Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:5]=2[N:6]=1.BrNC(=O)CCC(N)=O>C(OCC)(=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:5]=2[N:6]=1
Reactant: CCCc1ccc2c(c1)CCc1sc(C)nc1C2=O
Agent: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Product: CCCc1ccc2c(=O)c3nc(C)sc3ccc2c1

Procedure:
The product from step (ix) (2.8 g) and N-bromosuccinamide were dissolved in ethyl acetate (30 ml) and irradiated with a 500 Watt halogen lamp at reflux for 2 h. The solvent was evaporated under reduced pressure and the solid residue dissolved in dichloromethane (30 ml) and treated with triethylamine (10 ml). After 2 h the solvents were removed under reduced pressure and the residue partioned between water and ethyl acetate. The organic layer was collected and dried over MgSO4. The solvent was evaporated under reduced pressure and the product purified by flash chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:31]([O:33]CC)=[O:32])[O:10][C:9]2[C:11]3[CH2:12][CH:13]([N:18]4[CH2:22][CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=5)[O:20]C4=O)[CH2:14][C:15]=3[CH:16]=[CH:17][C:8]=2[O:7]1)=[O:5])C.[OH-].[Na+:37]>>[Na+:37].[Na+:37].[Cl:29][C:25]1[CH:24]=[C:23]([CH:21]([OH:20])[CH2:22][NH:18][CH:13]2[CH2:12][C:11]3[C:9]4[O:10][C:6]([C:4]([O-:5])=[O:3])([C:31]([O-:33])=[O:32])[O:7][C:8]=4[CH:17]=[CH:16][C:15]=3[CH2:14]2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc3c(c2O1)CC(N1CC(c2cccc(Cl)c2)OC1=O)C3
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C1(C(=O)[O-])Oc2ccc3c(c2O1)CC(NCC(O)c1cccc(Cl)c1)C3

Procedure:
To 1.60 g of product from Example 1, Step C, under argon, is added 22 ml of 2.5N sodium hydroxide. The reaction mixture is heated to its reflux temperature and maintained at this temperature for 20 hours. The gum that is originally present dissolves and the solution turns a dark brown. The reaction mixture is evaporated in vacuo and the residue treated with ethyl alcohol. The solids are isolated by filtration, rinsed with ethyl alcohol and diethyl ether and air dried briefly. The resulting solid is dissolved in water and loaded onto a column of XAD-4 resin (previously washed with 1 liter of 50:50 methyl alcohol:water, followed by 500 ml of water). The column is eluted with 1 liter of water followed by 1 liter of methyl alcohol. The methyl alcohol fractions containing the Rf 0.60 component (7:1 water:methyl alcohol; reverse phase tlc plates) are combined, evaporated in vacuo and the residue is triturated with ethyl alcohol. The solids are collected, rinsed with ethyl alcohol and air dried to give 0.86 g of the desired product as a light brown solid. 1H NMR(D2O): δ2.79(m,2H); 3.01(m,2H); 3.21(m,2H); 3.79(m,1H); methine next to OH approx. 4.86; 6.77(s,2H,Ar); 7.3-7.5(m,4H,Ar).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].N1C=CC=C(C)C=1.[NH2:26][CH2:27][CH:28]1[CH:32]([CH3:33])[CH2:31][NH:30][CH2:29]1>N>[NH2:26][CH2:27][CH:28]1[CH:32]([CH3:33])[CH2:31][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:29]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CC1CNCC1CN
Agent: N
Solvent: Cc1cccnc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)C(CN)C3)cc21
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), β-picoline (11 ml) and 3-aminomethyl-4-methylpyrrolidine (0.5 g) was refluxed for 8.5 hours, then the reacting mixture was cooled to room temperature. To the mixture was added concentrated aqueous ammonia (100 ml) and concentrated under reduced pressure. To the residue was added dichloromethane-ether (1:3, 37 ml), the resulting precipitate was collected by filtration, washed with ethanol-ether (1:3), recrystallized from ethanol and further recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.14 g) as pale yellow powder, mp 245°-248° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]4=[N:12][C:11]=3[CH3:20])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:23][O:24][N:25]([CH3:31])[C:26](=O)[O:27]CC.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:23][O:24][N:25]([CH3:31])[C:26]([C:18]1[C:13]2[N:14]([C:10]([C:7]3[S:6][C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=4[C:8]=3[CH3:9])=[C:11]([CH3:20])[N:12]=2)[N:15]=[C:16]([CH3:19])[CH:17]=1)=[O:27]
Reactant: Cc1ccc2nc(C)c(-c3sc4ccc(F)cc4c3C)n2n1
Reactant: CCOC(=O)N(C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
The solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.09 g, 6.73 mmol) in THF (56 mL) is stirred at −78° C. Ethyl N-methoxy-N-methylcarbamate (4.48 g, 33.7 mmol) is added. LDA (10 mL, 20.1 mmol) is added dropwise to maintain reaction temperature at −75° C. The reaction is stirred at −78° C. for 1 hour. The mixture is quenched with H2O, filtered through celite with CH2Cl2. The collect solution is washed with H2O, dried over Na2SO4, filtered and concentrated. The crude is purified by ISCO (50-100% EtOAc/Hexane) to give the title compound (0.85 g, 31%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 7.0 (s, 1H), 3.7 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H) ppm. MS (m/e): 399 (100%, M+1).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1.Cl.CO[C:16](=N)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.O.Cl>CO>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]2[NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=3[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(N)c(N)c1
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(C=Cc3ccc(OC)c(OC)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
A mixture of 4-methoxy-1,2-phenylenediamine dihydrochloride (1.55 g; 7.3 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.9 g; 7.3 mmol) in methanol (50 mL) was stirred at ambient temperature for 72 hours. The methanol was concentrated to 25 mL. A yellow solid was separated by filtration. The solid was suspended in MeOH (10 mL), and treated with hydrogen chloride. The precipitate that formed was collected to obtain 515 mg (21% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 246-249° C. Anal. Calcd. for C18H18N2O3HCl. H2O: C, 61.72, H, 5.20; N, 7.79. Found: C, 61.61; H, 5.37; N, 7.84 . Mass spectrum: (EI; M+) m/z 310. 1H-NMR (DMSO-d6; 400 MHz) δ14.8 (broad s,1H), 8.3-8.5(d,1H), 7.62-7.63 (d, 1H), 7.3 (d,1H), 7.21-7.23 (dd 1H), 7.2 (d, 2H), 7.07-7.16(m, 3H), 3.86-3.88 (d, 6H), 3.82-3.84 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:42]=[C:33]7[CH2:34][N:35]([CH:38]8[CH2:41][O:40][CH2:39]8)[CH2:36][CH2:37][N:32]7[N:31]=6)[C:26](=[O:43])[N:25]([CH3:44])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:45])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:42]=[C:33]3[CH2:34][N:35]([CH:38]4[CH2:39][O:40][CH2:41]4)[CH2:36][CH2:37][N:32]3[N:31]=2)[C:26](=[O:43])[N:25]([CH3:44])[CH:24]=1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A mixture of 163b (80 mg, 0.12 mmol) and NaBH4 (15 mg, 0.36 mmol) in methanol (5 mL) was stirred at 30° C. for 2 h. The mixture was quenched with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 163 (30 mg, 50%) as dark red solid. MS-ESI: [M+H]+ 611.4. 1H NMR (500 MHz, CHCl3) δ 8.48 (d, J=5.5 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.70 (d, J=2, 1H), 7.43 (s, 1H), 7.34 (d, J=5 Hz, 1H), 6.8 (s, 1H), 5.70 (s, 1H), 5.03 (t, J=6, 1H), 4.77-4.73 (m, 3H), 4.68 (t, J=6.5 Hz, 2H), 4.51-4.50 (m, 1H), 4.34-4.33 (m, 1H), 4.23-4.16 (m, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.86-3.85 (m, 1H), 3.79-3.74 (m, 1H), 3.71 (s, 3H), 3.56 (d, J=4, 2H), 2.83 (t, J=5.5 Hz, 2H), 2.58 (d, J=5.5 Hz, 2H), 2.52 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][CH:6]3[CH2:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][CH:6]3[CH2:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1CC1CCCN21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CC1CCCN21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of methyl 7-amino-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 29, 0.400 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.565 g) in pyridine (4 mL) and DCM (12 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution (10%) and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-2%. The resultant solid was re-purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, containing 1% triethylamine, with a gradient of 0-100% to give a yellow solid which was again purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane (50%), followed by DCM (100%). The resultant solid was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-30%, to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.317 g) as a yellow gum.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CCNCC1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 2.01 (10 mmol) of N-Boc4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO K+in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:21])[NH:17][CH:18]1[CH2:20][CH2:19]1)=O)C1C=CC=CC=1>[Pd]>[CH:18]1([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:21])[CH2:20][CH2:19]1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: O=C(NC1CC1)[C@@H]1CCCN1

