Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[Cl:2][CH:3]([CH2:6][C:7]([Cl:11])(Cl)[CH:8]=O)[C:4]#[N:5]>CN(C)C=O>[Cl:1][C:8]1[C:7]([Cl:11])=[CH:6][C:3]([Cl:2])=[CH:4][N:5]=1
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Reactant: Cl
Solvent: CN(C)C=O
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 66 %

Procedure:
Hydrogen chloride is passed into a solution of 25.0 g (0.125 mol) of 2,4,4-trichloro-4-formylbutyronitrile in 50 mml of N,N-dimethylformamide at a rate such that the temperature of the reaction mixture does not exceed 120° C. After completion of the reaction, the reaction mixture is poured into ice water. The beige-coloured precipitate is filtered off and dried. There is obtained 15.1 g (66% of theory) of 2,3,5-trichloropyridine, m.p. 48°-50° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][CH:11]([CH3:22])[CH2:12][CH2:13][C:14]1[S:18][C:17]([C:19]([NH2:21])=[O:20])=[CH:16][CH:15]=1>CS(C)=O.O>[OH:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH2:3][NH:10][CH:11]([CH3:22])[CH2:12][CH2:13][C:14]1[S:18][C:17]([C:19]([NH2:21])=[O:20])=[CH:16][CH:15]=1
Reactant: c1cncc(C2CO2)c1
Reactant: CC(N)CCc1ccc(C(N)=O)s1
Solvent: CS(C)=O
Solvent: O
Product: CC(CCc1ccc(C(N)=O)s1)NCC(O)c1cccnc1
Yield: 9.3 %

