Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C:5](=[O:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>P([O-])([O-])([O-])=O>[Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C@@H:5]([OH:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Sakaguchi flasks of 500 mL capacity were respectively charged with 50 mL of said medium A and, after sterilization, inoculated with the microbial strains indicated in Table 1, respectively. Aerobic shake culture was then carried out at 30° C. for 2 days. From each of the culture broths, the cells were harvested by centrifugation and suspended in 25 mL of 50 mM phosphate buffer (pH 6.5) containing 1% of tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate (synthesized by the process described in Example 1) and 2% of glucose. The suspension was put in a 500 mL Sakaguchi flask and a reaction was conducted under shaking at 30° C. for 20 hours. After completion of the reaction, the reaction mixture was extracted twice with one volume of ethyl acetate each and the ethyl acetate phase was analyzed by high performance liquid chromatography (column: Nakalai-Tesque, Cosmocil 5CN-R (4.6 mm×250 mm), eluent: 1 mM phosphoric acid/H2O:acetonitrile=5:1, flow rate 0.7 mL/min., detection: at 210 nm, column temperature: 30° C.) for reaction rate and for the diastereomer ratio of the product tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate. The results are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH2:9]=[CH:10][CH:11]([OH:13])[CH3:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: C=CC(C)O
Reactant: Clc1ccc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)CCc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Part A. To a mixture of 2-chloro-5-iodopyridine (6.76 g, 28.2 mmol) in 50 mL N,N-dimethylformamide was added 1-buten-3-ol (24.4 mL, 282.3 mmol), palladium acetate (0.64 g, 2.82 mmol), tetrabutylammonium chloride (0.79 g, 2.82 mmol), and sodium bicarbonate (5.94 g, 70.6 mmol). The resulting mixture was stirred at 50° C. for 5 hr, and then quenched with water (20 mL). Subsequently, the mixture was diluted with 20 mL of ethyl acetate and filtered through a pack of celite. The organic layer was separated from the filtrate, and the aqueous layer was further extracted with ethyl acetate. The organics were combined, washed with saturated NaCl solution, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) afforded the desired 4-(6-chloropyridin-3-yl)butan-2-one intermediate in the form of a yellow oil (4.01 g, 77% yield). MS MH+ for C9H10ClNO: calc. 184, found 184.
Reaction SMILES: F.[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([O:26][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:26])[CH2:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OC(CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Reaction time: 48 h

Procedure:
Hydrofluoric acid (40%, 4 ml) was added to a solution of (±)-3-(4-(3'-fluorobiphenyl-4-yloxy)-3-(tert-butyldimethylsilyloxy)butyl)pyridine in acetonitrile (30 ml) and the mixture stirred for 2 days. The solution was neutralised by careful addition to a saturated aqueous solution of sodium bicarbonate (200 ml). The mixture was extracted with ethyl acetate, the organic extract dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified twice by column chromatography over silica eluting with dichloromethane then ethyl acetate to give the title compound as a white powder (0.33 g).
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>C1COCC1>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
2-methyl-2-adamantanol (33 g, 0.2 mol) and triethylamine (0.22 mol) were dissolved in 300 ml of THF and then acryloyl chloride (19 g, 0.21 mol) was added slowly thereto using a dropping funnel. Then, the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The diethyl ether removed crude product was vacuum-distilled to yield the desired product (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:58]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:58].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:8](=[O:12])[CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)cc31)CCNCC2
Temperature: 135 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (114 mg, 0.479 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (165 mg, 0.435 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg, 0.087 mmol) and Cs2CO3 (156 mg, 0.479 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 2 d. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a yellow residue. 2 N HCl in Et2O (100 mL) was added to a solution of the yellow residue in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 45° C. for 2 h to afford 98 mg (48%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.02 (br s, 2H), 7.67 (dd, J=15.0, 9.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.35 (ddd, J=10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 436 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(OCCCCBr)cc1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,4-dimethoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,4-dimethoxyphenoxy)-butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C:12]1[N:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:14]=[C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]=12)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:13]2[C:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:4]([OH:29])=[O:3])=[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:15]3=[N:14]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Yield: 90.4 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid ethyl ester (337 mg, 812 umol) in MeOH (19 ml) and 4 N aqueous NaOH (3.05 ml, 12.2 umol) was heated for 14 h under reflux conditions. The solvent was removed under reduced pressure, ice water/2 N aqueous HCl solution/iPrOAc 1/1/2 was added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (284 mg, 734 umol; 90%) as off-white solid which was sufficiently pure to be used in the next step. MS: m/e=387.2 [M+H
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:7](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:6][O:5][CH2:4]1.C1CCCCC=1.[ClH:28]>C(O)C.[Pd].C(OCC)C>[ClH:28].[ClH:28].[NH2:1][CH2:2][C:3]1([NH2:7])[CH2:6][O:5][CH2:4]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: CCOCC
Product: NCC1(N)COC1