Procedure:
(S)-2-cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester (907 mg, 3.14 mmol) was hydrogenated using Pd/C (5%, 61 mg) to give (S)-pyrrolidine-2-carboxylic acid cyclopropylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1([C:14]([O:16]CC)=O)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14](=[O:16])[C:11]3([CH2:10][NH:9][C:3]=2[CH:4]=1)[CH2:13][CH2:12]3
Reactant: CCOC(=O)C1(CNc2cc(Br)ccc2N)CC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(Br)cc2NCC12CC2
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a stirred solution of ethyl 1-((2-amino-5-bromophenylamino)methyl)cyclopropanecarboxylate (624 mg, 2.0 mmol) in toluene (15 mL) was added dropwise tetraisopropoxytitanium (1.2 g, 4.0 mmol). After addition was complete, the reaction was stirred for 12 hours at 90° C. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL). The organic layer was separated, dried by sodium sulfate, filtered and concentrated to give the crude 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropan]-2(1H)-one (400 mg, 75%) as white solid, used for the next step without further purification.
Reaction SMILES: [CH:1]1([C:4](=[O:24])[C:5](=[C:19](SC)[S:20][CH3:21])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[Cl:18])=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:26]O.C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([C:4]2[O:24][N:26]=[C:19]([S:20][CH3:21])[C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[Cl:18])[CH2:3][CH2:2]1
Reactant: CSC(SC)=C(C(=O)c1ccc(S(C)(=O)=O)cc1Cl)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CSc1noc(C2CC2)c1C(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 3-cyclopropyl-2-(bis(methylthio)methylene)-1-(2-chloro-4-methylsulfonylphenyl)propan-1,3-dione (123 mg, 0.304 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (23 mg, 0.334 mmol) and sodium acetate (25 mg, 0.304 mmol). The resulting mixture was stirred at r.t. overnight, then evaporated to dryness and the residue was taken up in ethyl acetate, washed with water, dried and evaporated to dryness. The crude product was purified by preparative Thin-layer chromatography to give 90 mg of crystalline 5-cyclopropyl-3-methylthio-4-(2-chloro-4-methylsulfonylbenzoyl)isoxazole, m.p. 141° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][CH:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=O)[C:19]2=4)[NH:14][CH2:13]3)[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:2].[NH2:28]OS(O)(=O)=O.N>O>[C:23]([C:18]1[C:19]2=[C:22]3[C:15]([NH:14][CH2:13][CH:12]3[CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:26][CH3:27])[CH2:8][N:9]3[CH3:25])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C=O)ccc4c3C(CN4)C[C@H]2N(C)C1
Reactant: NOS(=O)(=O)O
Agent: N
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C#N)ccc4c3C(CN4)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
A suspension of 500 mg of 1,1-diethyl-3-(2,3-dihydro-12-formyl-6-methyl-8α-ergolinyl)urea and 460 mg of hydroxylamine-O-sulfonic acid in 5 ml of water is stirred for 20 hours at room temperature. The reaction mixture is poured on ice, set to be alkaline with 25% strength ammonia solution, and extracted with dichloromethane. The organic phase is dried (Na2SO4), concentrated, the residue chromatographed on silica gel with dichloromethane/methanol=95/5 as the eluting agent, and crystallized from ethyl acetate/pentane. Yield 26% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26](O)=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH2:50])[CH3:45].CCN(CC)CC>>[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH:50][C:26](=[O:27])[CH2:25][N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[C:21]1=[O:24])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1
