Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28]([OH:30])=O)=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[CH2:31]([O:33][CH2:34][CH2:35][NH2:36])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:31]([O:33][CH2:34][CH2:35][NH:36][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:30])[CH3:32]
Reactant: CCOCCN
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC
Yield: 82.6 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (72 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 510.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.27 (s, 1H), 8.34 (t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26 (s, 1H), 4.0 (s, 3H), 3.64 (s, 3H), 3.56-3.43 (m, 6H), 1.16 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([CH3:13])[CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19].C(O)C.Cl>[Cl-].[Zn+2].[Cl-].O>[O:19]=[C:18]1[O:1][C:2]2=[N:11][C:10]3[N:9]([CH3:12])[CH2:8][CH2:7][CH:6]([CH3:13])[C:5]=3[CH:4]=[C:3]2[C:16]([C:15]([F:25])([F:24])[F:14])=[CH:17]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1CCN(C)c2nc(O)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: CC1CCN(C)c2nc3oc(=O)cc(C(F)(F)F)c3cc21

Procedure:
The following procedure is typical of that used to prepare the various azacoumarins. 7-Hydroxy-1,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (0.19 g.), 1.2 ml. of ethyl trifluoroacetoacetate, 50 mg. of anhydrous zinc chloride, and 10 ml. of absolute ethanol were refluxed for 40 hours. The cooled solution was poured with stirring into 50 ml. of water plus 3 ml. of hydrochloric acid; the yellow precipitate was filtered, washed with water, and dried (0.31 g., 95%). Solvent used for recrystallization, melting point, fluorescence data and analytical data are summarized in the table below. The 1H nmr spectral data (deuteriochloroform, 100 MHz) on the analogous 6,8,9-trimethyl derivative are: δ1.37 (d, 6H, CH3CH), 1.47 (m,1H, H7b), 2.10 (dt, 1H, H7a,J=13 Hz, J=4 Hz), 2.80 (m, 1H, H6), 3.20 (s, 3H, NCH3), 3.70 (m, 1H, H8), 6.38 (s, 1H, H3), 7.41 (q, 1H, H5, JH5 --CF3 =~1.5 Hz).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[Na].[O:12]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(C)C>[O:12]([CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH2:24][CH2:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Agent: [Na]
Solvent: CC(C)O
Product: Nc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Yield: 63.9 %

Procedure:
9.45 g (0.07 mole) of adenine are added to a solution of 1.6 g (0.07 mole) of sodium in 250 ml of isopropanol and the reaction mixture heated under reflux for 10 minutes. It is then cooled and 21.4 g (0.08 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride in 50 ml of isopropanol added thereto. After stirring the reaction mixture under reflux for 6 hours, it is evaporated in a vacuum, the residue is taken up in methylene chloride, the methylene chloride solution is washed with 2N aqueous sodium hydroxide solution and subsequently with water, dried over anhydrous sodium sulfate, evaporated and the residue recrystallized from isopropanol. There are obtained 16.4 g (64% of theory) of 9-[3-(4-phenoxymethylpiperidino)-propyl]-adenine; m.p. 142° - 144° C.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[OH-].[Na+]>C(O)C>[CH3:3]/[C:2](=[CH:12]\[C:11]1[CH:14]=[CH:15][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)/[CH:1]=[O:4]
Reactant: CCC=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(C=O)=C\c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
Propionaldehyde (14.3 ml, 11.5 g, 0.20 mol) was added to a solution of 4-nitro benzaldehyde (20.0 g, 0.13 mol) in 50% aqueous ethanol (300 ml). An aqueous solution of 1M sodium hydroxide (36 ml, 0.04 mol) was then added dropwise, with stirring, at room temperature. After stirring for 1.5 h the precipitated solid was collected by filtration and recrystallised from aqueous ethanol to give 19.4 g (77%) of the product as a yellow solid, mp 112-114° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].Cl.C([O-])(=O)C.[Na+]>O.CC(=O)CC>[C:13]([CH2:14][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:15])[CH3:12]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC(=O)CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)CSc1nc2ccccc2[nH]1

Procedure:
2-Mercaptobenzimidazole (14.6 g, 0.1 mole) and chloroacetone (9.25 g, 0.1 mole) were added to 2-butanone (400 ml) and refluxed for 5 hrs. On cooling the product hydrochloride, 21.24 g, 88% was isolated by filtration, washed with acetone and air dried. The salt was dissolved in water (150 ml) and added to a solution of sodium acetate (7.2 g, 0.088 mole) in water (100 ml). The oil obtained was extracted into ethyl acetate, filtered to remove some insoluble material (0.4 g), dried and evaporated to dryness. The residue was crystallised from ethanol to give three crops of 2-(acetylmethylthio)benzimidazole (2), as colourless crystals, 15.0 g, 73%, mp. 112°-113° C. PMR was consistent with a tautomeric mixture of the open chain and ring closed forms.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:14]2[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:14]2[NH:13][N:12]=1
Reactant: N#Cc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2n1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To 10 mL of a solution containing 360 mg of 3-naphthalen-2-yl-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile obtained by Production example 15 in dichloromethane, 3 mL of trifluoroacetic acid was added at room temperature and stirred for 2 hours. The reaction solution was added with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating, the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=3:1), to afford 180 mg of the title compound as a colorless powder.
Reaction SMILES: II.[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].C(O)(=[O:15])C>>[CH3:3][C:4]1[C:5](=[O:12])[C:6]([CH3:11])=[CH:7][C:8](=[O:15])[C:9]=1[CH3:10]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: CC(=O)O
Agent: II
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 94.7 %

