Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[O:10][C:7]2=[N:8][CH:9]=1.C=O.[C:20]([O-])([O-])=O.[K+].[K+]>C(O)=O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH3:20])[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cnc2oc([C@@H]3CCCN3)cc2c1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2cc(Cl)cnc2o1

Procedure:
A 200 mg (0.80 mmol) sample of 5-chloro-2-(2-(S)-pyrrolidinyl)-furo[2,3-b]pyridine dihydrochloride, from Example 13c above, was dissolved in 4 mL of 88% formic acid and 8 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The product was converted to the salt by treatment with HCl/ether to give 140 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.29-2.38 (m, 2H), 2.49-2.68 (m, 2H), 2.95 (br s, 3H), 3.44 (m, 1H), 3.84 (m, 1H), 4.84 (m, 1H), 7.22 (s, 1H), 8.22 (d, 1H, J=2.3 Hz), 8.36 (d, 1H, J=2.4); MS m/z: 237 (M+H)+, 254 (M+NH4)+ ; Anal. Calcd for C12H13N2OCl.1.0 HCl.0.3 H2O: C, 51.74; H, 5.28; N, 9.73. Found: C, 51.74; H, 5.28; N, 10.16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: CCOC(CCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Clc1cc(Br)c2nccn2n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 4-bromo-6-chloropyridazin-3-amine (15.7 g, 75.3 mmol), 2-chloro-1,1-diethoxyethane (13.9 g, 90.3 mmol) and PTSA (17.2 g, 90.3 mmol) in isopropanol (150 mL) was heated to 80° C. for 20 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (300 mL), extracted with dichloromethane (200 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 8-bromo-6-chloroimidazo[1,2-b]pyridazine (17.2 g, 98%) as an orange solid. LC-MS: [M+H]+, 231.9, 233.9, tR=1.46 min.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:28]I>O1CCCC1>[C@H:1]([N:5]([CH3:28])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CI
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (R)-methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran (9 mL). sodium hydride (132 mg, 3.3 mmol, 10.00 equiv, 60%) was added. The resulting solution was stirred for 1 h at room temperature. This was followed by the dropwise addition of a solution of CH3I (922.5 mg, 6.50 mmol, 20.00 equiv) in tetrahydrofuran (2 mL) with stirring at 0° C. The resulting solution was stirred for overnight at 20° C. The resulting mixture was concentrated under vacuum and diluted by 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration. This resulted solid in 67 mg (59%) of (R)-3-(sec-butyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[C:13](Cl)(=[O:15])[CH3:14]>CC#N>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CC(=O)n1ccc2ccc(N)cc21

Procedure:
1-(6-Amino-indol-1-yl)-ethanone (B-3) was synthesized following the general scheme above starting from 6-nitroindole and acetyl chloride. Overall yield (˜40%). HPLC ret. time 0.54 min, 10-99% CH3CN, 5 min run; ESI-MS 175.1 m/z (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=3[N:7]=2)[CH2:2]1.[Cl:17][C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[C:23]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[NH:10][C:9]4[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=4[N:7]=3)[CH2:2]2)=[N:22][CH:21]=[CH:20][N:19]=1
Reactant: Clc1nccnc1Cl
Reactant: N#Cc1ccc2[nH]c(C3CCNC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)C3)nc2c1
Temperature: 80 °C
Yield: 49 %

Procedure:
The mixture of 2-pyrrolidin-3-yl-1H-benzoimidazole-5-carbonitrile (2 g, 9.43 mmol), 2,3-dichloro-pyrazine (1.43 g, 9.7 mmol) and K2CO3 (2.4 g, 17.6 mmol) in CH3CN (20 mL) was heated to 80° C. for 10 h, then it was concentrated and washed with DCM and H2O, the organic layer was dried over Na2SO4, and concentrated to give the desired compound (1.5 g, 79%). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH:24][CH3:25])([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isopropyl-N-methylamine (3.60 ml, 34.7 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.84 g, 79%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[N:14][CH:15]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CN3CCC2CC3)nc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. The mixture was then treated with 2-chloro-5-bromopyridine (7.1 g, 30 mmol) and stirred at 100° C. for 6 hours. The mixture reaction was treated with Na2CO3 (2M, 10 mL) at 10° C. and extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46-1.58 (m, 1H), 1.60-1.88 (m, 2H), 1.96-2.10 (m, 1H), 2.24-2.30 (m, 1H), 2.72-2.98 (m, 5H), 3.42-3.46 (m, 1H), 5.00-5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: CCn1nc(C)cc1N
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of 5-amino-1-ethyl-3-methylpyrazole (7.5 g, 0.06 mol), 2-iodobenzoic acid (14.88 g, 0.06 mol), DMF (50 ml) Cu(OAc)2 ·H2O (0.5 g) and K2CO3 (8.3 g, 0.06 mol) was refluxed under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water. The mixture was neutralized with acetic acid and the resulting solid was collected by filtration, washed with water and dried to afford 7.1 g (48%) of N-(1-ethyl-3-methylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Cl[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]>>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][CH:13]([C:14]([OH:16])=[O:15])[CH3:17])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(Cl)C(=O)O
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC(C)C(=O)O)cc(OC)c1

