Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1.C(OC(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butyl 4-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)-benzoate (293 mg) obtained in Example 2 is dissolved in chloroform (10 ml), and thereto is added 4N hydrogen chloride-dioxane solution (10 ml) followed by stirring at room temperature for 3 days. To the reaction solution is poured diisopropyl ether, and the solid precipitates are collected by filtration to give the title compound (280 mg). ESI-MS M/Z: 499/501[M−H]−
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:8][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(OCCCCCl)cc1
Product: COc1ccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-4-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].O[NH3+:13]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:13]
Reactant: [NH3+]O
Reactant: O=Cc1cccc(O)c1Cl
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-hydroxybenzaldehyde [(2 g, 12.8 mmol) WO 2005007633, p 34] and hydroxyl ammonium chloride (1.33 g, 19.6 mmol) in acetic acid (20 mL) was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a white solid. The solid was then dissolved in ethyl acetate washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid in quantitative yield. 1H NMR (400 MHz, CD3OD) δ: 7.18 (d, 1H), 7.26 (m, 2H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12][CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=1>CCO>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH:14]([CH3:15])[CH3:16])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)C(O)C#Cc1cccc(OCCN)c1
Solvent: CCO
Product: CC(C)C(O)CCc1cccc(OCCN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3-(2-Aminoethoxy)phenyl)-4-methylpent-1-yn-3-ol (0.56 g, 2.4 mmol) in EtOH (30 mL) was degassed and purged with nitrogen. To this was added Pd on C (0.05 g, 10%). The flask was evacuated and purged with hydrogen thrice. This suspension was then stirred at room temperature under hydrogen balloon for overnight. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with ethanol. The filtrate was concentrated to afford Example 1. Yield (0.38, 66%): 1H NMR (400 MHz, DMSO-d6) δ 7.14-7.18 (m, 1H), 6.71-6.76 (m, 3H), 3.91 (t, J=5.6 Hz, 2H), 3.12-3.17 (m, 1H), 2.89 (t, J=5.6 Hz, 2H), 2.65-2.73 (m, 1H), 2.46-2.50 (m, 1H), 1.46-1.64 (m, 3H), 0.8 (t, J=5.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 159.0, 144.8, 129.7, 121.1, 115.0, 112.0, 74.2, 69.6, 41.1, 36.2, 33.7, 32.4, 19.4, 18.0. MS: 238 [M+1]+.
Reaction SMILES: Cl.[C:2]1([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH:2]1([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C1=C(c2c[nH]cn2)c2ccccc2C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CCC2c1c[nH]cn1

Procedure:
4-(3H-Inden-1-yl)-1H-imidazole hydrochloride (80 mg) is dissolved in ethanol (6 ml). The reaction solution is hydrogenated at 40-50° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. Work-up of the reaction mixture gives the crude product which is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: O.O.O.[C:4]1([O-:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2ccccc2)cc1
Yield: 66.9 %

Procedure:
A mixture of sodium phenolate trihydrate (10.2 g; 60 mmole) and benzyl chloride (6.4 ml; 56 mmole) in methanol (150 ml) was pumped through the system (15 ml/minute; 146°-7° C.; 1000-1050 kPa). The MeOH was rotary evaporated off and the residue recrystallised from EtOH to afford colourless needles of phenyl benzyl ether (6.9 g; 67% yield), m.p. 36°-36.3° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:31])[CH2:14][NH:15][C:16](=O)[C@@H:17]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH3:18])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:31][C:16]([C@@H:17]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH3:18])=[N:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C[C@@H](C(=O)NCC(=O)c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C[C@@H](c1ncc(-c2ccc(Cl)cc2)o1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Yield: 20.9 %

Procedure:
Phosphoryl trichloride (1.m7 ml, 10.8 mmol) was added to a solution of (S)—N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.162 g, 5.83 mmol) in toluene and heated at 110° C. for 15 hours. Dilute with dichloromethane (50 ml), wash with saturated sodium bicarbonate solution, water, brine, dried and concentrated in vacuo. Flash column chromatography (silica, 80 g) eluting with 0-50% EtOAc/DCM afforded the pure product 430 mg (yellow foam). HRMS(B) tR=1.42 min; MS m/z 353.1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][NH2:20]>C(O)C.O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([CH3:18])[N:3]=[C:2]([NH:20][CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: CN
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(C)n1
Yield: 84 %

Procedure:
0.056 g (0.00017 mol) of 4-(2-bromo-6-methylpyridine-4-sulphonyl)-phenylamine and 1.1 ml of 8 M methylamine in ethanol were stirred at 120° C. in 5 ml of dioxane for 24 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. The product-containing fraction were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.04 g (84%) of [4-(4-aminobenzenesulphonyl)-6-methyl-pyridin-2-yl]-methylamine as light yellow crystals; m.p.: 126-127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]4[N:50]=[CH:49][C:48]([NH:51][C:52](=[O:54])[CH3:53])=[CH:47][CH:46]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]5[N:50]=[CH:49][C:48]([NH:51][C:52](=[O:54])[CH3:53])=[CH:47][CH:46]=5)[CH:40]=4)[O:35]3)[CH:31]=[CH:32][CH:33]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1

