Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[NH:18][C:19](=O)[O:20]C1C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[NH:18][C:19]([CH:3]1[C:2](=[O:1])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2)=[O:20]
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Nc1cccs1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1cccs1)C1C(=O)Sc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 7.5 g of 2,3-dihydro-2-oxo-benzo[b]thiophen in 50 ml of hexamethylphosphoric acid triamide is added dropwise, with cooling, to a suspension of 2.4 g of a 50% sodium hydride/mineral oil dispersion in 100 ml of hexamethylphosphoric acid triamide, the temperature being kept below 15° during the addition. After stirring for half an hour at room temperature, 52 g of phenyl N-(2-thienyl)-carbamate, dissolved in 50 ml of hexamethylphosphoric acid triamide, are added dropwise, with external cooling. The reaction mixture is stirred for a further 16 hours at room temperature and is poured into a mixture of 200 ml of 2 N hydrochloric acid and 1000 ml of ice-water. An oil separates out and this crystallises after about 2 hours. The crystalline product, which contains solvent, is dissolved in 2 N sodium hydroxide solution and the solution is washed four times with ethyl acetate. The organic phase is washed with water, the aqueous phases are combined and acidified to a pH of 1 and the crude product is filtered off with suction and recrystallised from tetrahydrofuran/ether. N-(2-Thienyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide with a melting point of 142°-144° (decomposition) is obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:24]2[N:23]=[C:22]([NH:21][C:20](=[O:29])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
To a solution of 4-(N-methylsulfamoyl)phenylboronic acid (17.2 g, 0.08 mol) and (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (21.9 g, 0.08 mol) in DMF (125 mL) and H2O (125 mL) were added Pd(PPh3)4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g, 0.12 mol). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. for 16 h. The mixture was evaporated under reduced pressure, then poured into H2O, and extracted with EtOAc. The organic phase was dried over Na2SO4, and was evaporated under reduced pressure to give tert-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyridin-2-ylcarbamate (21 g, 58%), which was used in the next step without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=1)[C:12]#[N:13].[Br:17]N1C(=O)CCC1=O>C(#N)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:14]([Br:17])=[CH:15][N:16]=1)[C:12]#[N:13]
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
In an aluminum foil-covered flask in a darkened hood, 2-amino-isonicotinonitrile TFA salt (125 mg, 0.54 mmol) was dissolved in acetonitrile (3.5 mL). Solid N-bromosuccinimide (89.2 mg, 0.501 mmol) was added to the stirred solution in one portion at RT. The reaction solution was stirred at room temperature in darkness for 90 minutes. After evaporation of the solvent, the crude material was further purified by silica gel chromatography to give 2-amino-5-bromo-isonicotinonitrile (53 mg, 49%). LC/MS (m/z): 197.9 (MH+), Rt 2.92 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[NH:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:17][CH:18]1[NH:19][CH:20]([CH3:24])[CH2:21][N:22]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC1CNCC(C)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)N1
Yield: 58.4 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.3 g, 10 mmol), 2,6-dimethylpiperazine (1.14 g, 10 mmol), and EDC (3.82 g, 20 mmol) and DMAP (catalytic) in 20 ml dichloromethane was stirred at room temperature overnight, concentrated, added water and extracted with ethyl acetate 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.9 g of desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16](=[O:18])[CH3:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]([OH:18])[CH3:17])[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanone (1.0 g) in THF (20 mL) was added dropwise DIBAL (0.99 M solution in toluene, 9.34 mL) at −78° C. The reaction mixture was warmed to 25° C. and stirred for 3 hours and a saturated aqueous Rochelle salt solution (50 mL) was added thereto, followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 90:10) to obtain 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanol (0.99 g) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(COCCN2CCOCC2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148 (h)] with 4-(2-chloroethyl)-morpholine there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(2-morpholin-4-yl-ethoxymethyl)-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 725 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31](OC)=[O:32])[C:6]=2[CH:35]=1.CO[BH-](OC)OC.[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:35]=1
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Agent: CO[BH-](OC)OC
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Yield: 41 %

