Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[CH:19](=O)[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[O:24]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:19]1[O:12][C:3]([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2]1
Reactant: O=Cc1ccco1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Product: O=C(c1ccccc1)C1(c2ccccc2)COC(c2ccco2)O1
Yield: 78 %

Procedure:
The procedure of Example 1 was repeated except that the starting materials were α-methylolbenzoin and furfural. The product 2-furyl-4-benzoyl-4-phenyl-1,3-dioxolane, was obtained in a yield of 78% and analyzed as follows:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 45, 398 mg, 0.95 mmol) in diethyl ether (30 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (54 mg, 1.4 mmol) in one portion. There was immediate gas evolution. The reaction mixture was allowed to slowly warm to 25° C. and was stirred at 25° C. 16 h. After such time, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl) propionamide (131 mg, 35%/) as a white foam: FAB-HRMS m/e calcd for C20H22Cl2N2O2(M+H)+392.1058, found 392.1062.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[CH:25]([O:38][C:39]1[C:40]2[C:52](=[O:53])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[CH2:50][C:41]=2[C:42]([OH:49])=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:25]([O:38][C:39]1[C:40]2[C:52](=[O:53])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[CH2:50][C:41]=2[C:42]([O:49][S:21]([CH2:20][CH2:19][N:10]2[C:9](=[O:8])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:18])(=[O:22])=[O:23])=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Triethylamine (50 μl), DMAP (catalytic amount) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (27.4 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture was stirred at room temperature for 18 hours under an inert atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 44=0.5, Rf 45=0, Rf 268=0.4) and LC/MS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethylacetate/hexane—3/7) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 268 (12.2 mg, 50%).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:18][O:19]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])(=[O:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:4][C@@H:5]([CH2:18][OH:19])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:14][CH3:15])[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COC(CCCCCOC[C@H](COCc1ccccc1)OC(C)=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(CCCCCOC[C@H](CO)OC(C)=O)OC
Yield: 99.9 %

Procedure:
2-O-Acetyl-3-O-benzyl-1-O-(6',6'-dimethoxyhexyl)-sn-glycerol (369 mg, 1.0 mmol) was hydrogenated in THF (10 ml) over Palladium/carbon (14 mg, 10%) until the uptake of hydrogen ceased (approx. 2.5 hr.). The solution was filtered through celite, and the filtrate was evaporated to yield a colourless oil (278 mg, 100%) which was used immediately. 1H N.M.R.δ: 5.04,q,l,J 5.0 Hz,H2; 4.40,t,l,J 5.7 Hz, --CH(OMe)2 ; 3.84, d,2,J 5.0 Hz, H3; 3.65, d,2J 5.2 Hz, OCH2 --; 3.56-3.44 m 2 H1; 3.35 s 6 OCH3 ; 2.5,s(b),1,OH; 2.14,s,3, COCH3 ; 1.7-1.3,m,8, --CH2 --.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:4]2[C:5]([N:7]([C:10]3[C:15]4[O:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:8](=[O:9])[C:3]=12)=[O:6].[OH-:25].[Na+].Cl>CO>[C:5]([C:4]1[C:3]([C:8]([NH:7][C:10]2[C:15]3[O:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:2]([Cl:1])[CH:23]=[CH:22][C:21]=1[Cl:24])([OH:25])=[O:6]
Reactant: [OH-]
Reactant: Cc1oc2c(N3C(=O)c4c(Cl)ccc(Cl)c4C3=O)cccc2c1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1oc2c(NC(=O)c3c(Cl)ccc(Cl)c3C(=O)O)cccc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo[b]furan (100 mg) in a mixture of aqueous 1N-sodium hydroxide (2 ml) and methanol (3 ml) was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N-hydrochloric acid. The separated solid was collected, washed with water and dried to give 7-(6-carboxy-2,5-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (60 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: O=c1[nH]ccc2cccc(Br)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cccc(Br)c2c1=O
Reaction time: 72 h
Yield: 94.5 %

Procedure:
A solution of (b) (180 mg, 0.8 mmol) in DMF (5 ml) was treated with potassium carbonate (140 mg) and methyl iodide (0.062 ml) and stirred for 3 days then evaporated. The residue was partitioned between dilute aqueous sodium chloride solution and dichloromethane, re-extracting with dichloromethane twice more. The combined organic extracts were dried and evaporated affording a yellow solid (180 mg, 94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10].[H-].[Na+].[NH:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)(O)[O-]>CN(C=O)C.O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:4]([I:10])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)c(I)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1I)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(bromomethyl)-4-fluoro-2-iodobenzene (Example 3, step 1) (5 g, 15.9 mmol) in dry DMF (50 mL) under argon was cooled to 2° C. and treated with NaH (60% dispersion in oil, 0.4 g, 17.5 mmol) and stirred for 5 minutes to give a fine slurry. A solution of di-tert-butyl iminodicarboxylate (Aldrich, 3.8 g, 17.5 mmol) in 20 ml dry DMF was added dropwise, keeping the temperature between 2 and 7° C. After stirring for 1 hr at 0° C., the solution was allowed to warm to room temperature and stirred overnight. The reaction was poured into bicarbonate solution and water was added until all the solids dissolved. The solution wag extracted with ether and the combined organic layers were dried over Na2SO4, filtered and evaporated and the crude product was purified on 120 g silica gel ISCO cartridge eluting first with a gradient of 0-5% EtOAc/Hexanes followed by a gradient of 5-10% EtOAc/Hexanes to give the product as a clear oil that solidified to a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3cc(N)cn3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1csc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)n1

