Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=1>CN(C=O)C>[ClH:3].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][CH:14]=2)[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CCc2cccnc2)cc1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1ccc(CCc2cccnc2)cc1

Procedure:
Methyl 4-(2-(3-pyridyl)ethyl)benzoate was dissolved in methanol (10 ml) and a solution of potassium hydroxide (2.1 g, 37.3 mmol) in water (2 ml) added. The mixture was stirred overnight and the pH lowered to ca. 7 by the cautious addition of concentrated hydrochloric acid. Methanol (20 ml) was added and the suspension filtered, the filtrate concentrated to give an oil to which 2M HCl was added to bring the pH to 8. A solid precipitate formed, the solvent was removed under reduced pressure and the residue azeotroped with toluene (1×100 ml, 1×50 ml) to give crude 4-(2-(3-pyridyl)ethyl)benzoic acid. Thionyl chloride (10 ml) and dry DMF (100 μl) were added to the crude 4-(2-(3-pyridyl)ethyl)benzoic acid and the mixture heated under gentle reflux for 1.5 h. The excess thionyl chloride was removed under reduced pressure and the residue azeotroped with toluene (×2) to give crude 4-(2-(3-pyridyl)ethyl)benzoyl chloride hydrochloride as a solid. DCM (20 ml) was added and the resultant suspension treated with L-leucine ethyl ester hydrochloride (733 mg, 3.73 mmol), triethylamine (5.2 ml, 37.3 mmol) and DMAP (30 mg). The mixture was stirred for 1 h at room temperature, diluted with DCM (50 ml) and the solution washed with water (2×20 ml) and saturated brine (20 ml). The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated to give a yellow oil. Column chromatography (silica: 4% methanol in DCM) gave N-4-(2-(3-pyridyl)ethyl)benzoyl-L-leucine ethyl ester (378 mg, 28%) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][O:9][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(CBr)sc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CBr)sc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of (5-bromomethyl-3-methoxy-thiophen-2-yl)-methanol (0.6 g, 2.5 mmol) in anhydrous dichloromethane (10 mL) is added imidazole (0.516 g, 7.59 mmol) and tert-butylchlorodimethylsilane (0.412 g, 2.75 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is quenched with water and concentrated. The residue is dissolved in DCM, washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (0.9 g). ESI/MS m/z (79Br/81Br) 351/353.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:20]([O-])=O)=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].CCO.[Cl-].[NH4+]>[Fe].O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Temperature: 50 °C
Yield: 158.9 %

Procedure:
4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (407 mg, 1.0 mmol, Example 20: step b) was dissolved into EtOH (6 mL). To this was added ammonium chloride (535 mg, 10 mmol) dissolved into water (3 mL). This mixture was heated to 50° C. with stirring and then iron (277 mg, 5 mmol) was added. The reaction was then heated to 80° C. with stirring for 12 hours. The reaction mixture was then filtered through Celite® and washed with 10% DCM/MeOH. Removal of the solvents in vacuo yielded the title compound (598 mg, quantitative yield) which was used without further purification. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 7.84–7.86 (m, 1H), 7.70–7.75 (m, 1H), 7.56 (s, 1H), 7.40 (m, 1H), 6.02 (br s, 2H), 3.85 (s, 3H). ESI-MS (m/z): Calcd. for C12H10BrNO4S2: 375.9 (M+H); found: 376.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.O[C@@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1NCC[C@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@@H]2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Cool a solution of 3-hydroxy-benzoic acid methyl ester (9.03 g, 59.4 mmol) in tetrahydrofuran (125 mL) to 0° C. and add (R)-3-hydroxy-pyrrolidin-2-one (5.00 g, 49.5 mmol) and triphenyl phosphine (15.6 g, 59.4 mmol). Slowly add to this mixture diethylazodicarboxylate (10.2 mL, 64.3 mmol). Warm the reaction mixture to room temperature and stir overnight. Concentrate the mixture under reduced pressure and purify the residue by flash silica gel chromatography to provide 11.2 g of 3-((R)-2-oxo-pyrrolidin-3-yloxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH:22]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)OS(C1C(C)=CC=CC=1)(=O)=O)[CH2:20]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.[I-:42].[Na+].C[C:45]([CH3:47])=O>O>[CH3:45][CH2:47][CH:1]([O:17][CH2:18][CH:19]([CH2:20][I:42])[CH2:22][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)=O
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCOCC(CC)C(OCc1ccccc1)OS(=O)(=O)c1ccccc1C
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCC(CC)OCC(CI)COCc1ccccc1

