Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 1 starting from Intermediate 11 (143 mg; 0.50 mmol) Intermediate 1 (88 mg; 0.50 mmol). Reaction mixture was filtered over a SPE-NH2 column, washed with THF followed by evaporation of the solvent under reduced pressure. Evaporation of the solvent gave a yellow oil which was recrystallized in a DCM/n-pentane mixture to give the title compound as an off-white solid. 1H NMR (DMSO, d6) δ 12.77 (s, 1H), 8.46 (dd, J=8.4, 2.1 Hz, 1H), 8.40 (m, 2H), 8.34 (s, 1H), 7.97 (dd, J=8.5, 1.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 3.20-3.14 (m, 1H), 2.99-2.94 (m, 1H), 2.67-2.57 (m, 1H), 1.79 (m, 2H), 1.68-1.27 (m, 4H), 0.76 (d, 6 Hz, 3H). HPLC (Method A) Rt 4.51 min (Purity: 99.4%). LC/MS (method B): 428.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:36][N:37]=[CH:38]S(O)(=O)=[O:40]>CN(C=O)C>[C:12]([OH:16])(=[O:40])[CH3:13].[C:12]([OH:16])(=[O:40])[CH3:13].[NH2:36][N:37]=[CH:38][N:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NN=CS(=O)(=O)O
Reactant: O=S(=O)(Oc1cccc(OCCN2CCNCC2)c1)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)O
Product: NN=CN1CCN(CCOc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 155.6 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperazin-4-yl)ethoxy]phenyl ester (397 mg, 1.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) in DMF (10 mL) was stirred at room temperature overnight. The DMF was removed in vacuo and residue was purified by flash column chromatography (85:15:2 methylene chloride:methanol:acetic acid) to give the title compound as a white solid (290 mg, 52%). 1H-NMR (300 MHz, CDCl3 /CD3OD) δ 2.01 (bs, 6H), 2.64 (t, 4H), 2.84 (t, 2H), 3.45 (t, 4H), 4.07 (t, 2H), 6.67 (dd, 1H), 6.77 (t, 1H), 6.83 (dd, 1H), 7.19 (t, 1H), 7.41 (dt, 1H), 7.65 (t, 2H), 7.95 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H23 N4O4SCl: 439.1(M+H), 461.1 (M+Na). Found: 438.8, 460.8.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:51][C:52]([C:54]1[N:55]=[C:56]([CH2:60][CH2:61][O:62][CH3:63])[S:57][C:58]=1[NH2:59])=[O:53])[CH3:50].Br[C:65]1[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=1>O1CCOCC1.C1COCC1>[CH2:49]([O:51][C:52]([C:54]1[N:55]=[C:56]([CH2:60][CH2:61][O:62][CH3:63])[S:57][C:58]=1[NH:59][C:65]1[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=1)=[O:53])[CH3:50]
Reactant: CCOC(=O)c1nc(CCOC)sc1N
Reactant: Brc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CCOC)sc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
A microwave vial was charged with Pd2dba3-chloroform complex (0.09 g, 0.09 mmol), Xantphos (0.17 g, 0.30 mmol) and cesium carbonate (1.00 g, 3.06 mmol), sealed and flushed with argon. A solution of 5-amino-2-(2-methoxy-ethyl)-thiazole-4-carboxylic acid ethyl ester (0.40 g, 1.75 mmol) and 3-bromopyridine (0.28 g, 1.75 mmol) in dioxane (5.80 ml) was degassed by sonicating and bubbling with argon, then transferred to the reaction vial. After stirring at room temperature for 5 min, the reaction mixture was irradiated in a microwave oven at 150° C. for 10 min. The mixture was diluted with THF, filtered and the mother liquors evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.18 g, 40%), MS (ISP): m/e=308.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:29]Br>C(O)(=O)C.O>[Br:29][C:13]1[CH:12]=[CH:11][C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:20])[CH3:18])=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:22])[F:23])[N:8]=2)[CH:14]=1
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ccnc(C(F)(F)F)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ccnc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
3 g N-[2-[2-(trifluoromethyl)4-pyrimidinyl]phenyl]-2,2-dimethylpropanamide was dissolved in 30 mL glacial acetic acid, 5 g anhydrous sodium acetate was added, and a solution of 2.8 g bromine in 5 mL acetic acid was added dropwise with stirring over 1 h. The reaction mixture was stirred at room temperature overnight, after which it was diluted with water. The precipitate was collected by filtration, washed well with water, then with hexane, and was dried in a vacuum oven overnight to yield 3.3 g of the title compound melting at 153°-157° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 7.40-8.4 (6H), 10.6 (s,1H,NH).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19]/[C:20](=[CH:22]/CO)/[CH3:21])[CH3:16].CO>C1(C)C=CC=CC=1>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH:14]=[C:15]([CH3:16])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: COC(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCOC(=O)c1ccc(N)cc1
Yield: 12.2 %

