Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:4]1([CH2:3][CH2:2]/[CH:1]=[CH:14]/[C:13]([O:12][CH3:11])=[O:34])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/CCc1ccccc1

Procedure:
A solution of hydrocinnamaldehyde (13.42 g, 0.1 mol) and methyl(triphenylphosphoranylidene)acetate (33.44 g, 0.1 mol) in THF was stirred at reflux for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography using hexane:EtOAc::9:1. The desired product was obtained as a clear, pale yellow oil (8.0 g, 0.042 mol, 42%); 1H NMR (300 MHz, CDCl3) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 7.1-6.9 (m, 1H), 5.85 (d, 1H, J=5.8 Hz), 3.75 (s, 3H), 2.8 (t, 2H, J=7.7 Hz), 2.55 (q, 2H, J=7.4 Hz); MS (NH3 -DCI) 191 (M+H)+.
Reaction SMILES: [C:1]1(/[C:7](=[N:14]/[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])/[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Na]>[C:1]1(/[C:7](=[N:14]/[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])/[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCO/N=C(\Cn1ccnc1)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCCO/N=C(\Cn1ccnc1)c1ccccc1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a stirred solution of 3.8 g (0.0115 moles) of ethyl (Z)-5-[1-phenyl-2-(imidazol-1-yl)-ethylidene]aminoxypentanoate in 20 ml of ethanol, 35 ml of aqueous sodium hydroxyde 1N are added at room temperature. Stirring is continued for 2 hours, and ethanol is removed under vacuum without heating. The aqueous solution is acidified with acetic acid till pH 6 with external cooling. The precipitated product is filtered, washed with ether and filtered again, yielding 2.63 g (75%) of (Z)-5-[1-phenyl-2-(imidazol-1-yl)-ethylidene]aminoxypentanoic acid.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:14][C:15]([O:17]C)=O)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[NH3:19]>O>[C:15]([CH2:14][CH:3]([CH2:2][SH:1])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:17])[NH2:19]
Reactant: N
Reactant: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
2.1 g of the product from Example 62, Step (d) is dissolved in a mixture of water (40 ml) and concentrated ammonia (40 ml). After one hour the reaction mixture is concentrated in 1/3 volume, and applied to a column of Dowex 50 resin in the hydrogen cycle. The product is eluted with water. The aqueous is extracted with ethyl acetate and then concentrated to dryness to yield 1.4 g of the named product, Rf =0.50 (silica gel-chloroform:methanol:acetic acid:water).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=2)=[N:27]\[OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cncc(Br)c1)c1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cncc(Br)c1)c1cccc(Br)c1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(5-bromo-pyridin-3-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=472.9850 ([M+H]+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 50.6 g (0.276 mol) of 6-amino-1-butyl-2,4-(1H,3H)-pyrimidinedione (VIII) dissolved in 1.8 l of wate at 80° C. was added 60 ml of 5N NCl and 20 g (0.29 mol) of NaNO2 which were dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 52.8 g (97%) (IX), NMR.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[CH3:11][N:12]([C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: CN(c1c([N+](=O)[O-])cnn1C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 36 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-(methylamino)piperidine-1-carboxylate gave tert-butyl 4-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)piperidine-1-carboxylate (75 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.15-4.05 (m, 2H), 3.75 (s, 3H), 3.32 (tt, J=11.1, 3.9 Hz, 1H), 2.81 (s, 3H), 2.72 (t, J=12.9 Hz, 2H), 1.79-1.70 (m, 2H), 1.48 (s, 9H), 1.40-1.25 (m, 2H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:20]([O-])=O)[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>CO.C1COCC1.[Pd]>[NH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=1)[CH:19]=[CH:18]2
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
10% Pd/C (0.29 g, 0.27 mmol) is added to 2-(1,3-benzodioxol-5-yl)-6-nitroquinoline (2.0 g, 6.80 mmol) in methanol/THF (80 ml/80 ml). The mixture is hydrogenated at r.t. for 2 hours. The catalyst is filtered off and the filtrate is concentrated to afford 1.31 g (73%) of the titled product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.Cl>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(-n5cccn5)c4)CC3)cccc2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
A 1M tetrahydrofuran solution of borane-tetrahydrofuran complex (3 eq) was added to a stirred solution of 2-methyl-5-(4-{[3-(1H-pyrazol-1-yl)phenyl]acetyl}-1-piperazinyl)quinoline (E97)(1 eq) in tetrahydrofuran at room temperature under an inert atmosphere. The solution was heated to 60° C. for 3 hrs. An aqueous 3N solution of HCl was added and the solution was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure. The crude material was purified by SCX cartridge affording the title compound in 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)=[O:13])=[CH:5][CH:4]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:18][CH:19]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: COc1ccc(CCNC(=O)c2ccc(Cl)nn2)cc1
Product: COc1ccc(CCNC(=O)c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)cc1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-methoxyphenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (12% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.93, 7.74, 7.63, 7.56, 7.36, 7.12, 6.92, 6.81, 4.08-3.46, 3.33, 2.87.
