Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1([CH3:32])[CH3:31])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[O:9][CH:8]=[N:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:13]=2)[CH2:27][C:26]1([CH3:32])[CH3:31])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1ncoc1-c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncoc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
To a stirred solution of 5-(4-iodo-phenyl)-oxazole-4-carboxylic acid ethyl ester (11.0 g, 32 mmol) in dry toluene (300 mL) was added 2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (7.53 g, 35.2 mmol), Pd(AcO)2 (580 mg, 2.56 mmol), biphenyl-2-yldicyclohexylphosphine (0.9 g, 2.56 mmol) and Cs2CO3 (20.7 g, 64 mmol) under a nitrogen atmosphere at room temperature. The mixture was heated to 80° C. and stirred for 24 hrs. The solution was allowed to cool to room temperature and was then partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed to give the crude product. It was purified by silica gel column chromatography (PE/EtOAc=40/1˜10/1 to recover unreacted starting material; PE/EtOAc=8/1˜5/1 to yield the title compound (6.0 g, 43%) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:12](=[O:14])[CH2:11][C@@H:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C[C@@H]1CCc2ccccc2C1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@@H]1CCc2ccccc2C1
Yield: 86 %

Procedure:
A colorless oil of 1-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester was prepared in the same manner as in Reference Example 1, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 86%).
Reaction SMILES: Cl.[CH2:2]([NH2:7])[CH2:3][CH2:4][C:5]#[CH:6].[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:7][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C#CCCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
Pent-4-yn-1-amine hydrochloride (5.48 g, 45.8 mmol) was added to a 6° C. solution of 2,4-dichloro-3-nitroquinoline (10.6 g, 43.6 mmol) and triethylamine (15.2 mL, 109 mmol) in dichloromethane (100 mL). After 30 minutes, the solution was allowed to warm to room temperature. After 5 hours, the volatiles were removed under reduced pressure and the solid residue was triturated with water and isolated by filtration. The filter cake was rinsed with water and toluene and was allowed to dry for several days to yield 2-chloro-3-nitro-N-pent-4-ynylquinolin-4-amine as an orange solid (13.16 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:26])[N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:13]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:26]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCN(C)C)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Yield: 98.8 %

Procedure:
A solution of 12 (1.15 g, 2.92 mmole) in 40% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 4 h. The solvent was removed by rotary evaporation, and the resulting organic residue was carefully partitioned between dichloromethane and a saturated solution of sodium bicarbonate (30 mL each). The organic extract was dried over anhydrous sodium sufate, filtered, and concentrated to give 13 (0.80 g, 95%) as a light brown oil. This amine was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: COC(=O)c1sccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1sccc1Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
5-Chloro-2-fluoro-nitrobenzene and methyl 3-amino-thiophene-2-carboxylate, m.p. 207°-208° C. (EtOAc/Hexane).
Reaction SMILES: Cl.Cl.[Cl:3]C1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.Cl.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C:36]=4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1>>[ClH:3].[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[C@@H:35]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C@@H:36]4[NH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Reactant: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Agent: Cl
Product: Clc1cccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole dihydrochloride the title compound was prepared: 1H NMR (DMSO-d6) δ 1.35, 1.55, 2.10, 2.71, 3.05, 3.28, 3.97, 4.20, 6.65, 7.12, 7.4-7.5, 8.8. HRMS (FAB) calcd for C18H21ClN2 (MH+) 299.1315, found 299.1306.
Reaction SMILES: [S:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH2:4][CH2:3][CH:2]([CH2:14][C:15]3[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=3)[S:1][C:6]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)COC(CC2CCc3c([nH]c4ccccc34)S2)=N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COC(CC2CCc3c(n(Cc4ccccc4)c4ccccc34)S2)=N1
Reaction time: 0.5 h