Procedure:
N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-yl)acetamide was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from N-{6-[2-(3-hydroxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide. 1H NMR (400 MHz, d6-DMSO) δ: 10.03 (s, 1H), 9.05 (d, 1H, J 2.1 Hz), 8.63 (d, 1H, J 8.9 Hz), 8.26 (s, 1H), 8.00 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 7.27-7.31 (m, 2H), 7.20 (m, 1H), 6.92 (d, 1H, J 8.9 Hz), 6.85-6.87 (m, 3H), 5.17 (d, 1H, J 10.4 Hz), 2.96 (m, 1H), 2.71 (m, 1H), 2.20 (m, 1H), 2.04 (s, 3H), 1.99 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:25])=[N+:7]2[O-].C(OC(=O)C)(=[O:28])C.CO>C(O)(=O)C>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:25][OH:28])=[N:7]2
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Temperature: 110 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A solution of S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline 1-oxide (497 mg, 1.21 mmol) in acetic acid (12 mL) was heated at 80° C. for 15 minutes. To the solution was added acetic anhydride (1.37 mL, 14.5 mmol) and the resulting solution was heated at 110° C. for 2 hours. The reaction mixture was cooled to 50° C. and methanol (6 mL) was added and stirred for 1 hour. The reaction was cooled to room temperature and concentrated. The resultant oil was taken up in tetrahydrofuran (20 mL) to which was added 6 M potassium hydroxide (20 mL) and stirred for 1 hour. The product was extracted with ethyl acetate and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (366 mg, 74%). LCMS-ESI+ (m/z):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:34])([C:30]([O:32]C)=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:34])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:22][CH:23]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1(C)CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 1-{5-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}-4-methylpiperidine-4-carboxylate (Example 631; 282 mg, 0.60 mmol) in MeOH (10 mL) was added a 2M solution of NaOH (1.5 mL). The resulting yellow solution was allowed to stir at ambient temperature overnight. The reaction mixture was then heated to 50° C. for 8 hours and allowed to stir at ambient temperature overnight. The volatile organics were removed by evaporation, the aqueous residue was washed with ether (50 mL) and aqueous phase adjusted to pH ˜1 with 2M HCl. The resultant suspension was filtered and dried under vacuum at ambient temperature to give the title compound (230 mg, 0.502 mmol, 84%); 1H NMR δ 1.21 (s, 3H), 1.47-1.54 (m, 2H), 2.03-2.08 (m, 2H), 3.29-3.36 (m, 2H), 3.95-4.00 (m, 2H), 7.30 (d, 1H), 7.37-7.41 (m, 1H), 7.48 (q, 1H), 7.69-7.75 (m, 1H), 8.15 (d, 1H), 8.54 (s, 1H), 11.25 (s, 1H), 11.37 (s, 1H); CO2H not seen; MS m/e MH+ 459.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>COCCOC>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:11]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnccn1
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Ethyl bromopyruvate (2.15 g, 11.04 mmol) was added to stirred solution of 2-aminopyrazine (1 g, 10.5 mmol) in 1,2-Dimethoxy ethane (10 mL). The reaction mixture was stirred at 20-35° C. for 2 h. The mixture was then filtered to obtain a solid precipitate which was dried well, dissolved in EtOH (10 mL) and refluxed for 2 h. This mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution, extracted with chloroform. The chloroform layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 60% EtOAc in Hexane as eluent) to afford 450 mg of the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/ethanol=5:1) C29H29N3O3
Reaction SMILES: BrBr.[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH:27]=[CH:28]N(C)C)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]2=[O:40])=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:48]([NH2:50])=[S:49])[CH:42]=1>C(Cl)Cl.O1CCCC1.O>[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[C:27]1[S:49][C:48]([NH:47][C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)=[N:50][CH:28]=1)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:21]2=[O:40])=[O:18])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: NC(=S)Nc1cccnc1
Agent: BrBr
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Reaction time: 0.17 h

