Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CC(O)=O.O>[O:19]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14]
Reactant: CN(C)S(=O)(=O)c1ccc(N)c(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A suspension of 4-amino-3-hydroxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.555 mmol) and phthalic anhydride (82 mg, 0.555 mmol) in AcOH (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled and diluted with water to afford a suspension. The precipitate was filtered, washed with water and dried under high vacuum to afford the title compound as a pink solid (142 mg, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:38][CH:37]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.1 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (38.1 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (73 μL) was added followed by 4-chloroaniline (58.9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.0 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 45 min then eluted directly on silica gel column (98:2 CH2Cl2:MeOH) then on one 250 μm silica gel plate (1:1 hexanes:acetone) to yield 9.5 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.46 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.98 (s, 1H); 7.90 (s, 1H); 7.82 (d, J=6.4 Hz, 1H); 7.75 (d, J=7.6 Hz, 1H); 7.65 (d, J=7.6 Hz, 1H); 7.58 (d, J=8.7 Hz, 2H); 7.51 (t, J=7.7 Hz, 1H); 7.33 (m, 3H); 6.80 (d, J=5.5 Hz, 1H); 5.94 (br s, 1H); 5.26 (br s, 1H); 1.67 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 469.2 (M+1).
Reaction SMILES: C(OC(N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[Cl:54]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][C:43]([C:51]3[CH:50]=[CH:49][C:48]([Cl:47])=[C:53]([Cl:54])[CH:52]=3)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1
Yield: 78 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid teri-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g) and 3,4-dichlorobenzeneboronic acid (0.61 g), to yield the title compound as a white solid (0.93 g, 78%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C[C:6]1[CH:7]=[CH:8]C(S(O)(=O)=O)=[CH:10][CH:11]=1.C1(C)C=CC=CC=1.[OH-].[Na+].CC[O:27][C:28]([CH3:30])=[O:29]>CCOCC.O>[CH3:10][C:11]1([CH2:6][CH2:7][CH2:8][CH2:30][C:28]([OH:27])=[O:29])[O:4][CH2:1][CH2:2][O:3]1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(CCCCC(=O)O)OCCO1
Reaction time: 2 h

Procedure:
A mixture of ketone 2-1 (18 g, 105 mmol), ethylene glycol (3.2 ml, 110 mmol), p-TSA (50 mg, 0.2713 mmol) and toluene (300 mL) was heated to reflux with azeotropic removal of water for 24 hours. The reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated. The residue was dissolved in EtOH (200 ml) and then treated with 1N NaOH (120 ml, 120 mmol). After 2 h, the reaction was poured into 600 mL 2:1 Et2O/10% KHSO4. The organic portion was separated, washed with brine, dried (MgSO4) and concentrated to give acid 2-2 as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[F:34][C:24]1[CH:25]=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[CH:27]=[C:28]([F:29])[C:23]=1[C:17]1[S:16][C:15]([NH:14][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])[N:7]=2)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=1
Reactant: CNC(=O)C(O)c1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CNC(=O)C(O)c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-2-hydroxy-N-methylacetamide (94 mg, 0.38 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (126 mg, 0.40 mmol) as starting materials.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Temperature: 100 °C
Reaction time: 54 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (1.5 g, 9.46 mmol), (4-amino-2-methyl-phenyl)-acetic acid methyl ester (3.39 g 18.9 mmol, 2 equiv), and a 4 N solution of HCl in dioxane (6.9 mL, 28.0 mmol, 2.9 equiv) in MeOH/dioxane (30 mL; 1:1, v/v) is stirred for 54 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (CH2Cl2/MeOH, 1:0→98:2) provides the title compound: ES-MS: 302.1 [M+H]+; tR=4.79 min (System 1); Rf=0.43 (CH2Cl2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[NH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[NH2:14][C@H:15](C(O)=O)[CH2:16][C:17]1[CH:26]=C2C(C=CC=C2)=C[CH:18]=1>C1(C)C=CC=CC=1>[CH3:12][CH:11]([CH3:13])[CH2:10][CH2:9][NH:8][CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[CH3:18][CH:17]([CH3:26])[CH2:16][CH2:15][NH:14][CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)CCN
Reactant: ClCc1ncon1
Solvent: Cc1ccccc1
Product: CC(C)CCNCc1ncon1

