Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=3[C:23](O)=[O:24])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]4[C:15]=3[C:23](=[O:24])[N:27]([CH:28]3[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]3=[O:30])[C:17]4=[O:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(Nc2ccc(C3CCCCC3)cc2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccc(C5CCCCC5)cc4)c3C2=O)C(=O)N1
Yield: 86 %

Procedure:
A mixture of 3-(4-cyclohexylphenylamino)phthalic acid (0.80 g, 2.4 mmol) and rac-α-aminoglutarimide hydrochloride (0.39 g, 2.4 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 1:1 hexanes-ethyl acetate, eluting 0.86 g of the product, in 86% yield: mp 219-221° C.; 1H NMR (DMSO-d6) δ 1.10-1.46 (m, 5H), 1.67-1.80 (m, 5H), 2.04-2.07 (m, 1H), 2.40-2.50 (m, 1H), 2.53-2.64 (m, 2H), 2.83-2.90 (m, 1H), 5.12 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.19-7.24 (m, 5H), 7.35 (d, J=8.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 8.34 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 25.6, 26.4, 31.0, 34.0, 43.2, 48.7, 111.3, 113.0, 119.0, 122.4, 127.6, 132.4, 136.2, 136.9, 143.3, 143.7, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C25H25N3O4: C, 69.59; H, 5.84; N, 9.74. Found: C, 69.38; H, 5.85; N, 9.41.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH2:5])=[O:4].[NH2:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[NH2:5][C:3]([CH:2]([NH:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: NC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 26, one can condense 2-oxo-4-phenylbutyramide and L-alanyl-L-proline in the presence of sodium cyanoborohydride to yield N-(1-amino carbonyl-3-phenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH:39]=O)=[N:36]2)=[CH:31][C:30]=1[CH3:41]>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:39]/[C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][C:29]([O:28][CH3:27])=[C:30]([CH3:41])[CH:31]=3)[N:36]=2)=[CH:8][CH:9]=1
Reactant: COc1cc2nc(C=O)ccc2cc1C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1C

Procedure:
tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (187 mg, 0.497 mmol) and 7-methoxy-6-methylquinoline-2-carbaldehyde (100 mg, 0.497 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>CS(C)=O>[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cccc(N)c1C
Solvent: CS(C)=O
Product: Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1C

Procedure:
In an entirely analogous manner, using 117.00 g (0.830 mol) of 1-fluoro-2-nitrobenzene and 222.00 g (1.826 mol) of 2,3-dimethylaniline in 585 ml of dimethyl sulphoxide as starting materials there is obtained N-(2,3-dimethylphenyl)-2-nitroaniline having a melting point of 118°-120° after recrystallisation from methylene chloride/hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].O[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[N:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:16]=[C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[C:21]([C:25]3[N:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])=[CH:29][N:30]=3)[CH:22]=[CH:23][CH:24]=2)[N:15]=[C:10]([C:4]2[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:12]1
Reactant: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1
Reactant: COC(=O)/C=C/c1cnc(-c2cccc(CO)c2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
47.2 90 mg (0.4 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one and 111 mg (0.41 mmol) of methyl (E)-3-[2-(3-hydroxymethylphenyl)-pyrimidin-5-yl]acrylate are suspended in 3 ml of THF with 200 mg (0.6 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. The mixture is cooled to 0° C., and 95 μl (0.6 mmol) of diethyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 24 h. The reaction mixture is purified by means of preparative
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.7 %

Procedure:
Using 7-(2,4-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.034 g, 62%) was obtained.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([N:14]2[CH:18]=[N:17]N=N2)C=[CH:10][C:11]=1[O:12][CH3:13].C([Li])CCC.C(=O)(O)[O-].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O1CCCC1.CCCCCC>[O:32]1[CH2:33][CH2:34][O:31][CH:29]1[C:30]1[CH:10]=[C:11]([O:12][CH3:13])[CH:6]=[CH:7][C:8]=1[NH:14][C:18]#[N:17]
Reactant: CCOC(C)=O
Reactant: COc1ccc(-n2cnnn2)cc1C1OCCO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(NC#N)c(C2OCCO2)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3-[1,3]dioxolan-2-yl-4-methoxy-phenyl)-1H-tetrazole (9.09 g) in dry tetrahydrofuran (200 ml) at -78° under nitrogen, n-butyl lithium solution in hexane (30 ml of 1.6 mol dm-3) was added. Nitrogen gas was evolved. After stirring under nitrogen for 5 min the mixture was allowed to warm to 0° over 10 min and 8% aqueous sodium bicarbonate (200 ml) was then added. After stirring for 10min ethyl acetate (150 ml) was added and the layers separated. The aqueous layer was then extracted with dichloromethane (2×200 ml) and the organic layers combined, dried (Na2SO4) and evaporated in vacuo to yield the title compound as an oil (8.0 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:14]=[O:15]>[OH-].[Na+]>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[C:8]([CH2:14][OH:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(O)ccnc2c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(O)c(CO)cnc2c1

