Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH2:25][CH3:26])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Reactant: CCCI
Product: CCCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
Starting from the compound of Example 46 and propyl iodide, and using procedure (a) of Example 49, 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole is obtained as an oily substance. This compound is hydrolyzed as in procedure (b) of Example 49. Yield of the title compound: 50%, m.p. 113°-15° C. (from ethanol).
Reaction SMILES: C([O:8][C:9]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[N:13]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[C:21]([O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:12]2[C:31]3[C:36]([C:9]([OH:8])=[CH:10][C:11]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 84 (0.096 g, 0.188 mmol, 1 equiv) in THF (3.0 mL) was treated with 10% Pd—C (0.042 g, 0.04 mmol, 0.2 equiv) followed by aqueous HCO2NH4 (1.0 mL, 25% w/v, 21 equiv) and the resulting mixture was stirred at 25° C. for 2.5 h. The mixture was filtered through Celite to afford a biphasic filtrate which was partitioned. The aqueous phase was extracted with EtOAc (2×2 mL) and the combined organic portions were dried (MgSO4), filtered, and concentrated to give 85 as an analytically pure white solid (0.072 g, 0.079 g theoretical, 91%): mp 141-142° C.; 1H NMR 400 MHz, DMF-d7) major rotamer δ 8.29 (d, J=8.2 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.62-7.59 (m, 1H), 7.54-7.50 (m, 1H), 6.82 (s, 1H), 4.59-4.47 (m, 1H), 4.43-4.25 (m, 3H), 3.02 (s, 3H), 2.98-2.76 (m, 1H), 2.35-2.20 (m, 1H), 2.13-1.95 (m, 1H), 1.71-1.67 (m, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, DMF-d7)major rotamer δ 154.0, 153.5, 141.8, 134.0, 127.7, 125.2, 125.1, 124.3, 123.3, 123.0, 110.3, 80.4, 71.4, 48.2, 36.8, 36.4, 28.2 (3C), 27.2, 25.0; IR (film) νmax 3262, 2974, 2933, 2872, 1692, 1662, 1594 cm−1; FABHRMS (NBA-NaI) m/z 444.1468 (M+Na+, C21H27NO6S requires 444.1457).
Reaction SMILES: OC1C(=O)NC=C(CCC2C=CC=CC=2C)C=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([O:35]C)[C:30]([O:33]C)=[N:31][CH:32]=2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([OH:35])[C:30](=[O:33])[NH:31][CH:32]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(C#Cc2ccc(F)cc2)cnc1OC
Agent: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Product: O=c1[nH]cc(CCc2ccc(F)cc2)cc1O

Procedure:
Prepared as described for 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 27) from 5-[(4-fluorophenyl)ethynyl]-2,3-dimethoxypyridine (Intermediate 36).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24].N12CCN(CC1)CC2>CN(C)C=O>[F:18][C:16]([F:19])([F:17])[C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:7][CH:6]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(C(F)(F)F)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1)c1ccccc1
Yield: 64.5 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-4-trifluoromethyl-benzamide (1.41 g, 5.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.85 g, 5.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.56 g, 5.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (1.34 g, 64% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1
Yield: 54.9 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 420 mg (yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([OH:17])[C:11]3[S:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:32])([F:31])[S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:32])([F:31])[S:27]([O:17][C:10]1[C:11]2[S:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:29])=[O:28]
Reactant: Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (1.9 g, 7.2 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (2.0 mL, 14.4 mmol) and trifluoromethanesulfonic acid (1.3 mL, 7.9 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (1.23 g, 44%) as a light yellow solid. MW=396.79. 1H NMR (CDCl3, 500 MHz) δ 8.35-8.32 (m, 1H), 8.24-8.20 (m, 1H), 7.48-7.38 (m, 2H), 3.59-3.49 (m, 4H); APCI MS m/z 397 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].FC(F)(F)C([N:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=O>CO.O>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CNCc1cccc([N+](=O)[O-])c1
Yield: 46.9 %