Procedure:
606 mg of 3-[(RS)-2-oxiranyl]pyridine and 991 mg of (RS)-5-(3-aminobutyl)-2-thiophenecarboxamide were heated to 100° for 25 hours in 5 ml of DMSO. The reaction mixture was diluted with water and extracted three times with methylene chloride. The methylene chloride solutions were washed with water, dried and evaporated in a vacuum. Chromatography of the residue on silica gel with ether/methanol gave 149 mg of 5-[(RS)-3-[[(RS)-2-hydroxy-2-(3-pyridyl)ethyl]amino]butyl]-2-thiophenecarboxamide, ε201 =14420; ε268 =11310.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.COC(=O)CC(=O)C(Br)C.COC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:28][C:29]=2[CH3:35])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: COc1ccc(-c2nc(CCO)c(C)s2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: COc1ccc(C(N)=S)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-methoxy-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][CH2:57][C@H:58]([NH2:69])[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[CH2:49]([O:56][CH2:57][C@H:58]([NH:69][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N[C@@H](COCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](COCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 71 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-2-benzyloxy-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 71%; Rf value: 0.63 (silica gel: dichloromethane/ethanol=9:1); C29H29ClN4O3 (517.03); mass spectrum: (M+H)+=517/519 (chlorine isotope).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1)=[O:12].[OH-].[Na+]>C(O)C.O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][CH2:14][N:13]1[C:3](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]1=[O:12]
Reactant: COC(=O)c1ccccc1NC(=O)NCCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A white mixture of 2-[3-(2-[1,3]dioxolan-2-yl-ethyl)-ureido]-benzoic acid methyl ester (0.50 g, 1.70 mmol) and 1N sodium hydroxide (2.0 mL) in ethanol (10 mL) was warmed until all the solids had gone into solution. The resulting colorless solution was cooled to ambient temperature and stirred for 30 minutes. Concentration yielded a colorless foam which was dissolved in water (15 mL); after 15 minutes, a white crystalline solid formed. The white crystalline solid was collected and dried to yield 3-(2-[1,3]dioxolan-2-yl-ethyl)-1H-quinazoline-2,4-dione (0.19 g, 43%). 1NMR CDCl3 δ7.92 (dd, J=1, 8 Hz, 1H), 7.67-7.61 (m, 1H), 7.22-7.15 (m, 2H) 4.88 (t, J=4 Hz, 1H), 4.00 (t, J=7 Hz, 2H), 3.89-3.71 (m, 4H), 1.93-1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20](O)=[O:21])[CH:13]1[CH2:15][CH2:14]1)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][NH:71][C:72](=[O:79])[C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([N:67]1[CH2:66][CH2:65][C:64]([CH2:70][NH:71][C:72](=[O:79])[C:73]2[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=2)([N:61]2[CH2:60][CH2:59][N:58]([CH:55]3[CH2:56][CH2:57]3)[CH2:63][CH2:62]2)[CH2:69][CH2:68]1)=[O:21])[CH:13]1[CH2:14][CH2:15]1)(=[O:10])=[O:11]
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CNC(=O)c2ccncc2)(N2CCN(C3CC3)CC2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)-ethoxy)acetic acid AC8 (0.225 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resulting solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropyl-piperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 55%. MS, Rt=2.8 min, m/z=673.4 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH2:15]O)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH2:15][Br:25])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCCc1cccc2oc(CO)c(C)c12
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCCc1cccc2oc(CBr)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-(3-methoxypropyl)-3-methyl-1-benzofuran-2-yl]methanol (181 mg, 0.774 mmol) in dichloromethane (4 mL) at 0° C. was added pyridine (0.1 mL) followed by phosphorous tribromide (0.109 mL, 1.16 mmol). The cooling bath was removed and the solution was stirred for 1 hour at room temperature. After recooling to 0° C. the reaction was quenched by the addition of ice chips. The mixture was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bromide. The solution was dried over sodium sulfate, filtered and reduced to dryness to furnish 188 mg (82%) of the [4-(3-methoxypropyl)-3-methyl-2-bromomethyl-1-benzofuran, which was directly carried on to the next step.
Reaction SMILES: [H-].[Li+].[OH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CN(C)C=O>[CH2:33]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a 0° C. mixture of lithium hydride (0.235 g, 29.4 mmol) in tetrahydrofuran and dimethylformamide (30 mL: 10 mL) is added the compound of Example 11 (3.0 g, 7.3 mmol) and the mixture stirred for 0.5 hr. Benzyl bromide (1.257 g, 7.3 mmol) is then added and the reaction stirred 12 hr at room temperature. The reaction is poured into ice-water (100 mL) and the quenched mixture extracted with ethyl acetate (2×100 mL). Concentration gives crude product that is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:9) to yield the title compound (2.5 g, 69%). MS m/z 499.0 (M+.1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN(OC)[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)N(C)OC
Reactant: Oc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 0.2 h

Procedure:
A mixture of 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol) in tetrahydrofuran (15 mL) was chilled to −78° C. and butyllithium (4.6 mL, 11.5 mmol, 2.5 M solution) was added rapidly, dropwise. The reaction was stirred 12 min and N-methyl-N-methoxypropionamide (the compound of Preparation 9, 0.735 g, 6.28 mmol in 1 mL of tetrahydrofuran with a 1 mL rinse) was added. The reaction was allowed to stir 5 min at −78° C. and then it was warmed to ambient temperature. A few drops of water were added; then the solvent was removed at reduced pressure. The residue was taken up in methylene chloride and washed with aqueous ammonium chloride and brine. The organic layer was dried and concentrated. The residue was flash chromatographed on silica gel (1×2.5 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), discarded forerun; 20% ethyl acetate/hexane (250 mL), 0.186 g of a yellow crystalline solid which had NMR identical to that of preparation 7.
Reaction SMILES: S(O)(O)(=O)=O.[CH:6]([NH:9][C:10]([NH2:12])=[NH:11])([CH3:8])[CH3:7].[CH:13](NC(N)=N)([CH3:15])[CH3:14].Cl.C(OC(OCC)CC(OCC)OCC)C.[OH-].[Na+]>O>[CH:6]([NH:9][C:10]1[N:12]=[CH:15][CH:13]=[CH:14][N:11]=1)([CH3:8])[CH3:7]
Reactant: CC(C)NC(=N)N
Agent: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)Nc1ncccn1
Reaction time: 2 h
Yield: 182.2 %

