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, 3-dimethylamino-piperidine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a light-brown solid (63%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cc(C)ncn2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (52 mg, 46%); 1H NMR δ (CDCl3): 8.99 (s, 1H), 7.32 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 7.17 (d, J=8.43 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H); LCMS m/z: 224.