Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102 %

Procedure:
To an ice water cooled solution of 6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-amine (3.08 g, 13.15 mmol), prepared as above, in THF (50 mL) was added pyridine (3.19 mL, 39.44 mmol) followed by benzyl chloroformate (1.9 mL, 13.15 mmol). The resulting suspension was allowed to stir at 0° C., then after 2 hrs a further 0.5 mL of benzyl chloroformate was added and reaction mixture was allowed to stir at ambient temperature overnight. It was partitioned between EtOAc (100 mL) and water (50 mL), the organic phase was separated and the aqueous phase re extracted into EtOAc (200 mL). The organic extracts were combined, dried and concentrated to leave crude product. This was purified on a 120 g silica SiliCycle cartridge, eluting with 30-50% EtOAc/isohexane using an Isco Companion, to provide the title compound (4.94 g, 100%); 1H NMR (CDCl3) δ 1.66-1.97 (m, 8H), 2.70-2.77 (m, 1H), 3.97 (s, 4H), 5.21 (s, 2H), 6.71 (s, 1H), 7.16 (d, 1H), 7.35-7.41 (m, 5H), 7.91 (s, 1H), 8.37 (s, 1H); MS m/e MH+ 369.
Reaction SMILES: [CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred suspension of 2-methyl-2-isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.0 g., 0.0244 mole) and aluminum chloride (9.0 g., 0.068 mole) in heptane (400 ml.) is refluxed for 1 hour and cooled. The heptane is decanted from the reaction mixture and the solid residue is poured into water (300 ml.) and concentrated hydrochloric acid (20 ml.). The crude product is extracted into ether (300 ml.), washed with water, dried over magnesium sulfate, distilled to a volume of 100 ml. and treated with hexane (100 ml.). The 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone which separates (6.5 g.) melts at 215°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br-:21]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: [Br-]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Yield: 95.3 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-fluoro-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 1 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was a pale yellow crystal in a yield of 95.3%, mp: 126-128 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.47 (1H, dd, J=14.28, 7.28 Hz), 3.74 (1H, dd, J=14.28, 7.28 Hz), 5.25 (1H, t, J=7.28 Hz, CHBr), 7.15 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.46 (2H, d, J=8.40 Hz, ArH), 8.03 (2H, dd, 3JHH=8.72, 4JFH=5.36 Hz, ArH), 8.17 (2H, d, J=8.40 Hz, ArH); ESI-MS (negative ion): 352.2 (M−1, 54), 350.2 (M-3, 52), 256.2 (100).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:19](Cl)([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:19]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[CH2:1][CH3:2])([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: CCNCCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC)CCc1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g. of 4-[2-(ethylamino)ethyl]-pyridine and 2.0 g. of triethylamine in 60 ml. of dry chloroform is treated at 0°C. with a solution of 2.1 g. of carboethoxy chloride in 10 ml. of dry chloroform. After stirring for two hours, the mixture is poured into ice water and 5 percent aqueous sodium hydroxide added. The chloroform layer is separated, washed with water and dried over potassium carbonate. The solvent is evaporated and the residue distilled in vacuo to give 4-[2-(N-carboethoxy-N-ethylamino)ethyl]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2]>C(O)(C)C>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH:40]([CH3:41])[CH3:42])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(C(=O)OC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Solvent: CC(C)O
Product: CCOc1cc(CC(=O)NC(C(=O)OC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Prepared analogously to Example 68 by catalytic hydrogenation of benzyl 2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in isopropanol.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14]C)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)O)cc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-tert-butyl-3-methoxy-benzoic acid (400 mg, 1.92 mmol) in anhydrous DCM (9 mL) under N2 at −78° C. was added BBr3 (5.76 mL of 1 M in DCM, 5.763 mmol) dropwise over 30 minutes. The mixture was allowed to stir at −78° C. for 1 hour, allowed to warm to room temperature over 1 hour and then stirred at room temperature for 1 hour. The mixture was poured onto crushed ice and was stirred for 10 minutes. The organic layer was removed and the aqueous layer was extracted with DCM (3×). The combined organics were combined, dried over Na2SO4 and then concentrated under reduced pressure to give 4-tert-butyl-3-hydroxybenzoic acid. ESI-MS m/z calc. 194.1, found 195.1 (M+1)+; Retention time: 1.45 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 9.71 (s, 1H), 7.39 (d, J=1.1 Hz, 1H), 7.32 (dd, J=8.0 Hz, 1.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 1.35 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](CC#N)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].OS(O)(=O)=O.O.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:21]([OH:24])=[O:23])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1cc(CC#N)cc(Br)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(CC(=O)O)cc(Br)c1O
Temperature: 25 °C
Yield: 47 %

