Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:5]([CH3:7])[N:6]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[N:16]([CH3:27])[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(Cl)sc1-c1c(OC(=O)C(C)C)c2nccnc2[nH]c1=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1nc(Cl)sc1-c1c(OC(=O)C(C)C)c2nccnc2n(C)c1=O
Temperature: 25 °C

Procedure:
Isobutyric acid 7-(2-chloro-4-methyl-thiazol-5-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 2.4) (0.10 g), methyl iodide (0.18 ml) and potassium carbonate (0.075 g) were heated in acetonitrile (4 ml) in a microwave to 100° C. for 10 minutes. The reaction mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with water, aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate and concentrated to give Compound No. B2 of Table B (0.078 g).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18](=O)[CH3:19].C1COCC1.CCOC(C)=O>[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:19]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=NS(=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
A 250 ml RBF was charged with 2-methyl-2-propanesulfinamide (3.64 g, 30.0 mmol) and 1-(2-fluoro-5-nitrophenyl)ethanone (5.00 g, 27.3 mmol). THF (55 ml) was added and the resulting slurry was stirred for 5 min until full dissolution was observed. Titanium(IV) ethoxide, technical grade (11.30 ml, 54.6 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was cooled to RT and diluted with 70 ml brine. After stirring for 15 min, EtOAc (50 ml) was added to the mixture and the organic layer was decanted. The aqueous suspension was extracted twice with EtOAc, and the organic fractions were combined, washed with brine and concentrated in vacuo. The residue was purified by FC on 120 g RediSep Gold column using a solvent gradient of 5-50% EtOAc in heptane to afford N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (5.88 g, 20.54 mmol, 75% yield) as yellow oil, which crystallized slowly.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](O)=[O:13].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12]([Cl:25])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1c(F)cc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(F)cc(C(=O)Cl)cc1F

Procedure:
To 17 ml of toluene were added 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid, 1 ml of thionyl chloride and 10 mg of DMF and the mixture was heated under reflux for 4 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain 1.9 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride represented by the formula:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=2[NH2:24])=[CH:2]1.[CH:25](O)=O>>[N:23]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:18]=2[NH:24][CH:25]=1
Reactant: Nc1cccc(OCCNCCCc2c[nH]c3ccccc23)c1N
Reactant: O=CO
Product: c1cc(OCCNCCCc2c[nH]c3ccccc23)c2[nH]cnc2c1
Temperature: 104 °C
Reaction time: 8 h

Procedure:
A solution of 3-{2-[3-(1H-indol-3-yl)-propylamino]-ethoxy}-benzene-1,2-diamine (0.75 g, 2.3 mmol) dissolved in 15 ml formic acid (98%) was heated to 104° C. for 6 hours. Upon standing overnight at 25° C., the excess formic acid was removed by vacuum distillaton. Water (100 ml) and ethyl acetate (100 ml) was added thereto. The ethyl acetate layer was separated and washed once with water (50 ml), once with brine (75 ml) and dried over anhydrous magnesium sulfate. Concentration of the solvent gave 0.7 g of product as a brown solid. Purification by chromatography (2 N ammonia in methanol:methylene chloride=20:1.5) and crystallization from ethyl acetate-ethanol afforded 0.345 g (44.8%) of product as a white solid: mp 121-124° C. decomposed. The HCl salt was prepared in ethanol: mp 256-258° C. decomposed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])nn1CC(=O)OC(C)(C)C

