Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CCN(c2ncccc2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(c2ncccc2Cl)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
At −78° C., DMSO (10 g, 138 mmol) was added slowly into a dichloromethane (40 ml) solution of oxalyl dichloride. After 15 minutes, N-(3-chloro-2-pyridyl)-4-hydroxy piperidine (compound 20) in methylene chloride was added dropwise into the reaction mixture. After 30 minutes, 31 g of triethylamine was slowly added, when the reaction solution was maintained at −78° C. Reaction mixture was slowly warmed to room temperature. Three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (13 g, 93%)
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:22]=3)[CH:18]=[CH:19]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3ccn(S(=O)(=O)c4cc(Cl)ccc4OC)c3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (70 mg, 0.14 mmol) in tetrahydrofuran (1.5 ml) and methanol (0.5 ml) was treated with a 1N solution of LiOH in water (0.5 ml). The mixture was stirred at room temperature for 4 hours, then acidified with 1N HCl (0.5 ml). Methanol and tetrahydrofuran were evaporated and the residual slurry was extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated, and the residue purified by flash chromatography (dichloromethane/methanol gradient), to yield 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid as a light yellow solid, 17 mg (25%). MS (ISP): m/e=483.0 (M−H); δH (300 MHz; d6-DMSO) 12.77 (1H, bs), 10.60 (1H, s), 8.34 (1H, s), 8.08 (1H, d), 7.91-7.97 (6H, m), 7.75-7.80 (2H, m), 7.23 (1H, d), 6.91 (1H, d), 3.70 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:16]4[NH:15][CH:19]=[CH:18][CH:17]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=Cc1ccc[nH]1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccc[nH]4)nc3cc21

Procedure:
Analogously to Example 2, from 3.8 g. (20 mmol) 5,6-diamino-3,3-dimethylindolin-2-one, 1.9 g. (20 mmol) pyrrole-2-aldehyde and 0.4 g. (2 mmol) p-toluene-sulphonic acid, after acidification and evaporation of the reaction mixture, there is obtained the crude product of the title compound. For purification, the residue is worked up with water and the filtrate is neutralised with 2N aqueous ammonia solution and filtered off with suction. The residue is recrystallised from isopropanol with the addition of ethanolic hydrochloric acid. The yield is 1.2 g. (20% of theory); m.p. of the hydrochloride>300° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][N:49]=1)[C:43]([NH:45][CH3:46])=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][N:49]=2)[C:43]([NH:45][CH3:46])=[O:44])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 56.2 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (1.30 g), 2-bromo-N-methylisonicotinamide (310 mg) and tetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound (480 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=1)=[O:33]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (310 mg) was reacted with 3-chlorophenol (125 μl) to obtain (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (257.24 mg).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.4 %

Procedure:
Under an argon atmosphere, to a solution of 1α,3β-bis(t-butyldimethylsilyloxy)-20-oxopregna-5,7-diene (4.10 g, 7.33 mmol) in dry tetrahydrofuran (80 ml), was added tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 74 ml, 74.0 mmol), and the mixture was refluxed for 16 hours. Then the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 10% hydrochloric acid, an aqueous saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography on silica gel (dichloromethane:ethanol=15:1) to give the title compound (1.68 g, 69%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[Li+].[CH3:36][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH:10]([CH3:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(C)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one (Example 71, Step A) (140.34 g, 298 mmol) in anhydrous THF (994 mL) was degassed by bubbling argon through the solution for 20 minutes while it cooled to −78° C. Iodomethane (23.32 mL, 373 mmol) was added followed by the addition of LHMDS (328 mL, 328 mmol) over 15 minutes. The reaction mixture was stirred for 15 minutes at −78° C. and then the reaction was removed from the cold bath and stirred at rt for 12 hours. The reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL) and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide an orange oil. Purification (wet loaded with small amount of DCM) using the Combiflash Companion XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 1.5 kg SiO2 column and eluting with 4 L each of 15-20-25-30-35% EtOAc/hexanes provided the title compound as a thick very pale yellow oil and a 3.7:1 mixture of C-3 diastereomers.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH3:15].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>CCOCC.O>[Cl:27][CH2:28][C:29]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH3:15])=[O:30]
Reactant: Cc1ccc(Cl)cc1NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(Cl)cc1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2-methyl-5-chloroaniline (8 grams), sodium bicarbonate (7 grams), dioxane (50 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. This mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.3 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about 1 hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from hexane to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2methyl-5-chloroaniline having a melting point of 88° to 89°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:15]
Reactant: CCOC(=O)c1csc(N(CC)CC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)c1nc(CO)cs1

Procedure:
The reaction described in Preparation 15 was then repeated, but using 1.9 g of the above ester, 0.31 g of lithium aluminum hydride, and 40 ml of tetrahydrofuran, giving 2-diethylaminothiazol-4-ylmethanol as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(O)[CH2:32]CCC[CH2:28]1>CCO.CCO.CCO.CCO.[Ti]>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:32][CH2:27][CH2:28][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 8 h