Procedure:
7-Ethyl-4-hydroxyquinoline was reacted with 40% aqueous formaldehyde in aqueous sodium hydroxide to give the novel compound 7-ethyl-4-hydroxy-3-hydroxymethylquinoline, m.p. 180°-182°.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([S:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([S:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH:22]([CH3:23])[CH3:24])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (350 mg, 0.87 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The resulting suspension was heated in an oil bath to 100° C. under a reflux condenser for 20 hours. LCMS showed complete conversion. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was taken up in water (30 mL) and sonicated briefly. The resulting suspension was filtered. The collected solids underwent purification by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 100% A (where A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). After removal of eluant solvents, the residue was redissolved in CHCl3, filtered, and concentrated in vacuo. The residue was taken up in water (15 mL) as a suspension. The solids formed were collected by filtration and dryed under vacuum at room temperature over P2O5 for 20 hours. These solids were washed with hexane (3×3 mL). Further drying under vacuum at 65° C. for 20 hours gave the title compound (282 mg) as a cream-colored solid. LC-MS (ES) m/z=414 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 2.65 (s, 3H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.2, 3.4 Hz, 1H), 4.11 (d, J=11.9 Hz, 1H), 6.40 (s, 1H), 7.40 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].C[OH:18]>>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:18])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Agent: [Al]
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2.2 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 3.3 g of the polyethyleneglycol (molecular weight: 600) and 7.8 g of polyethyleneglycol monomethyl ether (molecular weight: 750). The mixture was dropped on an aluminum plate and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled down to room temperature, immersed into methanol and dried. An ion-conducting thin membrane of styrene-maleic acid polyethyleneoxy ester crosslinked copolymer of an excellent adhesive strength and mechanical strength was prepared.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN4CCCC4C3)c3cccnc32)cc1

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C2CCC(C(=O)O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCC(C(=O)O)CC2)cc1

Procedure:
In analogy to example 1, step 2, from (S)-4-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)cyclohexanecarboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI−): m/z=471.4 [M−H]−.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.Cl>CS(C)=O>[CH:16]1([N:19]2[C:2]3[C:3](=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=3[F:8])[CH2:12][C:13]2=[O:15])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1C1CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.50 g, 11.5 mmol) and cyclopropylamine (6 eq., 4.78 ml, 0.0691 mol) are mixed in DMSO (10 ml) and stirred at 50 ° C. for 20 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and dried under vacuum. The residue is purified by flash column chromatography (20% Ethyl acetate/hexane) to give the title compound as a yellow solid. HPLC r.t. 4.90 min; MS for C11H9FN2O3 m/z 235.0 (M−H)−.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][N:3]=[N:2]1.N>C(O)C.[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cnnn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-n1cnnn1

Procedure:
A solution of 2-Tetrazol-1-yl-benzonitrile (1.3 g, 7.6 mmol) in ethanol saturated with ammonia (125 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere overnight. The reaction mixture was filtered over celite and concentrated to give 2-Tetrazol-1-yl-benzylamine; 1H NMR (CDCl3, 400 MHz) δ 9.28 (s, 1H), 7.59 (m, 2H), 7.47 (m, 2H), 3.70 (s, 2H).
Reaction SMILES: Cl[C:2](=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH3:12])[CH3:3].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:2](=[N:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH2:13][CH3:14])[CH3:3])[CH3:12]
Reactant: CCc1ccccc1N
Reactant: CCc1ccccc1N=C(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccccc1N=C(C)Nc1ccccc1CC
Reaction time: 1 h
Yield: 82.6 %