Procedure:
585 mg (2.07 mmol) of 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine [synthesis described in: US2008/103183 A1, 2008; p. 48] were initially charged in ethanol (29.2 ml), and 441 mg (0.41 mmol) of 10% palladium on activated carbon and 6.3 ml (62.2 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 8 h. Subsequently, the reaction mixture was filtered through a Millipore® filter and washed with methanol, and the filtrate was admixed with 2.6 ml (5.2 mmol) of 2 M hydrogen chloride in diethyl ether, concentrated and dried under high vacuum. This gave 423 mg (87% of theory, purity 75%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15].Cl.[CH3:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14](=[NH:15])[O:21][CH3:20]
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=N)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
Following the procedure described in Example 6, 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutyronitrile is reacted with methanol and hydrogen chloride to give methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate, which is then reacted with 3-phenoxybenzyl alcohol, yielding the desired compound 3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.CS(O[CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])(=O)=O>C(O)C>[N:1]([CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CCC#N)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CCC#N)N=[N+]=[N-]
Yield: 91.2 %

Procedure:
To a stirring solution of NaN3 (15 g) in boiling water (20 ml) was added a solution of crude 4-methanesulphonyloxypentanonitrile (37.7 g, ≈0.189 mol) in ethanol (240 ml) and the mixture refluxed for 1.5 h. After cooling the mixture was partitioned between H2O and CH2Cl2. The organic phase was dried and concentrated in vacuo to give 21.4 g of the title material as a light brown oil, (91.6): 1Hmr (CDCl3) δ: 4.05 (1H, q, J=13 Hz), 2.46 (2H, t, J=13 Hz), 1.8 (2H, t, J=13 Hz) and 1.35 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2242, 2100 cm-1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:24]1([S:30]([NH:33][C@@H:34]([CH2:42][NH2:43])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCOC(C)=O.CC#N>[C:38]([O:37][C:35](=[O:36])[C@@H:34]([NH:33][S:30]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:31])=[O:32])[CH2:42][NH:43][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
A mixture of 22-4 (300 mg, 1.0 mmol), 19-2a (329 mg, 1.0 mmol), NMM (430 gL, 4.0 mmol), and CH3CN (5 mL) at ambient temperature was treated with BOP (650 mg, 1.5 mmol). After 20 h the reaction mixture was diluted with EtOAc and then washed with 10% KHSO4 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 22-5 as a white solid. TLC Rf =0.16 (silica, 40% EtOAc/hexanes);
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH2:6][OH:7])([O-:3])=[O:2]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a suspension of 2,6-dinitrobenzaldehyde (19.6 g, 0.1 mole) in methanol (200 ml), sodium borohydride (5.8 g) was added in a small portion at 15°-25° C., the resultant mixture was stirred at room temperature for 1 hour and then concentrated. To the residue, H2O (100 ml) and chloroform (100 ml) were added, followed to by stirring for 1 hour, the chloroform layer was separated, washed with H2O, dried over anhydrous MgSO4 and evaporated to afford 15.0 g of 2,6-dinitrobenzyl alcohol as yellow crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[C:13][CH2:14][N:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][CH2:22][CH:23]([NH2:36])[C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)[C@@H:17]([C:37]([O:39]C)=[O:38])[CH2:16]1>O1CCOCC1.C(OC(C)C)(C)C>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[C:13][CH2:14][N:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][CH2:22][CH:23]([NH2:36])[C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)[C@@H:17]([C:37]([OH:39])=[O:38])[CH2:16]1
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(N)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4F)C[C@@H]3C(=O)O)c2c1
Reaction time: 16 h
Yield: 34.7 %