Procedure:
A solution of bromine (35.96 g) in dry methylene chloride (40 cc) is added dropwise to a solution, cooled to -75° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, E-form, (107.1 g) in dry tetrahydrofuran (600 cc). The mixture is stirred at this temperature for 10 minutes and pyrid-3-yl-thiourea (30.64 g) dissolved in a mixture (400 cc) of water and tetrahydrofuran (50:50 by volume) is then added. The cooling bath is removed and the mixture is stirred at 20° C. for 17 hours. The brown solution is diluted with ethyl acetate (1.5 liters) and is then washed successively with distilled water (1 liter), a half-saturated sodium bicarbonate solution (1 liter), distilled water (1 liter) and a saturated sodium chloride solution (500 cc). The organic phase is dried over anhydrous magnesium sulphate. After evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue is chromatographed on a column (height: 46 cm, diameter: 8.1 cm) of silica gel (0.06-0.20 mm), elution being carried out successively with a mixture (5 liters) of cyclohexane and ethyl acetate (50:50 by volume), a mixture (5 liters) of cyclohexane and ethyl acetate (25:75 by volume) and ethyl acetate (7 liters), 1 liter fractions being collected. Fractions 8 to 17, containing the pure product, are combined and concentrated to a residual volume of 250 cc. A yellow suspension is obtained, which is kept at 5° C. for 12 hours. The solid is filtered off, washed with ethyl ether (3×100 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa). 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (14.5 g) is thus obtained in the form of a yellow powder.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][S:4][N:3]=1.[Cu](C#N)[C:15]#[N:16].O>CN1CCN(C)C1=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([C:15]#[N:16])=[N:3][S:4][N:5]=1
Reactant: Clc1ccccc1-c1nsnc1Br
Reactant: N#C[Cu]C#N
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#Cc1nsnc1-c1ccccc1Cl
Yield: 53.3 %

Procedure:
In 1,3-dimethyl-2-imidazolidinone, were stirred 280 mg of 3-bromo-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 180 mg of copper cyanide at 150° C. for 12 hours. After spontaneous cooling, the reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The diethyl layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole. The obtained 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole (120 mg) was heated with 6 mL of 5% sodium hydroxide solution and 2 mL of ethanol, and refluxed for one hour. After spontaneous cooling, the reaction mixture was poured into a dilute hydrochloric acid solution, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 100 mg of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]([CH2:13][NH:14][CH2:15][CH:16]([OH:18])[CH3:17])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)O)[CH3:2].S(=O)(=O)(O)O.O.N>CCOCC>[CH2:1]([C:3]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[O:18][CH:16]([CH3:17])[CH2:15][NH:14][CH2:13]1)[CH3:2]
Reactant: CCC(O)(CNCC(C)O)c1cccc(OC)c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCC1(c2cccc(OC)c2)CNCC(C)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
METHOD A The product from Example 15 (1.77 g, 0.007 mole) was treated dropwise at 0° C. with concentrated sulphuric acid (2.3 ml). The resulting green gum was allowed to stand overnight at room temperature and was then treated with 25 ml of crushed ice and after thorough mixing, 50 ml of water. The solution was neutralised with excess ammonia and the solution shaken with ether (2×50 ml). The ether layers were washed, and dried (MgSO4) and evaporated to give 360 mg of the title compound as a 50:50 mixture of diastereoisomers.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH2:10][C:3]1=2
Reactant: NC1CCCc2sccc21
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2sccc21

Procedure:
Alternatively 5.7 grams of 4,5,6,7-tetrahydrobenzo-[b]thien-4-amine hydrochloride is stirred in 20 ml. of toluene at 97°C., and phosgene is slowly introduced into the mixture via a capillary delivery tube. The mixture is heated to reflux temperature, and the flow of phosgene is continued until most of the amine hydrochloride disappears. The mixture is then filtered to remove unreacted amine hydrochloride, and the filtrate is evaporated to dryness under reduced pressure to give the 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:4]([C:12]([NH:14][C@@H:15]([C:26]([NH:28][C@H:29]([C:45]([O:47]C)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1.O>[NH:3]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:4]([C:12]([NH:14][C@@H:15]([C:26]([NH:28][C@H:29]([C:45]([OH:47])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1.5 h

Procedure:
26 ml 1 N NaOH are added to a suspension of 16 g BOC-Phe-(D)Trp-Lys(Z)-OMe in dioxane/H2O (8:2) and the reaction mixture stirred for 1.5 hrs. at room temperature. The obtained solution is diluted to ca. 500 ml by the addition of H2O and then concentrated under vacuum. The pH is adjusted to 1.5 to 2 by the addition, with stirring, of 1 N HCl, the precipitated product is filtered off, washed with H2O until neutral and dried to yield the title compound:
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:17]
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1c(C#N)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a stirred mixture of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) (prepared according to the method described in Tetrahedron 40: 1863-1868 (1984)) and dimethylamine hydrochloride (0.74 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 2-((dimethylamino)methyl)-3-nitrobenzonitrile (0.75 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (br d, 1H, J=8.0 Hz), 7.85 (dd, 1H, J=8.0, 1.4 Hz), 7.55 (t, 1H, J=8.0 Hz), 3.94 (s, 2H), 2.24 (s, 6H).