Procedure:
To a stirring mixture of 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (3.5 gm, 20.5 mmol) dissolved in 150 ml of acetone was added cesium carbonate (8.01 gm, 24.6 mmol) followed by the addition of tert-butyl bromoacetate (3.61 ml). After 5 hours the solids were filtered and the mixture chromatographed on silica gel using 10% ethyl acetate/hexanes as the eluent to obtain 4.16 gm of pure title product. ESI M+1=286.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C.O>ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 1-methyl-[1,4]diazepane (2.19 mL) in dry dichloromethane (30 mL) was treated with a solution of 4-nitrobenzoyl chloride (3.6 g) in dry dichloromethane (30 mL) dropwise over 10 minutes. After stirring at room temperature for a further 10 minutes the reaction mixture was treated with triethylamine (2.8 mL) and then stirred for a further 3 hours. The reaction mixture was then treated with water (10 mL), the organic phase separated and further washed twice with a 2 M aqueous solution of sodium hydroxide (20 mL), then four times with water (15 mL). The organic phase was then dried over magnesium sulfate and evaporated to give the title compound (4.4 g) as brown oil, Rf 0.64 (dichloromethane:methanol, 4:1). MS: 264 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C)CC1)O2

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester was synthesized starting from the hydrochloride salt of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (500 mg, 1.43 mmol, Intermediate 3), according to the procedure for preparation of Example 23, Step A, using aqueous 37% formaldehyde solution (0.127 ml, 1.71 mmol), and NaBH(OAc)3 (461 mg, 2.14 mmol) giving a yellow solid (374 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Na].[CH2:10]([OH:13])[CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCCO
Reactant: ClCc1ccccn1
Agent: [Na]
Product: OCCOCc1ccccn1

Procedure:
2-Chloromethylpyridine is reacted with the sodium salt of ethylene glycol to give 2-(2-hydroxyethoxymethylpyridine. Treatment of 2-(2-hydroxyethoxymethyl)pyridine with thionyl chloride gives 2-(2-chloroethoxymethyl)pyridine.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[OH-].[K+].[K].[Cl-].[Mg+2].[Cl-].[F:18][C:19]1[C:24](C(Cl)=O)=[C:23]([F:28])[C:22]([F:29])=[C:21]([F:30])[C:20]=1[F:31]>C(O)C.C(#N)C.C(N(CC)CC)C>[F:18][C:19]1[C:24]([C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:23]([F:28])[C:22]([F:29])=[C:21]([F:30])[C:20]=1[F:31]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [K]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 20 g (125 mmol) of diethyl malonate in 80 ml of absolute ethanol was added with stirring a solution of KOH pellets (7 g) in 80 ml of absolute ethanol over a period of 12 minutes and the resulting mixture was stirred at room temperature for 2 hours. The solution was heated to boiling, filtered while hot, and the filtrate was cooled and filtered to afford, after drying, 11.14 g (53%) of potassium ethyl malonate. To a stirred and cooled (10° C.) mixture of the above potassium salt (11.14 g; 66 mmol) in 100 ml of acetonitrile was added triethylamine (6.5 g, 64 mmol) and magnesium chloride (7.5 g, 80 mmol) and the resulting mixture was stirred at room temperature for 2 hours. To the above mixture, cooled to 0° C., was added dropwise pentafluorobenzoyl chloride (7.4 g; 32 mmol) followed by the addition of 0.64 g of triethylamine, and the resulting mixture was allowed to stir at room temperature overnight and then was concentrated to dryness. The resulting mixture was diluted with 40 ml of toluene, concentrated in vacuo, and the residue was rediluted with 60 ml of toluene, stirred, and cooled to 10° C. An aqueous HCl solution (13%; 45 ml) was added in portions to the above reaction mixture at below 25° C., the organic layer was washed with 13% HCl solution (2×12 ml), water, and concentrated in vacuo. The residue was distilled to afford 8.4 g (93%) of ethyl pentafluorobenzoylacetate as an oil, b.p.139°-147° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([N:15]2[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1cccc(Br)c1
Product: OC1CCN(c2cccc(C(F)(F)F)c2)C1
Yield: 54 %

Procedure:
The title compound (2.67 g, yield 54%) was obtained from 3-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=3)[C:6]([CH3:19])([CH3:18])[C:5]=2[CH:4]=[CH:3]1>CCO.Cl.[Pd]>[CH3:1][N:2]1[CH2:14][CH:13]2[CH:5]([C:6]([CH3:19])([CH3:18])[C:7]3[C:12]2=[CH:11][C:10]([NH2:15])=[CH:9][CH:8]=3)[CH2:4][CH2:3]1
Reactant: CN1C=CC2=C(C1)c1cc([N+](=O)[O-])ccc1C2(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC2C(C1)c1cc(N)ccc1C2(C)C
Reaction time: 6 h

