Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:10]=[O:11])[C:4]([CH3:9])([CH3:8])[CH:5]=[CH:6][CH:7]=1.CCCCCCC=CCCC.[Cl-].[NH4+]>ClCCl>[CH3:1][C:2]1[CH2:7][CH:6]=[CH:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH:10]=[O:11]
Reactant: CC1=CC=CC(C)(C)C1C=O
Agent: CCCC=CCCCCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC1=C(C=O)C(C)(C)C=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
(V where R1, R2, and R3 are methyl) To a solution of 2,6,6-trimethyl-2,4-cyclohexadiene-1-carboxaldehyde IV (3.70 g, 24.8 mmol) in anhydrous dichloromethane (25 mL) was added 1,8-diazabicyclo 5.4.0!undec7-ene (DBU) (0.150 mL, 0.98 mmol) in three (3) portions over 30 min. while the mixture was stirred at 0° C. The solution was warmed to room temperature and the progress of the reaction was monitored by TLC (hexanes:EtOAc 9:1). The two isomeric aldehydes are separable on TLC (RfSM 0.85; Rf product 0.75). After 60 min., the reaction was complete. A saturated solution of ammonium chloride (20 mL) was added, followed by dichloromethane (100 mL). The organic layer was separated and washed with a saturated solution of brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (SGC) using a mixture of hexanes:EtOAc 15:1 as eluent to give 3.1 g of the desired aldehyde V (83% yield). IR (neat) 2960 CH), 1716 (C=O) cm-1 ; 1H-NMR (CDCl3 ; 400 MHz) δ (ppm): 10.18 (s, 1 H, CHO), 5.44, (m, 2 H, vinyl--CH), 2.81 (s, 2 H, --CH2 --), 2.12 (s, 3 H, CH3 ring), 1.25 (s, 6 H, 2×CH3 ring); 13C-NMR (CDCl3 ; 100 MHz) δ (ppm): 191.8, 152.1,138.4, 117.4, 35.6, 34.2, 28.1, 22.6, 18.47, 14.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH3:28])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (110 mg, intermediate E1) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 1.95 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodomethane (38 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (5:1) to give [(4S,5R)-1,4,5-trimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (72 mg) as a colorless foam. MS (ESI): m/z=377.4 [ M+H]+. The hydrogenation of the nitro group to give the aniline (intermediate F) was carried out as described in Scheme 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:3]1([N:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=C(Nc1ccccc1)c1ccccc1
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 70.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and benzanilide (118 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow solid (95 mg, 70%). mp 105-107° C. 1H NMR (DMSO) δ 7.24 (d, J=7.9 Hz, 1 H), 7.35-7.62 (m, 12 H), 7.84 (d, J=7.6 Hz, 1 H); 13C NMR δ 111.0, 118.1, 123.7, 124.1, 127.5, 127.9, 128.4, 129.2, 129.3, 130.0, 130.2, 135.5, 136.2, 139.3, 151.3. HRMS (FAB): cal. for C19H15N2 [M+H+]: 271.1235; found: 271.1230.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[O:26]1CCO[CH2:28][CH2:27]1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1)(=[O:26])[CH3:28]
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2[nH]c(N3CCC4(CC3)OC(=O)c3ccccc34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 1-ethoxyvinyltri-N-butyltin (0.49 g, 1.35 mmol) and bis (triphenyl-phosphine) palladium (II) chloride (0.05 g) to a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.12 g, 0.27 mmol) in dioxane (5 mL). Reflux the reaction mixture for 12 hours. After cooling to ambient temperature, concentrate the reaction mixture in vacuo, and add to a solution of 10% HCl (2 mL) in THF (5 mL). After stirring for 30 minutes, dilute the solution with EtOAc (30 mL), and wash with saturated NaHCO3 (30 mL) and saturated aqueous NaCl (30 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by preparative TLC (10% MeOH—CH2Cl2) to obtain 1′-(5-acetyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a yellow solid.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:11][CH:10](O)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O.[H-].[Na+].[C:29]1([CH:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:36]#[N:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1.C(CC(C)(C)C)(C)C>[CH:2]1([N:8]2[CH2:11][CH:10]([C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:36]#[N:37])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OC1CN(C2CCCCC2)C1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)C1CN(C2CCCCC2)C1
Reaction time: 3 h
Yield: 18 %