Procedure:
(3-acetyl-5-bromo-4-hydroxy-phenyl)-acetonitrile 213 (6 g, 23.6, mmol) is refluxed in a mixture of 50 mL acetic acid, 5 mL conc. H2SO4 and 5 mL water for about 2-3 h. This refluxed mixture is cooled to ambient temperature and poured onto ice forming a solid. The solid is isolated and recrystallized from a ethanol-water mixture to yield (3-acetyl-5-bromo-4-hydroxy-phenyl)-acetic acid 214 in a 47% yield.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Yield: 82.8 %

Procedure:
A solution of ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (36.10 g, 0.186 mol), N-methylthiourea (25.40 g, 0.282 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29.11 g, 0.191 mol) in ethanol (150 ml) was refluxed for 21 hrs. A half amount of ethanol was evaporated under reduced pressure and hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with water and dried. The precipitate was stirred in hot ethyl acetate (1 L), and the precipitate was collected by filtration and dried to give 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (33.91 g, 83%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH:20][CH2:21][CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:17][C:16]([O:15][C:13]([NH:20][CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:7])(=[O:8])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10])=[O:14])([CH3:19])[CH3:18]
Reactant: COC(=O)C1CS(=O)(=O)CCN1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1CS(=O)(=O)CCN1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a stirred solution of methyl 3-thiomorpholinecarboxylate 1,1-dioxide (D16; 1.08 g, 5.6 mmol) in 14 ml of anhydrous 1,2-dichloroethane was added N-boc-2-aminoacetaldehyde (1.1 g, 6.7 mmol) and acetic acid (0.316 ml, 5.6 mmol). After 30 min. sodium triacetoxyborohydride (1.78 g, 8.4 mmol) was added and the solution stirred at room temperature. Additional aliquots of N-boc-2-aminoacetaldehyde and sodium triacetoxyborohydride (1.0 g, 4.7 mmol) were added and the reaction continued overnight. The solvent was removed under reduced pressure and the residue was purified by SCX column, followed by chromatography (silica, cyclohexane:ethyl acetate 70:30 to 1:1) and again SCX, to give 295 mg of the target compound.
Reaction SMILES: C([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([CH2:15][CH3:16])[CH:8]=1)(C)(C)C.[ClH:18]>>[ClH:18].[CH2:13]([C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([CH2:15][CH3:16])[N:10]=1)[C:6]([OH:17])=[O:5])[CH3:14]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(CC)n1
Agent: Cl
Product: CCc1cc(C(=O)O)cc(CC)n1

Procedure:
A solution of 2,6-diethyl-isonicotinic acid tert-butyl ester (635 mg, 2.70 mmol) in 6 N aq. HCl (10 mL) is stirred at 95° C. for 15 h before the solvent is evaporated. The residue is dried under HV to give 2,6-diethyl-isonicotinic acid hydrochloride (523 mg) as a colourless solid, LC-MS: tR=0.42 min, [M+1]+=180.31; 1H NMR (D6-DMSO): δ 7.95 (s, 2H), 3.05 (q, J=7.5 Hz, 4H), 1.31 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:14][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:11][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:16]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)OCCCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)OCC
Yield: 92.9 %