Procedure:
Following general procedure B followed by C starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=421.22.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:25]=1)[C:18]1[CH:17]=[C:16]([C:19]#[C:20][CH:21]3[CH2:23][CH2:22]3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I[CH2:38][C:39]([O:42][CH3:43])([CH3:41])[CH3:40]>O.CCOC(C)=O>[CH:21]1([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([O:24][CH2:38][C:39]([O:42][CH3:43])([CH3:41])[CH3:40])=[CH:9][CH:10]=4)[C@:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:25]4)[C:18]=3[CH:17]=2)[CH2:23][CH2:22]1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(C#CC3CC3)cc12
Reactant: COC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Reaction time: 0.08 h

Procedure:
A 2-5 mL microwave vial was charged with (S)-2-amino-2′-(cyclopropylethynyl)-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (0.250 g, 0.752 mmol), cesium carbonate (0.980 g, 3.01 mmol), and DMF (3.01 mL). The mixture was stirred vigorously for 5 min, then 1-iodo-2-methoxy-2-methylpropane (0.303 mL, 2.257 mmol) was added via syringe. The vial was sealed and the reaction was microwaved at 110° C. for two hours. The mixture was diluted with water and EtOAc and the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-10% MeOH/DCM to provide (S)-2′-(cyclopropylethynyl)-7′-(2-methoxy-2-methylpropoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:29])[C:12]([OH:28])([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[NH2:30][C@H:31]([C:36]([O-:38])=[O:37])C(C)(C)C.O>CN(C=O)C>[C:4]([O:38][C:36](=[O:37])[CH2:31][NH:30][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH:11]([CH3:29])[C:12]([OH:28])([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=3[CH:27]=2)[C:13]([F:15])([F:14])[F:16])=[C:2]([Cl:1])[CH:3]=1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CC(C)(C)[C@H](N)C(=O)[O-]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 199.9 %

Procedure:
3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-benzoic acid (80 mg) and 1,1-carbonyldiimidazole (45 mg) were dissolved in dry DMF (2.0 mL) and stirred at 50° C. for 1 hour. The mixture was cooled to r.t. and a solution of tert-butylglycinate (391 mg) in DMF (0.7 mL) was added drop by drop. Stirring was then continued for 2 hours. The reaction mixture was poured into a mixture of water and ice and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to provide the title compound {3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl)-propyl]-benzoylamino}-acetic acid tert-butyl ester as a colorless solid (101 mg). MS (m/e)=560.3 [M+NH4+].
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(#N)C>[Si:24]([O:23][CH2:22][CH2:21][N:4]1[C:3]([CH2:1][CH3:2])=[C:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]([NH2:13])=[O:12])=[N:5]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO, 9849166), (4.9 g, 26.6 mmol), cesium carbonate (21.0 g, 64.5 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (7.0 g, 29.0 mmol) in acetonitrile (400 ml) was stirred at 80° C. for 20 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The layers were separated, the organic phase washed with water (3×50 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate as eluant, and repeated using an elution gradient of pentane:ethyl acetate (50:50 to 0:100), to give some of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6]([F:14])[CH:5]=1)([O-:3])=[O:2].P(Br)(Br)[Br:16]>CN(C=O)C.C1(C)C=CC=CC=1>[Br:16][C:7]1[C:6]([F:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(O)c([N+](=O)[O-])c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(Br)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 98.2 %

Procedure:
To a solution of 4,6-dinitro-2-fluorophenol (8 g, 39.60 mmol, 1 equiv) in DMF (24 mL) and toluene (160 mL), PBr3 (5.6 mL, 59.40 mmol, 1.5 equiv) was added at room temperature. Then the reaction mixture was heated at 110° C. for 1 hour. After allowing to cool to room temperature, the upper colorless layer was poured into a separate funnel and diluted with hexanes. The organic layer was washed with water, dried over MgSO4 and evaporated to dryness to give the product (10.3 g, 98%) as a yellow solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=3[S:13][C:12]=2[CH:21]=1)C>C(O)C>[Cl:20][C:16]1[C:15]2[C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:22])=[O:5])=[CH:21][C:12]=3[S:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1cccc(Cl)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)sc1cccc(Cl)c12