Procedure:
Into the same reactor as used in the previous step were poured 30 g (0.1 mol) of bis (isopropylguanidine) sulphate, 120 ml of water, 75 ml of pure hydrochloric acid solution (s.g. 1.18) and slowly (over 11/2 hours), at room temperature, 44 g (0.2 mol) of 1,1,3,3-tetraethoxy propane. The mixture was then heated to 50°-55° C. under stirring for two hours, then cooled and neutralized by an excess of pure sodium hydroxide solution. The mixture was extracted using 300 ml of diethyl ether. The extracts were washed with a saturated solution of sodium chloride, then dried and the diethyl ether was evacuated off. There was obtained 25 g (yield 91%) of a yellowish oil boiling at 91°-91.5° C. under 11 mm of Hg, the analysis of which showed good correspondence with the formula C7H11N3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[C:14]3=[O:25])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26][CH2:27][CH2:28]Br>>[Br:26][CH2:27][CH2:28][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH:16]=[CH:17][N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)[C:14]2=[O:25])=[CH:23][CH:22]=1
Reactant: BrCCBr
Reactant: O=c1n(-c2ccc(O)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Product: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 1,2-dibromoethane as described in example 5. The product with the molecular weight of 443.34 (C22H23BrN2O3); MS (ESI): 443 ([M+H]+) was obtained in this way.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>O>[F:9][C:10]([F:17])([F:16])[C:11]([NH:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)C[C@@H](N)CO
Solvent: O
Product: CC(C)C[C@H](CO)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Step AK (1): (R)-2-amino-4-methylpentan-1-ol (1.0 g, 8.53 mmol) was dissolved in ethyl trifluoroacetate (2.5 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine. The organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give (R)-2,2,2-trifluoro-N-(1-hydroxy-4-methylpentan-2-yl)acetamide (1.48 g, 81%) as a colorless oil. LC-MS (M+H)+=214.81.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].O>CC(O)C.Cl>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:2]1[C:3]2[N:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Fc1ccc2ncnc(Cl)c2n1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1

Procedure:
A solution of 4-chloro-6-fluoropyrido[3,2-d]pyrimidine (0.20 g, 1.1 mmol) and 3-bromoaniline (0.12 mL, 2.18 mmol) in propan-2-ol (20 mL) containing conc. HCl (1 drop) is heated under reflux for 15 min, then cooled, poured into water and extracted with EtOAc. The extract is worked up, and the residue chromatographed on silica gel, eluting with EtOAc/petroleum ether (1:2)to give after removal of the solvent under reduced pressure 4-(3-bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (0.18 g, 52%). 1H NMR (CDCl3) δ 8.82 (1H, s), 8.65 (1H, brs), 8.31 (1H, t, J=7.4 Hz), 8.27 (1H, brs), 7.77 (1H, m) 7.41 (1H, dd, J=8.9, 2.2 Hz), 7.29 (2H, brs).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C.O.[OH-].[Li+].S(=O)(=O)(O)O>C(OCC)(=O)C.O.O1CCCC1>[C:19]([CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:41]=[CH:40][C:34]4[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=4[C:32]=3[CH2:42][CH2:43][CH3:44])=[C:7]2[CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[CH:12][CH:13]=1)([OH:21])=[O:20]
Reactant: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OCC)cc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)O)cc3c2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 41.5 h
Yield: 102.3 %