Procedure:
A mixture of 5.3g of 3-[(hexadecyloxy)methyl]-4-(phenylmethoxy)-4-toluenesulfonyloxybutane, 4.2 g of sodium iodide and 50 ml of acetone is stirred at reflux for 2 days, then poured into water and extracted with dichloromethane. The extract is washed with saturated aqueous sodium bisulfite, dried and evaporated. The residue is purified by chromatography, to give 3.5 g of the desired compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:19]=[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]=O)=[CH:28][C:23]=2[CH2:22][O:21]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:30][CH2:29][C:27]3[CH:26]=[CH:25][C:24]4[C:20](=[O:19])[O:21][CH2:22][C:23]=4[CH:28]=3)[CH2:14][C:13]2=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc(CCN2CCNCC2=O)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-Chloro-4-[2-(2-oxopiperazin-1-yl)ethyl]benzonitrile (70 mg, 0.265 mmol), (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (82 mg, 0.466 mmol), NaBH3CN (43 mg, 0.68 mmol) and acetic acid (28 mg, 0.466 mmol) in methanol (2 mL) and DCM (2 mL) was stirred at RT for 3 hours. Then the mixture was purified by prep-TLC to give the title product. 1H-NMR (MeOD, 400 MHz) δ ppm 7.83 (d, J=7.6 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.38 (dd, J=1.6, 7.6 Hz, 1H), 5.36 (s, 2H), 3.78 (s, 2H), 3.68 (t, J=7.2 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.40-3.42 (m, 2H), 3.30-3.33 (m, 2h), 3.13-3.18 (m, 2H), 2.98 (t, J=7.6 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.N1C=CC=CC=1.Cl.[NH2:32][OH:33]>O>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:32][OH:33])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A solution of 4-(2-phenyl-oxazol-4-ylmethoxy)benzaldehyde (4.3 g, 15.3 mmol), ethanol (100 mL), pyridine (45 mL) and hydroxylamine hydrochloride (2.2 g, 30.8 mmol) was refluxed for 1.5 hours. The solution is cooled to 25° C. and poured into water (600 mL). The resultant precipitate was filtered and dried at 25° C. for 18 hours to give the product as a white solid in 97.1% yield, m.p. 184°-186° C. MS (EI, m/e): 294 (M)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26].O>C1COCC1>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc([Sn](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 152.2 %

