Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([PH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([CH:10]=[O:11])=[O:9]>>[CH:1]1([P:7]2[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]([OH:9])[CH:10]2[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: PC1CCCCC1
Reactant: O=CC=O
Product: OC1C(O)P(C2CCCCC2)C(O)C(O)P1C1CCCCC1
Yield: 92 %

Procedure:
Following the procedure of Example 2, 150 parts of monocyclohexyl phosphine are reacted with 190 parts of 40% aqueous glyoxal solution to give 207 parts (92% yield) of 1,4-dicyclohexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 182°-215° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26]C(C)(C)C)(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:50]([O:49][C:47]([NH:26][S:23]([C:15]1[S:16][C:17]([CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:18][C:14]=1[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:9]=1)(=[O:25])=[O:24])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(CN3CCCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(CN2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-(3-pyrrolidine-2-one-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (66.7 mg, 0.149 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (44.1 mg, 0.297 mmol) and butyl chloroformate (189.1 μL, 1.49 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound in 74% yield, over two steps, (54 mg, 0.110 mmol).
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)([OH:3])=[O:2].O.[C:29]1(C)C=CC(S(O)(=O)=O)=C[CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(O)C.CN(C)C1C=CN=CC=1>[CH2:29]([O:2][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:3])[CH3:30]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 333.9 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (35.6 mg) was dissolved in ethanol (3 mL), then p-toluenesulfonic acid hydrate (˜1 mg) was added. The reaction was heated to 80° C. for 20 h after which no reaction progress was observed by thin layer chromatography. To this mixture was then added triethylamine (69 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg) and 4-dimethylaminopyridine (˜1 mg). Stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure. This residue was purified first by silica gel column chromatography (98.5:1.5 CH2Cl2:MeOH) then on a 250 μM silica gel prep plate (1:1 hexanes:acetone) to yield 6.8 mg of the title compound. 1H NMR (500 MHz, CDCl3 partial): δ 8.49 (br s, 1H); 8.45 (d, J=5.4 Hz, 1H); 8.15 (s, 1H); 7.97 (m, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.65 (d, J=7.8 Hz, 1H); 7.46 (t, J=7.7 Hz, 1H); 6.81 (d, J=5.5 Hz, 1H); 5.72 (br s, 1H); 5.27 (br s, 01H); 4.40 (q, J=7.2 Hz, 2H); 1.66 (d, J=7.1 Hz, 3H); 1.41 (t, J=7.2 Hz, 3H). Mass Spectrum (ESI): m/e 388.1 (M+1).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH2:31]([OH:34])[C:32]#[CH:33].C(N(CC)CC)C>C1COCC1.[Cu]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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:33]#[C:32][CH2:31][OH:34])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: C#CCO
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C#CCO)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (195 mg, 0.372 mmol), propargyl alcohol (0.033 mL, 0.558 mmol), copper(I) iodide (7.09 mg, 0.037 mmol), bis(triphenylphosphine)palladium(II) chloride (10.45 mg, 0.015 mmol) and triethylamine (0.156 mL, 1.117 mmol) in THF (1.7 mL) was stirred under an atmosphere of nitrogen at 70° C. for 3 h. The mixture was allowed to cool to RT, with stirring, over the weekend. The mixture was then partitioned between a saturated aqueous solution of NaHCO3 (25 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with additional ethyl acetate (25 mL). The organic extracts were combined, washed with brine (25 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-100% cyclohexane in ethyl acetate. Further purification on silica, eluting with 0-50% cyclohexane in ethyl acetate, afforded the title compound (14 mg) LCMS (A) m/z: 499 [M+1]+, Rt 1.24 min (acidic).
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH:21]([C:24]1[S:25][CH:26]=[C:27]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[N:28]=1)([CH3:23])[CH3:22].C(O)(=O)C>CN1CCCC1=O>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][N:39]1[CH2:40][CH2:41][C:35]2([O:34][CH2:33][CH2:32][N:31]([C:29]([C:27]3[N:28]=[C:24]([CH:21]([CH3:22])[CH3:23])[S:25][CH:26]=3)=[O:30])[CH2:36]2)[CH2:37][CH2:38]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1ccc(F)c(CCO)c1F
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2,4-Difluoro-3-(2-hydroxyethyl)benzaldehyde (example 45, step b) (0.35 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.67 g) and acetic acid (0.09 mL) in N-methyl-2-pyrrolidinone (1 mL). The resulting mixture was stirred for 1 h then quenched by portionwise addition of sodium triacetoxyborohydride (0.335 g) over 5 min. The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile, (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient to give the subtitled compound as a yellow gum. Yield 0.74 g.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:5][CH:4]=1.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH:37][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([S:15](=[O:16])(=[O:17])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:27]=[CH:28][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:11][C:12]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=O.[H-].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[CH3:17][O:16][C:14]1[C:13]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:12]=2[O:11][C:2]=1[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1ccccc1CBr
Reactant: COC(=O)c1cc(C)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COc1c(-c2ccccc2C#N)oc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
2-(Bromomethyl)benzonitrile (17.6 g) was added to a mixture of methyl 2-hydroxy-5-methylbenzoate (15 g) and sodium hydride (2.7 g, 80% dispersion in oil) in dry THF (150 ml) and the resulting mixture heated at reflux for 5 h. Further sodium hydride (2.7 g, 80% dispersion in oil) was added and heating continued overnight. The mixture was cooled (0° C.), sodium hydride (2.7 g, 80% dispersion in oil) and dimethyl sulphate (17 ml) were added, and the resulting solution stirred at room temperature for 4 h. Solvent was removed in vacuo, the residue taken up in dichloromethane (200 ml) and cone. ammonia solution (200 ml) added carefully. The organic solution was removed and the aqueous solution extracted with dichloromethane (2×200 ml). The combined, dried organic phases were evaporated in vacuo and the residue purified by chromatography, eluting with dichloromethane: hexane (1:1) to give the title compound as a white solid (17 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C@H:11]([CH2:16][OH:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:17][CH2:16][C@@H:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[C@@H:12]([CH3:13])[CH2:14][CH3:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-thiophenesulfonyl chloride (1 g, 5.48 mmol) in CH2Cl2 (5 mL) and (S)-isoleucinol (642 mg, 5.48 mmol) was added Hunig's base (1. 05 mL, 6.02 mmol). The reaction mixture was stirred at 25° C. for 24 h. The solvent was removed and the oil was dissolved in EtOAc (100 mL). The solution was washed with water (2×100 mL), brine (1×100 mL), and dried over Na2SO4. The desired sulfonamide (m/z=264.0(M+H), rt=0.79 min) was isolated by semi-preparative RP-HPLC using the conditions outlined for example 195.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30](Br)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CC#N.C(Cl)Cl.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CCNC1
Reactant: CCC(Br)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCC(c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-bromopropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (67.1 mg, 0.106 mmol) in MeCN (200 μL) was added pyrrolidine (1 mL, 12.0 mmol). The reaction was stirred at room temperature for 16 hours and then purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA). The resulting solution was diluted with EtOAc (25 mL), washed with 1 M NaHCO3 (20 mL), extracted with EtOAc (25 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. To the residue was added 200 μL CDCl3, which resulted in a mixture that was diluted with CH2Cl2 (20 mL) and water (5 mL), and washed with 1 M NaOH solution (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-pyrrolidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. Rf=0.14 (25% EtOAc/hexanes). LCMS=583.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, diastereomers present) δ 7.94 (s, 1H), 7.84 (s, 2H), 7.67-7.48 (m, 3H), 5.70-5.68 (m, 1H), 5.08-4.96 (m, 1H), 4.64-3.34 (m, 1H), 4.02-3.94 (m, 1H), 3.48-3.39 (m, 1H), 2.54-2.35 (m, 5H), 2.01-1.91 (m, 1H), 1.76-1.72 (m, 4H), 0.79-0.77 (m, 3H), 0.72-0.66 (m, 3H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.O>[Br:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH:51]1[CH2:56][CH2:55][N:54]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:53][CH2:52]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.075 g, 0.00029 mol) in DMF (2 mL), was added DIPEA (0.1139 g, 0.00088 mol) HOBt (0.0398 g, 0.00029 mol) and EDCI.HCl (0.06758 g, 0.00035 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.09639 g, 0.00029 mol) was added and the resulting mixture was stirred at the same temperature for overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration, washed with hexane followed by ether and dried to afford 0.067 g (46%) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 492.0 (M+1)+, 90.08%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.94 (d, 2H), 7.79 (m, 4H), 7.5 (t, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 6.84 (d, 1H), 6.57 (d, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.6 (d, 1H), 2.7 (t, 1H), 1.9 (bs, 2H), 1.5-1.2 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:35])[N:14]([CH3:34])[N:15]=[C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:21])=[O:20])[C:17]=1[OH:18])[CH3:2].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:35])[N:14]([CH3:34])[N:15]=[C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:21])=[O:20])[C:17]=1[O:18][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCS(=O)(=O)c1nn(C)c(=O)c(-c2c(CC)cc(C)cc2CC)c1O
Product: CCCCCCCCCCCCS(=O)(=O)c1nn(C)c(=O)c(-c2c(CC)cc(C)cc2CC)c1OCc1ccc(OC)cc1
Yield: 57 %

Procedure:
The procedure was performed by the method similar to Production Example 21 using 4-(2,6-diethyl-4-methylphenyl)-6-dodecylsulfonyl-5-hydroxy-2-methyl-3(2H)-pyridazinone and 4-methoxybenzyl chloride as a starting material to give 4-(2,6-diethyl-4-methylphenyl)-6-dodecylsulfonyl-5-(4-methoxybenzyl)oxy-2-methyl-3(2H)-pyridazinone (yield: 57%).