Procedure:
Halogenation and subsequent oxidation were conducted in the same manner as in Example 8 except for adding 0.068 g of iodine to the acetic acid solution of 2,3,6-trimethylphenol upon chlorination. Thus, there was obtained 14.2 g (94.7 percent in yield) of 2,3,6-trimethyl-p-benzoquinone.
Reaction SMILES: CI.[C:3]1([CH2:9][O:10][C:11]([C:13]2([NH:19][C:20]([N:22]3[CH2:26][CH2:25][NH:24][C:23]3=[O:27])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:3]1([CH2:9][O:10][C:11]([C:13]2([NH:19][C:20]([N:22]3[CH2:26][CH2:25][N:24]([CH3:28])[C:23]3=[O:27])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)C1=O
Yield: 45.9 %

Procedure:
1.83 g (12.9 mmol) of methyl iodide was added to a solution of 1.50 g (4.3 mmol) of 1-[[(2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 1.78 g (12.9 mmol) of potassium carbonate in 100 ml of acetonitrile, and the mixture was heated under reflux overnight. The reaction solution was concentrated, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 710 mg (50%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Sc3ccccc32)CC1
Temperature: 0 °C

Procedure:
12.5 g of 1-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 13 g of powdered potassium carbonate, 0.2 g of potassium iodide and 1 litre of toluene, with 13.2 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 25 hours. Then the mixture is poured on to ice-water and diluted with benzene. The benzene solution is washed neutral with water and extracted with 2-N hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide and extracted with benzene. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained crude 3-[2-[4-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is converted into the maleate of melting point 170°-172° C by treatment with maleic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>CO>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(C)cc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CO
Product: Cc1cc2nc3ccc(C(=O)O)cn3c(=O)c2s1
Temperature: 180 °C

Procedure:
A mixture of 1.7 g (0.01 mol) of 3-amino-5-methyl-2-thiophenecarboxylic acid, methyl ester (German Patent 1055007, April 16, 1959) and 1.6 g (0.01 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) is heated in an oil bath at 180° C. for two hours. The mixture is cooled, dissolved in hot methanol, cooled and 0.23 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid is collected; mp 338°-340° C. after recrystallization from methanol.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[OH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[NH2:4])[CH2:14]1
Reactant: OC1CCNC1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Product: Nc1cc([N+](=O)[O-])ccc1N1CCC(O)C1
Yield: 46.6 %

Procedure:
According to a process similar to that described in Example II-1, starting from 3 g (19.22 mmol) of 2-fluoro-5-nitroaniline and 1.76 ml (21.14 mmol) of 3-hydroxypyrrolidine, 2 g of expected compound are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16](Cl)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(OCc3ccccc3)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
Under inert gas, 4.89 g of (4-benzyloxyphenyl)methanesulfonyl chloride were initially charged in 120 ml of THF, then, at a temperature of −20° C., 6.10 ml of 2,4-dimethoxybenzylamine were added dropwise and the reaction solution was allowed to come to 0° C. within 30 minutes. The reaction solution was diluted with 150 ml of ethyl acetate and washed with water, dilute aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (3.23 g) with a molecular weight of 427.5 g/mol (C23H25NO5S).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].CCOCC>CN(C=O)C>[Si:31]([O:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCc1cc(O[Si](C)(C)C(C)(C)C)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 20 h
Yield: 99.2 %

