Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43][O:44]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:44][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)([CH3:14])[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 26, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H, J=8.60 Hz), 7.69 (d, 2H, J=8.21 Hz), 7.63 (d, 2H, J=6.65 Hz), 7.48–7.45 (m, 2H), 7.40 (d, 2H, J=7.04 Hz), 7.20–7.15 (m, 4H), 6.82 (d, 3H, J=8.60 Hz), 4.22 (s, 2H), 3.24 (d, 1H, J=13.30 Hz), 3.13–3.07 (m, 3H), 2.43 (s, 3H), 1.25 (s, 3H). MS (ES+) m/z mass calcd for C34H31ClNO5 568.19, found 568.2
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:20]2[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[Na+].ClCCl>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:18]1[C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][C:20]=2[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc2c1sc1ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reaction time: 24 h
Yield: 47.9 %

Procedure:
A mixture of 9H-carbazole (10 g, 59.8 mmol), 4-bromodibenzo[b,d]thiophene (18.89 g, 71.8 mmol), and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.982 g, 2.392 mmol) in 200 mL of Xylene was bubbled with N2 for 20 min. Pd2dba3 (0.548 g, 0.598 mmol) and sodium 2-methylpropan-2-olate (8.62 g, 90 mmol) were then added, and the mixture was heated to reflux under N2 for 24 h. TLC indicated the reaction did not go to completion. 0.3 g of Pd2(dba)3 and 0.6 g of dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine was added. The reaction was continued to reflux. The reaction was monitored by GC. After another 24 h, there was still carbazole starting material remaining. Again, 0.3 g of Pd2(dba)3 and 0.6 g of dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine were added. The reaction was refluxed again for 24 h. The reaction was stopped and worked up for purification. Column was used for purification. (1:3 dichloromethane:hexanes) 10 g (47.8% yield) of product was obtained.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][NH:20]C(=O)OCC4C=CC=CC=4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(O)(=O)C.C(OCC)C>Br>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
In a 200 mL flask, benzyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylcarbamate (0.599 g, 1.28 mmol) was suspended in hydrogen bromide in acetic acid (33 wt %, 8.00 mL, 45.7 mmol). The suspension was stirred vigorously at room temperature for 1 hour. To the resulting suspension was added diethyl ether (100 mL), and the reaction mixture was stirred for 30 minutes at room temperature. The resulting precipitate was collected via filtration and treated with sodium hydroxide (1 N) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (0.395 g, 92% yield): 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.25-8.03 (m, 4H), 7.74-7.62 (m, 2H), 7.60-7.48 (m, 2H), 3.85 (s, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESMIS m/z 318 ([M+H]+) (—NH2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[C:7]([CH:19]=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-bromopyridine(5.13 g, 3.2 mmol) in THF (90 ml) at −78° C. was slowly added lithium diisopropylamide (LDA) (2 M in THF, 17.9 ml, 3.6 mmol) and the resulting reaction mixture allowed to stir for three hours. To the reaction mixture was then slowly added DMF (9.49 g, 130 mmol) in THF (10 ml). The reaction mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature. Water (100 mol) was added and then the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4. The solvent was removed and the resulting residue purified over silica gel chromatography eluted with hexane, to yield 2-bromo-pyridine-3-carbaldehyde as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH:13](O)=O>>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[CH:13]1
Reactant: O=CO
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Product: O=C(O)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4-Diaminobenzoic acid (20 g, 0.13 mol) was suspended in formic acid (120 ml) while cooling. After that hydrochloric acid (12 ml) was added. An obtained reaction mass was agitated for 24 hours at a room temperature. Reaction mixture was filtered through fiber glass filter. Then filter cake was dissolved in water (400 ml), pH was adjusted to 2.0 with ammonia solution and reaction mass was agitated overnight. Resulting suspension was filtered, pH of filtrate was adjusted to 3.0 with ammonia solution and reaction mass was agitated for two hours. Precipitate was filtered and dried at ˜100° C. H1NMR (Brucker Avance-300, DMSO-d6, δ, ppm): 7.695 (d, H, CHAr(7)); 7.877 (dd, H, CHAr(6)); 8.25 (d, H, CHAr(4)); 8.44 (s, H, (s, H, CHAr(2)); 12.82 (s, 2H, NH, COOH). Yield was 11.3 g (54%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=1.C([BH3-])#N.[Na+]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][NH:17][C:18]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1n[nH]cc1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Yield: 48 %

