Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[Br:23][C@@H:24]([CH2:28][OH:29])[C:25]([OH:27])=O.[Cl-].[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH2:37][NH2+:38][CH2:39][S:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>O1CCCC1>[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]([CH2:39][S:40][C:41]([CH3:42])([CH3:44])[CH3:43])[C:25](=[O:27])[C@@H:24]([Br:23])[CH2:28][OH:29])=[CH:35][CH:34]=1
Reactant: O=C(O)[C@@H](Br)CO
Reactant: COc1ccc(C[NH2+]CSC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN(CSC(C)(C)C)C(=O)[C@@H](Br)CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.13 g (20 mmol) of dicyclohexyl carbodiimide and 2.79 ml (20 mmol) of triethylamine are added at room temperature while stirring to a mixture of 3.38 g (20 mmol) of 2-(S)-bromo-3-hydroxypropionic acid and 5.151 g (20 mmol) of p-methoxybenzyl-tert.-butylthiomethylammonium chloride (Example 24) in 100 ml of tetrahydrofuran. The mixture is stirred for two hours at room temperature and the dicyclohexylurea that has precipitated is filtered off with suction. The filtrate is concentrated by evaporation under reduced pressure and the residue is chromatographed over 500 g of silica gel using toluene/ethyl acetate (9:1). The title compound is obtained in the form of a colourless, viscous oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:30])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (5.70 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (2.85 g) and methyl iodide (930 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (5.67 g, yield 96%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 434 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].C.[CH2:14]([OH:16])[CH3:15]>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:16][CH2:14][CH3:15])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1=COCC1
Reactant: CCO
Agent: C
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (10 g) was dissolved in Ethanol (50 ml) and Methane sulphoic acid (0.1 ml) was added to it. The reaction mass was stirred at 40-50° C. for 12 hrs. Reaction mass was concentrated to residue under vacuum. Residue was dissolved in dichloromethane (50 ml) and washed with water (50 ml). Reaction mass was concentrated to residue to get ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 9.2 g).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][CH2:20][NH2:21].Cl.Cl>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH2:20][NH2:21])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)CCCN
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Product: NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
It is also possible according to the present invention to employ a non-proteinogenic amino acid as a nucleophile. Mal-Tyr-OEt, an electrophile, and Orn-OEt.2HCl, a nucleophile, were reacted using α-CT as a catalyst. After a reaction time of 20 minutes, the solution was concentrated, the enzyme was separated off by ultrafiltration with a membrane with MWCO 10,000, and the dissolved fraction was lyophilized. Both Mal-Tyr-Orn and the Orn delta-lactam cyclization product were isolated by preparative HPLC and identified by 1H-NMR. The combined yield of the two products (about 1:1) was about 45-50%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[C:9]2[C:17]([OH:19])=[O:18])([O-:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:18][C:17]([C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)=[O:19])[CH3:21]
Reactant: CCO
Reactant: O=C(O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12

Procedure:
52 parts of 8-nitro-naphthalene-1,4-dicarboxylic acid are dissolved in 700 parts of absolute ethyl alcohol and the solution is boiled under reflux for 12 hours whilst continuously passing in hydrogen chloride gas. The resulting solution is evaporated in vacuo. The 4-ethoxycarbonyl-8-nitro-naphthalene-1-carboxylic acid of the formula ##STR15## which is obtained in this way, melts at 178° to 180°.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C@H:41]([OH:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:41](=[O:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
220 mg (0.59 mmol) of pyridinium dichromate were added to a solution of 48 mg (0.08 mmol) of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide in 1 ml of dimethylformamide and the mixture was stirred at room temperature for 18 hours. 10 ml of water were added and the mixture was extracted with two 10 ml portions of ethyl acetate. The combined extracts were washed with two 10 ml portions of water, dried over anhydrous magnesium sulphate and evaporated. The crude product was chromatographed on a column of silica gel using 4% methanol in dichloromethane for the elution to give 31 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2-oxo-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 186°-188° C.; MS m/e 578 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cl)cc1Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1Oc1ccc(CBr)cc1
Yield: 52.7 %