Procedure:
71 mg of 2-(2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)methyl-4,4-dimethyl-2-oxazoline (prepared as described in Example 80) in 1 ml of dimethylformamide was added to a suspension of 11 mg of sodium hydride (55% w/w dispersion in mineral oil) in 1 ml of dimethylformamide, with stirring and ice-cooling. Stirring was continued at this temperature for 30 minutes and then 0.03 ml of benzyl bromide was added to the reaction mixture, with stirring and ice-cooling. Stirring was continued for a further hour. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a mixture of 20% v/v ethyl acetate in hexane as the eluent, to afford 71 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22](Cl)=[O:23].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([NH:15][C:12]1[S:13][C:14]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[N:11]=1)=[O:23]
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Reactant: COCCOCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1nc2[nH]nc(-c3ccccc3)c2s1
Temperature: 70 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a vial charged with 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.139 mmol), PS-DMAP (Argonaut resin, 6 equiv.), and a stirring bar was added THF (2 mL) and 2-(2-methoxyethoxy)acetyl chloride (106 μL, ca. 5 equiv.). The reaction mixture was stirred at 70° C. for 24 h, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 20 equiv.) for 1.5 h. The resin was filtered, washed with THF and the solvent was evaporated. The residue was treated with a (5:1:1) mixture of THF/H2O/Et3N (2 mL) at 50° C. for 24 h, then the solution was directly adsorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 30 mg (65%) of 2-(2-methoxy-ethoxy)-N-(3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-acetamide as a white solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.6 (2 broad s, 1H, NH+tautomer), 12.2 (broad s, 1H, NH), 7.74 (m, 2H, tautomers), 7.54 (m, 2H, tautomers), 7.38 (m, 1H, tautomers), 4.28 (s, 2H), 3.68 (t, 2H), 3.51 (t, 2H), 3.29 (s, 3H); HPLC/MS m/z: 333 [MH]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1>>[C:18]([CH2:17][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=[CH:15][CH:14]=1)#[N:19]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: N#CCc1cccc(N)c1
Product: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (1.68 g, 8.80 mmol) was coupled to aniline (80) (1.16 g, 8.80 mmol), using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([CH3:26])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:10]2=[N:9][C:8]=1[CH3:27])=[O:6].ClC(Cl)(Cl)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[CH2:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:5]([NH:4][CH2:3][C:2]([CH3:29])([NH:1][CH2:36][C:37]([F:40])([F:39])[F:38])[CH3:28])=[O:6])=[C:8]([CH3:27])[N:9]=2)[CH:12]=[C:13]([CH3:26])[CH:14]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)NCC(F)(F)F)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) of N-(2-amino-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (Example 74) were initially charged in 2 ml of DMF, 0.041 ml (0.25 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate, 69 mg (0.50 mmol) of potassium carbonate and 4.1 mg (0.025 mmol) of potassium iodide were added and the mixture was then stirred at RT overnight. 0.082 ml (0.50 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was then added, and the mixture was once more stirred at RT overnight. Another 0.123 ml (0.75 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate were added, and the mixture was once more stirred at RT overnight. For work-up, 1 ml of water was added, the mixture was filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.5% ammonium hydroxide). The product fractions were combined, evaporated and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([C:7]#[N:8])[N:6]=1.O.[Sn](Cl)[Cl:21]>C(O)(C)C.Cl>[ClH:21].[CH3:1][C:2]1[S:3][C:4]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:7]([NH2:8])[C:5]=2[N:6]=1
Reactant: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile (36 g, 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RB flask equipped with a reflux condenser, thermometer, magnetic stirrer bar and heat with stirring to 65° C. (orange solution). Add tin (II) chloride hydrate (78.7 g, 415.4 mmol) in hydrochloric acid (400 ml; 5M) and heat the resulting solution at reflux. After 2.5 h., cool the reaction to 15° C., filter the suspension, wash with isopropanol/water (2:1) and dry at 50° C. under reduced pressure to leave a yellow solid (36.7 g). Evaporate the filtrate to around 200 mL to form a yellow slurry. Filter the slurry again and dry at 50° C. under reduced pressure to leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl (700 mL) and heat to reflux for 20 min, cool to 15° C. Filter the resulting yellow slurry and dry at 50° C. under reduced pressure to leave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231 (M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 2.5(s, 3H), 6.78(dd, 1H), 6.85(dd, 1H), 6.98(t, 1H), 7.02(t, 1H), 8.80(s, 1H), 9.10(s, 1H), 9.98(s, 1H), 10.78(s, 1H). 13CNMR(75 MHz, DMSO, ppm): δ 19.6, 120.1, 120.8, 123.6, 125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C11H11N4S.
Reaction SMILES: [F-:1].CC(CC(O)CO)C.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C1(C)C(C)=CC=CC=1>>[Cl:17][C:16]1[C:11]([F:1])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [F-]
Agent: CC(C)CC(O)CO
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 1.5 liter flange flask and fitted with a distillation bridge and impeller stirrer, 279 g (4.8 tool) of fluoride, 218.5 g (0.3 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride and 11.5 g (0.023 mol) of polyethylene glycol dimethyl ether 500 were introduced at 100° C. into the melt of 768 g (4 mol) of 2,3-dichloronitrobenzene. Subsequently, the mixture was azeotropically dried using 200 g (1.9 mol) of xylene and stirred for 24 hours at a temperature of 100° C. Amount of 3-chloro-2-fluoronitrobenzene formed: after 5 hours: 18 GC area-%. after 24 hours: 47 GC area-%.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[Cl:8][C:9](Cl)(Cl)[S:10]Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[S:10][N:5]=[C:4]([CH:3]([CH3:7])[CH3:2])[N:6]=1
Reactant: CC(C)C(=N)N
Reactant: ClSC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1nsc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2-methyl propanimidamide hydrochloride (5.0 g, 40.8 mmol), trichloromethanesulfenyl chloride (7.14 g, 38.4 mmol) in methylene chloride (200 mL) at 0° C. was added dropwise an aqueous solution of sodium hydroxide (50%, 9.9 mL) over 20 minutes. The reaction mixture was stirred for 2 h at 0° C. and then was allowed to warm to room temperature, and stirred for an additional 3 h. Ice was added to the reaction mixture, the mixture was separated, and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a oil (3.8 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:22][C:16]1[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(O)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 84.5 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.00 g, 0.003 mol) in tetrahydrofuran (18 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 18 mL, 0.009 mol). The mixture was stirred at 0° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.82 g, 86%) as a pale orange solid.
Reaction SMILES: [CH2:1]([S:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O-:11])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:18][C:19]1[C:20]([S:28][CH3:29])=[N:21][C:22]([CH3:27])=[CH:23][C:24]=1[S:25][CH3:26].C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][S:28][C:20]1[C:19]([NH:18][C:9](=[O:11])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[C:24]([S:25][CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1
Reactant: CCCCCCSC(C(=O)[O-])c1ccccc1
Reactant: CSc1cc(C)nc(SC)c1N
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCSC(C(=O)Nc1c(SC)cc(C)nc1SC)c1ccccc1
Yield: 7.6 %

