Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([C:15]([OH:17])=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CO>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH2:4][CH2:3]1
Reactant: C=C(C(=O)O)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C(=O)O

Procedure:
A process as claimed in step (x) of claim 1, wherein reduction in step (x) comprises (i) dissolving artemisinic acid and NiCl2.6H2O in dry methanol; (ii) adding sodium borohydride to the resultant solution at 0° C. over a 2 hr. period; (iii) neutralising the solution obtained in step (ii) with 5% aqueous HCl solution and (iv) isolating and crystallizing the dihydro artemisinic acid in ethyl acetate to obtain pure dihydro artemisinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]=[O:11]
Reactant: OCc1c(Cl)ccc(F)c1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=Cc1c(Cl)ccc(F)c1Cl
Temperature: -7 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2,6-Dichloro-3-fluorophenyl)methanol (100 g, 0.51 mol) in dichloromethane (450 mL) was added a solution of sodium bromide (54 g, 0.53 mol, in 90 mL water). The rapidly stirred biphasic mixture was cooled to −7° C. and TEMPO (1.54 g, 0.0100 mol) was added. A solution of 0.81M sodium hypochlorite (823 mL, 0.66 mol) saturated with sodium bicarbonate (75 g) was added dropwise over a period of 1 h while maintaining the temperature below −2° C. After the addition the reaction mixture was stirred for 30 min. The two layers separated and the DCM layer was washed with aq. solution of sodium thiosulfate. The DCM layer was dried (Na2SO4) and concentrated on rotary evaporator without using vacuum (aldehyde is volatile) to give the title compound as a solid, mp. 63-65° C. 1H NMR (CDCl3, 300 MHz): δ=7.23 (dd, 1H, J=7.8, 9.0 Hz), 7.35 (dd, 1H, J=4.5, 9.3 Hz), 10.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>ClCCl.CO.[Pd]>[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C
Yield: 185.9 %

Procedure:
The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in dichloromethane (50 mL) was charged with a solution of 2-aminoethylmethylsulfone (3.2 g, 11.7 mmoL) in methanol (25 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion. The reaction mixture was charged with 5% Pd—C (750 mg) and stirred under hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite® pad and rinsed with methanol (5 mL) and dichloromethane (15 mL) mixture. The filtrate was distilled to low volume and the solution was charged with dichloromethane (25 mL) followed by addition of the solution of p-toluenesulfonic acid monohydrate (4.4 g, 23.3 mmoL) in methanol (10 mL). The yellow solid which precipitated out was filtered after 2-8 hours and washed with 1:1 mixture of methanol and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45° C. to provide Lapatinib (11.4 g, Yield=93%, HPLC purity>99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c(Br)c1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[CH3:44][NH:45][O:46][CH3:47]>C(Cl)Cl>[CH3:44][N:45]([O:46][CH3:47])[C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
(3,4-Dimethoxyphenyl)acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH2Cl2 followed by addition of EDCI (15.3 g, 79.7 mmol), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol), and N,O-dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol). The reaction was stirred 3 days at ambient temperature after which the solvent was evaporated at reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with aq. HCl, sat NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo to give 10.5 g (66%) of N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide as a pale brown oil.
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1.CN.CC(O)C.Br>CC(O)C>[CH3:1][NH:2][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=1
Reactant: CN
Reactant: Oc1ccc(CCBr)cc1
Agent: Br
Solvent: CC(C)O
Product: CNCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 11 h
Yield: 90 %

Procedure:
1000 mL of IPA was placed in a 3 L flask and cooled to 0° C. A steady stream of methylamine gas from a cylinder was slowly passed through the IPA until the total volume reached 1750 ml. 100 g of (2-[4-hydroxyphenyl]ethyl) bromide (A11) was added to the cooled methylamine IPA solution in several portions. The cooling bath was removed after all A11 was added. The reaction mixture was allow to warm to room temperature and continue to stir for another 10-12 h. The excess methylamine was distilled into another 1000 mL of pre-cooled to 0° C. IPA by heating the reaction mixture at 50° C. When most of the methylamine was distilled off, the bath temperature was raised to 100° C. and the IPA was distilled out. After most of the IPA had been distilled out, about 300 mL of IPA was added to the reaction mixture and distillation was continued to aid removal of the methylamine. After the volume was reduced to 250 mL, the reaction mixture was allowed to cool down to room temperature. The precipitate was collected by filtration and washed by toluene to give 104 g (90% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine as an HBr salt (A12 HBr). 1H NMR (CDCl3) δ 2.69 (3H, s, CH3), 2.90 (2H, t, J=7.2 Hz), 3.18 (2H, t, J=6.3 Hz), 6.76 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz)
Reaction SMILES: [NH3:1].N.N.N.N.N.[OH2:7].O.O.O.[OH:11][Mo:12](O)(=O)=O.[OH:16][Mo](O)(=O)=O.[OH:21][Mo](O)(=O)=O.[O:26]=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>[OH-].[NH4+].O>[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[OH2:11].[OH2:16].[OH2:21].[OH2:26].[OH2:7].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12]
Reactant: O=[Mo](=O)(O)O
Reactant: O=[Mo](=O)=O
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: [Mo]

