Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH3:10].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
365.3 mg thiophene-2-sulfonyl chloride was dissolved in 5 ml THF, to which at 0° C. was added 1.7 ml NH3 solution drop wise. The resulting mixture was stirred at r.t. for 2 hrs and acidified with conc. HCl at 0° C. to pH=˜2. The organic solvent was removed via rotavap and the aqueous suspension was extracted with ethyl acetate. The extract was combined and washed with saturated NaHCO3 solution, water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated affording the title compound 212 mg (65%) as a white solid, m.p.: 137-139° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[F:18][C:19]([F:25])([F:24])[S:20]([O:10][CH:8]1[CH2:9][CH:3]2[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]2)[CH2:7]1)(=[O:22])=[O:21]
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tropine (14.2 g, 0.10 mol) was dissolved in methylene chloride (210 mL) and triethylamine (23 mL, 0.16 mol). Trifiuoromethanesulfonyl chloride (9.3 mL, 0.12 mol) was added dropwise at a rate such that the methylene chloride boiled gently. The reaction was stirred at ambient temperature for 1 h; then it was washed with cold 0.5 N sodium hydroxide, water, and brine. The organic phase was dried and concentrated to a yellow solid which had: NMR δ 4.88 (t, 1 H), 3.10-3.05 (m, 2 H), 2.94 (s, 3 H), 2.22 (s, 3 H), 2.20-2.10 (m, 2 H), 2.02-1.88 (m, 6 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:28])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:26]([CH3:28])[CH3:25])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)=O
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
A round bottomed flask was charged with 4.9 g (0.015 mol) 2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 50 mL ClCH2CH2Cl, 1.2 mL (0.016 mol) acetone, 0.93 mL (0.016 mol) HOAc, and 5.2 g (0.024 mol) NaBH(OAc)3. After stirring for 15 h at rt the reaction was quenched with 50 mL 2M K2CO3. The organic layer was separated, dried and concentrated in vacuo to give 5.5 g (100% yield) of the desired material as a yellow-orange oil. MS (APCI): 381 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.47–7.42 (m, 1H), 7.35–7.31 (m, 1H), 7.03–7.00 (m, 2H), 6.54–6.50 (m, 2H), 3.61–3.55 (m, 5H), 2.75–2.71 (m, 6H), 2.65–2.60 (m, 2H), 1.18 (d, J=6 Hz, 6H).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:38][CH:39]3[CH2:41][CH2:40]3)=[N:19][C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:21][C:22]=2[C:23]([F:26])([F:25])[F:24])=[CH:11][C:10]=1[CH3:42])([CH3:7])[CH3:6])C.[Li+].[OH-]>>[CH:39]1([CH2:38][C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:43])=[O:3])=[C:10]([CH3:42])[CH:11]=3)=[C:22]([C:23]([F:26])([F:24])[F:25])[CH:21]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)[N:19]=2)[CH2:41][CH2:40]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2CC2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2CC2CC2)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 26C], 2-{4-[2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as off-white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])[CH:5]=[N:6][CH:7]=1
Reactant: NCc1cncc(Br)c1
Reactant: CC(C)N=C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)NCc1cncc(Br)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the hydrochloride salt of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 176 mg, 0.65 mmol) in 1,4-dioxane (10 mL) at room temperature was added diisopropylethylamine (0.550 mL, 3.27 mmol) followed by isopropyl isocyanate (CAS#1795-48-8, 0.13 mL, 1.3 mmol). The reaction was then heated to 80° C. and stirred for 15 minutes. The reaction was then cooled to room temperature, quenched with methanol, and stirred for an additional 15 minutes. The resulting solution was then concentrated in vacuo to near dryness, and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to furnish 1-(5-bromo-pyridin-3-ylmethyl)-3-isopropyl-urea without the need for further purification; MS: (ES+) m/z 271.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([NH:14][NH2:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)/[CH:20]=[N:21]/[C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])=[N:21][CH:20]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Reactant: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: CC(=O)O
Product: Fc1ccc(-c2ncnn2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A suspension of (8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-hydrazine (312 mg, 1 mmol) and N-[1-dimethylamino-meth-(E)-ylidene]-2,4-difluorobenzamide (232 mg, 1.1 mmol) in acetic acid (6 mL) was heated at 90° C. for 3 h, allowed to cool down to RT and filtered. The precipitate was washed with diethyl ether and dried to afford the title compound as a beige solid (300 mg, 65%). LCMS (Method B): RT=4.51 min, [M+H]+=461 and 463. 1H NMR (DMSO-d6): 8.50 (1H, s), 7.82 (1H, td, J=8.4, 6.4 Hz), 7.57 (1H, ddd, J=10.4, 9.4, 2.5 Hz), 7.39-7.30 (2H, m), 7.23 (1H, d, J=2.0 Hz), 7.13 (1H, dd, J=8.6, 2.0 Hz), 4.33 (2H, t, J=5.0 Hz), 3.34 (2H, t, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C1C=CC=CC=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2O)c1Cl
