Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (2.00 g, 11.5 mmol) in dichloromethane (50 ml) was added ethyl 4-aminobenzoate (1.90 g, 11.5 mmol), and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (3.41 g, 16.1 mmol) was added, and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1-1:1, v/v) to give the title compound (3.52 g, 95%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:6]=2[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([N:51]3[CH2:52][CH2:53][N:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 eq), HATU (1.5 eq), hydrochloride salt of 1-methanesulfonylpiperazine (1.5 eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes. The solid that precipitated out from the reaction was filtered to give 2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanone. MS (Q1) 430 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(Cl)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and ethanesulfonyl chloride (67 mg, 0.63 mmol) were dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford ethanesulfonic acid [3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (142 mg, yield: 54%) as yellow solid. MS (ESI+APCI) M+1=445.1.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[S:13]1C=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[NH:11][C:10]1[C:5]2[N:6]([CH:2]=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: OB(O)c1cccs1
Reactant: CNc1nccn2c(Br)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1csc(Nc2nccn3ccnc23)c1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a solution of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (50 mg, 0.2 mmol) in tetrahydrofuran (2 ml) under nitrogen was added 2-thiopheneboronic acid (41 mg, 0.3 mmol), K2CO3 (1.1 ml of a 1 M solution in water) and 16 mg (0.1 mmol) of PdCl2(Dppf)CH2Cl2 (16 mg, 0.1 eq). The mixture was heated at 70° C. in a sealed tube overnight. The product was precipitated by adding methanol. The filtrate was evaporated and purified by preparative thin layer chromatography on silica gel to give additional title compound for a total of 45 mg (100% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH:13]=[N:12][O:11][CH2:10][C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of 200 mg (0.60 mmol) 5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid methyl ester in 2.4 ml THF were added 1.2 ml 1M aqueous LiOH solution and the reaction mixture was heated to 70° C. for 5 h. Water was added, the mixture was acidified and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was evaporated to give 190 mg (0.59 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carbox-ylic acid; exact MW [M+H] calc'd: 320.06; MW found [M+H]: 320.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([NH2:11])=[N:7][CH:8]=[CH:9][N:10]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[S:21](Cl)(=[O:23])=[O:22]>CN1CCCC1=O>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[S:21]([NH:11][C:6]1[C:5]([O:4][CH3:3])=[N:10][CH:9]=[CH:8][N:7]=1)(=[O:23])=[O:22]
Reactant: COc1nccnc1N
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1nccnc1NS(=O)(=O)c1ccc(F)c(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.4 g of a 60% dispersion in oil) was added to a solution of 3-methoxy-2-pyrazinamine (0.25 g) in N-methylpyrrolidinone (10 mL). After 0.5 h, 2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a) (0.63 g) was added. After 16 h at room temperature the reaction mixture was quenched with 2M aqueous HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Yield 0.16 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:20]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:20])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2O)cc1
Yield: 81 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 11.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.8.5 g (81%) of the title compound was obtained as a white solid: mp 101-102° C. (lit. 104° C.); IR (KBr) 1637, 1611, 1513, 1459, 1346. 1301, 1237, 1174, 1148, 1026 797, 787, 626, 522 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.72 (br s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.17 (d, J=8.6 Hz. 2H), 6.86 (d, J=8.6 Hz, 2H), 6.40-6.44 (m, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.73, 166.55, 166.27, 159.07, 132.42, 130.78, 126.73, 114.61, 113.53, 108.21, 101.42, 55.99, 55.67, 44.37.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([CH3:34])[CH:28]=[C:27]2[NH:35]N>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([CH3:34])[CH:28]=[C:27]2[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(C)nc4ccc(F)cc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=428.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 54 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-methoxyphenylboronic acid were reacted to give 234 (0.087 g, 54%). 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.10 (s, 1H), 7.39 (dd, J=31.7, 7.5, 3H), 7.09 (dt, J=14.7, 9.8, 3H), 5.82-5.69 (m, 1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.47 (s, 2H), 1.51 (d, J=6.5, 6H). MS (ESI(+)): m/z 419.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[CH2:30]([CH2:32][NH2:33])[OH:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([S:13]([NH:33][CH2:32][CH2:30][OH:31])(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 1 h

Procedure:
Compound 496 (0.07 g, 0.15 mmol) was dissolved in pyridine (0.4 mL) and ethanolamine (0.011 mL, 0.18 mmol) was added. The solution was kept at room temperature for 1 h after which it was concentrated in vacuo. The residue was dissolved in EtOAc and H2O and the phases were separated. The water phase was extracted with EtOAc (×2) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 3:7→1:0 as the eluent. This afforded the title compound as a solid. 13C NMR (CD3OD) δ 196.5, 161.2 (dd), 158.0 (dd), 151.9, 143.3, 142.0, 139.5, 136.5, 135.2, 133.2, 129.9, 128.2, 127.8, 127.8 (dd), 125.7 (dd), 116.5, 113.1, 112.7 (dd), 105.8 (dd), 61.8, 46.3, 20.3
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-Methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.6 g 2-methylsulfonylbenzenesulfonyl chloride is added portionwise to a solution, at a temperature in the region of 0° C. and under argon, of 0.83 g of 5-amino-3-phenethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in 13 ml of pyridine. The reaction mixture is then stirred for 0.5 hours at a temperature in the region of 0° C. then 2 hours at a temperature in the region of 20° C., and is then diluted with 13 ml of water. After settling out, the aqueous phase is extracted with 3 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 15 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 70 g of silica (particle size 20-40 μm), eluting successively with pure cyclohexane then with a cyclohexane/ethyl acetate (80/20 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide are obtained in the form of a brown-colored paste (Rf=0.32, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:24]([OH:26])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1>>[C:24]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1c[nH]cn1)C(=O)O
Product: O=C(O)c1cc2ccccc2nc1NC(Cc1c[nH]cn1)C(=O)O
Yield: 33 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-histidine to provide the title compound in 33% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:9][CH:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:12]=1)[CH3:23]
Reactant: [H][H]
Reactant: CCOC(COc1ccc(C=C2SC(=O)NC2=O)cc1)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Yield: 100 %