Procedure:
N-(1-chloroethylidene)-2-ethylbenzenamine (HS Imine I) (1.82 g, 10 mmol) was dissolved in 50 mL of toluene. 2-ethylaniline (1.24 mL, 10 mmol) was added dropwise at room temperature, resulting in a light pink solution, which was refluxed overnight. Toluene was removed under vacuum. Sodium hydroxide (100 mL of 0.10 M solution, 10 mmol) was added and the solution was stirred for 1 hour. The solid that deposited was extracted into 150 mL of diethylether. The ether layer was dried with MgSO4, filtered and taken to dryness, leaving 2.20 g of pink solid. The pink solid was dissolved in 60 mL of pentane and cooled to −30° C. A white crystalline solid was collected and dried (2.11 g, 79%). The 1H NMR spectrum is complex and is consistent with a mixture of E/Z isomers.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:28](=[O:29])[N:17]3[CH:18]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]23)=[O:13])=[O:10])=CC=1)([O-])=O.C([N:40](CC)CC)C.C(Cl)(Cl)Cl.N>CO>[C:9]([CH:11]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]([NH:14][CH:15]1[C:28](=[O:29])[N:17]2[CH:18]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]12)=[O:13])(=[O:10])[NH2:40]
Reactant: CCN(CC)CC
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(N)=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 4 h

Procedure:
To a stirred solution of 523 mg. (0.001 mole) of 6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 101 mg of triethylamine in 50 ml. of chloroform is added 1 ml of a 1M solution of ammonia in methanol, at -30° C. Stirring is continued for 4 hours without external cooling and then evaporation in vacuo leaves the crude product as its triethylamine salt.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23](Br)([CH3:25])[CH3:24]>CN(C=O)C.O>[CH:23]([O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1)([CH3:25])[CH3:24]
Reactant: O=Cc1ccc(O)c2oc3ccccc3c12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C=O)c2c1oc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
Intermediate 19 (500 mg, 2.358 mmol) was dissolved in dry DMF (5 ml). Anhydrous potassium carbonate (650 mg, 4.716 mmol) was added to the above solution and was stirred for 10 min. at 80° C. To this was added isopropyl bromide (431 mg, 3.537mmol) and the reaction mixture was stirred for 4 hrs. The reaction mixture was cooled to room temperature and diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (50 ml) and brine solution (25 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave the product as a white solid (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-hydroxybenzoate (600 mg, 2.714 mmol), N-tert-butoxycarbonylprolinol (546 mg, 2.714 mmol), and Ph3P (854 mg, 3.257 mmol) in THF (10 mL) was added dropwise DIAD (0.68 mL, 3.283 mmol) at room temp and the mixture was stirred for 3 days at room temp, and for 18 hr at 70° C. The reaction mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane-EtOAc (6:1, v/v) as eluent to give 988.8 mg (90%) methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3,5-dichlorobenzoate a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.88–2.15 (br m, 3H), 2.34 (br s, 1H), 3.40–3.44 (m, 2H), 3.92 (s, 3H), 3.92, 4.14 (m, 1H), 4.18 (br s, 2H), 7.98 (s, 2H); MS (FAB) m/z 404 (M++1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:37])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)=[O:16]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:37])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:36]=[CH:35][CH:34]=[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCNCC2)c1
Yield: 69.4 %

Procedure:
The solution of tert-butyl 4-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benzyl)piperazine-1-carboxylate (160 mg, 0.314 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at 27° C. for 16 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (89 mg, Yield 69.0%). 1H NMR (D2O, 400 MHz): δ 7.66-7.56 (m, 2H), 7.51-7.44 (m, 1H), 7.44-7.37 (m, 1H), 7.16-7.06 (m, 3H), 7.02 (d, J=7.3 Hz, 1H), 4.11 (quin, J=5.9 Hz, 1H), 3.73-3.60 (m, 2H), 3.56-3.49 (m, 2H), 3.49-3.42 (m, 1H), 3.41-3.32 (m, 1H), 2.86-2.75 (m, 8H), 2.68-2.58 (m, 2H), 2.56-2.32 (m, 4H). LCMS (m/z): 409.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].C(Cl)Cl.[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[C:15]=2[N:16]=1>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([NH:11][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:16][C:15]=2[C:17]=1[CH3:22]
Reactant: COC(=O)N=C=O
Reactant: Cc1c(Cl)ccc2sc(N)nc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)NC(=O)Nc1nc2c(C)c(Cl)ccc2s1
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of 2 parts by weight of methoxycarbonylisocyanate in 15 parts by weight of methylene chloride was added gradually with stirring to a solution, at room temperature, of 4 parts by weight of 2-amino-5-chloro-4-methylbenzothiazole in 75 parts by weight of methylene chloride and 50 parts by weight of tetrahydrofuran. After stirring the reaction mixture at room temprature overnight, a product was isolated by filtration giving a 40% yield of methyl 4-(5-chloro-4-methylbenzothiazol-2-yl)allophanate having a melting point greater than 275° .