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2OCc2ccccc2)c1Cl
Reaction time: 2 h
Yield: 89 %

Procedure:
1.43 g (0.005 mol) of 4-(2,4-dichloro-3-methylbenzoyl)-1-methyl-5-hydroxypyrazole was dissolved in 20 ml of benzene containing 0.50 g (0.005 mol) of triethylamine, and 0.86 g (0.005 mol) of benzylbromide was added thereto. Then, the reaction mixture was refluxed with stirring for 2 hours. After cooling, the precipitated salt was filtered off, and benzene was distilled off from the residual solution under reduced pressure. The resulting oily product was purified through a silica gel column chromatography (eluent:benzene) to obtain 1.67 g of the title compound (yield 89%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N(CCCCCCCC(=O)O)c2ccc(OC)cc2)cc1

Procedure:
As described in example 1(b), 10 g (24 mmol) of 8-[4-methoxy-N-(4-methoxyphenyl)-benzamido]-caprylic acid methyl ester is reacted with 2 g (50 mmol) of sodium hydroxide and 200 cc. of methanol. Reaction time: 6 hours, reaction temperature: 25° C.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1
Reactant: c1cc2c3c(c1)C1CCNCCC1N3CCO2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCC2c3cccc4c3N(CCO4)C2CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1,2,7,8,9,10,11,11a-octahydro-6bH-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole (97.8 mg, 0.42 mmol), 4-chloro-1-(4-fluorophenyl)-1-butanone (172 mg, 0.86 mmol), KI (71.2 mg, 0.43 mmol), and DIEA (550 mg, 4.3 mmol) were suspended in dioxane (2 mL). The reaction mixture was refluxed for 18 hrs. After cooling to rt, the solution was concentrated. The residue was immediately purified by column chromatography to afford the title compound. MS-ESI: 395[MH]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[C:12]([CH3:24])[S:11][C:10]=2[CH:25]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)=[C:12]([CH3:24])[S:11][C:10]=2[CH:25]=1
Reactant: CNCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1
Reactant: Cc1nccc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N(C)CCOc2ccc3c(-c4ccc(C(F)(F)F)cc4)c(C)sc3c2)n1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 40 mg (0.109 mmol) Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine (example 51.1), 0.0211 g (0.164 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.038 ml (0.22 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 37.3 mg (74.5%) Methyl-(2-methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine as light brown solid, MS: 458 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:28])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Br:28][C:11]1[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:25])([F:1])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)[N:12]=1
Reactant: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c(Br)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (30 g, 85.9 mmol), POBr3 (3.7 g, 429.5 mmol), TEA (43.5 g, 429.5 mmol) and DMF (0.1 mL) in toluene (300 mL) was heated with stirring at 100° C. for 4 h. The mixture was concentrated and the residue was suspended in water (1 L) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (2×50 mL) and brine, and then concentrated at 35° C. under reduced pressure until a solid began to precipitate. The mixture was allowed to cool, and the solid was collected by filtration and washed with a small quantity of cold EtOAc to afford methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (23 g, 65%). LC-MS (ESI) m/z 412.7, 414.7 (M+H+). The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford additional methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (3.0 g, 8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([Br:17])[CH:19]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.33 mmol, 1.07 g) in THF at room temperature, NaH (100 mg, 4.5 mmol) was added and stirring continued for 30 min then 4-(3-Bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (3.50 mmol, 1.5 g) was added. The resulting mixture was stirred at 50° C. for over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10-20% ethyl acetate in hexanes to provide 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (1.6 g).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:41])([F:40])[C:21]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)([OH:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([C:21]([OH:26])([C:22]([F:23])([F:24])[F:25])[C:20]([F:41])([F:19])[F:40])=[CH:28][CH:29]=4)[CH2:35][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cc1ccc(C(=O)[O-])cc1)NCC1CC1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NCC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.9 %