Procedure:
To a solution of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (8 g) in ethylene glycol dimethyl ether (50 ml) is added sodium trimethoxyborohydride (6 g), and the mixture is refluxed for 4 hours. To the mixture is added sodium trimethoxyborohydride (3 g), and the mixture is refluxed for two hours. The reaction solution is gradually poured into diluted aqueous hydrochloric acid solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.1 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=O)[C:10](=[N:18]O)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[CH3:22][NH:23][NH2:24]>CO>[NH2:18][C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:24][N:23]([CH3:22])[C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CCOC(=O)C(=O)C(=NO)C(=O)c1c(Cl)cccc1Cl
Reactant: CNN
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(-c2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(2,6-dichlorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate (14 g, 44 mmol) in MeOH (400 mL) at 0° C., add dropwise concentrated HCl (10 mL) followed by methyl hydrazine (2.02 g, 44 mmol). Stir the reaction mixture at ambient temperature for 8 h and concentrate in vacuo. Partition the residue between EtOAc (400 mL) and saturated aqueous NaHCO3 (150 mL) and separate the layers. Add water (200 mL) to the organic layer, followed by sodium hydrosulfite (150 g) and stir the resulting mixture vigorously for 4 h. Separate the organic phase, wash with water (200 mL), brine (200 mL), dry over MgSO4 and evaporate to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C=O>[CH3:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:49][CH2:48]1
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and 4-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: C(C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)#N.[NH3:21]>O1CCCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH2:21])=[O:4])=[CH:12]1
Reactant: N#CCOC(=O)CCCCCc1c[nH]c2ccccc12
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)CCCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
A solution of 6-(1H-Indol-3-yl)hexanoic acid cyanomethyl ester (5.72 g, 21.16 mmol) in tetrahydrofuran (160 ml) was added to a 25 percent strength ammonia solution (125 ml) and the mixture was stirred at RT for 40 h. Working up of the mixture was carried out by phase separation and extraction of the aqueous phase with THF (2×40 ml). The organic extracts were combined and washed with saturated NaCl solution (50 ml). After drying and concentration of the organic phase, the product was isolated as a colourless solid in a yield of 98% (4.75 g) with an m.p. of
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14](=O)[NH:13][N:12]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:11]([C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(OC)c(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Product: COc1ccc(OC)c(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(2,5-dimethoxyphenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Solvent: O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A 35 ml stainless steel autoclave equipped with a magnetic stirring bar was charged under argon with 1.18 g (2.5 mmol) of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione, 0.985 g (3.75 mmol) of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-diethyl ester, 3.56 g of Dowtherm A and 0.18 ml (1.25 mmol) of triethylamine. The autoclave was closed and immersed into an oil bath at 230° C. The reaction was run with stirring (800 rpm) for 20 min, then the autoclave was cooled in water to room temperature, opened and a sample was taken from the clear, yellowish solution for HPLC analysis (conversion was 99.8%). The reaction mixture was transferred into a 50 ml round flask and the autoclave was rinsed with a total of 16 ml of ethanol. Immediately after the ethanol was added, crystals started to form. The yellowish suspension was stirred for 1 h at room temperature and in an ice bath (ca. 2° C.) for 4 h. The precipitate was filtered with suction, the filter cake was washed with a total of 7 ml of ethanol and dried (60° C., 25 mbar, 17 h) to afford 0.94 g (77.3%) of 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione as a yellowish solid, which according to quantitative HPLC analysis (column: XTerra TM RP18, 3.5 mm, Waters Art. 186000442, mob. phase pH 4.5 buffer/acetonitrile with gradient, flow 1 ml/min, UV detection, retention time of starting material 16.3 min, retention time of product 12.5 min) was 95.5% pure.
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.O.NN.[OH-].[Na+].O>C(O)C>[CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C=CC2CC2)s1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCc1ccc(C=CC2CC2)s1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2-(5-(2-Cyclopropylvinyl)thiophen-2-ylmethyl)isoindol-1,3-dione described in Preparation Example 150 (330 mg, 1.02 mmol) was dissolved in ethanol (50 mL), hydrazine monohydrate (500 mg, 10 mmol) was added thereto, and the solution was stirred under reflux for 2 hours. After cooling to room temperature, 2N sodium hydroxide solution (10 mL) and water (100 mL) were added to the reaction solution, which was then washed twice with hexane (50 mL). The organic layer was dried over anhydrous sodium sulfate, then, the solvent was evaporated in vacuo, and the title compound (180 mg, 1.01 mmol, 98.6%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]2=[N:3]1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])=[CH:10][C:4]2=[N:3]1
Reactant: O=C1CSC(=O)N1
Reactant: Cn1nc2ccc(C=O)cc2n1
Product: Cn1nc2ccc(C=C3SC(=O)NC3=O)cc2n1

