Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][CH3:4].[C:6]([O:14]CC)([O:11][CH2:12][CH3:13])(OCC)[CH3:7].C(O)(=O)CC.C(O)(=O)C>CCOCC.O>[CH3:4][CH:3]([CH:2]=[CH2:1])[CH2:7][C:6]([O:11][CH2:12][CH3:13])=[O:14]
Reactant: CC=CCO
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=CC(C)CC(=O)OCC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 36.06 g of crotyl alcohol, 162.2 g of triethyl orthoacetate and 2.22 g of propionic acid was slowly heated to 100° C. (1.25 hours), stirred and heated at 100°-115° C. for 1 hour, at 115°-145° C. for 2.5 hours, then at 145°-155° C. for 6 hours. The mixture was cooled in an ice bath and treated with 50 ml of glacial acetic acid and 50 ml of water. The mixture was stirred at room temperature for 45 minutes, diluted with ether, extracted with saturated sodium bicarbonate solution, then with brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue was distilled under reduced pressure to give ethyl 3-methyl-4-pentenoate (3A), as a colorless liquid, b.p.: 88°-91° C. (60 Torr.).
Reaction SMILES: O=O.[F:3][C:4]([F:28])([F:27])[C:5]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[C:12]2[C:7](=[C:8]([C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:10][CH:11]=2)[N:6]=1>C1(C)C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]([C:13]1[C:12]2[C:7](=[C:8]([C:23]([F:24])([F:25])[F:26])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:4]([F:28])([F:3])[F:27])[CH:14]=1)[OH:16]
Reactant: O=C(c1ccccn1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: O=O
Solvent: Cc1ccccc1
Product: O[C@@H](c1ccccn1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A 500 ml autoclave was loaded in a glove box (O2 content<1 ppm) with 14.8 g (40 mmol) of 2-pyridyl 2,8-bis(trifluoromethyl)-4-quinolyl ketone, with the catalyst solution prepared above and with 134 ml of toluene. The hydrogenation was carried out at 60°, at a constant pressure of 60 bar H2 and while stirring intensively. After a hydrogenation time of 19 hours the conversion was 100° (TLC). The hydrogenation solution was evaporated on a rotary evaporator at 45°/20 mbar. For the crystallization of the product, the residue (13.8 g) was dissolved in 21 ml of hot toluene, cooled slowly to RT and stirred for 16 hours. The crystallization was completed by cooling to 1° and stirring for 3 hours. The yellow crystals were filtered off, washed with cold toluene and dried for 18 hours and 50°/20 mbar. There were obtained 12.7 g (92%) of (R)-α-(2-pyridyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol; m.p. 130°-131°; 91.8% e.e.; [α]D20 +17.1 ° (c=1, MeOH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[O:8])=[CH:3][CH:2]=1.[H][H]>C1COCC1.C(O)C.[Pd]>[N:1]1[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([OH:16])=[O:15])=[O:8])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CCCN1C(=O)c1ccncc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCCN1C(=O)c1ccncc1

Procedure:
Benzyl 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylate (4.0 g, 11.5 mmol) is dissolved at RT in a mixture of THF and ethanol abs. (1:1, 30 ml), and treated with palladium on active carbon (10%, 0.7 g). Evacuation is then carried out three times and the vacuum is replaced by hydrogen from a balloon.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](OC)=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][OH:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(CO)c2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Alternatively,a solution of 2-dipropylamino-8-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (480 mg, 1.66 mMol) in tetrahydrofuran (5 mL) was added dropwise to a suspension of lithium aluminum hydride (100 mg, 2.49 mMol) in tetrahydrofuran (10 mL), and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then cooled to 0° C., and to it were added sequentially water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL). The suspension was then stirred at room temperature for one-half hour and was then filtered through a bed of Celite. The filtrate was concentrated in vacuo to give the title compound as a colorless, viscous oil (400 mg, 92%). The hydrochloride salt was formed and recrystallized (ethanol/diethyl ether) to give colorless crystals (m.p.=142° C.). Analysis: Calculated for C17H27NO·HCl: Theory: C, 69.02, H, 8.86, N, 4.73; Found: C, 69.03, H, 8.72, N, 4.61.
Reaction SMILES: [CH:1](=[N:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[SiH](C)C1C=CC=CC=1.CO.FC(F)(F)C(O)=O>C1C=CC=CC=1.C(OCC)C>[C:12]1([S:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(N=Cc1ccccc1)c1ccccc1
Agent: C[SiH](C)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NCc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
In a 5 mL flask opened to the air, to a clear solution of N-benzylidenebenzene sulfonamide (100 mg, 0.408 mmol) in benzene (0.4 mL) was added dimethylphenylsilane (125 μL, 0.816 mmol). The flask was placed in a 60° C. bath and iodo[bis(triphenylphosphine)] oxorhenium(V) (18 mg, 0.021 mmol) was added. The resulting brown solution was heated at 60° C. for 2 hours. To the reaction mixture was added methanol (0.4 mL) followed by trifluoroacetic acid (35 μL), and heating continued for an additional 2 h. The crude reaction mixture was directly applied to a SiO2 column and chromatographed eluting with 1:1 hexanes:diethyl ether to afford N-phenylsulfonylbenzylamine (87 mg, 86% yield) as a slightly yellow solid.
Reaction SMILES: C([N:8]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[C:31]([C:43](=[O:45])[NH2:44])[CH:30]=1)[CH2:9][CH:10]([OH:25])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>CO>[C:43]([C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[OH:35])[O:28][CH2:27][CH2:26][NH:8][CH2:9][CH:10]([OH:25])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:17][CH:18]=1)(=[O:45])[NH2:44]
Reactant: Cn1ccnc1-c1ccc(OCC(O)CN(CCOc2ccc(OCc3ccccc3)c(C(N)=O)c2)Cc2ccccc2)cc1
Solvent: CO
Product: Cn1ccnc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 0.85 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[1-methyl-1H-imidazol-2-yl]-phenoxy]-2-propanol in 10 ml of methanol is hydrogenated analogously to Example 8. After working up, the 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 108°-112° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C([O:12][CH:13]=[C:14]([C:20]([O-])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[OH:12][C:13]1[C:7]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:9][CH:8]=2)[N:6]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1cccc(N)c1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O