Procedure:
(S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (1.0 g, 4.197 mmol) and 4-(4-nitrophenyl)butyl methanesulfonate (1.204 g, 4.406 mmol) were mixed in acetonitrile (20 ml). Potassium carbonate (anhydrous, 870 mg, 6.295 mmol) was added. The mixture was heated to reflux overnight. It was then evaporated in vacuum. Water and ethyl acetate were added into the residue. The two phases were separated. The organic phase was washed with water and brine and dried with magnesium sulfate. The solvent was removed by evaporation in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (25:75) as eluant gave the desired product (1.62 g), yield 93%.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].II>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][C@H:24]([O:26][C:27]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CN(C)CCN
Agent: II
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Compound XIV was synthesized by mixing a solution of cholesteryl chloroformate (0.5 mmol) in chloroform with a solution of N,N-dimethylethylenediamine (9.1 mmol) in chloroform in a dry ice-ethanol bath. The solvent and the unreacted amine were removed in vacuo. Compound XIV was purified by two successive recrystallizations in ethanol. (Yield, 65%) TLC (chloroform:methanol=65:35) showed a single spot (Rf=0.37) when developed with iodine. The product was characterized by proton NMR.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=1>CN(C=O)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2[C:7]([CH3:8])=[C:6]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[N:5]=[CH:4][N:3]=2)=[C:33]([F:38])[CH:32]=1
Reactant: Cc1c(Cl)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 150 °C
Yield: 47.8 %

Procedure:
A mixture of 4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine (1.51 g, 4.46 mmol), potassium carbonate (1.25 g, 9.03 mmol), and 4-bromo-2-fluorophenol (1.11 g, 5.82 mmol) in 15 mL DMF was heated in microwave for 1 hour at 150° C. The mixture was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1 v/v) to give Compound C40 as an oil (1.05 g, 48%). 1H NMR (CDCl3, 400 MHz) δ 1.20-1.22 (d, 6H), 1.83-1.91 (m, 2H), 1.98-2.05 (m, 2H), 2.11 (s, 3H), 2.77-2.87 (m, 1H), 3.53-3.59 (m, 2H), 3.74-3.80 (m, 2H), 5.31-5.36 (m, 1H), 6.99-7.03 (m, 1H), 7.22-7.29 (m, 2H), 8.13 (s, 1H). Exact mass calculated for C21H23BrFN5O3 491.1, found 492.4 (MH+).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[NH:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([OH:31])=[O:30].N12CCCN=C1CCCCC2>CN(C)C=O>[O:28]=[C:27]1[NH:23][CH:24]([C:29]([O:31][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:30])[CH2:25][CH2:26]1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)N1
Yield: 69.4 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), DL-pyroglutamic acid (3.9 g) and 1,8-diazabicyclo[5.4.0]-undec-7ene (4.6 g). After recrystallization in dimethylformamide, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-oxo-2-pyrrolidinecarboxylate (8.8 g), m.p. 255° C. (decomposition), is obtained.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].I[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1>>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1OC
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1OC
Yield: 76 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.66 g (6.8 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2 g (6.9 mmol) of methyl 4-iodo-2-methoxybenzoate, 2.1 g (75%) of the expected ester were obtained, after chromatography on a silica column eluted with dichloromethane, in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)c(Cl)c1
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Reaction time: 0.25 h

Procedure:
1 g (4.85 mmol) of 2-chloro-4-nitrobenzylchloride is slowly added dropwise to 2 mL (16.22 mmol) of 4-methylpiperidine at ambient temperature and the mixture is stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate and extracted twice with water. The organic phase is dried over sodium sulfate and evaporated down. Yield: 1.3 g (99.7% of theory); C13H17ClN2O2 (M=268.74); calc.: molecular ion peak (M+H)+: 269/271; found: molecular ion peak (M+H)+: 269/271; Rf value: 0.4 (Alox, petroleum ether).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11].S(OC)(O[CH3:16])(=O)=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:16][O:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: O=Cc1cccc(C=O)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COc1c(C=O)cccc1C=O
Temperature: 75 °C
Yield: 54 %