Procedure:
Sodium hydride (600 mg, cat. 60% disp in oil) was added to a suspension of methyl 4-aminobenzoate (50 g, 330 mmol), geraniol (51 g, 330 mmol) in PhMe (100 mL). The suspension was heated under reflux for 8 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane:isopropanol (95:5) as eluant to give the crude ester (X) as a pale yellow oil. Recrystallization from methanol gave the ester (11 g, 12%) as needles.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]/[C:21](=[N:24]/[H])/[NH:22][OH:23])=[CH:16][CH:15]=1.[O:26]=[C:27]1[C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][N:28]1[CH2:45][C:46](O)=O>ClC(Cl)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[N:24]=[C:46]([CH2:45][N:28]3[CH2:29][CH2:30][CH2:31][C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:26])[O:23][N:22]=2)=[CH:16][CH:15]=1
Reactant: [H]/N=C(/Cc1ccc(Cl)cc1)NO
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(Cc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.160 g, 0.837 mmol), (Z)-2-(4-chlorophenyl)-N-hydroxyacetimidamide (0.103 g, 0.558 mmol) and 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.173 g, 0.558 mmol; Example 68E) were stirred together in dichloroethane at room temperature for 2 hours, then heated to 85° C. for 16 hours. The reaction was cooled and concentrated. The residue was dissolved in dichloromethane (3 mL) and washed with water (1 mL). The organic layer was concentrated and the residue was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.38-7.15 (m, 14H), 4.82 (s, 2H), 4.06 (s, 2H), 3.53 (t, J=6.5, 2H), 2.73-2.58 (m, 2H), 1.95-1.76 (m, 2H); MS (ESI+) m/z 458.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCCN1C(=O)C(c2ccc3c(c2)OCO3)c2ccccc21
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 3-(1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (1.00 g, 3.10 mmol) and methyl bromoacetate (0.44 mL, 4.60 mmol) in THF (20.0 mL) was degassed by bubbling through argon for one hour. Sodium hydride (0.19 g, 4.60 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 h and quenched with ammonium chloride solution. The mixture was poured into water (150 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.94 g, 76%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.25 (dd, 1H), 7.06 (td, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 6.74-6.65 (m, 2H), 5.90-5.87 (m, 2H), 3.71-3.64 (m, 2H), 3.45 (d, 1H), 3.41 (s, 3H), 3.18 (d, 1H), 1.74-1.60 (m, 2H), 1.39-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3,) δ 177.8, 170.0, 147.9, 147.0, 143.9, 133.1, 131.3, 128.6, 124.6, 122.3, 119.9, 108.7, 108.1, 107.4, 101.2, 52.8, 51.6, 41.8, 40.4, 29.0, 26.8, 22.3, 14.0; MS (ES+) m/z 418.1 (M+23), 396.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:29])[CH:15]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COC(C)C)C3)cc21