Procedure:
To a 100 ml. flask, fitted with a condenser and containing a solution of 0.28 g. of potassium hydroxide in 50 ml. of ethanol was added 1.1 g. of 9-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for four hours, the solvent was removed in vacuo on the steam bath, the residue was dissolved in 50 ml. of water, and the aqueous solution was acidified with dilute hydrochloric acid. The product was filtered, washed with 20 ml. of water, and dried at 60° in a vacuum oven for 12 hours. The yield of 9-chlorodibenzothiophene-3-acetic acid, after crystallization from methanol, was 0.8 g. (m.p. 203°-206°).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (12.5 g, 76.65 mmol), N-chloro succinimide (12.28 g, 92 mmol), and benzoyl peroxide (2.78 g, 11.5 mmol) in carbon tetrachloride (150 ml) was refluxed for 24 hr. After cooling to room temperature, the mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, from hexane to 2% ether in hexane) to afford 6 g (40%) of 2,4-dichloro-6-chloromethyl-pyrimidine as a white solid. 1H NMR (200 MHz, CDCl3) δ 4.58 (2H, s), 7.55 (1H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]([O-])([O-])[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(OC=C(C([O-])=O)C(OCC)=O)C>[Cl-].[Zn+2].[Cl-].CCOCC>[CH2:14]([O:13][CH:12]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of diethyl malonate (160 g., 1.0 mole), ethyl ortho-formate (148 g., 1.0 mole), acetic anhydride solvent (204 g., 2 moles) and anhydrous zinc chloride catalyst (0.5 g) was heated in an oil bath for 6.5 hr (temperature of contents 104°-113° C). The mixture was then distilled through a short column during 3.5 hr, raising the pot temperature to 124°and yielding 120 ml of distillate. The residue was treated with additional ethyl orthoformate (148 g., 1.0 mole) and acetic and acetic anhydride (204 g., 2.0 moles) and distillation was continued for 3 hr to yield 160 ml of distillate (pot temperature 120°-130°). After standing at 25° for 18 hr the residue was diluted with 250 ml of ether and washed thoroughly with water. The combined extracts were dried over magnesium sulfate and distilled to yield a forerun (26 g.) containing principally diethyl malonate and 156 g. (72%) of ethyl ethoxymethylenemalonate, b.p. 109°-111° (0.9mm) (85% yield based on unrecovered diethyl malonate); NMR (CDCl3): δ 7.62 (s,l,=CH), 4.22 (q. J = 7Hz, 2, CH2), 4.19 (q, J = 7 Hz, 4, CH2), 1.37 (t, J = 7 Hz, 3, CH3), 1.30 (t, J = 7 Hz, 6, CH3).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:32]=[CH:31][C:25]3[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=3[C:23]=2[CH2:33][CH2:34][CH3:35])=[C:11]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH:10]=1)C.O.[OH-].[Li+].S(=O)(=O)(O)O.C(OCC)(=O)C>O1CCCC1.O>[C:38]([CH2:37][CH2:36][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=2[C:23]=1[CH2:33][CH2:34][CH3:35])([OH:40])=[O:39]
Reactant: CCCc1c(OCCCCCOc2ccc(CCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(CCCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 46 h
Yield: 61.3 %

Procedure:
To a solution of 1.93 g (3.23 mmol) of 4-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, in 30 mL of tetrahydrofuran and 30 mL of water, was added 0.407 g (9.71 mmol) of lithium hydroxide monohydrate and the resulting solution was stirred at room temperature for 46 hr. The reaction mixture was acidified with 60 mL of 3N aqueous sulfuric acid, and worked-up with ethyl acetate in the usual manner. The crude product was purified by flash chromatagraphy on 500 g of silica gel, eluting with hexane-ethyl acetate (1:1) affording 1.07 g (61.0%) of the title compound as a white solid, mp 101°-104° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:24])[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:24])[CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: O=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 4.22 g of 8-[2-(phenylmethyl)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol of Example 3 in 120 ml of methanol is added 10 ml of 5% HCl, and the mixture is stirred at room temperature for 31/2 hours. The solvent is removed under reduced pressure, and 200 ml of water and 10 ml of 5% NaOH are added. The product is collected, washed with water and dried over P2O5 and then recrystallized from 35 ml of methanol to give 2.40 g (64.9% yield) of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol, m.p. 138.5°-139.5° C.
Reaction SMILES: [C:1]1([C:7]2([C:12](OC)=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1(c2ccccc2)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(c2ccccc2)CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of methyl 1-phenylcyclopent-3-enecarboxylate (298 mg) in ether (10 mL) at 0° C. was added lithium aluminum hydride (1.0 M solution in ether, 1.48 mL), and the resulting suspension was stirred at 0° C. for 30 min. The reaction was quenched with saturated sodium sulfate and then diluted with ether (100 mL). Anhydrous sodium sulfate was added, and the ether solution was filtered. The filtrate was evaporated in vacuo to give the title compound as an oil (257 mg). 1H NMR (400 MHz, CDCl3) δ 2.70 (4H, s), 3.54 (2H, d, J=5.6 Hz), 5.75 (1H, s), 7.22-7.35 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]=1[CH3:30]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][C:22]=3[CH3:30])[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(C(N)=O)ccc1N
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(C(N)=O)cc1C

Procedure:
37C, R═Br was cyclized following step 3 of Scheme 1 with 4-amino-3-methylbenzamide with a different solvent, dioxane.