Procedure:
To 191 g. (1.0 mole) of 1-cyclohexyl-3-azetidinol hydrochloride in methylene chloride was added a dilute sodium hydroxide solution, the organic layer was extracted, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in dry benzene and stirred with 116 g. (1.05 mole) of triethylamine and cooled with an ice bath. One mole (115 g.) of methanesulfonylchloride was added, dropwise, and stirring was continued at room temperature for three hours and the mixture was filtered. The filtrate was added at a fast dropwise rate to a reaction mixture of 50.0 g. (1 mole) of sodium hydride in one liter of dry toluene to which 193 g. (1 mole) of diphenylacetonitrile had been added slowly at 45°-50° C. and had already stirred at reflux for two hours. After addition was complete, reflux was continued for two hours, and the solution was stirred overnight. An equivalent amount of isooctane was added, and after extracting four times with a dilute hydrochloric acid solution, the acid layers were combined and made basic with 50% sodium hydroxide, with ice cooling, and extracted with chloroform. The organic layer was dried, filtered and concentrated in vacuo. The solid which formed when the residue was treated with isopropyl ether was recrystallized from isopropyl ether twice. The product weighed 58.0 g. (18% yield) and melted at 111°-114° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.CC1C=CC(S(O[CH:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)(=O)=O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:11]([CH3:12])[C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[CH:16][C:6]=2[C:7]=1[CH3:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(O)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
A solution of 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized above, tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) and tripotassium phosphate (1.26 g) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 3 hr then at 100° C. for 14 hr. Tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) was added to the mixture, and the mixture was stirred at 100° C. for 20 min. Tripotassium phosphate (600 mg) was added to the mixture, and the mixture was stirred at 100° C. for 2 hr then at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (886 mg, 61%) as an orange oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:12][C:13]([N:15]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:16][CH3:17])=[O:14].[CH:28]([C@@H:30]1[C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][N:32]([C@H:41]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:42]([O:44]CC2C=CC(OC)=CC=2)=[O:43])[CH2:31]1)=O>>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:12][C:13]([N:15]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][C@@H:30]2[C@@H:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:33][N:32]([C@H:41]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[C:42]([OH:44])=[O:43])[CH2:31]2)[CH2:20][CH2:19]1)[CH2:16][CH3:17])=[O:14]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: CCN(C(=O)Cc1ccc(F)c(F)c1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Cc1ccc(F)c(F)c1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 54.4 %

Procedure:
The title compound was prepared from 4-(N-((3,4-difluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate (40 mg, 0.1 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.06 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 19 mg (54%) of the title compound. ESI-MS: 582.5 (M+H); HPLC A: 2.35 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:30](Cl)(=[O:41])[O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:41])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3[nH]ccc3c2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate, Example 31-C, (1 g, 2.73 mmol) in 20 mL of THF, sodium hydride (0.164 g, 4.09 mmol, 60% in mineral oil) is added at 0° C. After 1.5 h, a solution of 4-nitrophenyl carbonochloridate (1.65 g, 8.19 mmol) in THF (10 mL) is added. The mixture is allowed to warm to rt and stir overnight before being quenched with ice water and extracted with EtOAc. The combined organic layers are washed with water and brine before being dried (Na2SO4) and concentrated. The residue is then separated by FCC (20-80% EtOAc/heptane) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1H), 8.34-8.43 (m, 2H), 7.79 (d, J=3.8 Hz, 1H), 7.49-7.57 (m, 2H), 7.41 (d, J=2.3 Hz, 1H), 7.17 (dd, J=9.0, 2.4 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 5.31 (s, 1H), 4.65 (s, 2H), 3.80 (t, J=5.8 Hz, 2H), 2.95 (t, J=5.6 Hz, 2H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].CC1CCCCC1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: Cc1ccc(CCO)cc1
Solvent: CC1CCCCC1
Product: Cc1ccc(CCOCC(=O)O)cc1
Yield: 83.5 %

Procedure:
6.8 g of 4-methylphenethyl alcohol were reacted with 4.73 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 8.1 g (84%) of 2-(4-methylphenyl)ethoxyacetic acid of melting point 65°-67° C. (from methylcyclohexane).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:17]=[O:18])=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:6]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:19]1([CH:17]([C:3]2[C:2]([CH3:1])=[CH:6][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[CH:4]=2)[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (2.3 g) synthesized above in tetrahydrofuran (20 mL) was added dropwise 1M cyclohexylmagnesium bromide-tetrahydrofuran solution (12 mL) at 0° C. After stirring at 0° C. for 1 hr, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (1.8 g, 52%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:29]([CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: COc1cccc(CN)c1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1cccc(OC)c1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with m-methoxybenzylamine (0.17 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 104 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([O:34][CH2:33][O:32][CH3:31])=[CH:36][CH:37]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: COCOc1ccc(CCl)cc1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COCOc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)cc1
Yield: 92.4 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 4-methoxymethoxybenzyl chloride obtained above, 3.0 g (87%) of the expected compound were obtained in the form of a white powder having a melting point of 106°-108° C.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3].Br[CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: OCCBr
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(C2CCN(CCO)CC2)c1
Yield: 55.7 %