Procedure:
A 150 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(1-methylethoxy)methyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid was dissolved in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for one hour and then evaporated. A 5 ml portion of water was added, the solution neutralized with 5N sodium hydroxide and the solid collected, giving 76 mg of the desired product, mp 184°-186° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1cc(C(=O)c2ccccc2)ccc1-c1cccc(C)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(C(=O)c3ccccc3)cc2O)c1
Temperature: -78 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Ketone 17 was dissolved in dry DCM and the resulting solution was cooled to −78° C. BBr3 (1.5 eq, 0.49 mM) was then added drop wise and the reaction mixture was allowed to warm to room temperature and was stirred for an additional 12 hours. After the completion of the reaction as determined by TLC, the reaction mixture was diluted with methanol, and then washed with bicrab, water brine. The product was then subjected to column chromatography using 20% EtOAc/hexanes as the solvent system. Yield=46.5% (Rf=0.3 1; 20% EtOAc/Hexanes) 1H NMR, 300 MHz Varian, CDCl3 δ 7.88 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (m, 2H), 7.43 (d, J=6.3 Hz, 2H), 7.38 (s, 1H), 7.34 (s, 2H), 7.27 (m, 1H), 2.46 (s, 3H), MS: m/z (ESI, pos.)=325.5 ([M+23]). HPLC retention time: 11.246 min. and 10.804 min; purity 97.92%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH:13]=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2](=[O:1])[O:3][CH2:4][CH2:5]3)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=CCc1ccc2c(c1)CCOC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)CCOC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Oxo-3,4-dihydro-1H-isochromen-6-yl)acetaldehyde (2.40 g, 12.6 mmol) was combined with 1-Boc-piperazine (3.53 g, 18.9 mmol) and sodium triacetoxyborohydride (13.4 g, 63.1 mmol) in DCM (90 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with brine, then dried over MgSO4. The crude product was purified first by MPLC (silica), eluting with 3% of a 10% NH4OH/methanol solution in DCM, then a second MPLC purification eluting with ethyl acetate, to afford the title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:13][O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:9](/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:11])=[O:10])[CH:19]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: COC(=O)C=Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Yield: 70.2 %

Procedure:
A solution of (E)-2-phenylethenesulfonyl chloride (24a) (0.59 g, 2.82 mmol) in dioxane (3 ml) was added to a mixture of 3-(3-aminophenyl)-acrylic acid methyl ester (23) (0.50 g, 2.82 mmol) in dioxane (12 ml) and NaHCO3 (0.36 g, 4.28 mmol) in water (8 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (100:2, v/v) as eluent to give the title compound (0.68 g, 70%) as a white solid. 1H NMR (CDCl3, HMDSO), δ: 3.78 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.77 (1H, d, J=15.8 Hz); 6.78 (1H, s); 7.17-7.48 (9H, m); 7.49 (1H, d, J=15.8 Hz); 7.58 (1H, d, J=16.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH:12]([CH3:17])[CH3:13])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Solvent: CC(C)O
Product: CC(C)OC(=O)C(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 735.1 %

Procedure:
A mixture of 2 g of ethyl 5-chloro-2-hydroxyoxanilate, 100 ml of isopropyl alcohol, and 100 mg of p-toluenesulfonic acid was refluxed for 24 hours. The reaction mixture was allowed to cool to room temperature and then allowed to stand overnight. Crystals formed were recovered by filtration and recrystallized from isopropyl alcohol to provide 1.1 g of isopropyl 5-chloro-2-hydroxyoxanilate.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]=1[C:15]#[N:16]
Reactant: OCCCOc1ccccc1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OCCCOc1ccccc1

Procedure:
Prepared as in Example 22b from 3-phenoxy-1-propanol and 2-amino-6-fluorobenzonitrile as a yellow oil (93%). 1H NMR (400 MHz, DMSO-d6) δ 2.14 (m, 2H), 4.10-4.16 (m, 4H), 5.98 (s, 2H), 6.23 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.89-6.94 (m, 5H), 7.16 (t, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18](=[O:20])[CH3:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>[Zn]>[OH:20][C:18]([CH3:19])([CH:17]=[CH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Yield: 94.4 %

Procedure:
Using 900 mg of 6-[p-(p-fluorobenzyloxy)phenyl]-3-hexen-2-one, 660 mg of ethyl bromoacetate and 260 mg of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.10 g of ethyl 3-hydroxy-3-methyl-7-[p-(p-fluorobenzyloxy)phenyl]-4-heptenoate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]1(O)[CH2:16]CC[CH2:13]1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:16])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: OC1CCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21