Procedure:
A mixture of 10 g (24 mmol)of tert.butyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 30 g (300 mmol) of cyclohexanol and 1.80 g (8 mmol) of tetraethyl orthotitanate is stirred at 125° overnight, the solution obtained is evaporated to dryness, the residue is taken up in chloroform and stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution. The resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained cyclohexyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 167°-168°.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 56.3 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline (7.5 g) obtained in Example 133 was dissolved in acetone (500 ml) at 50° C. To the resultant solution was added active manganese dioxide (35.6 g) in portions under stirring. The resulting suspension was heated under reflux for 1.5 hr, then filtered through celite and washed with acetone. The filtrate was concentrated under reduced pressure and the resulting pale yellow solid was recrystallized from ethyl acetate to give the title compound (4.2 g) as awhite powder (yield: 56%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCO2
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCO2
Yield: 26.1 %

Procedure:
The title product was prepared in 26.1% yield from 2,3-dihydro-5-benzofuransulfonamide and 4-chlorophenylisocyanate following the procedure of Example 1, m.p. 190°-194° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][C:7]=1[O:23][CH3:24])(=[O:4])=[O:3].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:24][O:23][C:7]1[CH:8]=[C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[C:29]3[S:25][C:26](=[O:31])[NH:27][C:28]3=[O:30])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1cc(CCOc2ccc(C=O)cc2)ccc1OS(C)(=O)=O
Reactant: O=C1CSC(=O)N1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)ccc1OS(C)(=O)=O
Yield: 72.2 %

Procedure:
34 g (97 mmole) 4-[2-(4-formylphenoxy)ethyl]-2-methoxyphenyl methanesulfonate, 12.5 g (107 mmole) 2,4-thiazolidinedione, 0.5 ml piperidine and 0.5 ml acetic acid in 500 ml toluene was refluxed with water separation in a Dean-Stark apparatus for 4 hours. The solvent was evaporated, acetic acid was added and the mixture was heated. The formed precipitate was filtered and washed with diethyl ether to give 31.5 g (yield 72%) of 5-(4-[2-(3-methoxy-4-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CC[Mg+].[Br-].C(OCC)C.[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[OH:19])[CH2:21][CH2:22]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(C(O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-bromo-4-iodobenzene (17.16 g, 60.7 mmol) in THF (130 ml) was immersed in a dry ice-methanol bath. EtMgBr 3M in diethylether (27.0 ml, 81 mmol) was added slowly via syringe at −44° C. to −40° C. (exothermic reaction, grey precipitation!). The reaction mixture was allowed to warm up to −10° C. and after 2 hrs 1-bromo-4-iodobenzene was gone. Then a solution of benzyl 4-formylpiperidine-1-carboxylate (10 g, 40.4 mmol) in THF (30 ml) was added slowly below −65° C. The reaction was allowed to warm up to room temperature and stirred for 14 hrs. The reaction mixture was quenched with saturated aqueous ammonia chloride solution and diluted with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude material which was purified by automated column chromatography (normal phase, ethyl acetate/n-heptane) to obtain the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)=[N:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2>C(Cl)(Cl)Cl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[N:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: COc1ccc(Cc2nnc(Oc3ccc4[nH]c(C)cc4c3F)c3ccccc23)cn1
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(F)c(Oc3nnc(Cc4ccc(O)nc4)c4ccccc34)ccc2[nH]1

Procedure:
In analogy to Ex. 3, treatment of a solution of 1-(4-fluoro-2-methyl-1H-indol-5-yloxy)-4-[6-methoxy-(pyridin-3-yl)-methyl]phthalazine in CHCl3 with Me3Sil, followed by hydrolysis gives the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:19])([CH3:18])[CH2:5][O:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.[CH3:21][NH2:22]>CO>[NH2:7][O:6][CH2:5][C:4]([CH3:19])([CH3:18])[C:3]([NH:22][CH3:21])=[O:2]
Reactant: COC(=O)C(C)(C)CON1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)C(C)(C)CON
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (800 mg) obtained in Step A was added a 40% solution of methylamine in methanol (6 ml), and the mixture was stirred at 60° C. for 13 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and insoluble matter was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (202 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[O:9]1[CH:15]2[CH:10]1[C:11]([CH3:22])([CH3:21])[O:12][C:13]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=12.O>CS(C)=O.C(OCC)(=O)C>[CH3:21][C:11]1([CH3:22])[C@@H:10]([OH:9])[C@H:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[C:14]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:13]=2[O:12]1
Reactant: Cc1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 1 h

Procedure:
2-Pyrrolidone (1.02 g) was added to a suspension of sodium hydride (0.3 g, 80% dispersion in oil) in dry dimethyl sulphoxide (20 ml) under nitrogen at room temperature, and the mixture stirred for 1 h. A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran in dry dimethyl sulphoxide (10 ml) was then added, and the reaction mixture stirred for an additional 16 h. Cautious addition of water and extraction via ethyl acetate gave a crude product (1.84 g) which was chromatographed on silica gel and eluted with 60°-80° C. petroleum ether-ethyl acetate mixtures to give a foam (0.7 g) which was recrystallised from 60°-80° C. petroleum ether-ethyl acetate (0.53 g). Two further recrystallizations from ethyl acetate-pentane gave the analytical sample of the title compound mp 187°-188° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][C:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:41]([C:38]2([CH3:37])[CH2:40][CH2:39]2)=[O:42])[CH2:7]1)#[N:2]
Reactant: CC1(C(=O)O)CC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: CC1(C(=O)N2CC(CC#N)(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 1-methylcyclopropanecarboxylic acid. LCMS (M+H)+: m/z=578.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.