Procedure:
The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde with 3-amino-4-pyrazolecarboxylic acid in the presence of sodium cyanoborohydride produces 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid in 48% yield. Treatment with excess borane-tetrahydrofuran complex in tetrahydrofuran solution gives 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (Example 1) in 40% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:18][C:19]1[CH:29]=[CH:28][C:22]([C:23](OCC)=[O:24])=[CH:21][CH:20]=1.O>C1COCC1.C(#N)C.O.CCCCCC>[F:18][C:19]1[CH:29]=[CH:28][C:22]([C:23](=[O:24])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
4-picoline (40 g, 0.43 mol) was added to a LiHMDS solution (0.45 mol, 450 mL of a 1.0 M solution in THF) over 30 minutes at room temperature (a slight exotherm was observed) The resulting solution was stirred for 1 h. This solution was added to ethyl 4-fluorobenzoate (75.8 g, 0.45 mol, neat) over 1 h. The mixture was stirred overnight (16 h). Water (200 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The organic layer was washed with brine (1×200 mL) and dried over Na2SO4. The organic layer was filtered and the solvent was removed to leave oily solid. Hexane was added to the oil and the resulting solid was filtered and washed with hexane (cold). A yellow solid was isolated (50 g, 54%): 1H NMR (CDCl3) δ 8.58 (d, J=5.7 Hz, 2H), 8.02 (dd, J=5.5, 8.0, 2H), 7.12-7.21 (m, 4H), 4.23 (s, 2H); 19F NMR (CDCl3) δ −104.38 (m); LC/MS, tr=2.14 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50° C.), M+H=216; High Resolution MS Calcd for C23H20N4O2F (M+H): 216.0825. Found: 216.0830 (Δ mmu=0.5).
Reaction SMILES: [C:1]([S:4][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:15]([O:19][C:20](=[O:28])[CH2:21][NH:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[CH2:21][N:22]([C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:5]=1[S:4][C:1](=[O:3])[CH3:2])[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)Sc1c(Cl)cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Solvent: ClCCl
Product: CC(=O)Sc1c(Cl)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Acetylthio-3-chlorobenzoic acid (11.5 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (350 ml) were cooled to 0°-5° C., and N,N1 -dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (50 ml) was added. The mixture was stirred overnight. The DCC-urea was filtered and washed with CH2Cl2. The filtrate was then washed 2×125 ml 1 N HCl, 2×125 ml saturated NaHCO3, 2×125 ml brine, dried (MgSO4), filtered and concentrated to give 20.6 g of an oil. The crude product was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:9]1.[NH2:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][C:29]([Br:33])=[C:30]([F:32])[CH:31]=1>CCOC(C)=O>[NH2:25][C:26]1[C:27]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:9]2)=[O:35])=[N:28][C:29]([Br:33])=[C:30]([F:32])[CH:31]=1
Reactant: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1

Procedure:
Following Method 9, 2-(3-(3-aminopyridin-4-yl)cyclohexyl)-isoindoline-1,3-dione and 3-amino-6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 538.1/540.1 (MH); LC Rt=3.46 min.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:30])[CH2:14][N:13]([C:15]([C:17]2[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=2)=[O:16])[CH2:12][C:11]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:10]1.[Si:31]([O:38][CH2:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:46]=O)[S:44][CH:45]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[Si](OCCC1C=CSC=1C=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O.CC(O)=O>[Si:31]([O:38][CH2:39][CH2:40][C:41]1[CH:42]=[C:43]([CH2:46][N:27]2[CH2:28][CH2:29][C:11]3([O:10][C:9]([F:8])([F:30])[CH2:14][N:13]([C:15]([C:17]4[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=4)=[O:16])[CH2:12]3)[CH2:25][CH2:26]2)[S:44][CH:45]=1)([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:33])[CH3:32]
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)[Si](C)(C)OCCc1ccsc1C=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
(2,2-Difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone trifluoroacetate (example 44, step b) (0.40 g) was added to a stirred solution of a 4:1 mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde and 3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 27, step b) (0.36 g) and AcOH (0.05 mL) in N-methyl-2-pyrrolidinone (5 mL). After 5 min, sodium triacetoxyborohydride (0.28 g) was added. After 16 h water was added and the mixture extracted with ethyl acetate. The ethyl acetate layer was washed three times with water and evaporated in vacuo. Purification by silica gel chromatography eluting with 20:80:5 ethyl acetate:isohexane:triethylamine separated the two isomeric products and gave the subtitled compound as a gum. Yield 0.24 g.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:39])[C@@H:10]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C@H:9]([CH3:39])[C@@H:10]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:36])([F:37])[F:38])[CH:28]=1)[C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:15]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1

Procedure:
To a pre-cooled (−70° C.) solution of 4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzonitrile (1 g, 1.83 mmol) in THF (200 mL) was added TBAF (1.83 mL, 1.83 mmol, 1 M solution in THF) dropwise over 10 minutes. Upon complete addition the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes then 100% EtOAc) to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (90 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (329 mg, 39%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.24 (d, J=8.8 Hz, 2 H), 8.16 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=9 Hz, 1H), 7.01 (d, J=8 Hz, 1 H), 5.19 (dd, J=6, 8 Hz, 1 H), 4.59 (d, J=6 Hz, 1 H), 4.49-4.42 (m, 1H), 3.2 (s, 3H) and 1.42 (d, J=7 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]([CH3:22])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]([CH3:22])[CH3:21])[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1F