Procedure:
Using the procedure of Steps A and B of Example 19, 3-methoxy-aniline and ethyl ethoxymethylenemalonate were reacted to obtain ethyl 4-hydroxy-7-methoxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.[CH3:14]O>>[CH3:14][O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([NH2:4])[CH:6]=1
Reactant: CO
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Product: COC(=O)c1ccnc(N)c1

Procedure:
2-Acetylamino-isonicotinic acid (3.10 g, 17.2 mmol) was stirred in 35 mL MeOH at 0° C. HCl (g) was bubbled through the solution for 10 minutes and then the reaction was heated to reflux. After 16 hours the reaction was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 7 with Na2CO3 (s). A white precipitate formed which was filtered to afford a portion of pure desired product. The aqueous phase was extracted three times with 95:5 dichloromethane (DCM)/nBuOH. The organic phases were dried over Na2SO4, filtered and concentrated to afford more of the pure product as a white solid. 1H NMR (CDCl3) δ 8.19 (d, 1H, J=5.3 Hz), 7.17 (dd, 1H, J=1.4, 5.3 Hz), 7.07 (d, 1H, J=1.3 Hz), 4.64 (bs, 2H), 3.92 (s, 3H). MS [M+H]+=153.0.
Reaction SMILES: [OH-].[K+].O.[OH:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][CH:10]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[Br:21][CH2:22][CH2:23][CH2:24][O:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][CH:10]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCBr
Reactant: Oc1cccc2c1OCCC2N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: BrCCCOc1cccc2c1OCCC2N1CCCCC1
Reaction time: 8 h

Procedure:
Crushed potassium hydroxide (4.1 g) and tetrabutyl ammonium chloride (2.2 g) and H2O (5 ml) are added to a stirred mixture of the product obtained in Step 3. (17.2 g) and 1,3-dibromopropane (74.8 ml). The reaction mixture is stirred under nitrogen overnight, diluted with diethyl ether, and extracted with 5% aq. HCl. The acidic solution is washed with ether, sat'd NaCl, dried, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:20]2[C@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=[CH:17][CH:16]=1)[NH:25][CH2:24][CH2:23][CH2:22]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[C@@H:26]4[C@H:21]([C:20]5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=[CH:18][C:19]=5[CH2:28][CH2:27]4)[CH2:22][CH2:23][CH2:24]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1cccc2c1[C@@H]1CCCN[C@H]1CC2
Product: COc1cccc2c1[C@@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 51 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 51% of theory; LC (method 2): tR=3.63 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.Cl.[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][CH2:20][CH2:19][C@H:18]2[NH2:23].C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:23][C@H:18]2[C:17]3[C:22](=[C:13]([F:12])[CH:14]=[CH:15][CH:16]=3)[O:21][CH2:20][CH2:19]2)[C:5]=1[NH2:9]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[CH2:21][CH2:20][CH2:19][C:18]5[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=5[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]3[CH2:21][CH2:20][CH2:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]3=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCCc2ccccc2-4)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCCc1cnc3[nH]ncc3c1-2
Yield: 67.9 %