Procedure:
3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene (700 mg) was dissolved in EtOH (20 mL) with aqueous HCl (1N, 5 mL) and suspended with Pd/C (10%, 100 mg). The flask was capped with a balloon filled with H2. The reaction was completed in 6 h at RT. The reaction mixture was filtered through a layer of Celite® with MeOH. The combined filtrate was concentrated to give desired compound. (MS: M+H=231).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([N:17]1[C:21]([N:22]2[N:31]=[C:30]3[C:24]([CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][C:29]=43)=[CH:23]2)=[N:20][CH:19]=[N:18]1)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:36]([C:33]2[CH:34]=[CH:35][C:28]3[O:27][CH2:26][CH2:25][C:24]4[C:30](=[N:31][N:22]([C:21]5[N:17]([CH:14]([CH3:15])[CH3:16])[N:18]=[CH:19][N:20]=5)[CH:23]=4)[C:29]=3[CH:32]=2)=[O:37])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
A mixture of N-Boc piperazine (101 mg, 0.54 mmol), 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carboxylic acid (180 mg, 0.53 mmol), EDCI (151 mg, 0.79 mmol), HOBt (107 mg, 0.795 mmol) and triethylamine (216 L, 1.54 mmol) in DMF (2 mL) was stirred at RT for 20 h. The mixture was diluted with ethyl actetate and washed (water, saturated aqueous sodium hydrogen carbonate and then brine), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 4-[2(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (258 mg, 96%). The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (20 mL) and treated with 4N HCl in dioxane (4 mL) and stirred for 3 h at RT before adding diethyl ether (20 mL). The resultant precipitate was collected by filtration and washed with diethyl ether to give 145 as a white solid (209 mg, 93%). 1H NMR (400 MHz, DMSO-d): δ 9.32 (s, 2H); 8.37 (s, 1H); 8.31 (d, J=2.20 Hz, 1H); 8.06 (s, 1H); 7.44 (dd, J=8.37, 2.21 Hz, 1H); 7.15 (d, J=8.37 Hz, 1H); 5.32-5.23 (m, 1H); 4.37 (t, J=4.98 Hz, 2H); 3.77 (s, 4H); 3.15 (t, J=6.94 Hz, 6H); 1.51 (d, J=6.59 Hz, 6H). LCMS: RT=6.02 min, M+H+=408
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=O)=O)=CC=1.Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: O=C(Nc1cc(O)c(Cl)cc1F)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1

Procedure:
Then, benzyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (12.2 g, 41.3 mmol), potassium carbonate (5.97 g, 432.1 mmol), cyclopentyl p-toluenesulfonate (11.2 g, 46.4 mmol) and acetone (150 ml) as a solvent were charged into a 500 cc round-bottom Flask and heated for 9 hours while refluxing. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid. After thoroughly stirring, the precipitated benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as a pale yellow solid (14.9 g, 40.9 mmol, 994 yield) was isolated by filtration and well dried. 1H-NMR Spectrum (CDCl3, TMS, ppm): δ1.48-2.07 (8H, m), 4.83 (1H, m), 5.26 (2H, s), 6 92 (1H, br, s) 7.14 (1H, d, JHF =11.5 Hz), 7.47 (5H, s), 7.93 (1H, d, JHF =8.3 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH3:17])=[N:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)[C:6]([CH2:16][CH3:17])=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1
Reactant: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Product: CCc1nn(C2CCCC2)c2cc(-c3ccccc3)ccc12
Yield: 77.2 %