Procedure:
The title compound was prepared according to the procedure described in U.S. Pat. No. 3,598,859 (or Example A above) using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:18]3=[O:33])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH2:25][C:26]([OH:28])=[O:27])[C:18]3=[O:33])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)OC(C)(C)C)C3=O)S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)C3=O)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (140 mg, 0.291 mmol) in dry DCM (4 ml) cooled to 0° C., TFA (0.449 ml, 5.83 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The volatiles were removed under vacuum and the crude residue was dried affording 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (152 mg, 0.282 mmol, 97% yield, MS/ESI+ 424.8 [MH]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[CH:62]([C:63](O)=[O:64])[CH2:61][CH2:60][N:59]1[C:66]1[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:63]([CH:62]1[CH2:61][CH2:60][N:59]([C:66]2[CH:67]=[CH:68][C:69]([C:72]([F:75])([F:73])[F:74])=[CH:70][CH:71]=2)[C:58]1=[O:57])=[O:64]
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 6.4 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (0.236 g; 0.865 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane and 1 to 7% methanol in dichloromethane) to yield 0.025 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][C:8]([CH3:24])=[C:9]([CH:23]=1)[C:10]([CH:12](C(OCC)=O)C(OCC)=O)=[O:11].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][C:8]([CH3:24])=[C:9]([C:10](=[O:11])[CH3:12])[CH:23]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Yield: 48.3 %

Procedure:
A mixture of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g) and sulfuric acid (1 ml) in acetic acid (6 ml) and water (5 ml) was refluxed for hours. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The oily residue was purified by column chromatography on silica gel (25 g) eluting with a mixture of toluene and ethyl acetate (10:1) to give crystals of 5'-(2,4-difluorophenoxy)-2'-methyl-4'-nitroacetophenone (0.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2cccc(Cl)c21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2 (M+H)+.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:12][S:13](Cl)(=[O:15])=[O:14].ClCCl>N1C=CC=CC=1>[CH2:1]([S:4]([N:7]1[CH2:8][CH:9]([O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:10]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCS(=O)(=O)N1CC(O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 1-(propane-1-sulfonyl)-azetidin-3-ol (236 mg, 1.317 mmol) in pyridine was added drop wise methane sulfonyl chloride (205 μl, 2.63 mmol) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 3 h. Dichloromethane was added. The mixture was subsequently washed with water, saturated NaHCO3 and brine, dried (MgSO4), and filtrated. The solvent was evaporated to obtain 293 mg of crude product which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([N:22]1[CH2:23][CH2:24][CH:25]([O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:26][CH2:27]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3-Nitro-5-trifluoromethyl-phenol (8.81 g) was dissolved in THF (76 ml). 1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph3P (11.15 g) were added and the solution was cooled to −20° C. A solution of DEAD (6.8 ml, Aldrich) in THF (36 ml) was added dropwise, maintaining the temperature between −20 and −10° C. The reaction was warmed to RT and stirred overnight. The reaction was concentrated in vacuo and triturated with hexane. The yellow solid was removed by filtration and washed with Et2O (25 ml), and hexane. The white filtrate was washed with 1N NaOH (2×), brine (1×) and the hexane layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified with flash chromatography (SiO2, 5-10% EtOAc/hexane) to obtain 1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.
Reaction SMILES: [N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:31])[C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1.CC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:31])[C@H:20]([C:28]([NH:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CN(C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 31 %

Procedure:
Condensation of BocPro-DTrp-MePheOH (0.800 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 0.721 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 in 31% yield. De-t-butoxycarbonylation of BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 (0.400 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-MePhe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 23% yield.
Reaction SMILES: [Br-:1].[C:2]([CH:5]([CH2:18][CH3:19])[CH2:6][CH2:7][N+:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[CH3:17])([OH:4])=[O:3].C(O[C:24](=O)[CH3:25])(=O)C>C(O)(=O)C>[Br-:1].[NH:8]([CH:7]=[CH:24][CH:25]=[CH:17][C:9]1[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:8]=1[CH2:7][CH2:6][CH:5]([C:2]([OH:4])=[O:3])[CH2:18][CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1
Reactant: CCC(CC[n+]1c(C)sc2ccccc21)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: CC(=O)O
Product: CCC(CC[n+]1c(C=CC=CNc2ccccc2)sc2ccccc21)C(=O)O

Procedure:
The desired compound is prepared by heating 3.44 g of 3-carboxypentyl-2-methylbenzothiazolium bromide, 5.14 g of malonaldehyde dianil hydrochloride and 2 mL of acetic anhydride in 30 mL of acetic acid for 6 hours.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])[CH:17]=[CH:16][N:15]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH:22]([CH3:1])[C:21]2=[O:25])[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1CCCN1c1ccnc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCN(c2ccnc(Cl)n2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.79 mL) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 3.5 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., and 1-(2-chloropyrimidin-4-yl)pyrrolidin-2-one (370 mg) obtained in Step A was added thereto. The reaction mixture was stirred at the same temperature for 1 hr, iodomethane (0.35 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (38 mg).
Reaction SMILES: [Se](=O)=[O:2].[ClH:4].[CH3:5][O:6][C:7]1[C:35]([O:36][CH3:37])=[CH:34][C:10]2[CH2:11][C:12](=[O:33])[N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>O>[ClH:4].[CH3:5][O:6][C:7]1[C:35]([O:36][CH3:37])=[CH:34][C:10]2[C:11](=[O:2])[C:12](=[O:33])[N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: O=[Se]=O
Agent: Cl
Solvent: O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Reaction time: 0.25 h

Procedure:
3.5 gm of selenium dioxide were added to a mixture of 150 ml of diozane and 6 ml of water at 70° C.; the mixture was stirred for 15 minutes and then admixed with 3 gm of diatomaceous earth and 14.8 gm (0.03 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane hydrochloride. The mixture was refluxed for 6 hours, cooled and filtered. The filtrate was evaporated in vacuo and the residue was purified on a silica gel column with methylene chloride +1% of ethanol as the eluant. The fractions were evaporated in vacuo; the residue was dissolved in acetone, and the hydrochloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>O>[CH:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:27])([CH3:26])[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and isobutyryl chloride (117 mg, 1.10 mmol) followed by stirring at 60° C. for 2 hours. The reaction solution was poured into cold water, and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 128 mg (47%).