Procedure:
The title compound was prepared from (5-chloro-4-fluoro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B6) (4.94 g, 17 mmol) and Me2NH (40% in H2O, 7.9M, 10.9 mL, 86 mmol) in DMSO (35 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (4.93 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.C1(NC2SC(C(Cl)=O)=C(C)N=2)CC1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:34][CH:35]([C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[C:36]#[N:37]>C(N(CC)CC)C>[C:36]([CH:35]([NH:34][C:11]([C:7]1[S:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[CH3:10])=[O:13])[C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)#[N:37]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1nc(NC2CC2)sc1C(=O)O
Agent: Cc1nc(NC2CC2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1ccco1
Yield: 38.9 %

Procedure:
1.4g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.2g of amino-furan-2-yl-acetonitrile hydrochloride and 3.2ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.83g (Yield 35%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCSc1ccc(Br)cc1
Yield: 85 %

Procedure:
4-Bromothiophenol (15 g, 0.0794 m) was stirred and heated at 80° C. for 18 hours with n-heptylbromide (14.9 g, 0.0833 m) sodium hydroxide (3.3 g, 0.0833 m) and water (15 mls). The mixture was then added to water (50 mls) and extracted with petroleum spirit 400°-60° (3×50 mls). The combined organic phase was dried over magnesium sulphate and evaporated to yield 4-n-heptylthiobromobonzene (19.5 g, 89% GLC, 85% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:21]([CH2:1][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(COc2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a stirred solution of methyl 4-((3-formylphenoxy)methyl)benzoate (464 mg, 1.72 mmol) in anhydrous DCM (8 mL) was added aniline (0.63 mL, 6.87 mmol) followed by glacial acetic acid (0.46 mL, 6.87 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (1.52 g, 6.87 mmol) was added and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with DCM (100 mL). The organic layer was washed with 1 N HCl (3×30 mL) and saturated aqueous NaHCO3 (30 mL) and passed through a hydrophobic fit. The solvent was removed in vacuo to afford the title compound as an oil that solidifies on standing (380 mg, 64% yield).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 74 %

Procedure:
This compound was synthesized as a colorless oil from pent-4-yn-1-ol (145.0 mg, 132 mmol), TsCl (426.3 mg, 2.24 mmol), Et3N (349.4 mg, 3.44 mmol), and DMAP (210.1 mg, 1.72 mmol) in 74% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.77 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.24-3.97 (m, 2H), 2.42 (s, 3H), 2.23 (td, J=6.9, 2.6 Hz, 2H), 1.99-1.67 (m, 3H); 13C NMR (100 MHz, CDCl3, δH) 145.06, 133.09, 130.09, 128.12, 82.33, 69.68, 68.98, 27.91, 21.85, 14.90. ESI-MS: 239.1 (M+H+), 261.1 (M+Na4).
Reaction SMILES: C([O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:15][O:14][CH2:13]2)=[C:8]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:7]=1)(C)C.[OH-].[Na+]>CO>[O:14]1[CH2:15][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:26])=[O:4])=[CH:7][C:8]=2[O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH2:13]1
Reactant: Cc1cccc(CCOc2cc(C(=O)OC(C)C)ccc2C2COC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(CCOc2cc(C(=O)O)ccc2C2COC2)c1
Reaction time: 144 h
Yield: 99.3 %

Procedure:
120 mg of 4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid isopropyl ester were dissolved in 3 ml of methanol and 0.2 ml of a 2 N aqueous solution of sodium hydroxide added. The mixture was left at room temperature for 6 days and then evaporated. The residue was dissolved in 10 ml of water, the pH adjusted to 2 with an aqueous sodium hydrogensulfate solution, and the mixture extracted three times using 20 ml each of DCM. The combined extracts were dried with magnesium sulfate and evaporated to yield 105 mg of the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>CS(C)=O>[C:1]1([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: ClCC1CO1
Solvent: CS(C)=O
Product: c1ccc2c(OCC3CO3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 1-naphthol (3.0 g, 0.02 mol) in DMSO (10 mL), potassium hydroxy (flakes, 2.0 g, 0.06 mol) was added. The combined mixture was stirred at room temperature for 30 min and then epichlorohydrin (5.6 g, 4.7 mL, 0.06 mol) was added slowly over a period of 45 min and stirring was continued for 16 hours. The reaction was quenched with water (30 mL) and extracted with chloroform (2×50 mL). The combined organic layers were washed with 1N aqueous NaOH (2×50 mL), water (2×100 mL) and brine (2×100 mL) and dried over MgSO4. The solvent was removed under reduced pressure to provide Compound 1 as a yellow liquid (3.26 g, 78%). This product was used without further purification. The structure of Compound 1 is given below: