Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH3:19])[C@H:9]1[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)(O)=[O:6]>C1C=CC=CC=1>[O:18]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2[C:5](=[O:6])[C:21]3[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[C:9]=2[N:10]1[CH3:19]
Reactant: COc1cc([C@H]2[C@@H](C(=O)O)c3ccccc3C(=O)N2C)cc(OC)c1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1OC)C(=O)c1c-2n(C)c(=O)c2ccccc12
Reaction time: 4 h
Yield: 9.1 %

Procedure:
Thionyl chloride (10 mL) was added with stirring to 12j (200 mg, 0.5 mmol). After 4 h, the reaction mixture was diluted with benzene (50 mL) and evaporated to dryness. The dark orange solid was dissolved in chloroform and ether was added to give a dark orange solid (16 mg, 10%): mp 194-195° C.; IR (neat) 2938, 1665, 1463, 1400, 1292, 1125, 1007, 976 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.67 (d, 1H, J=7.8 Hz), 8.32 (d, 1H, J=8. 0 Hz), 7.68 (t, 1H, J=8.0 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.04 (s, 1H), 4.09 (s, 3H), 4.06 (s, 3H), 3.97 (s, 3H), 3.89 (s, 3H); CIMS m/z (relative intensity) 352 (MH+, 100). Anal. Calcd for C20H17NO5: C, H, N.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].C[O:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(CO)CCC
Reactant: CCCCCCCC(=O)OC
Product: CCCCCCCC(=O)OCC(CCC)CCCCC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
500 g 2-propylheptanol, 500 g octanoic acid methyl ester and 50 g Novozym 435 (Novo, Denmark: immobilized lipase—lipase B—from Candida antarctica) were heated under nitrogen for 5 h to 45° C. The temperature was then increased to 60° C. and vacuum (20 mbar) was applied. After 48 h under these conditions, the reaction was terminated. After the enzyme had been filtered off, the product accumulated as a colorless oil. Less than 1% of the educts could be detected by GC.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:45][C:42]3[S:43][CH:44]=[C:40]([CH3:39])[N:41]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1csc(N)n1
Reactant: CN1CCC(Oc2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(C(=O)O)c2)C1=O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.16 mL, 1.2 mmol) was added to a solution of 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-(1-methyl-2-oxo-pyrrolidin-3-yl)oxy-benzoic acid (Intermediate 10) (288 mg, 0.68 mmol) in DCM (5 mL) and stirred at ambient temperature for 30 minutes. 4-Methyl-1,3-thiazol-2-amine (156 mg, 1.36 mmol) and pyridine (0.11 mL, 1.4 mmol) were added and the reaction stirred for 16 hours. The solvent was evaporated under reduced pressure. The residue dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-5% methanol in DCM, to afford the product (117 mg, 34%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 4H), 2.38 (quintet, 2H), 2.50-2.63 (m, 1H), 2.93 (s, 3H), 3.33-3.56 (m, 2H), 4.26 (t, 2H), 4.69 (t, 2H), 4.84 (t, 1H), 6.54 (s, 1H), 7.15 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 8.32 (s, 1H), 8.82 (s, 1H), 10.43 (s, 1H); m/z 509 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](O)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1.Cl.[F:25][C:26]([F:37])([F:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].FC(F)(F)S(Cl)(=O)=O.N1(C(OC(C)(C)C)=O)CCNCC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:33]3[CH2:32][CH2:31][N:30]([S:27]([C:26]([F:36])([F:37])[F:25])(=[O:28])=[O:29])[CH2:35][CH2:34]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH2:16]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: O=S(=O)(N1CCNCC1)C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=S(=O)(Cl)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C(F)(F)F)CC4)[nH]c3cc2Br)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid; hydrochloride (example 1, intermediate a) and 1-trifluoromethanesulfonyl-piperazine (prepared in analogy to International Patent Application Publ. No. WO 2003/064413 by using trifluoromethanesulfonyl chloride and tert-butyl 1-piperazinecarboxylate) to afford the title compound as a yellow solid (48%).
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[S:21]([O:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)C1(C(C)O)COCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a mixture of ethyl 5-(1-hydroxyethyl)-1,3-dioxane-5-carboxylate (16.8 g, 83 mmol) in dry pyridine (40 mL) at 0° C. was added 4-toluenesulfonyl chloride (19.1 g, 99 mmol). The mixture was stirred at rt for 16 h. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×400 mL). The organic layer was washed with brine (3×). After concentrated in vacuo, the crude product was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate 25:1 to 5:1 to provide the title compound (22.7 g, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (m, 3H), 1.34 (d, J=6.8 Hz, 3H), 2.45 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.87 (d, J=11.6 Hz, 1H), 4.02 (d, J=11.6 Hz, 1H), 4.08 (d, J=12.0 Hz, 1H), 4.20-4.17 (m, 2H), 5.03-4.98 (m, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H).
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14]Br)[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][O:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(CCON2C(=O)c3ccccc3C2=O)C1
Reaction time: 5 h
Yield: 47.6 %

Procedure:
To a suspension of (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (6.90 g, 20 mmol) and triethylamine (4.04 g, 40 mmol) in DMF (30 ml) was added N-hydroxyphthalimide (3.26 g, 20 mmol). The mixture was stirred for 5 h, filtered and the solvent was evaporated from the filtrate in vacuo. The residue was dissolved in dichloromethane (50 ml) and the resulting mixture washed with 10% aqueous potassium carbonate (3×20 ml) and water (20 ml). The solvent was evaporated in vacuo and the residue crystallised from absolute ethanol (25 ml). The precipitate was collected, washed with cold absolute ethanol and dried in vacuo to give 3.3 g of (R)-1-(2-((phthalimido)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2ccc(F)c(F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Methyl 2-(3,4-difluorobenzyl)piperidine-4-carboxylate (8.115 g, 30.14 mmol) was dissolved in DCM (200 mL) and DIPEA (6.30 mL, 36.16 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl satd NaHCO3. The organic phase was passed through a phase separator and evaporated. The residue was redissolved in ether/pentane, 80/20, the solution washed with 1 M HCl 5 times, then with satd NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield dimethyl 2-(3,4-difluorobenzyl)piperidine-1,4-dicarboxylate (7.05 g, 71%). MS m/z 328 (M+H)+
Reaction SMILES: C([N:4]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:7](I)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=O)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.O.[Cu](I)I.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>[C:14]1([C:6]2[C:7]([C:27]#[C:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]([NH:9][C:10](=[O:12])[CH3:11])[NH:4][N:5]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1c(I)c(-c2ccccc2)nn1C(C)=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
Nitrogen was bubbled through a mixture of N-(2-acetyl-4-iodo-5-phenyl-pyrazol-3-yl)acetamide (31.87 g, 86.4 mmol), phenyl acetylene (17.6 g, 173 mmol), triethylamine (200 mL) and DMF (100 mL) for 15 min. Copper iodide (1.64 g, 8.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3.0 g, 4.3 mmol) were added and the reaction mixture was stirred at 90° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 5:1 to 1:1) yielding the title compound as a solid (12.5 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1O.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: Oc1c(CBr)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccc3ccccc3c1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 2-Bromomethylnaphthol (436 mg, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-naphthalen-2-ylmethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A7) (260 mg, 34% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].C(Cl)(=O)[C:17](Cl)=[O:18].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]=[C:17]=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.0 g, 5 mmol) in toluene (50 mL) was added dropwise to a solution of oxalyl chloride (2.0 g, 10 mmol) in toluene (20 mL) with stirring. The reaction mixture was stirred at room temperature for 1 hour and then heated to reflux for 4 hours until HCl evolution ceased. The mixture was cooled down to room temperature and the solvents were removed at reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-cylcopentyloxyphenyl isocyanate as an oily product. This was used in the next step without further purification.
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[O:8][CH:7]([CH:23]=[CH2:24])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:1]([N:5]1[CH2:6][CH:7]([CH2:23][CH3:24])[O:8][C:9]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 55 °C
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 4-tert-butyl-2-vinyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (550 mg, 1.62 mmol) in methanol (10 mL) was added Pd(OH)2 (447 mg, 3.18 mmol) and ammonium formate (2.19 g, 34.7 mmol) and the reaction mixture heated at 55° C. for 20 min. The reaction mixture was filtered, concentrated to −10 mL and then diluted with dichloromethane and 1:1 saturated NaHCO3 solution/1M NaOH. The dichloromethane layer was separated and the aqueous layer extracted with dichloromethane (5×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (530 mg, 1.56 mmol, 96%) as a colorless oil. ESI-MS m/z calc. 340.3. Found 341.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 3.59 (t, J=11.7 Hz, 2H), 3.48-3.36 (m, 1H), 3.11 (br s, 1H), 2.91 (br s, 1H), 2.80 (d, J=10.7 Hz, 1H), 2.71 (dd, J=11.1, 1.7 Hz, 1H), 2.23 (d, J=14.0 Hz, 1H), 1.81 (d, J=11.1 Hz, 1H), 1.71 (t, J=10.6 Hz, 1H), 1.39 (s, 9H), 1.38-1.22 (m, 5H), 0.96 (s, 9H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[C:25]1[CH3:33].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH:22][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C:5]=23)(=[O:31])=[O:30])[N:26]=[C:25]1[CH3:33]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4cn(C)c(C)n4)c23)c1

Procedure:
Following general method outlined in Example 52, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (35 mg, 0.112 mmol) (Description 21) and 1,2-dimethylimidazole-4-sulfonyl chloride (21.8 mg, 0.112 mmol), the title compound (9.0 mg) was isolated as a TFA salt. LCMS (B) m/z: 471 [M+1]+, Rt 2.14 min.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[Cl:1][C:2]1[C:21]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 56.1, 5.7 g, 12.75 mmol), pyrimidine-5-boronic acid (2.5 g, 19.77 mmol), PdCl2(dppf)-(CH2Cl2) (0.625 g, 0.765 mmol), Na2CO3 (19.13 mL, 38.3 mmol) and DME (100 mL) was stirred at 80° C. for 2.5 h under argon atmosphere. The RM was filtered through Hyflo®, diluted with EtOAc (100 mL), washed with a sat. aq. solution of NaHCO3 and with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Biotage Silica gel column, 120 g, Eluent: n-hexane/EtOAc from 20% to 60% EtOAc) to give the title compound product as a pink crystalline solid. UPLC-MS (Condition 2) tR=1.01 min, 393.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.99 Hz, 2H) 7.88 (d, J=9.38 Hz, 2H) 8.56 (d, J=2.35 Hz, 1H) 9.03 (d, J=2.35 Hz, 1H) 9.10 (s, 2H) 9.32 (s, 1H) 10.69 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].[C:34](=[O:37])(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])=[N:18][N:19]=[C:20]1[CH2:17][N:16]1[CH2:20][CH2:34][O:37][CH2:9][CH2:10]1
Reactant: O=C([O-])O
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(CN2CCOCC2)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 13, 2',5-dichloro-2-[3(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension then neutralized with sodium bicarbonate to give 2',5-dichloro-2-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4yl]-benzophenone.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5]([CH:17]=O)[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1.[CH3:26][C@@H:27]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][C:29](=[O:37])[CH2:30]P(=O)(OC)OC>>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5](/[CH:17]=[CH:30]/[C:29](=[O:37])[CH2:28][C@@H:27]([CH3:26])[CH2:38][CH2:39][CH2:40][CH3:41])[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1
Reactant: CCCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Product: CCCC[C@H](C)CC(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1

Procedure:
By the same procedure as the reaction of Example 6 using methyl (5Z)-7-[(1R,2R,3R,5R)-5-chloro-2-formyl-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate (Reg. No. 261772-21-8) instead of the compound 5 and using dimethyl [(4S)-4-methyl-2-oxooctyl]phosphonate instead of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, the title compound (360 mg) having the following physical data was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[N-:11]=[C:12]=[O:13].[Na+]>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: [N-]=C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCN(C(N)=O)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
N-Acetylpiperazine (25.0 g) was added to water (100 ml) and dissolved under stirring at ambient temperature. Then, the solution was adjusted to pH 3.0 with 6 N hydrochloric acid (about 33 ml). After the solution was cooled, sodium isocyanate (15.2 g) was added in one portion thereto at a temperature of 5 to 10° C. Thereafter, the mixture was reacted for 4 hours at ambient temperature and then cooled on ice to −2 to 2° C. The mixture was stirred at the same temperature for 2 hours to precipitate 4-acetyl-1-piperazinecarboxamide crystals. The crystals were collected at the same temperature by filtration, washed with cold water (25 ml) and dried under reduced pressure to give primary crystals of 4-acetyl-1-piperazinecarboxamide (17.7 g). The mother liquor containing the primary crystals was concentrated to 63 ml under reduced pressure and then stirred at −2 to 2° C. for 2 hours to precipitate secondary crystals of 4-acetyl-1-pipeazinecarboxamide. The crystals were collected at the same temperature by filtration, washed with cold water (13 ml) and dried under reduced pressure to give secondary crystals of 4-acetyl-1-piperazinecarboxamide (9.3 g). NMR (DMSO-d6, δ): 2.00 (3H, s), 3.21-3.41 (8H, m), 6.04 (2H, Broad s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[C:11](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2)C1
Product: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-cyclohexane-1,3-dione (1.0 g, 4.5 mmol) was suspended in N,N-dimethylformamide dimethylacetal (5 ml) and heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and the precipitate was filtered, washed with diethyl ether and dried under air suction. The required product was obtained as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])(=[O:5])=[O:4])[CH3:2].[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Br:15][CH2:13][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[O:14]
Reactant: CCS(=O)(=O)c1ccccc1C(C)=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 164 %

Procedure:
A mixture of 1.0 g of 2′-ethylsulfonylacetophenone, 1.86 g of phenyltrimethylammonium tribromide and 10 ml of THF was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 1.37 g of 2-bromo-2′-ethylsulfonylacetophenone.