Procedure:
A solution of 3-(4-methoxybenzyl)-3,6,7,8-tetrahydrobenzo[6,7]cyclohepta[1,2-d]pyrazolo[3,4-b]pyridine (2.0 g, 5.63 mmol) in trifluoroacetic acid (10 mL) was heated at 100° C. for 6 hours. On completion of the reaction, the solvent removed under reduced pressure. The residue was dissolved in water (20 mL) and then it was basified to pH=10 using ammonium hydroxide. The aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The organic extracts were combined, dried using sodium sulfate and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient 100% dichloromethane to 2% methanol in dichloromethane) to give the pure desired product (0.9 g, 68%) as off-colored solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.58 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.32 (t, J=8.0 Hz, 1H), 2.60-2.38 (m, 4H), 2.15 (quintet, 3H); LCMS [M+H]: 236.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Reactant: Clc1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccccn2)CC1)NC1CC1
Yield: 46.6 %

Procedure:
1-[4-Chlorophenyl-(2-pyridyl)methyl]piperazine (7.90 g, 27.5 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (7.24 g, 30.2 mmol) were refluxed in N-ethyldiisopropylamine (20 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[4-chlorophenyl-(2-pyridyl)methyl]-1-piperazinyl]hexanesulfonamide (6.29 g) as an oil (yield based on 1-[4-chlorophenyl-(2-pyridyl)methyl]piperazine: 92.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].C(=O)([O-])[O-].[K+].[K+].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:21])[CH2:19][S:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of mercapto-acetic acid methyl ester (1.0 g, 9.42 mmol) in dimethylformamide (10 mL) at room temperature was added potassium carbonate (1.69 g) followed by bromo-acetic acid tert-butyl ester (1.84 g, 9.42 mmol). The resulting suspension was stirred at ambient temperature overnight and then diluted with hexanes. The organic layer was washed with water three times and brine once, dried over sodium sulfate, filtered and concentrated to give a colorless oil, which was used directly in next step without purification. 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.72 (s, 3H), 3.37 (s, 2H), 3.27 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=O)C.[CH3:27][NH:28][NH:29][CH3:30]>C1(C)C=CC=CC=1.O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:29]([CH3:30])[N:28]([CH3:27])[C:4](=[O:3])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OC)cc1
Reactant: CNNC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)n(C)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 53 %

Procedure:
3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)-3-oxo-propionic acid ethyl ester was dissoved in 20 ml of toluene and then 0.24 g of dimethyl hydrazine was added to the solution. The apparatus containing the mixture was heated and refluxed at 120° C. for 24 hours in the Dean-Stark trap apparatus. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The obtained organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was recrystalized with n-hexane to give 160 mg of the title compound as a yellow solid(yield 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:34])[C:22](=[O:33])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:24][C:14]3=2)[N:8]([CH2:35][CH3:36])[N:7]=1)=O)C.[BH4-].[Na+].C(Cl)Cl.CO>C(O)C>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23]1[C:22](=[O:33])[N:21]([CH3:34])[C:15]2[N:16]([CH3:20])[C:17]3[C:13]([C:14]=2[CH:24]=1)=[CH:12][C:11]([C:9]1[N:8]([CH2:35][CH3:36])[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1)=[CH:19][CH:18]=3
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCn1nc(CO)cc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
450 mg (0.86 mmol) of compound from Example 59, 5-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-1-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester, are dissolved in 10 ml of absolute ethanol and 42 mg (1.12 mmol) of NaBH4 are added. The mixture is refluxed overnight. The reaction medium is allowed to return to ambient temperature, CH2Cl2 and MeOH are added, and the product is adsorbed onto silica. Purification is carried out on a silica column, elution being carried our with EtOAc, and then with a 95/05 EtOAc/MeOH mixture. The oil obtained is triturated in ether.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].C([O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[N:17][C:16]=1Cl)=O)C>COCCOC>[CH2:8]([O:7][C:3]([C:4]1[O:5][C:16]2[N:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:13]=1[OH:12])=[O:6])[CH3:9]
Reactant: CCOC(=O)CO
Reactant: CCOC(=O)c1ccnnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1oc2nnccc2c1O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (44.7 mmol) in 100 mL 1,2-dimethoxyethane was added ethyl glycolate (43 mmol) under ice cooling and stirring. The ice bath was removed and stirring was continued at RT. After 30 min, a solution of 3-chloropyridazine-4-carboxylic acid ethyl ester (17.2 mmol) in 40 mL 1,2-dimethoxyethane was slowly added and the mixture was heated to 75° C. for 2 h. The solvent was then evaporated off and the residual solid was redissolved in aq. NaHCO3 solution and EtOAc. The aqueous layer was acidified with AcOH and extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (1/1) gives the desired product as brown solid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: COCC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 60.2 %

Procedure:
In a manner similar to the method described in Example 100b, [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 110a (3.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (0.94 g, 3 mmol) prepared in Example 52a, AgF (0.58 g, 4.6 mmol), and triethylamine (1.06 mL, 7.6 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (20 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:34][CH:35]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (1.19 g, 2 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (708 μL, 4 mmol) to give 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was then treated according to general procedure AD to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c(Cl)c2)S1
Temperature: 100 °C

Procedure:
A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated for five hours at 100° C. Yield 1.9 g (70%), mp 299-301° C.