Reactant: C#C[C@@H](N)CC(=O)OCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C#C[C@H](CC(=O)OCC)NC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-5 (150 mg, 0.39 mmol), HOBT (63 mg, 0.46 mmol) and EDC (111 mg, 0.58 mmol) was added 3(S)-(ethynyl)-β-alanine ethyl ester hydrochloride (1-32) (U.S. Pat. No. 5,272,162; 82 mg, 0.46 mmol) and Et3N (80.7 gl, 0.58 mmol). The mixture was stirred at room temperature under argon for 16 hours and then partitioned between EtOAc and 10% citric acid. The aqueous phase was extracted with EtOAc (x3) and the combined organic layers then washed with saturated aqueous NaHCO3 followed by brine. Removal of the dried (MgSO4) solvent afforded a yellow oil which was purified by column chromatography (silica gel; hexane/EtOAc 1:1) to give 1-33 as an oil. Rf (silica; EtOAc/hexane 2:1) 0.57 ##STR51##
Reaction SMILES: Br.[N:2]1[C:3](=[O:11])[CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.Br[CH2:13][C:14]1[C:15]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1>C1COCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][CH:4]3[N:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]4=[N:2][C:3]3=[O:11])[C:15]=2[CH:22]=1
Reactant: O=C1CN2C=CC=CC2=N1
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: Br
Solvent: C1CCOC1
Product: O=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
A mixture of 100 mg (0.47 mmol) of imidazo[1,2-a]pyridin-2-one hydrobromide salt and 122 mg (0.47 mmol) 3-bromomethyl-5-chloro-benzo[b]thiophene in 5 mL of THF is treated with 1 mL (1.0 mmol) of 1M lithium bis(trimethylsilyl)amide THF solution at −78° C. The resulting mixture is stirred this temperature for 1 h and the mixture is quenched with saturated ammonium chloride solution. The product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[N:35]2[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].N1C=CC=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:35]1[CH:40]=[CH:41][CH:42]=[C:43]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:44]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cccnc1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cccnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyridin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (9%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40 (d, 1H), 7.29 (t, 2H), 7.18-7.08 (m, 2H), 7.00 (d, 1H), 6.81 (d, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10-2.90 (m, 2H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.O.O.[Sn](Cl)Cl.C[CH2:19][OH:20].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[NH:9][C:19](=[O:20])[O:8][C:6]=2[CH:7]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1O
Agent: Cl[Sn]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(F)c(Br)cc2o1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a 100 mL of round bottom flask was added 5-bromo-4-fluoro-2-nitrophenol (0.98 g, 4.15 mmol), tin(II) chloride dihydrate (4.73 g, 20.76 mmol) and 5 mL of EtOH. The reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was concentrated and washed with saturated NaHCO3 solution, and extracted with DCM (100 mL×3), and concentrated providing the crude product. 1,1′-Carbonyldiimidazole (808 mg, 4983 mmol) was added to the crude product in 20 mL of THF. The reaction mixture was heated at reflux overnight. The reaction mixture was concentrated and purified with silica gel column chromatography, eluting with 0-30% EtOAc/hexane to give 6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (690 mg, 71.6% yield). MS m/z: 232 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.Cl.Cl.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][NH:28][CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH3:29])[C:12](=[O:14])[CH2:11][N:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][C:8]1=[O:10]
Reactant: O=C(O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: CNCc1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(Cc1nc2ccccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetic acid (731 mg), 1-(1H-benzimidazol-2-yl)-N-methylmethanamine dihydrochloride (736 mg), and dichloromethane (20 mL) were added HOBt (448 mg), WSC.HCl (633 mg), and TEA (1.05 mL), followed by stirring at room temperature overnight. The resulting solid was collected by filtration and then washed with chloroform to obtain N-(1H-benzimidazol-2-ylmethyl)-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (925 mg).