Reaction SMILES: CC(C)[CH2:3][CH2:4][NH2:5].[Br:7][C:8]1[S:9][C:10]([C:13]([NH2:15])=[O:14])=[CH:11][N:12]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21]C=1)([O-])=O>>[Br:7][C:8]1[S:9][C:10]([C:13]([NH:15][CH2:23][C:22]2[CH:26]=[CH:27][C:19]3[N:16]([CH:3]=[CH:4][N:5]=3)[CH:21]=2)=[O:14])=[CH:11][N:12]=1
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1cnc(Br)s1
Product: O=C(NCc1ccc2nccn2c1)c1cnc(Br)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting imidazo[1,2-a]pyridin-6-ylmethanamine for 3-methylbutan-1-amine and 2-bromothiazole-5-carboxamide for 4-nitrobenzoic acid.
Reaction SMILES: [O-2].[Ca+2:2].[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].O>CCCCCC>[NH2:3][C@H:4]([C:10]([O-:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[Ca+2:2].[NH2:3][C@H:4]([C:10]([O-:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: CCCCCC
Solvent: O
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 5 h
Yield: 99.3 %

Procedure:
5.6 grams (0.1 Mole) of calcium oxide and 29.2 grams (0.2 Mole) of lysine were placed into a beaker provided with a reflux condenser and a Dean Stark water trap. 100 ml hexane was added and the mixture was stirred and boiled at atmospheric pressure for 5 hours. The reaction mixture was cooled, and was thereafter filtered yielding 32.8 grams of calcium lysinate having the physical characteristic of a fine white powder. In the course of reaction about 3.6-3.8 ml water was removed from the reaction media and acquired in the Dean Stark apparatus.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[N:10]=[N:9][C:8](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>ClCCl.O.C1(C)C=CC=CC=1>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:8]1[N:9]=[N:10][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=1)(=[O:41])[CH3:39]
Reactant: CC(O)=S
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of (E)-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.5 g) in a mixed solvent of dichloromethane (30 ml) and toluene (30 ml) was added thioacetic acid (2.2 ml) and N,N-dimethylformamide dineopentyl acetal (8.5 ml). After the mixture was stirred at 50° C. for 2 hours, it was cooled, water and dichloromethane were added and the layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using hexane, ethyl acetate, and dichloromethane (2:1:1) as an eluent to afford (E)-4-(acetylsulfanyl)-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (containing impurity, gross amount: 880 mg, gross yield: 58.4%).
Reaction SMILES: [N+](C(=[C:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@:19]([OH:24])([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C:14]4(OCC[O:25]4)[CH2:15][CH2:16]2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)C)#[C-].Cl.O.[CH2:31]([O:33]CC)[CH3:32]>O1CCCC1.[OH-].[Na+]>[OH:24][C@:19]12[CH2:9][CH2:8][C@@:22]3([CH3:23])[C@@H:21]([CH2:7][CH2:6][C@@H:5]3[C:31](=[O:33])[CH3:32])[C@@H:20]1[CH2:10][CH2:11][C:12]1[C@:17]2([CH3:18])[CH2:16][CH2:15][C:14](=[O:25])[CH:13]=1
Reactant: [C-]#[N+]C(C)=C1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C

Procedure:
A solution of 20-isocyano-3,3-ethylenedioxypregna-5,17(20)-dien-9α-ol (2.30 g) in a mixture of tetrahydrofuran (60 ml) and aqueous 2N hydrochloric acid (20 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature after which water (25 ml) and diethyl ether (100 ml) were added. The mixture was neutralised with IN sodium hydroxide solution. After separating the layers the aqueous phase was extracted twice with diethyl ether (50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 2.02 g of the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[I:45])[C:40]#[N:41].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[CH:26]=[CH:27][C:5]([CH2:4][C@H:3]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][O:36][C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=3[I:45])[C:40]#[N:41])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCl)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COc1cc(C#N)ccc1I)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
1.3 g (2.6 mmol) of benzyl 4-[4-[(2S)-3-chloro-2-(t-butoxycarbonylamino)propyl]phenoxy]piperidine-1-carboxylate, 686 mg (2.8 mmol) of 3-hydroxy-4-iodobenzonitrile and 390 mg (2.8 mmol) of potassium carbonate were dissolved in dimethylformamide. The solution was stirred at 65° C. for 4 days, and then treated with ethyl acetate as the extractant in an ordinary manner to obtain the title compound, which was then subjected to the subsequent reaction without further purification.