Procedure:
2,6-Dichloro-9-(2-propyl)purine is prepared from 2,6-dichloropurine and isopropanol essentially as described in Example 1, Scheme A, step a, but substituting isopropanol for cyclopentanol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[CH:5]=1)=[O:3].CC(C)=O.C(OCC)(=O)C>O1CCCC1>[F:11][C:6]1[CH:5]=[C:4]([C@H:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(S,R)-cis-1-amino-2-indanol (284.3 mg, 1.91 mmol, 0.1 eq) was dissolved in tetrahydrofuran (25 mL) in a dry two-necked round-bottomed flask fitted with a dropping funnel and nitrogen inlet. The solution was chilled to approximately 0° C. and N,N-diethylaniline-borane complex (3.50 mL, 19.2 mmol, 1 eq) added dropwise. The mixture was allowed to stir at 0° C. for 30 minutes at which time a solution of 3,4-difluoroacetophenone (2.40 mL) in tetrahydrofuran (40 mL) was added via the dropping funnel over approximately 90 minutes. The solution was allowed to slowly warm to room temperature and stirring continued overnight. Acetone (16 mL) was added to the reaction mixture and the solution allowed to stir for a further hour before being concentrated in vacuo. The residue was treated with toluene (100 mL) and washed with 1 M sulphuric acid (4×50 mL), water (2×50 mL) and brine (50 mL). The organic phase was then dried (Na2SO4) and concentrated in vacuo to afford the crude alcohol. Gradient flashmaster chromatography (20 g silica cartridge; 100% petroleum spirits to 100% ethyl acetate) afforded the desired alcohol as a clear oil (2.242 g, 74%).
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:38][C:35]2[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:8])([CH3:7])[CH3:9]
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 4-bromo-2-trifluoromethyl-benzenethiol yielded (2S,4R)-4-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 436.2 and 434.2 [M+H-Boc]+.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1.[OH-].[K+].I[CH3:16].Cl>O.C(O)C>[CH3:16][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COc1ccc2[nH]c(S)nc2c1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c(SC)nc2c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
First, 18.00 g (100 mmol) of 2-mercapto-5-methoxy-1H-benzimidazole, 16.83 g (300 mmol) of potassium hydroxide, 75 ml of ethanol, and 50 ml of water were added to a 3-necked flask (300 ml volume) equipped with a thermometer, a mechanical stirrer and a dropping funnel, and cooled to 5° C. Next, 15.00 g (105 mmol) of iodomethane was added dropwise to this solution over a period of 30 minutes while keeping internal temperature at 10° C. or lower. Then the solution was agitated for 2 hours at 10° C. or lower. The reaction solution was neutralized with an aqueous 2N hydrochloric acid solution, then the ethanol was removed under reduced pressure to precipitate a colorless solid. This solid was filtered and dried under reduced pressure to give 19.19 g of 2-methylthio-5-methoxy-1H-benzimidazole (yield of 98.9%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4]=[O:5].[CH3:6][C:7]([CH:9]=[CH:10]C)=[CH2:8].C=O.O.N1CC[CH2:17][CH2:16]1.C(O)(=O)CC>C([O-])(O)=O.[Na+]>[CH3:1][CH:2]1[CH:8]=[C:7]([CH3:6])[CH2:9][CH2:10][C:3]1([CH:16]=[CH2:17])[CH:4]=[O:5]
Reactant: C/C=C/C=O
Reactant: C=C(C)C=CC
Reactant: C1CCNC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: C=CC1(C=O)CCC(C)=CC1C
Temperature: 80 °C
Yield: 50 %

Procedure:
To a mixture of crotonic aldehyde (165.2 g, 2.36 mol), 2-methyl-penta-1,3-diene (361.6 g, 4.41 mol) and formalin (37% in water (200 g, 2.46 mol) was added a mixture of pyrrolidine (16.0 g, 0.22 mol) and propionic acid (17.0 g, 0.23 mol). The mixture was placed in an autoclave and heated to 60-100° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with sat. NaHCO3 and extracted 3 times with MTBE (200 ml). The combined org. layers were washed with brine (200 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by distillation to give 2,4-dimethyl-1-vinylcyclohex-3-enecarbaldehyde (50% yield). Boiling point: 50-53° C./0.15 mbar.