Procedure:
Sodium 4-(2-(cyclopropylmethylamino)-2-oxoethyl)benzoate (5.26 mmol, 1.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (5.26 mmol, 1.800 g), and triethylamine (18.40 mmol, 2.56 mL, 1.862 g) were combined in dichloromethane (25 mL) and the reaction mixture stirred at room temperature for 15 minutes. 1-Propanephosphonic acid cyclic anhydride (7.89 mmol, 4.69 ml, 5.02 g; 50% solution in ethyl acetate) was added dropwise and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated and concentrated under vacuum to obtain crude product. The crude product was purified by SCX column chromatography, silica column chromatography (eluting with 90:10:1 dichloromethane/methanol/ammonia) and acidic preparative HPLC to afford the title compound (55.3 mg). MS (ESI) m/z 558.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH:10]([CH3:14])[C:11](Cl)=[O:12]>ClCCl.O>[Br:9][CH:10]([CH3:14])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloroaniline (400 mg, 3.13 mmol) in anhydrous dichloromethane at room temperature under N2 was added slowly 2-bromopropanoyl chloride (474 μL, 4.7 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give 2-bromo-N-(4-chlorophenyl)propanamide, which was used without further purifications.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])(=O)=O)=CC=1.O>O1CCCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a stirred solution of the product of step (b) (25 g) in tetrahydrofuran (500 mL) at −20° C. was added a solution of potassium tert-butoxide in tetrahydrofuran (1.61M, 50 mL) over 1 hour, maintaining the temperature at about −20° C. The reaction mixture was stirred for a further 15 minutes then a solution of the product of step (a) (29.7 g) in tetrahydrofuran (100 mL) was added over 90 minutes, maintaining the temperature at about −20° C. After stirring at −20° C. for a further 3 hours, the mixture was allowed to warm to 20° C. and stirred for 16 hours. Water (125 mL) was then added and the resultant mixture was concentrated in vacuo to 140 mL. Sodium chloride (12.5 g) was added to the stirred concentrate, which was then washed with diisopropyl ether (4×125 mL). The aqueous phase was diluted with water (50 mL) and extracted with dichloromethane (3×125 mL). The combined dichloromethane extracts were concentrated in vacuo to give the title compound as an orange-brown oil (27.93 g). GC retention time 21.8 mins
Reaction SMILES: C1(S([C:10]2([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]1([S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:11][CH2:12][CH2:13]1
Reactant: BrCCCCBr
Reactant: O=S(=O)(c1ccccc1)C1(S(=O)(=O)c2ccccc2)CCC1
Product: O=S(=O)(c1ccccc1)C1(CCCCBr)CCC1

Procedure:
The title compound was prepared as described in Description 7 from 1,1-bis(phenylsulfonyl)cyclobutane and 1,4-dibromobutane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccnc1-c1cccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1-c1cccc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.21 g (0.30 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 2.5 g (10.05 mmol) of methyl 6′-chloro-2,2′-bipyridine-3-carboxylate (1) in 70 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 1.98 g (12.08 mmol) of para-chlorophenylboronic acid, 4.17 g (30.17 mmol) of K2CO3 and 7 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently left to stand overnight at RT. For work-up, the reaction mixture is poured into 100 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by column chromatography over silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.7 g (82.7%) of product as a solid. M.p.: 120.5° C.; 1H NMR (CDCl3) δ 8.75 (dd, 1H), 8.17 (dd, 1H), 8.00 (m, 2H, C6H4Cl), 7.95 (dd, 1H), 7.92 (dd, 1H), 7.28 (dd, 1H), 7.45 (m, 2H, C6H4Cl), 7.40 (dd, 1H), 3.60 (s, 3H, COOMe).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:31]([OH:33])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)#[N:45].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:20])([Cl:19])[Cl:21])=[O:15])[CH2:10][CH:9]1[C:31]([N:55]1[CH2:54][CH2:53][N:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[C:44]#[N:45])[CH2:57][CH2:56]1)=[O:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 4-[(2,4-difluoro-benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (3.5 g, 6.6 mmol), HOBt (1.4 g, 10 mmol), 1-(2-cyanophenyl)piperazine (1.5 g, 7.9 mmol) in DCM (50 ml) were added Et3N (1.8 ml, 13.2 mmol) and EDC.HCl (1.9 g, 10 mmol). The mixture was stirred overnight, then washed with 10% citric acid, Na2CO3, brine, dried and concentrated to give the title product as a colorless oil (4.5 g, 6.4 mmol). MS m/e=700.3 [M+H]+.