Procedure:
A mixture of 0.86 g (1.39 mmol) of 2-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-7-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, 0.177 g (4.21 mmol) of lithium hydroxide monohydrate, 10.1 mL of tetrahydrofuran, and 10.1 mL of water was stirred at room temperature for 41.5 hr. A second saponification was carried out with 0.188 g (0.3 mmol) of the starting ester, 38 mg (0.9 mmol) of lithium hydroxide monohydrate, 2.2 mL of tetrahydrofuran and 2.2 mL of water. After combining the two reaction mixtures, 30 mL of 3N aqueous sulfuric acid was added, and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was crystallized from hexane-ethyl acetate to give 0.803 g (84.3%) of the title compound as an off-white solid, mp 175°-177.5° C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[OH-].[Na+].OS(O)(=O)=O>O.O1CCOCC1.C(OCC)(=O)C>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([S:8]([OH:10])=[O:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(S(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 317 mmol sodium sulfite in 200 ml water at RT was added dropwise over 30 min a solution of 42.3 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 80 ml dioxane and stirring continued for a further 30 min. 5 M aq NaOH was then added dropwise until the reaction mixture was pH 14, and the mixture was then allowed to stir at RT for a further 2 h. The mixture was then cooled to 0° C. and concentrated H2SO4 added until the reaction mixture was pH 1. Ethyl acetate was added, and the phases were separated. The organic phase was dried with Na2SO4. Evaporation in vacuo yielded the title compound.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[S:24][C:23]([C:25]3([O:31][CH3:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[F:12][C:9]([F:10])([F:11])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([C:13]2[CH:14]=[CH:15][C:16]([S:19][C:20]3[S:24][C:23]([C:25]4([O:31][CH3:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:1])=[CH:8][CH:7]=1
Reactant: COC1(c2ccc(Sc3ccc(C(O)c4ccc(C(F)(F)F)cc4)cc3)s2)CCOCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC1(c2ccc(Sc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)s2)CCOCC1
Yield: 75 %

Procedure:
Using the procedure described in Example 18, 4-[5-(4-(alpha-hydroxy-4-trifluoromethylbenzyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran was reacted with pyridinium chlorochromate to give 4-[5-(4-(4-trifluoromethylbenzoyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran in 75% yield, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].CN(C)CCN(C)C.C([Li])CCC.[I:24]I.S(=O)(=O)(O)O>CCCCC.C1COCC1>[I:24][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([CH3:1])=[CH:3][C:4]=1[CH2:5][OH:6]
Reactant: Cc1ccc(CO)cc1C
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(I)c(CO)cc1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
A solution, cooled to 0° C., of 6.81 g of 3,4-dimethylbenzyl alcohol and 11.62 ml of N,N,N′,N′-tetramethyl-ethylenediamine in 150 ml of pentane was treated with 62.5 ml of n-butyllithium solution (1.6M in hexane). The reaction mixture was boiled at reflux for 11 hrs. Then, 12.69 g of iodine in 50 ml of THF were added dropwise at −30° C. The mixture was stirred for 15 min. at −30° C. and then left to warm to room temperature. The reaction mixture was added to 100 ml of 10% sulphuric acid. The crude product was isolated by extraction and purified by chromatography on silica gel. There were obtained 2.95 g of (2-iodo-4,5-dimethyl-phenyl)-methanol as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 479.8 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.7 g, 0.00233 mole), 1,1'-carbonyldiimidazole (4.0 g, 0.025 mole), and anhydrous tetrahydrofuran (150 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 21/2 hours. The nitrogen flow was stopped and a solution of N,N-dimethylethylenediamine (2.3 g, 0.0257 mole) in dry tetrahydrofuran (50 ml) was stirred at room temperature under nitrogen for 2 hours. The reaction was concentrated in vacuo and partitioned between methylene chloride (75 ml) and water (75 ml). The layers were separated and the aqueous portion washed with methylene chloride (25 ml). The combined organic portions were washed with potassium bicarbonate solution (2×50 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue, 5.7 g (68%) was recrystallized from isopropyl alcohol-isopropyl ether to give 4.0 g of off-white granular solid, mp b 124°-125° C.