Procedure:
A solution of the product of Step B (200 mg, 0.690 mmol), NBS (117 mg, 0.95 eq) and AIBN (10 mg, catalytic amount) in CCl4 (5 mL) was heated at reflux for 2 hours and then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (30×130 mm) eluted with 5% ethyl acetate/hexane to yield 128 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21](=[NH:24])OC)[CH:16]=2)[NH:11][N:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21](=[NH:24])[N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: C1COCCN1
Reactant: COC(=N)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=N)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A solution of methyl 3-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzimidate from Step in MeOH (1.0 mL) was added morpholine (15.3 mg, 0.176 mmol) and triethylamine (90 mg, 0.88 mmol), the mixture was stirred at room temperature for 3 days. The solvent was then removed and the crude product purified by reverse phase HPLC to afford C-{3-[3-(2-Methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-C-morpholin-4-yl-methyleneamine (3.7 mg, 10% yield two steps) as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.86 (d, 2 Hz, 1H), 8.45 (d, 2 Hz, 1H), 8.37 (br s, 1H), 8.02 (m, 1H), 7.96 (t, 1.8 Hz, 1H), 7.76 (t, 7.8 Hz, 1H), 7.66 (dd, 1.8 Hz, 7.8 Hz, 1H), 7.63 (m, 1H), 7.49 (m, 1H), 7.21 (d, 8 Hz, 1H), 7.12 (dt, 1 Hz, 7.8 Hz, 1H), 3.95 (m, 2H), 3.88 (s, 3H), 3.82 (m, 2H) 3.78 (m, 2H), 3.59 (m, 2H). MS: m/z 414.1 [MH+].
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>O>[Cl:17][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: N#CC(Cl)(c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
A mixture of 25 g (0.13 m) of diphenylacetonitrile and 27 g (0.13 m) of phosphorus pentachloride is heated at 125° for 4 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is evaporated to give 27 g of crude α-chlorodiphenylacetonitrile.
Reaction SMILES: [CH3:1][C:2]1([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[S:15]([NH2:18])(=[O:17])=[O:16])OCC(C)(C)C[O:3]1>C1COCC1.Cl>[C:2]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[S:15]([NH2:18])(=[O:16])=[O:17])(=[O:3])[CH3:1]
Reactant: CC1(C)COC(C)(c2ccsc2S(N)(=O)=O)OC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccsc1S(N)(=O)=O
Yield: 66.5 %

Procedure:
The product from Step A (174.05 g, crude) was dissolved in a mixture of THF (1000 mL) and 1N HCl (1000 mL) and heated at reflux temperature for 1.5 hr. The THF was evaporated and the aqueous solution made basic by the addition of a saturated aqueous sodium bicarbonate solution. The mixture was cooled and the precipitate collected by filtration, washed with cold water and dried in vacuo to give the crude product (109.1 g,). Recrystallization from acetonitrile gave the desired product (81.5 g, 79%): mp 193°-196° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(C(C)C)CC)(C)C.N1([C:29]([O:31][C:32]([CH3:61])([CH2:34][CH2:35][CH2:36][O:37][C:38]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:33])=[O:30])C=CN=C1>CN(C)C=O>[CH3:60][O:59][C:56]1[CH:55]=[CH:54][C:53]([C:38]([C:45]2[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:37][CH2:36][CH2:35][CH2:34][C:32]([CH3:61])([O:31][C:29]([NH:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:30])[CH3:33])=[CH:58][CH:57]=1
Reactant: COc1ccc(C(OCCCC(C)(C)OC(=O)n2ccnc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)CCCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution composed of L-phenylalanine methyl ester hydrochloride (1.4 g, 6.1 mmol), diisopropylethylamine (1.1 mL, 6.2 mmol), and N,N-dimethylformamide (40 mL) was added to the solution of Example 1. The reaction was stirred overnight at room temperature. The solvents were evaporated at reduced pressure, and then the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. The solvents were evaporated once again. Chromatography on silica gel eluting with hexane-ethyl acetate 70:30 afforded purified Cmoc-protected phenylalanine methyl ester. MS (EI+): 626 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH3:13][O:14][C:15](=[O:27])[C:16]1[C:17](=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19].Cl>CO>[CH3:13][O:14][C:15](=[O:27])[C:16]1[C:17](=[CH:22][C:23]([NH:26][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1C(=O)OC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(NCc2ccccc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.8 %