Procedure:
1.37 cm3 of 5N aqueous sodium hydroxide solution are added with stirring, at a temperature in the region of 20° C., to a solution of 0.9 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop 2-ynyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 9 cm3 of dioxane and then the combined mixture is brought to a temperature in the region of 60° C. for 16 hours. The mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; mass 40 g), elution being carried out with a dichloromethane/methanol (90/10 by volume) mixture, a dichloromethane/methanol (80/20 by volume) mixture, a dichloromethane/methanol (60/40 by volume) mixture and a dichloromethane/methanol/triethylamine (74/25/1 by volume) mixture, with 100-cm3 fractions being collected Fractions 16 to 29 (which contain the purified product) are combined and then concentrated to dryness under the above conditions. The residue obtained is taken up in 30 cm3 of isopropyl ether, filtered off, washed 2 times with 20 cm3 of diethyl ether and then purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 2.3 cm; mass 25 g), elution being carried out with a dichloromethane/methanol (95/05 by volume) mixture. Fractions 4 to 7 are combined and then concentrated to dryness under the above conditions. The solid obtained is taken up in 25 cm3 of isopropyl ether, filtered off, washed 3 times with 10 cm3 of pentane and dried to afford 0.304 g of (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:48])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][N:26]([CH3:46])[C:27]([C:29]3[O:30][C:31]4[CH:45]=[CH:44][CH:43]=[CH:42][C:32]=4[C:33]=3[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:28])[CH:21]=2)[C:16]=1[Br:47])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:47][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][N:26]([CH3:46])[C:27]([C:29]3[O:30][C:31]4[CH:45]=[CH:44][CH:43]=[CH:42][C:32]=4[C:33]=3[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:48])=[O:4]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Yield: 72.7 %

Procedure:
A mixture of 1 N NaOH (5 mL, 5 mmol) and 2-(1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (1.68 g, 2.49 mmol), prepared in the previous step, in 110 mL of methanol plus 5 mL of water was stirred under nitrogen at room temperature overnight. 1 N HCl (50 mL, 50 mmol) was added and the reaction was concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (1.20 g, 73%) as a white solid, mp 87-90° C.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH2:33][CH3:34]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCCC(=O)CBr
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCCc1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromopentan-2-one using the same procedure as reported for 2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Cl:16])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Temperature: -5 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A 50-mL three-necked round-bottomed flask equipped with a nitrogen inlet and a reflux condenser was purged with nitrogen and charged with 296b (438 mg, 1.76 mmol) and chloroform (10 mL). The reaction was cooled to −5° C. using an ice/acetone bath and SOCl2 (628 mg, 5.28 mmol) was added portion-wise. The cooling bath was removed and the reaction was stirred at 70° C. for 3 h. After this time, the solvent was removed under reduced pressure. ethyl acetate was added to the residue and the resulting solution was cooled to −5° C. Saturated aqueous sodium bicarbonate (3 mL) was added until a pH of 8.5 was reached. The mixture was partitioned between ethyl acetate and water. The combined organic layer was washed with saturated aqueous sodium carbonate (2×5 mL), brine (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford 296c (284 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CN(C)C=O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].[OH-].[Na+]>O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: [O-]c1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 44 h
Yield: 79.3 %

Procedure:
Sodium phenoxide trihydrate (7.50 g, 44.1 mmol) was dried under vacuum at 65° C. for 18 h at 0.6 mm Hg to yield 5.08 g of sodium phenoxide. Under a nitrogen atmosphere, 3,5-dibromopyridine (4.00 g, 16.9 mmol) and anhydrous N,N-dimethylformamide (40 mL) were added to the sodium phenoxide (5.08 g, 43.8 mmol). The resulting mixture was stirred at 110° C. for 44 h. After cooling to ambient temperature, water (75 mL) was added, and the pH was adjusted to 13.0 using 30% NaOH solution. The solution was extracted with diethyl ether (4×60 mL). The combined ether extracts were washed with saturated NaCl solution (50 mL), dried (NaSO4), filtered and concentrated by rotary evaporation to a brown oil (4.0 g). The oil was vacuum distilled, collecting a forerun (317 mg), bp 48-65° C. at 0.05 mm Hg. Further distillation afforded 3.35 g (79.8%) of 3-bromo-5-phenoxypyridine as a pale-yellow oil, bp 75-112° C. at 0.05 mm Hg (lit. bp 110-115° C. at 1.7 mm Hg, see K. Fujikawa, et al. Agr. Biol. Chem. 34:68 (1970).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=S.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nn1c(=S)[nH]c2ccccc2c1=O
Reactant: C1CCNC1
Solvent: O
Product: Nn1c(N2CCCC2)nc2ccccc2c1=O
Temperature: 150 °C
Yield: 75.2 %

Procedure:
3-Amino-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (0.200 g, 1.04 mmol) was dissolved in pyrrolidine (0.850 mL, 10.4 mmol) and the mixture was heated at 150° C. for 20 minutes under microwave conditions. After cooling the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give the title compound (0.180 g, 75%).