Procedure:
Following the general method as outlined in Example 1, starting from 2-Methyl-2H-benzotriazole-5-carbaldehyde (intermediate 33) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]2[C@:21]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:30])[CH2:20]2)[CH:14]=1>>[O:30]=[C:22]1[C@:21]2([CH2:20][C@@H:19]2[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1cccnc1
Product: O=C(O)c1ccc(CN2C(=O)[C@]3(C[C@@H]3c3cccnc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H18ClN2O3: 370, observed (M+H)+: 371.2 1H NMR (400 MHz, DMSO-d6) δppm 2.14-2.23 (m, 1 H) 3.30 (t, 1 H) 5.10 (s, 2 H) 6.14 (d, 1 H) 6.70 (t, 1 H) 6.93 (d, 1 H) 7.10 (t, 1 H) 7.45 (d, 2 H) 7.57-7.65 (m, 1 H) 7.93 (d, 2 H) 8.06 (d, 1 H) 8.61 (d, 1H) 8.71 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C@@H:8]([C:13]([OH:15])=[O:14])[NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].Cl.[Cl-].[Na+]>[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@H:8]([C:13]([OH:15])=[O:14])[NH:9][C:10](=[O:12])[CH3:11])=[CH:16][CH:17]=1)#[N:2]
Reactant: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)N[C@H](Cc1ccc(C#N)cc1)C(=O)O
Reaction time: 20 h
Yield: 28.1 %

Procedure:
A mixture of DL-4-cyano-N-acetylphenylalanine (114.0 g), cobalt chloride(II) (0.63 g) and acylase Amano 15000 (Trademark) (6.27 g) in 1N sodium hydroxide aqueous solution (492 ml) was adjusted to pH=7.5 with 0.1N hydrochloric acid and 0.1N sodium chloride aqueous solution, and then was stirred at 33°-36° C. for 20 hours. The reaction mixture was adjusted to pH=1 with 10% hydrochloric acid, and was washed with ethyl acetate, and the resulting precipitate was collected by filtration. The precipitate was washed with 10% hydrochloric acid and water to give 4-cyano-N-acetyl-D-phenylalanine (32.00 g).
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(CNC(SC)=C(C#N)C#N)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1cccc(CNc2n[nH]c(N)c2C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 25.57 g (98.6 mmol) of 2-cyano-3-(3-methoxy-benzylamino)-3-methylmercapto-acrylonitrile, 5.16 ml (104 mmol) of hydrazine hydrate and 140 ml of methanol is stirred at RT for 1 hour, heated under reflux for 2.5 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethanol/hexane yields the title compound; m.p. 151-153° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.8 %

Procedure:
A solution of but-3-yn-1-ol (10.00 g, 143 mmol) in dichloromethane (310 mL) was treated with dihyropyran (18.10 g, 215 mmol) and pyridinium p-toluene sulfonate (3.60 g, 14.30 mmol). The reaction mixture was stirred at room temperature for 4 days. Water was added and the layers were partitioned. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 1:1 ethyl acetate:heptane to give 21.57 g (98%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 4.65 (m, 1H), 3.90–3.80 (m, 2H), 3.60–3.50 (m, 2H), 2.50–2.45 (m, 2H), 1.95 (m, 1H), 1.90–1.80 (m, 1H), 1.79–1.10 (m, 1H), 1.65–1.50 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][NH:28][N:27]=1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[C:26]([CH3:25])=[N:27][NH:28][CH:29]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1n[nH]cc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)sc2n1
Yield: 20 %

Procedure:
The titled compound (yield=20%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.59 (br. s., 3H) 3.49 (br. s., 2H) 7.57 (d, J=8.34 Hz, 2H) 7.74 (d, J=8.59 Hz, 1H) 8.02 (br. s., 1H) 8.05-8.13 (m, 3H) 12.86 (s, 1H); ESI-MS: m/z 408.0 (M+H)+.