Procedure:
A solution of ammonium paramolybdate was prepared by dissolving 120 gm of (NH4)6Mo7O24. 4H2O in 250 ml of concentrated ammonium hydroxide. The resulting solution was diluted subsequently with distilled water to make 500 ml of solution. A 1-ml portion of the solution contained the equivalent of 0.20 gm of MoO3. An 11-ml portion of the above-prepared solution was diluted to 250 ml with distilled water and the resultant aqueous solution was added to 219 gm (500 cc) of the 14-to-20-mesh alumina. This amount of solution just wetted all of the alumina. The impregnated alumina was then calcined in static air at a temperature of 1,000° F. for a period of 11/2 hours. The finished catalyst, hereinafter identified as Catalyst A, was found to have a surface area of 198 m2 /gm and to contain 1.22 wt.% MoO3, based upon the total catalyst weight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(OCC)(=O)C>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 46 %

Procedure:
4-Bromobenzotrifluoride (1 g, 4.44 mmol) was dissolved in THF (15 ml), to which n-butyllithium (1.5 M) hexane solution (3.1 ml, 4.67 mmol) was added dropwise at −70° C. Then a solution of 1-benzyl-4-piperidone in THF (15 ml) was added dropwise to the mixture, and the resulting mixture was stirred for 2 hours and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-benzyl-4-(4-trifluoromethylphenyl)piperidin-4-ol (692 mg, yield 46%) as a colorless crystalline powder.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[C:31](=[O:32])[N:30]2[CH:25]1[S:26][CH2:27][C:28]([CH3:36])=[C:29]2[C:33]([OH:35])=[O:34])=[O:22])([CH3:19])([CH3:18])[CH3:17].N[C@H](C(O)=O)[C@@H](C)O>C(#N)C>[CH:7]([O:35][C:33]([C:29]1[N:30]2[CH:25]([S:26][CH2:27][C:28]=1[CH3:36])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2=[O:32])=[O:34])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A solution of diphenyldiazomethane (116.5 g) in acetonitrile (800 cc) is added dropwise, in the course of 45 minutes, at a temperature of between 25° and 30° C., to a solution of 7-tert.-butyoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (188.6 g) in acetonitrile (2,100 cc). Thr reaction mixture is stirred for 16 hours at 22° C. and is then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is redissolved in ethyl acetate (2 liters) and the solution is washed with 2 N hydrochloric acid (700 cc) and then with a saturated aqueous sodium bicarbonate solution (70 cc) and a saturated aqueous sodium chloride solution (700 cc). The solution is dried over sodium sulphate, treated with decolorising charcoal, filtered, and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is dissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) is added, and the mixture is heated to the reflux temperature and then allowed to cool. The crystals which have appeared are filtered off, washed with diethyl ether (3×250 cc) and then dried. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (191 g) is obtained in the form of white crystals (m.p.=179° C.). On concentrating the mother liquor to 500 cc, a second fraction of product (32.6 g, m.p.=178° C.) is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:14]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a solution of compound 27 (815 mg, 4.08 mmol) in DMF (15 mL) were added t-butyldimethylsilyl chloride (738 mg, 4.9 mmol) and imidazole (556 mg, 8.16 mmol). The thus obtained solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with 15% to 50% to give the compound 28 as a white solid (1.087 g, 85%). LCMS-ESI (POS), M/Z, M+1: Found 314.1, Calculated 314.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 mL round-bottomed flask was charged with 2-(3-nitrophenyl)ethanol (1.0235 g, 6.12 mmol), 4-dimethylaminopyridine (0.075 g, 0.612 mmol) and p-toluenesulfonyl chloride (1.401 g, 7.35 mmol) in CH2Cl2 (61.2 ml). Triethylamine (1.707 ml, 12.25 mmol) was added, and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was washed with water and brine, dried (MgSO4), filtered and concentrated onto silica gel. The crude product was purified by flash chromatography using an Argonaut Flashmaster Solo 25 g column (100% hexanes to 30% ethyl acetate:hexanes over 25 minutes, then to 100% ethyl acetate over 10 minutes) to provide the title compound. MS (ESI(+)) m/e 338.9 (M+NH4)+.
Reaction SMILES: [OH-].[Na+].O.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:5][C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: ClCCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Reaction time: 18 h
Yield: 9 %