Procedure:
This compound was prepared according to the method of Example 55, using 128 mg (0.437 mmol, 1.0 equiv) 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole and 75 mg (0.612 mmol, 1.4 equiv) phenyl boronic acid as starting materials, to give 98 mg (77%) of white crystals: mp 72-74° C.; Anal. calcd for C20H22N2: C, 82.77; H, 7.64; N, 9.65. Found: C, 81.95; H, 7.82; N, 9.75.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]2=[N:8][CH:9]=[CH:10][N:5]2[N:4]=1.C1C(=O)N([I:18])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N>[I:18][C:10]1[N:5]2[C:6]([S:7][C:3]([S:2][CH3:1])=[N:4]2)=[N:8][CH:9]=1
Reactant: CSc1nn2ccnc2s1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CSc1nn2c(I)cnc2s1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-Methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazole (100.00 mg; 0.43 mmol; 1.00 eq.) was dissolved in CH3CN (4.00 ml) protected from light. Then, n-iodosuccinimide (97.22 mg; 0.43 mmol; 1.00 eq.) was added and the reaction was stirred overnight. The reaction was not completed. N-iodosuccinimide (388.88 mg; 1.73 mmol; 4.00 eq.) was added and the reaction was stirred at room temperature. After 1 day, the reaction was finished. A saturated solution of sodium thiosulfate was added and the aqueous phase was extracted 2 times with DCM. The combined organics were washed with saturated aqueous NaHCO3, NH4Cl, brine, dried over MgSO4 to give 127.6 mg of the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(Cl)c3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][C:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH:13]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)=CC(=O)O1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
To 6-t-butyldimethylsilyloxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one (0.26 parts) in dichloromethane (3 cm3) at ambient temperature was added pyridine (0.1 parts) and then acetyl chloride (0.1 parts). After approximately 30 minutes at ambient temperature the reaction mixture was washed with water, dried over MgSO4 and evaporated to yield 4-acetoxy-6-t-butyldimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.2 parts).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:21](=[O:22])[O:20]/[C:9](=[C:10](/[C:17]([OH:19])=[O:18])\[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:8]=2O)=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[CH:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:17](=[O:19])[O:18][C:8]3=[C:7]([C:4]4[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:21]([O:20][C:9]=23)=[O:22])=[CH:12][CH:13]=1
Reactant: O=C1O/C(=C(/C(=O)O)c2ccccc2)C(O)=C1c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC2=C(c3ccccc3)C(=O)OC2=C1c1ccccc1

Procedure:
Pulvinic acid (19.0 g., 0.0616 mol.) was refluxed in 250 ml. of acetic anhydride for 15 minutes. The cooled solution was stirred into 1200 ml. of ice and water and the oily mass was crystallized by stirring in 500 ml. of ethanol. The yellow solid was removed, washed with ethanol and dried to yield pulvinic acid lactone, m.p. 221.5°-223°.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:7]([CH2:16][N:17]([C@@H:25]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH:37]1[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]1>C(O)C.C(Cl)(Cl)Cl>[C:20]([O:19][C:18]([N:17]([CH2:16][C@@H:7]1[C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:37]2[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]2)[CH2:6]1)[C@@H:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1CCN(CCC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A mixture of 750 mg of tert-butyl {[(3R,4S)-1-acryloyl-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 8 ml of an ethanol:chloroform (4:1) mixed solvent was mixed with 487 mg of ethyl isonipecotate and stirred at 60° C. for 6Hours, and the reaction solution was concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 700 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}piperidine-4-carboxylate as a pale yellow amorphous substance. By carrying out the Boc-elimination from the thus obtained compound in the same manner as in Example 2, ethyl 1-{3-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}pyridine-4-carboxylate dihydrochloride was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(N)c(-c2ccc(Cl)cc2)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(-c2ccc(Cl)cc2)c2ccccc2n1C

Procedure:
To ten grams of 2-amino-3-(p-chlorophenyl)-1-methylindole hydrochloride in 80 ml. of pyridine, 5.4 ml. acetic anhydride are added under stirring at 20°-25° C. After five hours the pyridine is distilled off in vacuo at 40°-45° C and the oily residue solidifies with water. The product is crystallized from methanol. Yield 7.9 g. M.p. 196°-197° C.