Procedure:
K2CO3 (1.5 g, 11 mmol) was added to a solution of 52B (800 mg, 2.2 mmol) in MeOH/H2O (2:1, 9 mL) and the mixture was refluxed for 2 h. Volatiles were removed in vacuo and the remaining aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield 52C (275 mg, 47%) as a clear oil. MS (ESI) m/z 267.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:11][C:10]([C:12]#[N:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.FC1C=CC(O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.CO.C(OCC)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:11][C:10]([CH2:12][NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Oc2ccc(F)cc2)s1
Agent: Oc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1ccc(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-fluorophenoxy)thiophene-2-carbonitrile described in Preparation Example 27 (containing 4-fluorophenol) (3.7 g) in tetrahydrofuran (40 mL) was added lithium aluminum hydride (1.3 g, 34 mmol), and the solution was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=4:1), and the title compound (1.2 g, 5.4 mmol) was obtained as a brown oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[CH:32][CH:31]=[C:30]([F:41])[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:18]2=[N:19][CH:20]=1)=[O:13]>C(Cl)(Cl)Cl>[Br:1][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[C:30]([F:41])=[CH:31][CH:32]=[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:10]=3[F:9])[CH:16]=2)[NH:21][C:22]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccccc4)cc3c2)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccccc4)c(Br)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
N-Bromosuccinimide (1.1 eq.) was added to a slurry of 2,6-difluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (11 mg, 1.0 eq.) in CHCl3 (1.0 mL), and the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was filtered, and the solids were washed with CH2Cl2. The resulting solids were then purified by silica gel chromatography (eluting with 5% MeOH/CH2Cl2) to afford N-(3-bromo-2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide as a solid (9 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 11.08 (s, 1H), 9.82 (s, 1H), 8.47-8.44 (m, 1H), 8.39-8.37 (m, 1H), 7.95-7.91 (m, 2H), 7.61-7.53 (m, 3H), 7.51-7.45 (m, 1H), 7.32-7.26 (m, 1H), 3.16-3.11 (m, 2H), 1.83-1.74 (m, 2H), 1.03-0.98 (m, 3H); m/z (APCI-neg) M−1=549.1.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH:16]=[N:17][CH:18]=1)=O>>[CH3:3][O:2][N:4]=[CH:11][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH:16]=[N:17][CH:18]=1
Reactant: N#Cc1cccc(C#Cc2cncc(C=O)c2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2cccc(C#N)c2)c1
Yield: 74.6 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using methoxylamine hydrochloride (2.88 g, 34.45 mmol), potassium carbonate (2.97 g, 21.53 mmol) and 3-(5-formylpyridin-3-ylethynyl)-benzonitrile (1.00 g, 4.31 mmol), (prepared as described in EXAMPLE 90), to give the title compound (0.84 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH2:24][CH3:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: CCN
Product: CCNC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (10.0 g) and ethylamine gas, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethylaminoacrylate (9.0 g, white crystals), which is then treated with 60% sodium hydride (1.30 g) as in Reference Example 22 to give ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.76 g), as pale yellow needles (recrystallized from dichloromethane - n-hexane), m.p. 197°-198° C.
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22](O)=[O:23])([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.[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:37]([C@@H:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[O:38])[CH:34]=2)[N:29]=[CH:28][N:27]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O>[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:37]([C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:22](=[O:23])[CH2:21][NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:38])[CH:34]=2)[N:29]=[CH:28][N:27]=1
Reactant: Nc1ncnc2ccc(NC(=O)[C@@H]3CCCN3)cc12
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Nc1ncnc2ccc(NC(=O)[C@@H]3CCCN3C(=O)CNC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
N-Tritylglycine (1.58 g, 5.0 mmol) and (2S)-N-(4-amino-6-quinazolinyl)-2-pyrrolidinecarboxamide (1.15 g, 4.5 mmol) were dissolved in 11 mL N,N-dimethylformamide and cooled to 0° C. HOBt (0.770 g, 5.0 mmol) was added and pH was set to 8 with N-methylmorpholine. After 10 minutes EDC (0.978 g, 5.0 mmol) was added and the mixture was stirred for 12 hours. The solvent was evaporated and the crude product was purified with column chromatography using chloroform/methanol (9/1) as eluant.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[CH:6]=[C:7]([F:11])[CH:8]=[C:9]([F:10])[C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1cc(F)cc(F)c1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(F)cc(F)c2F)cc1OC
Yield: 84 %

Procedure:
2,3,5-Trifluorobenzaldehyde (320 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (536 mg, yield: 84%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.[NH2:29][CH2:30][C@@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:32][C@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[CH2:30][NH:29][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([CH2:20][N:17]2[CH2:16][CH2:15][C:13]3([O:12][CH2:11][CH2:10][N:9]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH2:14]3)[CH2:19][CH2:18]2)[CH:22]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C=O)c4)CC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 0 °C

