Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:13]([O:15][C:16](=[O:22])[CH:17](Cl)[O:18][CH2:19][CH3:20])[CH3:14]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH3:20])[N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]1=[O:3])[CH3:14]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCC)n1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.228 g=0.74 g NaH) was suspended in DMF (45 ml) under an argon atmosphere. The stirred suspension was cooled to 0° C. and 2-hydroxy-3-nitropyridine (4 g) was added portion wise over a period of 45 min. The mixture containing a compact yellow precipitate was then stirred at r.t. for 30 min and was cooled again to 0C. A solution of 2-chloro-2-ethoxyacetic acid ethyl ester (4.99 g) in DMF (5 ml) was then added and stirring at r.t. was continued for 2 h 30. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane=>cyclohexane/EtOAc 3:2) to give (RS)-ethoxy-(3-nitro-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (4.32 g) as yellow solid. MS 270.1 ([M]+)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C@@H:11]([OH:13])[CH3:12].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([O:13][C@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[CH3:12])[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@H](O)[C@H]1COC2(CCCCC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethanol (prepared according to J. Org. Chem. 1995, 60, 585-587, 0.183 g of ˜2:1 mixture of diastereomers) in dry THF (5 ml) was cooled to 0° C. and to it was added (in portions) sodium hydride (46 mg as 60% dispersion in mineral oil) followed in portions by 4,6-dichloro-2-(2,3-difluoro-benzylsulfanyl)-pyrimidine (product of example 1 step ii, 0.252 g). The reaction mixture was stirred at room temperature for 24 h then quenched with saturated aqueous ammonium chloride (2 ml) and diluted with EtOAc. The layers were separated and the aqueous layer extracted with further EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to leave a yellow oil which was purified by column chromatography on silica using a 0.5 to 4% mixture of EtOAc in iso-hexane as eluent to afford the subtitle compound as a white solid. Yield: 0.10 g
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:51](OC(=O)C)(=[O:53])[CH3:52].[Cl-].[NH4+]>>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=2)[C:13]2[N:14]=[CH:15][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][N:31]([C:51](=[O:53])[CH3:52])[C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:17][N:18]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(C)=O)cn2)cc1
Temperature: 25 °C

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), pyridine (45 μl, 0.556 mmol) and N,N-dimethylaminopyridine (2.3 mg, 0.0185 mmol) were added, and further acetic anhydride (52 μl, 0.556 mmol) was added, followed by refluxing for 3 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic phase was concentrated under reduced pressure, to obtain 1-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone as a crude product. To this, TFA (2 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 4 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. After filtering the solid, dichloromethane (5 ml) was added, followed by stirring at room temperature for 30 minutes, and the solid was filtered off, to obtain the desired compound as a colorless solid (29.3 mg, yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (98.6 mg, 86%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:8][C@@H:9]([CH3:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])(=[O:3])[CH3:2]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@H:9]([CH3:16])[O:8][C:6]1=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C(NC(C)=O)C(=O)O[C@H]1C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H](C)OC(=O)[C@@H]1NC(C)=O
Reaction time: 21 h

Procedure:
0.45 g of rhodium/Al2O3 catalyst is added to 15 g of (S)-2-acetamido-3-ethoxycarbonyl-2-penten-4-olide dissolved in 100 ml of ethyl acetate and the whole is hydrogenated at 50° C. and 50 bars for 21 hours and worked up as in Example 14. The ratio of the diastereoisomers of the crude product exhibited by HPLC analysis is (2R,3S,4S):(2S,3R,4S):(2R,3R,4S)=approximately 85:13:2. Diastereoisomerically pure title compound is obtained by crystallisation from ethyl acetate, [α]D20 =-183.2° (3% in CHCl3), m.p. 165°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1OC[C@H]1CCN21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCN21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.091 g) was added to a solution of tert-butyl (R)-6-amino-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 44, 0.092 g) in pyridine (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between DCM and 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give tert-butyl (R)-6-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta-[a]naphthalene-5-carboxylate (0.062 g).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Yield: 97.1 %

Procedure:
0.28 g of 1-[(S)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran and hydrogenated for 3 h at room temperature using 0.2 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.21 g (100%) of the title compound as a white solid. (+)-APCI-MS: 307 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]([N:14]1[CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A solution of 1-benzhydrylazetidine-3-carboxylic acid (4.20 g) in N,N-dimethylformamide (45 ml) were added potassium carbonate (6.53 g) and iodomethane (0.976 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=5:1, then 3:1). Fractions containing the target compound were concentrated to provide the titled compound as yellow crystals (3.57 g, 80.8%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]([NH:31][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=2)[CH2:24][NH:23][C:22](=[O:32])[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)COCc1ccc(Br)cc1
Reactant: Nc1cccc(CNC(=O)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COCc1ccc(Br)cc1)Nc1cccc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 67A (245 mg, 1 mmol) and 66A (268 mg, 1.05 mmol) in DMF (4 mL), was added EDCI (288 mg, 1.5 mmol), HOAt (14 mg, 0.1 mmol) and DIEA (0.54 mL, 3 mmol). The mixture was stirred rt for 16 h, then was quenched with water and extracted with EtOAc (3×20 mL). The organic layer washed by brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-40% EtOAc in hexanes) gave 67B (300 mg, 62%). MS (ESI) m/z 483.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: CC(C)(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.94–7.81 (br, 1H), 7.53–7.40 (br, 1H), 7.39–7.15 (m, 6H), 6.82 (d, 1H, J=7.2 Hz), 6.68–6.49 (br, 1H), 3.33–3.19 (m, 2H), 3.19–3.06 (m, 2H), 2.63–2.39 (m, 3H), 2.31–2.09 (m, 2H), 1.89–1.62 (m, 7H), 1.54 (s, 6H), 1.13–0.98 (m, 2H), 0.90–0.72 (m, 2H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]#[N:7])C.[N+:16]([O-])(O)=O.NNC(N)=N.[OH-].[Na+]>C(O)C>[NH2:2][C:4]1[C:5]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])=[CH:6][NH:7][N:16]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1n[nH]cc1C(=O)c1ccccc1
Yield: 24.9 %