Procedure:
32 g (112 mmol) of 1-hydroxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one were initially introduced in 200 ml of DMF, 10 g of imidazole (145 mmol) were added, a solution of 21 g (135 mmol) of tert-butyldimethyl-silyl chloride in 100 ml of DMF was added dropwise at 0° C., and the mixture was stirred at room temp. for 20 h. MTB ether was subsequently added to the batch, which was then washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography with heptane/ethyl acetate (6:1), giving 44.5 g (94%) of 1-tert-butyl-dimethylsilyloxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:35][CH2:36][CH3:37])([CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:36]([O:35][C:5]([CH3:34])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:38])=[O:3])[CH3:37]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (0.19 g, 0.347 mmol) and 5N NaOH (0.5 mL) in ethanol (5 mL) is refluxed for 1 h, cooled to ambient temperature, and concentrated. The residue is diluted with CH2Cl2, washed, dried, and concentrated in vacuo to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.63 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.08 (d, 2H, J=8.7 Hz), 6.76 (d, 2H, J=8.7 Hz), 4.37, 4.35 (ABq, 2H, J=16.4 Hz), 3.99-3.89 (m, 2H), 3.63-3.53 (m, 1H), 3.43-3.23 (m, 2H), 2.98 (t, 1H, J=8.8 Hz), 2.86, 2.84 (ABq, 2H, J=15.4 Hz), 2.71 (s, 3H), 2.51-2.49 (m, 3H), 2.23-2.13 (m, 1H), 1.86-1.74 (m, 1H), 1.15 (s, 3H), 1.08 (t, 3H, J=6.9 Hz). MS [ES+] m/z exact mass calcd for C26H32N2O5F3 509.2263, found 509.2288.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43](Cl)(=[O:45])=[O:44])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:45])=[O:44])([CH3:29])[CH3:30]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C(C)C)c1
Yield: 34 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,4,6-triisopropylbenzenesulfonyl chloride under the conditions used in example 2 giving 34% of the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]#[C:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:5][CH:4]=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26](P(=O)(OCC)OCC)Cl)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:1][C:3]2[S:7][C:6]([C:8]#[C:9][C:10]3[S:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[CH:14]=3)=[CH:5][CH:4]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(C#Cc2cc3ccccc3s2)s1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(C#Cc2ccc(C#Cc3cc4ccccc4s3)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
A stirred solution of 0.75 gram (0.0028 mole) of 2-(5-formylthien-2-ylethynyl)benzothiophene and 0.83 gram (0.0028 mole) of diethyl (4-chlorophenyl)chloromethylphosphonate in 10 ml of dimethylformamide was cooled to 0° C., and 0.94 gram (0.0084 mole) of potassium tertbutoxide was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes and then was allowed to warm to ambient temperature where it was stirred for 18 hours. After this time the reaction mixture was subjected to column chromatography on silica gel. Elution was accomplished using hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.20 gram of 2-[5-(4-chlorophenylethynyl)thien-2-ylethynyl]benzothiophene; m.p. 189°-191° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:11][NH2:12]>C(O)(C)C>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[NH:12][N:11]=1
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(N)n[nH]1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Isopropanol 800 ml was added to pivaloylacetonitrile 600 g and heating and stirring were applied. Hydrazine hydrate 288 g was dropped thereto and heating and stirring were applied for 3 hours. After finishing the reaction, isopropanol 400 ml was distilled off under reduced pressure. Ethyl acetate 2000 ml and a saturated salt aqueous solution were added to a residue and stirring was applied. After leaving for standing for a while, an aqueous layer was removed and an ethyl acetate layer was washed twice with the saturated salt aqueous solution, followed by drying an ethyl acetate solution over magnesium sulfate anhydrous. This ethyl acetate solution was concentrated under reduced pressure and then n-hexane 2000 ml was added to a residue to precipitate crystal. This crystal was filtered off and dried, whereby 3-amino-5-t-butylpyrazole (Compound (A)) 643 g (96.2%) was obtained. The melting point was 74.0 to 75.0° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH3:5]>>[C:1]([CH2:2][CH2:3][NH:5][CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: N
Reactant: C=CC#N
Product: N#CCCNCCC#N

Procedure:
It is advantageous to introduce the acrylonitrile into the reactor at a space velocity of about 0.05 to 0.6 hr-1. Simultaneously, a gaseous ammonia charge is introduced into the reactor via a distribution device; e.g. a frit at the lower floor of the column, preferably in such an amount that the acrylonitrile and ammonia flow through the reaction chamber at a mole ratio of 2 : 1. According to the method of the present invention, the ammonia is completely absorbed as the gas bubbles rise. Furthermore, the ascending gas bubbles insure an intimate mixing of the reactants and thus an immediate reaction occurs resulting in the formation of bis-(2-cyanoethyl)-amine. The reaction product is removed at the lower end of the reactor above the distribution device. It is recovered as a clear liquid with a water content between 8 and 15% depending on the water concentration in the acrylonitrile. The yields obtained are greater than 90%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][C:13]([F:14])([F:15])[F:16]
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: Nc1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of 3-bromo-5-nitro-2-(2, 2, 2-trifluoro-ethoxy)-pyridine (2.4 g, 7.97 mmol) in ethanol (100 ml) were added HCl (0.3 ml) and stannous chloride (10.5 g, 55.81 mmol) at 25° C. and the reaction mixture was stirred for 4 h at 25° C. After total consumption of starting material (monitored by TLC), ethanol was evaporated under reduced pressure, diluted with ethyl acetate, neutralized with aqueous Na2CO3 solution, and filtered through a bed of celite. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×120 ml). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo to get the desired compound (2.1 g, 97%) as brown liquid. This was used as such for the next step without further purification. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDCl3): δ 4.70 (m, 2H), 7.30 (d, 1H), 7.54 (d, 1H).