Procedure:
2-Hydroxy-1,3-benzenedicarboxaldehyde (1.05 g, 7 mmol), dimethyl sulfate (1.06 g, 8.4 mmol), and 55 mL of acetonitrile were charged into a 1-necked flask equipped with a mechanical stirrer. 1.45 g (10.5 mmol) of potassium carbonate was added at room temperature under nitrogen. The mixture was stirred at 75° C. until GC-MS indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether, washed with NaCl/H2O, and dried over MgSO4. The ether was evaporated off. The crude product was recrystallized from diethyl ether. Pale yellow solid (0.62 g, 54% yield) was obtained. 1H NMR in CDCl3 was consistent with the proposed structure. 1H NMR (CDCl3): δ 10.4 (2H), 8.1 (2H), 7.4 (1H), 4.1 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1.[OH-].[Na+].C1(C)C=CC=CC=1.[Na:34].COC1C=CC2N=C(S(CC3C(C)=C(OC)C(C)=CN=3)=O)NC=2C=1>C(C(C)=O)C>[Na:34].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of 650 mg (1.89 mmol) of (+)5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole in 6.5 mL of methyl ethyl ketone (MEK) in a 50 mL flask was added, at ambient temperature 0.39 mL of a 5M aqueous sodium hydroxide solution. To that mixture was added 13 mL of toluene. The resulting mixture was turbid, so an additional 6.5 mL of MEK was added and the mixture became a clear, yellow solution. This mixture was allowed to stir at ambient temperature overnight. The following morning, several crystals of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt were added to act as seed crystals, but no product crystals formed. A stream of dry nitrogen gas was blown over the mixture to begin removing the solvent After approximately 10 minutes, the product precipitated. The solids were isolated by vacuum filtration and washed with a small amount of diethyl ether. The solids were then placed into a vacuum desiccator to remove the last traces of ether, to yield approximately 500 mg of the desired product as an off-white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Mix 4-hydroxybenzaldehyde (1.23 g, 10.1 mmol), imidazole (1.37 g, 20.2 mmol), and triisopropylsilyl chloride (2.60 mL, 12.1 mmol) in DMF (10 mL) and stir at room temperature for 2 hours. Quench the reaction with saturated aqueous NH4Cl (50 mL) and extract with EtOAc (3× 100 mL). Wash the organic layers with H2O and brine (50 mL each). Combine the organic layers, dry over MgSO4, concentrate and purify by flash chromatography, eluting with 2.5% Et2O/hexanes to afford 4-triisopropylsilyloxybenzaldehyde (2.78 g, 99%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([S:10]([NH:13][CH:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](OC)=[O:24])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])[CH3:9]>O1CCCC1>[OH:24][CH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:14]([NH:13][S:10]([CH:8]([CH3:9])[CH3:7])(=[O:12])=[O:11])[CH2:15][CH2:16]2
Reactant: COC(=O)c1ccc2c(c1)CCC2NS(=O)(=O)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
At 0° C. Lithium Aluminium Hydride (2.102 mL, 5.04 mmol) was added dropwise to a stirred solution of methyl 1-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (1 g, 3.36 mmol) in Tetrahydrofuran (dry) (25 mL). Mixture warmed to rt and stirred for 4 hr. After this time the reaction mixture was again cooled to 0° C. and more Lithium Aluminium Hydride (2.102 mL, 5.04 mmol) added and the whole stirred at room temperature for 30 min before being carefully quenched with H2O (10 mL) and 2N NaOH (10 mL). The resulting mixture was filtered and partitioned between EtOAc and brine. The organic layer was separated, dried on Na2SO4 and solvent evaporated in vacuo to give a dark yellow oil Purification by flash chromatography (0-100% EtOAc in Heptane) afforded the title compound as a colourless oil (670 mg, 74%). MS (ESI): m/z [M−H]− 268.0