Procedure:
Butyllithium (1.2M in hexane; 2.8 ml; 3.4 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1 g; 3.22 mmol) in THF (50 ml) at -78° C. After 1.5 hr., a solution of trimethyltin chloride (1.3 g, 2.0 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred overnight at room temperature, poured into water, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product. Purification by chromatography using 1:10 methanol:methylene chloride gave 1.2 g of the desired product which was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([N:14]([CH3:16])[CH3:15])[S:11][N:10]=1.[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)(Cl)Cl>[CH3:17][NH:18][C:19]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([N:14]([CH3:16])[CH3:15])[S:11]1)=[O:20]
Reactant: CN(C)c1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)n1sc(N(C)C)nc1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
0.53 ml of triethylamine were added to a solution of 18 g of 3-hydroxy-5-dimethylamino-1,2,4-thiadiazole in 150 ml of chloroform and 11.5 g of methyl isocyanate were added thereto in small fractions. The mixture was stirred for 30 minutes at 20° C and was filtered and the filtrate was evaporated to dryness. The residue was crystallized from ethyl acetate to obtain 18.5 g of 2-(N-methylcarbamoyl)-5-dimethylamino-1,2,4-thiadiazole-3-one melting at 164° C.
Reaction SMILES: Cl.NO.C(O)C.CC[N:9](C(C)C)C(C)C.[Cl:16][C:17]1[C:18]([NH:23][C:24]([NH:26]CCOC(=O)C)=O)=[N:19][CH:20]=[CH:21][N:22]=1>CO>[Cl:16][C:17]1[C:18]2[N:19]([N:9]=[C:24]([NH2:26])[N:23]=2)[CH:20]=[CH:21][N:22]=1
Reactant: CC(=O)OCCNC(=O)Nc1nccnc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2c(Cl)nccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g (23.2 mmol) hydroxylamine hydrochloride are suspended in 20 ml of a 1:1 mixture of ethanol and methanol. Then 2.4 ml (13.9 mmol) DIPEA are added and the mixture is stirred at ambient temperature for 1 h. At that time, the reaction suspension is added to 2 g (4.6 mmol, 62% content) 1-(3-chloro-pyrazin-2-yl)-3-acetoxyethyl-urea and refluxed for 2 h. The reaction is cooled to room temperature filtered and washed with water. The product is isolated after drying in a vacuum oven (60° C.) (790 mg, 4.65 mmol, 100%); LCMS (method C): mass found (M+H+, 170), HPLC (method D) Rt (min): 2.14 area % 100 (220 nm); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.83 (d, J=4.3, 1H), 7.92 (d, J=4.3, 1H), 6.77 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1C=CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(C(=O)OC(C)(C)C)C1C=CCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution containing 62 (6.0 g, 0.025 mol) in DCM (25 mL) at 0° C. was added Et3N (4.5 mL, 0.032 mol). After 5 min, a solution containing methanesulfonylchloride (2.33 mL, 0.03 mol) in DCM (5 mL) was added drop wise. After 2 h, TLC analysis revealed complete consumption of 62 [1:1 hexanes/EtOAc, Rf(63)=0.5, Rf(62)=0.4]. The reaction mixture was poured onto ice-water and extracted with DCM. The organic extracts were washed with water, brine, and dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.05 g (89%) of crude 63 as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ5.8-5.5 (m, 2H), 4.69 (d. J=6.15 Hz, 2H), 3.85-3.3 (m, 3H), 3.0 (s, 3H), 2.0-1.9 (m, 1H), 1.55-1.30 (m, 1H), 1.40 (s, 9H), 1.0 (d, J=6.74 Hz, 3H) ppm.
Reaction SMILES: C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>O.C1COCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:24]([C@@H:23]2[CH2:27][CH2:28][CH2:29][N:22]2[C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])=[O:26])=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
Under ice-cooling, 1.73 mL (12.4 mmol) of triethylamine and 0.88 mL (7.23 mmol) of 2,2-dimethyl propanoyl chloride were added to a THF (10 mL) solution comprising 1.50 g (6.97 mmol) of 1-(tert-butoxycarbonyl)-L-proline, and the mixture was stirred under ice-cooling for 30 minutes. Subsequently, 269 mg (4.65 mmol) of methyl 2-amino-5-chlorobenzoate was added thereto under ice-cooling, and the mixture was heated under reflux for 19 hours. After condensation and addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1% hydrochloric acid, water, saturated sodium bicarbonate water, and saturated saline, followed by drying over magnesium sulfate. After condensation, the resultant was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1→4/1), thereby giving 1.65 g of tert-butyl (2S)-2-{[4-chloro-2-(methoxycarbonyl)phenyl]carbamoyl}pyrrolidine-1-carboxylate (yield: 93%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31]([NH:1][CH:2]1[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]1=[O:20])=[O:32])=[CH:25]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2cc(O)ccc2[nH]1
Reaction time: 48 h
Yield: 126.2 %

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmole) and 5-hydroxyindole-2-carboxylic acid (75 mg, 0.44 mmole) were combined at room temperature in a mixture of 1 ml of dimethylformamide and 5 ml of methylene chloride. To this reaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.40 mmol). The pH of the reaction mixture was then adjusted to 8.5 with triethylamine and stirring was continued at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 10% citric acid solution. The phases were separated and the organic layer was washed in succession with 20% citric acid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml) and brine. The dried (MgSO4) extracts were concentrated to yield 200 mg of the product. Preparative thick layer chromatography (chloroform - ethanol - ammonia, 90:10:1, v/v) afforded the analytical sample (80 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[C:10]1=[O:19].[CH2:20]([O:22]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:21]>>[C:20]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[C:10]1=[O:19])(=[O:22])[CH3:21]
Reactant: O=C1c2ccc(Cl)cc2CC1Cc1ccncc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CC(=O)c1cnccc1CC1Cc2cc(Cl)ccc2C1=O

Procedure:
The title compound 110 is prepared according to the procedure reported in Example 36.5 with compound 109 (317 mg, 0.94 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.31 mL, 0.94 mmol) as reactants. White solid. (Yield 221 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:12])=O.[CH2:14](O)[CH3:15]>>[ClH:12].[CH2:14]([O:8][C:7]([C:2]1([NH2:1])[CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:9])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: NC1(C(=O)O)CCCC1
Reactant: CCO
Product: CCOC(=O)C1(N)CCCC1
Product: Cl
Yield: 93 %