Procedure:
A solution of 3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzaldehyde (example 96, step a) (0.303 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.330 g) and acetic acid (0.043 mL) in methanol (5 mL) was stirred at room temperature for 30 minutes, then cooled in an ice-water bath under nitrogen and treated with sodium triacetoxyborohydride (0.243 g) in one portion. The mixture was stirred in ice-water for 2 hours, then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the phases were separated, and the aqueous phase was extracted twice more with ethyl acetate. Any insoluble gummy residues were dissolved in methanol. The combined ethyl acetate phases were washed with brine, dried over magnesium sulphate and combined with the methanol solution. The whole was purified by flash chromatography on silica eluted with 1:7:92 triethylamine:methanol:dichloromethane to afford the slightly impure subtitled product as a yellow foam. Yield 0.324 g.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:28])[NH:20][C@H:21]1[CH2:25][C@@H:24]([CH2:26]Br)[CH:23]=[CH:22]1)([CH3:17])([CH3:16])[CH3:15].CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:26][C@H:24]1[CH2:25][C@@H:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:28])[CH:22]=[CH:23]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Temperature: 60 °C
Reaction time: 19 h
Yield: 58.3 %

Procedure:
Diethyl malonate (1.29 mL, 8.5 mmol) was added to a mixture of NaH (60%, 0.34 g; 8.5 mmol) in DMF (10 mL). After stirring at room temperature for 15 min a solution of cis-(4-bromomethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (1.95 g, 7.1 mmol) in DMF (12 mL) was added, and the reaction mixture was stirred at 60° C. for 19 h. EtOAc was added and the organic phase was extracted with water and brine, dried and concentrated under reduced pressure to give 2.44 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded of 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid diethyl ester (1.47 g, 58%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[SH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([CH2:2][CH2:3][S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: C=CC#N
Reactant: O=C(O)CCS
Product: N#CCCSCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
The mixture of acrylonitrile (5.31 g.) and 3-mercaptopropionic acid (10.6 g.) was stirred for 1 day at ambient temperature and distilled under reduced pressure to give colorless liquid of 3-(2-cyanoethylthio)propionic acid (7.5 g.). B. p. 124°-126° C./10-13 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]([CH2:15][C:16]([NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH3:14])[N:5]=[C:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][CH:26]=2)[N:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]([CH2:15][C:16]([NH:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH3:14])[N:5]=[C:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NCC3CCCCC3)cc2)nc1N(C)CC(=O)NC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CC(=O)NC1CCCC1)c1nc(Cc2ccc(NCC3CCCCC3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 13 h
Yield: 29 %

Procedure:
A solution of methyl {4-chloro-2-{4-[(cyclohexylmethyl)amino]benzyl}-6-[[2-(cyclopentyl-amino)-2-oxoethyl](methyl)amino]pyrimidin-5-yl}acetate (0.083 g, 0.15 mmol) in THF (5 mL) was treated with 1N NaOH (2.5 mL) and the resulting mixture was stirred at room temperature for 13 hours. Subsequent to neutralization with 6N HCl, the quenched reaction mixture was evaporated to dryness and the remaining residue dissolved with EtOH. The insoluble inorganic salts were removed by filtration and the filtrate was concentrated in vacuo. The crude product thus obtained was purified with preparative TLC eluting with 15% EtOH in CH2Cl2 to give {4-chloro-2-{4-[(cyclohexylmethyl)amino]benzyl}-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)amino]-pyrimidin-5-yl}acetic acid (0.023 g, 28% yield) as a clear oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:1](=[O:11])[C:2]3[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)cc1

Procedure:
From para-anisic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+28.2° (c=0.33 CHCl3), ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(O)C>[CH3:9][C:2]1[N:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: COC(=O)C(=O)C(C)Br
Solvent: CCO
Product: COC(=O)c1nc2ccc([N+](=O)[O-])cn2c1C
Yield: 23.1 %

Procedure:
An ethanol suspension (400 mL) of methyl 3-bromo-2-oxobutyrate (46.6 g) and 2-amino-5-nitropyridine (33.3 g) was stirred at 90° C. for 24 hours. The precipitated solid was taken out through filtration, and the obtained solid was suspended in ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution, and purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain methyl 3-methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate (13.0 g) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Mg].[Cl-].[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH3:14].S(=O)(=O)(O)O>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-]>[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:23])[CH2:4][C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[CH3:1])[CH3:14]
Reactant: Cc1ccc(CBr)c(C)c1
Reactant: CCOC(=O)CCCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Cd+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCC(=O)Cc1ccc(C)cc1C
Yield: 88 %

Procedure:
14.5 g of 2,4-dimethylbenzyl bromide, magnesium and cadmium chloride are used to prepare the corresponding cadmium-dialkyl by Huisgen's method. This compound is then reacted, in benzene solution at the boil, with 11.2 g of pimelic acid ethyl ester chloride. Sulphuric acid is added to the mixture, the organic phase is washed and the benzene is evaporated off. The residue is distilled in a high vacuum, giving 12.8 g of 8-(2,4-dimethylphenyl)-7-oxo-octanoic acid ethyl ester.