Procedure:
2.0 g (7.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 20 ml of N,N-dimethylformamide, and then 1.3 g (10.2 mmol) of 2-bromoethanol and 3.2 g (23.4 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 100 ml of water and extracted with ethylacetate (70 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH2Cl2) to obtain 1.14 g (yield 56%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH2:22][C:23]([OH:25])=[O:24])[C:4]2[CH:5]=[C:6]([F:21])[CH:7]=[CH:8][C:9]=2/[C:10]/1=[CH:11]\[C:12]1[CH:13]=[CH:14][C:15]([S+:18]([O-:20])[CH3:19])=[CH:16][CH:17]=1.[OH-].[Ca+2:27].[OH-]>C(O)C>[Ca:27].[CH3:1][C:2]1=[C:3]([CH2:22][C:23]([OH:25])=[O:24])[C:4]2[CH:5]=[C:6]([F:21])[CH:7]=[CH:8][C:9]=2/[C:10]/1=[CH:11]\[C:12]1[CH:13]=[CH:14][C:15]([S+:18]([O-:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: [Ca+2]
Agent: CC1=C(CC(=O)O)c2cc(F)ccc2/C1=C\c1ccc([S+](C)[O-])cc1
Agent: [OH-]
Solvent: CCO
Product: [Ca]

Procedure:
100 g Sulindac is suspended in 4 l. of 75% v/v ethanol. Apply heat until a clear solution is formed. Add 10.38 g of calcium hydroxide and mix. A clear solution is formed initially followed by massive precipitation of calcium sulindac. Filter the slurry to remove the solvent and air dry to give calcium sulindac.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10]([C:13](O)=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1>CC(OC(C)=O)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:16](=[O:18])[O:17][C:13](=[O:14])[C:10]3=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylic acid (25.3 g, 92 mmol) and Ac2O (200 mL) was stirred for 3 h at 120° C. The reaction mixture was concentrated in vacuo, dissolved in toluene (200 mL) and re-concentrated in vacuo again to give 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylic anhydride. This material was dissolved in EtOH (200 mL) and the mixture was heated at reflux for 3 h and then stored at rt overnight. The reaction mixture was concentrated in vacuo, dissolved in toluene and concentrated again to afford the product as the major isomer. This material contained ca. 30% of the corresponding 3-ethyl ester 2-carboxylic acid isomer. Major isomer: 1H NMR (d6-DMSO) δ 13.5 (1H, br), 8.67 (1H, d, J=2 Hz), 8.06 (1H, d, J=2 Hz), 7.31 (2H, dd, J˜9, 6 Hz), 7.11 (2H, t, J˜9 Hz), 4.25 (2H, q, J=7 Hz), 1.24 (3H, t, J=7 Hz); ES+ MS: 304 (M+H+, 80), 326 (M+Na+, 30).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cn1cc(I)c2cc(Br)cnc21
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCN(c2cn(C)c3ncc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.445 mmol), 1-methylpiperazine (356.7 mg, 3.56 mmol), copper(I) iodide (84.8 mg, 0.445 mmol), K3PO4 (378 mg, 1.78 mmol), 1,2-ethanediol (138 mg, 2.225 mmol) in isopropyl alcohol (5 mL) in a sealed tubes was heated at 70° C. for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried and concentrated. Purification by flash chromatography afforded the title compound. LCMS-ESI+: calc'd for C13H17BrN4 309.1 (M+H+); Found: 309.1 (M+H+).
Reaction SMILES: C(OC(N1C2C=CC=CC=2N=C1CN(C[C:30](=C)[CH2:31][CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])C1C2N=CC=CC=2CCC1)=O)(C)(C)C.O.NN.[CH2:48]([OH:50])[CH3:49]>>[OH:50][CH2:48][CH2:49][C:31](=[CH2:30])[CH2:32][N:33]1[C:34](=[O:43])[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]1=[O:42]
Reactant: C=C(CCN1C(=O)c2ccccc2C1=O)CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Reactant: CCO
Agent: NN
Solvent: O
Product: C=C(CCO)CN1C(=O)c2ccccc2C1=O
Yield: 55 %

Procedure:
To a solution of 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.239 g, 0.40 mmol) in ethanol (8 mL) was added hydrazine monohydrate (0.40 mL, 8.26 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 86 mg (55%) of the free base of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(O)=[O:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:2][CH2:1][C:4]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: COc1ccc(C2(C(=O)O)CCC(=O)CC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(CO)CCC(=O)CC2)cc1OC
Reaction time: 6 h
Yield: 62.7 %

Procedure:
A solution of 19 g. (0.059 mole) of 4-carboxy-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal (prepared in Example 28) in 290 ml. of tetrahydrofuran is added to 5.35 g. (0.141 mole) lithium aluminum hydride in 80 ml. of tetrahydrofuran. Following about 6 hours of heating at reflux the mixture is cooled in ice and treated successively with 5.4 ml. of water, 5.4 ml. of 15% sodium hydroxide solution and 16.2 ml. of water. The resulting inorganic gel is collected on a filter and rinsed with ether. The combined filtrates are evaporated to dryness to give 11.4 g. (62.7% yield) of 4-hydroxymethyl-4-(3,4-dimethoxyphenyl)-cyclohexanone, ethylene ketal as an amorphous gum.