Procedure:
Benzaldehyde (1.64 ml, 16.2 mmol) and sodium cyanoborohydride (1.02 g, 16.2 mmol) were added to a solution of 4-aminophthalic acid dimethyl ester (1.7 g, 8.1 mmol) in dry methanol (50 ml) and pH was adjusted to 5.5-5 with 2 M hydrogen chloride in methanol (approx. 1 ml). The reaction mixture was stirred at room temperature for 20 hours and evaporated to dryness in vacuo. The residue was partitioned between methylene chloride (50 ml) and water (30 ml). pH was adjusted to 8 and the organic phase was isolated, dried over magnesium sulphate and evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: ether:heptane (1:1)) to give 4-benzylaminophthalic acid dimethyl ester as a golden oil (yield: 0.94 g, 39%). 1H—NMR (CDCl3) in ppm: γ 3.82 (3H,s); 3.88 (3H,s); 4.35 (2H,d); 4.66 (1H, broad d); 6.57 (1H,d.d.); 6.65 (1H,d); 7.23-7.35 (5H,m); 7.73 (1H,d).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](#[N:23])[CH3:22]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:22][C:21]#[N:23])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: O=Cc1cccc(OCCCOCc2ccccc2)c1
Product: N#CCC(O)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(3-benzyloxy-propoxy)-benzaldehyde gave 3-(3-(3-benzyloxy-propoxy)-phenyl)-3-hydroxy-propionitrile as yellow oil. Yield (0.94 g, 54%): 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 6H), 6.90-6.96 (m, 2H), 6.81-6.86 (m, 1H), 5.00 (m, 1H), 4.53 (s, 2H), 4.10 (t, J=6.2 Hz, 2H), 3.67 (t, J=6.0, 2H), 2.75 (t, J=6.4, 2H), 2.04-2.13 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[C:4]#[CH:5].Cl[CH:9]([F:11])[F:10].[NH4+].[Cl-].O.CC(OC)(C)C>CCCCCC.O1CCCC1>[F:10][CH:9]([F:11])[C:5]#[C:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: FC(F)Cl
Reactant: C#CC(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: COC(C#CC(F)F)OC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
At −70° C., an n-buthyllithium solution (2.5 M, in hexane, 260 ml, 0.65 mol) was added dropwise to a solution of propargylaldehyde dimethyl acetal (52.8 g, 0.5 mol) in dried tetrahydrofuran (THF, 1000 ml). The reaction mixture was then stirred at −70° C. for 30 min and cooled to −100° C. At this temperature, chlorodifluoromethane (216.6 g, 2.5 mol) was introduced into the reaction mixture (strongly exothermic). The reaction mixture was slowly warmed to −50° C. and stirred at this temperature for 1 h. Aqueous saturated NH4Cl solution (400 ml) was then added, the reaction mixture was warmed to 0° C., a water/MTBE mixture (500 ml) was added and the aqueous phase was removed. The aqueous phase was extracted twice with MTBE (200 ml). The combined organic phases were washed twice with dilute hydrochloric acid (100 ml), dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was separated by fractional distillation. 1,1-Difluoro-4,4-dimethoxybut-2-yne (46.7 g; transition temperature 50-52° C. at 30 mbar) was obtained in a purity of 96% (according to GC analysis). This corresponds to a yield of 65%. More product was found in the cold trap and in the solvent that had been distilled off. Accordingly, the nonisolated yield is 71%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].ClC(Cl)C.[C:10]([OH:20])(=[O:19])[C:11]1[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-].[Na+]>>[Cl:1][S:2]([C:15]1[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([CH:16]=1)[C:10]([OH:20])=[O:19])(=[O:5])=[O:3]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 65 %