Procedure:
To a solution fo 7.36 g. (0.184 mole) of sodium hydroxide in 75 ml. of water and 75 ml. of acetone there is added 17.16 g. (0.074 mole) of 1-(3-chlorophenyl)piperazine hydrochloride and 11.59 g. (0.074 mole) of 1-bromo-3-chloropropane, and the resulting mixture is stirred at 27° for 18 hrs. The organic layer is then separated and concentrated to an oil under reduced pressure. The oil is treated with hot (85°) 6 N HCl until solution is complete, and the resulting solution is filtered and stored at 5° for 18 hrs. The precipitate which forms is collected on a filter to afford 17.52 g. (87%) of the hydrochloride salt of the product, m.p. 198°-200°. Concentration of the mother liquor under reduced pressure and recrystallization of the residue from water affords an additional 1.82 g (9%) of product, m.p. 196°-198°.
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.C([O-])(=O)C1C=CC=CC=1.[CH3:38][C:39]1([CH3:67])[CH2:48][CH:47]=[C:46]([C:49]2[S:50][CH:51]=[CH:52][CH:53]=2)[C:45]2[CH:44]=[C:43]([C:54]#[C:55][C:56]3[CH:66]=[CH:65][C:59]([C:60]([O:62]CC)=[O:61])=[CH:58][CH:57]=3)[CH:42]=[CH:41][C:40]1=2>>[CH3:38][C:39]1([CH3:67])[CH2:48][CH:47]=[C:46]([C:49]2[S:50][CH:51]=[CH:52][CH:53]=2)[C:45]2[CH:44]=[C:43]([C:54]#[C:55][C:56]3[CH:57]=[CH:58][C:59]([C:60]([OH:62])=[O:61])=[CH:65][CH:66]=3)[CH:42]=[CH:41][C:40]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: O=C([O-])c1ccccc1
Product: CC1(C)CC=C(c2cccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2- thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 70.0 mg (0.17 mmol) of ethyl 4-1(5,6- dihydro-5,5-dimethyl-8-(2-thienyl)-2-naphthalenyl)ethynyl]benzoate (Compound 33a) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O. PMR (d6-DMSO): δ 1.27 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.23 (1H, t, J=4.9 Hz), 7.14 (2H, m), 7.38-7.56 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz).
Reaction SMILES: CC1C=CC(CO[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])=CC=1.[C:28](=S)=[S:29]>[OH-].[Na+].CO.N>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:28]([N:16]=2)=[S:29])[N:12]=1
Reactant: Cc1ccc(CON=C(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2N)cc1
Reactant: S=C=S
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 72 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-(p-methylbenzyl)-oxime was dissolved in a mixture of 0.30g of sodium hydroxide, 5 ml of methanol and 0.5 ml of carbon disulfide, and the resulting mixture was allowed to react in an autoclave at 130° C for 4 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in water. The resulting aqueous solution was adjusted to a pH of 2 with hydrochloric acid, and the precipitated crystals were filtered to obtain crude 2-thioadenosine. The crude product was dissolved in aqueous ammonia, filtered and adjusted to a pH of 2 with hydrochloric acid to obtain 0.27 g of pure 2-thioadenosine having a melting point of 198° C (with decomposition) in a 72% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:11]2[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:17])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Reaction time: 17 h
Yield: 68.1 %

Procedure:
A mixture of 12.0 g (300 mmol) of powdered sodium hydroxide, 24.7 g (120 mmol) of 2,6-di-tert-butylphenol, 15.7 g (100 mmol) of 1-chloro-4-nitrobenzene, and 120 mL of DMSO was stirred for 17 hours at 90° C. and poured into one liter of IN HC1. The resulting aqueous mixture was extracted with three 250 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by two recrystallizations from ethanol-dichloromethane to give 22.3 g (68% yield) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol which can also be named 3,5-bis-(1,1-dimethylethyl)-4'-nitro-(1,1'-biphenyl)-4ol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)O.OS(O)(=O)=O>ClCCl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]2[C:17]3[C:3](=[C:2]([Cl:1])[CH:20]=[C:19]([Cl:21])[CH:18]=3)[CH2:4][N:5]([CH3:16])[CH2:6]2)=[CH:10][CH:11]=1
Reactant: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(4-bromophenyl)ethanol (1.0 g, 2.57 mmol, 1.00 equiv) in dichloromethane (3 mL). This was followed by the addition of conc.H2SO4 (2 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 3 h at 20° C. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide. The resulting solution was extracted with dichloromethane (2×30 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.9 g of the title compound which was used without further purification. MS (ES, m/z): 372 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Potassium t-butoxide (1.83 g, 14.9 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (4 g, 14.9 mmol) in 150 ml of THF at 0° C. and the mixture was stirred for 1 hour at the same temperature. To the above mixture was added 10.58 g (74.6 mmol) of methyl iodide, and the reaction mixture was stirred at 0° C. for 0.5 hour, at room temperature for 6 hours, and decomposed with saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride and the organic layer was washed with brine, dried, and concentrated in vacuo to afford 4.19 g (quantitative) of 2-phenylmethyl-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[C:25]#[N:26])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)S(O)(=O)=O>[C:25]([C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:9]=1[OH:8])#[N:26]
Reactant: COC(=O)c1ccnc(-c2ccc(OCc3ccccc3)c(C#N)c2)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: O=S(=O)(O)C(F)(F)F
Product: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1

Procedure:
Methyl 2-[4(benzyloxy)-3-cyanophenyl]isonicotinate and pentamethylbenzene were stirred at room temperature in trifluoromethanesulfonic acid to obtain methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate. F: 255.