Procedure:
This was synthesised according to Standard Procedure 1, using 1-amino-1-cyclopentanecarboxylic acid (5.0 g, 38.6 mmol) with thionyl chloride (5.72 mL, 58 mmol) and anhydrous ethanol (29 mL). The product was isolated as a white solid (6.98 g, yield 93%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].CCN(C(C)C)C(C)C.[CH3:71][O:72][CH:73]([O:83][CH3:84])[CH2:74][NH:75][CH:76]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>CN(C=O)C>[CH:76]1([N:75]([CH2:74][CH:73]([O:83][CH3:84])[O:72][CH3:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]2[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]3[CH2:42][CH2:43][C:44]4([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]5[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=5)=[O:51])[CH2:45]4)[CH2:60][CH2:61]3)[C:26]=2[F:25])[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Reactant: COC(CNC1CCCCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)C1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of HATU (0.143 g) in DMF (0.5 mL) was added to a solution of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.133 g), Hunig's base (0.22 mL) and N-(2,2-dimethoxyethyl)cycloheptanamine [WO 2008075025] (0.050 g) in DMF (0.5 mL). The resulting dark solution was stirred overnight at RT. The solvent was evaporated and the residue partitioned between ethyl acetate (25 mL) and 20% aqueous brine (25 mL). The organic layer was separated and washed with 20% aqueous brine (2×25 mL). The organic solution was evaporated and the residue purified by silica gel chromatography, elution gradient 65:30:5 to 47.5:47.5:5 isohexane:ethyl acetate:triethylamine. The fractions containing the product were combined and evaporated to give the subtitled compound as an oil. Yield 0.165 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH3:19])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 100 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
In methanol (250 ml) was suspended 5-nitrosalicylic acid (50.0 g, 273 mmol), and to the mixture was added sulfuric acid (6 ml). The mixture was stirred at 100° C. for 24 hours and the cooled to room temperature. The precipitated insoluble materials were filtered, which were washed with hydrous methanol (containing 20% of water) and methanol, and dried under reduced pressure to give methyl 5-nitrosalicylate (38.5 g, 195 mmol, 72%).
Reaction SMILES: C[CH:2]([CH2:8][CH2:9][NH2:10])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].[C:11](#N)C(C)=C.C(#N)/C=C/C>>[CH3:11][CH:8]([CH2:9][NH2:10])[CH2:2][CH:3]([C:5]([OH:7])=[O:6])[NH2:4]
Reactant: CC(CCN)C(N)C(=O)O
Reactant: C=C(C)C#N
Agent: C/C=C/C#N
Product: CC(CN)CC(N)C(=O)O

Procedure:
γ-Methyl-DL-thiocitrulline (where R is H, R' is CH2 and R" is C(H)(CH3) and x is zero and Q is =S). This compound may be prepared by using y-methyl-DL-ornithine in place of L-ornithine in Example I. γ-Methyl-DL-ornithine is prepared as described above for β-methyl-DL-ornithine except methacrylonitrile is substituted for crotononitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:17]=3)[C@@H:12]3[CH2:28][CH2:29][CH2:30][N:11]3[CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N>C(O)C.C(Cl)Cl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:16][CH:17]=3)[C@@H:12]3[CH2:28][CH2:29][CH2:30][N:11]3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCOS(C)(=O)=O)ccc32)cc1
Reactant: C1COCCN1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCOCC4)ccc32)cc1
Temperature: 50 °C
Yield: 257.7 %

Procedure:
A mixture of crude cis-methanesulfonic acid 3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl ester (28.5 mmol), Na2CO3 (4 equiv.), KI (0.5 equiv.), and morpholine (7.52 mmol, 10 equiv.) in ethanol (0.2 M) was heated to 50° C. overnight. The mixture was cooled to rt, diluted with CH2Cl2, and filtered. The filtrate was concentrated to give the crude product. Column chromatography (NH3 in MeOH/CH2Cl2) followed by HPLC give the desired product (8.19 g, 68%). The enantiomers were separated using a Chiralcel AD-h column on a SFC HPLC eluting with IPA/MeOH with 0.2% DEA. MS: exact mass calcd for C26H34N2O3, 422.3; m/z found, 423.5 [M+H]+. 1H NMR (MeOH-d4): 7.06 (d, J=8.5, 2H), 6.82 (d, J=8.5, 2H), 6.70 (d, J=2.5, 1H), 6.67 (d, J=8.5, 1H), 6.61 (dd, J=2.5, 8.5 1H), 4.08 (dd, J=8.5, 5.5, 1H), 3.97 (t, J=6.5, 2H), 3.79 (m, 1H), 3.74 (s, 3H), 3.67 (m, 4H), 2.91 (m, 3H), 2.78 (dd, J=5.0, 11.2, 1H), 2.47 (m, 6H), 2.34 (m, 1H), 1.91 (m, 5H).