Procedure:
Chlorosulphonic acid (55 ml) was added over 6 hrs at 20° to a stirred mixture of dichloroethane (72 ml), o-anisic acid (26.8 g) and sodium chloride (10 g). The mixture was warmed to 40° and after a further hour warmed to 65°. The mixture was maintained at 65°-70° for 17 hrs, cooled and poured into ice water (300 g) to give the title compound as a colourless solid (28.7 g; 65%). ##STR16##
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:38])[CH2:25][C@@H:26]([NH:34][C:35](=[O:37])[CH3:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:38])[CH2:25][C@@H:26]([NH:34][C:35](=[O:37])[CH3:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 30 °C
Reaction time: 30 h

Procedure:
To a solution of 100 g of (2S,3S,5S)-2-(N,N-dibenzylamino)-5-acetylamino-1,6-diphenyl-3-hexanol in 500 ml of methanol, was added 5 g of 5%-palladium-carbon (product of N. E. Chemcat), and the reaction mixture was stirred at 30° C. for 30 hours under a hydrogen atmosphere of 10 atm.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:2][C:3]1[C:4]([S:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:29])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2nc1SCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccn1
Yield: 67.2 %

Procedure:
In a mixture of 36 ml of chloroform and 18 ml of methanol was dissolved 2.6 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was added 1.77 g of m-chloroperbenzoic acid (purity 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture under chilling. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ether/hexane to give 1.63 g of 3-methyl-2-(2-pyridylmethylsulfinyl)quinoxaline as an orange crystalline powder, m.p. 85°-88° C. (decompn.).
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[C:9](O)(=O)[C:10]1C=CC(C(O)=O)=CC=1.P(=O)(O)(O)O>>[C:6]([C:5]1[CH:10]=[CH:9][C:2]([C:1]#[N:8])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#CCCCCC#N
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=P(O)(O)O
Product: N#Cc1ccc(C#N)cc1

Procedure:
650 g (6.0 mol) of a mixture of dinitriles (85% MGN, 12% ESN, 3% AdN by weight) which are by-products of adiponitrile synthesis are introduced into a 2000-ml reactor. 167 g of terephthalic acid (1.0 mol) are added to this heterogeneous medium, followed by 5 g of 85% orthophosphoric acid. The reaction medium is heated at the reflux of the dinitriles and these conditions are maintained for 5 h. Respective yields of imide mixture and of 1,4-dicyanobenzene of 96% and 95% are obtained by GC analysis.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([O:41][CH3:42])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:31]4=[O:40])[CH2:28][CH2:29]3)=[O:23])=[C:17]([O:41][CH3:42])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 250 mL of dry ethyl acetate under N2 was added 1-(1-(4-(N-tert-Butyloxycarbonyl-4-piperidinyloxy)-2-methoxyphenylacetyl)-piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (1.2 g, 2 mmol) from Example 194, and the solution was cooled to 0° C. in an ice-water bath. Anhydrous HCl gas was bubbled into the solution at 0° C. for 30 min. The solution was stirred for an additional 30 min at 0° C. then the ice bath was removed and N2 was bubbled through the solution to remove the excess HCl. Addition of hexane caused precipitation of the HCl salt. The solid was dried in vacuo to remove solvent and then was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine and was dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:11][NH2:12])[CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][N:22]2C(=O)CS[C:23]2=[O:28])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CO>[CH2:7]([N:11]1[C:23](=[O:28])[NH:22][CH2:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)=[N:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(CN1C(=O)CSC1=O)c1ccc(Cl)cc1
Reactant: CCCCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCCN1N=C(c2ccc(Cl)cc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
Butylhydrazine oxalate (41 g, 230 mmol) and 40 g of 3-(2-(4-chlorophenyl)-2-oxo-ethyl)-thiazolidine-2,4-dione (161 mmol) in 2200 mL of methanol were cooled in an ice bath and treated with 30.3 g (300 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 30 minutes, then refluxed overnight. The reaction mixture was cooled and 400 mL of water was added. This mixture was extracted with ethyl acetate. The organic phase was washed twice with 10% aqueous sodium hydroxide solution, then dried and stripped. The solids obtained were recrystallized from ethyl acetate/hexane to give 9.6 g of 2-n-butyl-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one.