Procedure:
A solution of 5-[4-[(2,2-diethoxy)ethoxy]phenyl methylene]thiazolidin-2,4-dione (8.0 g, 23.7 mmol) obtained in example 1, in 1,4-dioxane (100 mL) was reduced with hydrogen in the presence of 10% palladium on charcoal (16.0 g) at 60 psi for 60 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure; purified by column chromatography using EtOAc:pet. ether (1:1) as an eluent to afford the title compound (8.04 g, 67%) as a colourless liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([CH:35]=O)=[CH:25]2)=[CH:19][CH:18]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.O>CN(C)C=O>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26](/[CH:35]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:25]2)=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, oily, 190 mg) was added to a solution of 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolecarbaldehyde (1.05 g) and ethyl diethylphosphonoacetate (1.05 g) in N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to obtain ethyl(E)-3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propenoate. The crystals were dissolved in ethanol (80 ml), and hydrogenated on 5% palladium-carbon (800 mg) at room temperature under a normal pressure. The catalyst was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1.05 g, yield: 86%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume 5 ratio).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21].C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH3:29][O:28][C:26]([C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:30])=[O:27]
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1C(=O)OC
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1C(=O)OC

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.73 g of dimethyl 4-(2-oxopropoxy)phthalate (prepared as described in Preparation 54), 70 ml of benzene, 60 ml of absolute methanol and 1.32 g of sodium borohydride, the title compound was obtained having an Rf=0.29 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [H-].[Na+].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=CC=1.[Br-].[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=O>CS(C)=O>[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=[CH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC2CCC1C2
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=C1CCC2CCC1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
A mixture of 3.92 g (93 mmol) of sodium hydride (57% oil dispersion) and 30 ml of dry dimethylsulfoxide was heated at 70°-80° under nitrogen until gas evolution ceased (2.5 hr). The mixture was cooled, and 19.7 g (44.3 mmol) of 4-(carboxybutyl)triphenylphosphonium bromide (Aldrich No. 15,794-5) was added, followed by 20 ml of dimethylsulfoxide. The resulting deep red mixture was stirred for 45 min at room temperature under nitrogen before a solution of 5.0 g (40.2 mmol) of bicyclo[3.2.1]octan-2-one (Aldrich No. 11,903-2) in 20 ml of dimethylsulfoxide was added dropwise over 1.75 hr. The resulting mixture was stirred for 16 hr at room temperature before it was quenched by the addition of 125 ml of water. The resulting solution was extracted with three 250 ml portions of ether/ethyl acetate-1:1 (V/V) to remove neutral by products. The remaining aqueous phase was acidified by the addition of 15 ml of concentrated hydrochloric acid and extracted with three 250 ml portions of ether-hexane-1:1 (V/V). These combined acidic ether-hexane extracts were dried (MgSO4), and evaporated in vacuo to yield 6.0 g of crude 5-(bicyclo[3.2.1]oct-2-ylidene)-pentanoic acid as an oil. This oil was purified by chromatography on silica gel 60 (elution with CHCl3 containing 0.5 % formic acid) to yield 4.1 g (49%) of pure material as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[CH:25]1([C:28]2[S:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:27][CH2:26]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:33][C:31]2[S:32][C:28]([CH:25]3[CH2:27][CH2:26]3)=[N:29][N:30]=2)=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnc(C2CC2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C3CC3)s2)cc1
Temperature: 115 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
1.1 g 4-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-benzenesulfonyl chloride, 483 mg 5-Cyclopropyl-[1,3,4]thiadiazol-2-ylamine and 35.0 mg 4-dimethylaminopyridine were dissolved in 5 ml pyridine and stirred under microwave irradiation at 115° C. for two hours. The pyridine was removed in vacuo and the residue coevaporated three times with portions of 20 ml toluene. The residue was purified by RP-HPLC to obtain 590 mg 5-Chloro-N-{2-[4-(5-cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-2-methoxy-benzamide.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:11]=[C:12]([NH:13][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
15.53 g (155 mmol) Acetylacetone, 5.00 g (31 mmol) 3-trifluoromethylaniline, and 0.53 g (3.1 mmol) 4-toluenesulfonic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)/[CH:2]=[CH:3]\[CH2:4][CH3:5]
Reactant: CC/C=C\CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][S:8][CH2:9]Cl.C(N(CC)CC)C>>[C:1]([O:6][CH2:7][S:8][CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting butyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 71°-73° C./12 mm Hg, n20 1.4521.