Procedure:
A reaction mixture comprisng 73.36 g of α-[(dimethylamino)methylene]-β-oxo-2-benzenepropanenitrile, 63.45 g of aminoguanidine nitrate, 500 ml of ethanol and 36.6 ml of 10N sodium hydroxide was refluxed for 10 hours and then cooled. The resulting precipitate was collected and washed with water, giving 17.1 g of the desired product, mp 177°-179° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].CC(C)([O-])C.[K+].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20]>>[F:17][C:18]([F:22])([F:21])[CH2:19][O:20][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccnc(OCC(F)(F)F)c1
Temperature: 170 °C
Reaction time: 120 h

Procedure:
A mixture consisting of 7.5 g of 2-chloroisonicotinic acid, 16 g of potassium tert-butoxide and 100 ml of 2,2,2-trifluoroethanol was stirred at 170° C. for 5 days in a sealed tube. After evaporation of the solvent, the residue was mixed with water and 4 N hydrochloric acid and extracted with chloroform. The solvent was washed with water, dried over anhydrous magnesium sulfate and then concentrated, and the thus formed crystals were washed with hexane to obtain 7.7 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Reactant: Oc1ccccc1N1CCCCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Oc2ccccc2N2CCCCC2)c1
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-N-(3-(aminosulfonyl)phenyl)benzamide (0.10 g, 0.28 mmol), 2-(piperidin-1-yl)phenol (74 mg, 0.28 mmol), K3PO4 (0.12 g, 0.56 mmol), and CuI (53 mg, 0.28 mmol) in DMF (1 mL) and water (20 μL) was sealed in a glass tube and heated in a microwave oven at 150° C. for 15 min. The reaction was filtered and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-(piperidin-1-yl)phenoxy)-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 452.0 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H-].[Na+]>CN(C=O)C>[O:12]=[C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][N:9]1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C1NCCN1c1ccccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccccn2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-pyridin-2-ylimidazolidin-2-one from Step A (150 mg, 0.92 mmol) and tert-butyl bromoacetate (197 mg, 1.01 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (40 mg of a 60% dispersion in mineral oil, 1.00 mmol). The mixture was stirred at 0° C. for 30 min, then quenched with saturated aqueous NaHCO3 and extracted with CHCl3 (2×35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH3:10].CCOCC>C1(C)C=CC=CC=1>[N:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc2nccnc2c1

Procedure:
1,2-phenylenediamine (2.3 g) and acetic acid (1 ml) were added to a solution of the compound mentioned above (7.54 g) in toluene (50 ml), and the mixture was heated under reflux for an hour. The solid formed upon addition of ether to the reaction mixture at 0° C. was filtered to give a quinoxaline derivative (1.91 g). The compound was dissolved in tetrahydrofuran (500 ml), and sodium hydride (60%, 1.0 g) and 2-trimethylsilylethoxymethyl chloride (8.6 ml) were added to the solution at room temperature. The mixture was stirred for an hour. Aqueous ammonium chloride was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with water and aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a compound protected by the SEM group.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C(#N)C.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 21 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and acetonitrile (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in acetonitrile (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (349 mg, yield: 54%/(S)-2-octanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1(Cl)[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]1(Cl)[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: ClCCCOC1(Cl)C(Cl)=CC=CC1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1
Yield: 27.7 %

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-1,2-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white crystalline solid, m.p. 101.5°-103° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:18]1([C:21]([N:15]2[CH2:14][CH2:13][N:12]([CH:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH2:7][CH2:8]3)[CH2:17][CH2:16]2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)C(N1CCN(C(=O)C3CC3)CC1)CC2
Reaction time: 6 h
Yield: 75 %

Procedure:
A mixture of (6-methoxy-indan-1-yl)piperazine (3.0 g, 15.5 mmol), cyclopropane-carbonyl chloride (1.6 g, 15.5 mmol), and excess powdered potassium carbonate was stirred for 6 hr. The insoluble material was removed and the solution concentrated in vacuo. The residue was dissolved in ether and washed with 1N HCl. The acid washes were made basic with NaOH solution and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was converted to the hydrochloride salt with ethereal HCl to give a solid (75%, mp: 187°-188° C.). Calc'd for C18H24N2 O2.HCl: C, 64.18%; H, 7.48%; N, 8.32%. Found: C, 63.96%; H, 7.18%; N, 8.18%.