Procedure:
In analogy to the general synthesis of the amines, 3-(chloromethyl)-1,2,4-oxadiazole and 1-amino-3-methylbutane and Nal in toluene gave (3-Methyl-butyl)-[1,2,4]oxadiazol-3-ylmethyl-amine (3-Methyl-butyl)-[1,2,4] oxadiazol-3-ylmethyl-amine, MS: 170 (MH+).
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(NCC)C.CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[N+:9]([C:7]1[CH:8]=[CH:2][C:3]([NH2:4])=[CH:5][CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
Into a 300 mL four-necked flask, 2-iodo-4-nitroaniline (22.5 g, 85.4 mmol), bis(triphenylphosphine)palladium dichloride (1.20 g, 1.71 mmol), and copper iodide (0.651 g, 3.42 mmol) were charged, and nitrogen substitution was carried out, and then diethylamine (43.7 g, 598 mmol) and N,N-dimethylformamide (128 mL) were added thereto, followed by addition of the above-described t-butyl N-propargylamino-N-t-butoxycarbonyl acetate while stirring with ice-cooling, and further stirring at room temperature for 20 hours. After completion of the reaction, 1 L of ethyl acetate was added thereto, and then washing with 150 mL of a 1 mol/L ammonium chloride aqueous solution was carried out three times and washing with 150 mL of a saturated sodium chloride aqueous solution was carried out once, followed by drying by magnesium sulfate. Thereafter, the solvent was removed by evaporation under reduced pressure to precipitate a solid material, and then the solid material was dissolved in 200 mL of ethyl acetate, followed by addition of 1 L of hexane to carry out recrystallization. The solid material was collected by filtration and dried under reduced pressure, thereby to obtain a yellow solid material of 2-{3-(N-t-butoxycarbonyl-N-t-botxycarbonylmethylamino)-1-propynyl)}-4-nitroaniline (compound (A7)). The total amount of yield was 23.0 g, and the yield rate was 66%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].CCOC(C)=O.O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:20][CH2:21]1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(N2CCOCC2)cncc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (1 eq.), in neat morpholine in a sealed tube was heated at 120-140° C. overnight. The solution was poured into a mixture of EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated to get a residue. The crude product was purified on a silica gel column eluting with chloroform:MeOH gradient. The fractions containing product were mixed and concentrated under vacuum. The residue was triturated with hexane to give 3-morpholino-5-nitropyridin-4-amine (LIII).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[C:11]1([CH3:22])[CH:16]=[CH:15][C:14]([S:17]([O:20]C)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO>[C:11]1([CH3:22])[CH:12]=[CH:13][C:14]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[CH3:11][N+:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: C1=NCCc2ccccc21
Solvent: CO
Product: C[N+]1=Cc2ccccc2CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Yield: 88 %

Procedure:
The title compound was prepared using the procedure described by Koelsch et al in J. Am. Chem. Soc, (1953) 75, 2095. In a 250-mL one-necked round-bottomed flask equipped with a magnetic stir bar and a reflux condenser were placed 3,4-dihydroisoquinoline (8.27 grams, 63 mmol) and 40 ml of methanol. The mixture was stirred and cooled to 0° C. A solution of methyl p-toluenesulfonate (11.73g, 63 mmol) and 70 ml of methanol was added dropwise. The color of the solution remained clear and yellow. The mixture was heated to reflux for 6 hours. The methanol was then removed in vacuo to provide a quantitative yield (20 g) of an off-white solid (top 115°-119° C.). The solid was pulverized and washed with 40 ml of acetone at room temperature. Suction filtration provided a white solid in 88% yield: mp 124°-127° C. 1H NMR (D2O): δ2.27 (s,3H), 3.15 (t,2H), 3.73 (S,3H), 3.93 (t,2H), 7.18-7.78 (m,8H), 8.77 (s,1H). Impurities observed at 4.46 (s), 8.0-8.3 (m), 9.4 (s) were due to N-methyl-isoquinolinium p-toluenesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N)c3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(N)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(2-aminopyridin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (8 mL, 1:1) was added aqueous NaOH solution (200 mg in 2 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 5 using 1 M HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.3 (b, 1H), 9.30 (b, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.69 (b, 2H), 7.25 (d, J=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 6.59 (dd, J=7.2, 2.8 Hz, 1H), 6.00 (d, J=2.4 Hz, 1H), 5.49 (dd, J=9.6, 2.4 Hz, 1H), 3.05 (dd, J=15.6, 2.4 Hz, 1H), 2.28 (s, 3H), 2.08 (dd, J=15.2, 9.6 Hz, 1H). MS (ESI) m/z=313 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:21]1[C:20]2[C:25](=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][CH:19]=2)[N:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1ccnc2c(S(C)(=O)=O)cccc12

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 5-chloro-2-methyl-1H-indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].CCN(C(C)C)C(C)C.[Cl:36][C:37]1[CH:42]=[N:41][C:40](Cl)=[CH:39][N:38]=1>CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]1[N:38]=[CH:39][C:40]([N:14]2[CH2:15][CH2:16][CH:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([O:4][C:3]4[CH:18]=[C:19]([F:26])[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:21][C:2]=4[F:1])[C:6]3=[O:17])[CH2:12][CH2:13]2)=[N:41][CH:42]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cc1F
Yield: 3.9 %