Procedure:
To a stirred solution α-hexylthio-phenylacetate (204 mg) and 3-amino-2,4-bis(methylthio)-6-methyl-pyridine (146 mg) in methylene chloride (5 ml) was added dropwise 2M solution of trimethylaluminum in toluene (0.4 ml), and the mixture was refluxed for 16 hours. After cooling to 0° it was acidified slowly with 1N hydrochloric acid, and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried (magnesium sulfate) and evaporated to give a solid residue. It was purified by a column chromatography on silica gel with elution by 2:8 ethyl acetate-hexane to give a solid residue. Crystallization from ethyl ether and hexane to provide pure N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-α-hexylthio-phenylacetamide (24 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].C1N2CCN(CC2)C1.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:2]([CH3:20])([NH:1][S:36]([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:38])=[O:37])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])=[CH:16][CH:15]=1)[CH3:19]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C#CCNC(=O)C(C)(N)COc1ccc(OCC)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: C#CCNC(=O)C(C)(COc1ccc(OCC)cc1)NS(=O)(=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
0.880 g 2-Amino-3-(4-ethoxy-phenoxy)-2methyl-N-prop-2-ynyl-propionamide and 0.233 g DABCO are dissolved in 8 ml tetrahydrofurane. After addition of 0.232 phenyl-methansulfonyl chloride the mixture is stirred for 20 hours. This mixture is then subjected to flash chromatography without further work-up to yield 320 mg of a white solid. M.p. 155-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=O)[N:11]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:10]=2[CH:22]=1)=O.C([SiH](CC)CC)C.B(F)(F)F>ClCCCl.CC#N>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[CH2:4][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][CH2:12][N:11]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C:10]=2[CH:22]=1
Reactant: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)C(=O)CO2)c1cc(I)ccc1Br
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(N1CCOc2ccc(Cc3cc(I)ccc3Br)cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a stirred solution of 6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-3-one (16.0 g, 29.252 mmol) in 1,2-dichloroethane/MeCN (1:2 mixture, 60 mL) was added triethylsilane (9.9 mL, 62.43 mmol) and borontrifluoride diethyletherate complex (4.9 mL, 38.51 mmol) simultaneously at −10° C. After stirring overnight at room temperature, the reaction was heated at 50° C. for 3 h. The reaction was quenched by the addition of aq. sodium bicarbonate (50 mL). Volatiles were evaporated under reduced pressure, and the resulting residue was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with water and brine, then dried over sodium sulfate and concentrated to a residue which was purified by silica gel column chromatography to furnish 1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (12.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:20]([NH:27][CH2:28][C:29](O)=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([NH:27][CH2:28][C:29]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1)=[O:30])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)CC1Cc2ccc(N)cc2CN(C)C1=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: COC(=O)CC1Cc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2CN(C)C1=O
Yield: 55 %

Procedure:
Methyl (±)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with Boc-glycine according to the procedure of example 5(b). Purification by chromatography (silica gel, 2%-5% CH3OH/CH2Cl2) gave the title compound as a pale yellow foam (55%): 1H NMR (CDCl3) δ8.22 (br s, 1H), 7.48 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.27 (d, J=16.6 Hz, 1H), 5.25 (br s, 1H), 3.92 (d, J=5.4 Hz, 2H), 3.82 (m, 1H), 3.80 (d, J=16.6 Hz, 1H), 3.71 (s, 3H), 3.03 (s, 3H), 2.90 (m, 3H), 2.41 (dd, J=16.8, 5.5 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:24])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)O
Solvent: ClCCl
Product: COC(=O)C1CCn2c1cc(SC)c2C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 200 mg of 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.