Procedure:
A stirred solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 40 mg, 0.103 mmol), DIEA (90 μL, 0.515 mmol), and 2,5-dichloropyrazine (30.7 mg, 0.206 mmol) in DMF (1 mL) was heated at 100° C. in a sealed tube for 2 hours. The mixture was cooled, diluted with EtOAc (25 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to afford (S)-1′-(5-chloropyrazin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (2 mg, 0.004 mmol, 4% yield) as a white solid. Mass spectrum (apci) m/z=501.1 (M+H).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1N=[C:9]([CH3:21])[C:10]2C([CH:16]=1)=C[C:13](OC)=[C:12](OC)[CH:11]=2)(=O)=O.C(C1C=C(B(O)O)C=[CH:32][CH:33]=1)(C)(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=[O:72].[K+].[K+]>CCOC(C)=O.O.O1CCOCC1>[CH3:16][CH2:7][O:6][C:32]([CH3:33])=[O:72].[CH3:21][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)nc(C)c2cc1OC
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cccc(B(O)O)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCC
Temperature: 100 °C

Procedure:
6,7-Dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (300 mg), 3-t-butylphenylboronic acid (183 mg, 1.2 eq.), Pd(OAc)z (19 mg, 0.1 eq.), XPhos (81 mg, 0.2 eq.), and K2CO3 (354 mg, 3 eq.) were combined in a flask with 9 mL dioxane and 3 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. for 2 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 40% EtOAc/hexane yielding product as a clear oil (245 mg, 83% yield). 1H NMR (400 MHz) (CDCl3) δ 8.14 (s, 1H), 7.92-7.89 (m, 1H), 7.81 (s, 1H), 7.45-7.44 (m, 2H), 7.31 (s, 1H), 7.15 (s, H), 4.08 (s, 3H), 4.07 (s, 3H), 3.00 (s, 3H), 1.44 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 155.86, 152.59, 151.39, 149.88, 149.70, 139.95, 133.48, 128.37, 125.13, 124.16, 123.88, 122.16, 114.45, 105.67, 103.92, 56.03, 55.99, 34.88, 31.48, 22.79.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3,4-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.8 Hz), 7.98–7.93 (2H, m), 7.60 (1H, d, J=7.4 Hz), 7.49 (1H, dd, J=8.7, 2.8 Hz), 7.35–7.29 (2H, m), 7.14 (1H, q, J=8.9 Hz), 6.88–6.78 (2H, m), 6.73–6.66 (1H, m), 5.31 (1H, dq, J=7.4, 6.9 Hz), 3.91 (3H, s), 1.51 (3H, d, J=6.9 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13]=[O:14]>C(O)(C)(C)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: C=O
Reactant: Cc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to a mixture of 2,4-dichloro-6-nitrotoluene (1.03 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. It was stirred for 5 min at room temperature and for 30 min at 70° to 80° C. (oil bath temperature). The mixture was then allowed to cool to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (30 ml). The aqueous phase was post-extracted with EtOAc (2×30 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 30 ml, PE/EtOAc 10:1 110 ml, 9:1 100 ml, 8:1 360 ml, 7:1 80 ml). 2-(2,4-dichloro-6-nitrophenyl)ethanol (769 mg, 65%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A stirred solution of 20.0 g (0.137 mole) of 2-chloro-4-fluorophenol in 150 mL of pyridine was cooled in an ice bath. To this solution was added portionwise 31.2 g (0.164 mole) of 4-methylphenylsulfonyl chloride. After complete addition, the mixture was stirred for 2 hours, then allowed to stand in a freezer for approximately 16 hours. The mixture was poured into ice water, filtered, and the filter cake washed with water. The solid was dried in a dessicator to yield 41.0 g of 2-chloro-4-fluorophenyl 4-methylphenylsulfonate, mp 92°-94° C.
Reaction SMILES: C(Cl)CCl.C(N(CC)CC)C.[C:12]12([OH:22])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[C:23]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[C:12]12([O:22][C:39](=[O:40])[C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP, and 316 mg (2.1 mmol) of 1-adamantanol were added at RT to a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml dichlormethane. The reaction composition was stirred overnight, then diluted with 50 ml Dichlormethane and successively washed in a solution of 10% of aqueous citric acid, water, and saturated saline. The organic phase was dried over magnesium sulphate and then evaporated, and the residue purified with preparative HPLC. The yield was 336 mg (43% o. th.) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)C>CN1C(=O)CCC1>[CH2:27]([O:26][C:24]([N:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:22][CH2:23]1)=[O:25])[CH3:28]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
To a solution of 3-fluoro-1-nitrobenzene (3.37 ml; 31.6 mmol) in NMP (5 ml) was added triethylamine (4.38 ml; 31.16 mmol) and ethyl 1-piperazinecarboxylate (4.63 ml; 31.6 mmol) and the mixture was heated to 120° C. for five days. The cooled mixture was poured into ice-water and a small volume of ethanol was added. Vigorous stirring caused the product to precipitate. The product was filtered off, washed with petroleum ether and dried to leave 6p (3.34 g; 38%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:12]=[CH:13][NH:14][CH2:15][CH2:16][C:3]=12.[Cl:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[ClH:17].[CH2:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH:12]=[CH:13]1)=[O:19])[CH3:22]
Reactant: Cc1c2c(nc3ccccc13)C=CNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1C=Cc2nc3ccccc3c(C)c2CC1
Product: Cl
Yield: 42 %

Procedure:
1,2-Dihydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2-dihydro-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155.