Reaction SMILES: Br[CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][OH:9].[OH-].[Na+].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH2:10][C@@H:7]1[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CBr
Reactant: N[C@H](CO)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1COC[C@H](COCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Bromoacetyl chloride (5.06 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (10 g) in toluene (100 mL) and a 2 N sodium hydroxide solution (100 mL) under ice-cooling. The reaction solution was stirred at 0° C. for 30 minutes and then at 60° C. for one hour. The reaction solution was returned to room temperature. Then, a toluene-THF (1:1) mixed solution was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.36 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([CH:20](O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:30])=[CH:11][CH:10]=1.CO>C(O)(C(F)(F)F)=O>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:18]1[CH:17]=[CH:16][C:15](=[O:30])[N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:32][CH:31]=2)[CH:19]=1
Reactant: COc1cccc(C(O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cccc(Cc2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
According to Scheme 7 Method D: Triethylsilane (3 eq, 0.84 mmol, 0.10 g) was added to a solution of 1-(4-chlorobenzyl)-5-(hydroxy(3-methoxyphenyl)methyl)pyridin-2(1H)-one (1 eq, 0.28 mmol, 0.10 g, Example 41) in TFA (2 mL). The mixture was stirred 1 hour at room temperature. Upon completion, MeOH was added and the solution was evaporated. The crude residue was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic layers were successively washed with brine, dried over MgSO4 and concentrated under vacuum to afford the crude product. Purification by flash chromatography (AIT Flashsmart prepacked column 10 g SiO2) (CH2Cl2/AcOEt 95/5 to 90/10) of the crude product afford the title compound 5-(3-methoxybenzyl)-1-(4-chlorobenzyl)pyridin-2(1H)-one (0.20 mmol, 0.07 g, 71%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]([OH:5])[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: O=Cc1c(Cl)cc(F)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])CC(O)c1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,6-dichloro-4-fluorobenzaldehyde (10.0 g, 51.8 mmol), nitromethane (2 mL) and K2CO3 (3.57 g, 25.9 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide compound A31-1 (26.0 g, crude) as yellow gum. The crude product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]2(Br)[CH2:13][C:12]2(Br)Br)=[CH:4][CH:3]=1.C[Li].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][C:11]2[CH2:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(SCCC2(Br)CC2(Br)Br)cc1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(SCCC2=CC2)cc1
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
A solution of 0.500 g (0.0011 mol) of 2-(2-(4-chlorophenylthio)ethyl)-1,1,2-tribromocyclopropane in 6 ml of diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling in an ice water bath, 2.38 ml (0.00334 mol) of 1.4 M methyl lithium in diethyl ether was added slowly via syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.100 g of 1-(2-(4-chlorophenylthio)ethyl)cyclopropene as an oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[K].[C:14]([NH2:25])(=[O:24])[C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](N)=[O:18]>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3](=[O:12])[CH2:2][N:25]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: O=C(CCl)Cc1ccc(F)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of example 23 (85 mg, 0.45 mmol) in DMF (1 mL), under a nitrogen atmosphere, was added potassium salt of phthalamide (96 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a mixture of ice-water and filtered. The slightly pink solid was washed with water to give the titled compound as a white product (79 mg, 62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:69]=[CH:68][C:53]3[N:54]([CH3:67])[C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([CH:64]([CH3:66])[CH3:65])[CH:59]=4)=[N:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:64]([C:60]1[CH:59]=[C:58]([NH:57][C:55]2[N:54]([CH3:67])[C:53]3[CH:68]=[CH:69][C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]5)=[O:17])[CH:48]=4)=[CH:51][C:52]=3[N:56]=2)[CH:63]=[CH:62][CH:61]=1)([CH3:66])[CH3:65]
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(N)c4)ccc3n2C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(NC(=O)CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3n2C)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1 eq) in N,N-dimethyl formamide and N,N,disopropylethylamine (4 eq) was added HATU (2 eq) and the mixture was stirred at ambient temperature until it becomes homogeneous. To it was added 5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (1 eq) and 4-(dimethylamino)pyridine (0.05 eq) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting tert-butyl 4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate was purified by HPLC. HPLC=4.63 min; MS: MH+=599.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1([S:10](Cl)(=[O:12])=[O:11])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1>C1COCC1>[CH3:1][NH:2][S:10]([C:4]1([Cl:3])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reaction time: 0.5 h

Procedure:
21 g of a 30% strength aqueous methylamine solution were added dropwise at approx. -75° C. in the course of 45 minutes to 25.25 g (0.1 mol) of 2,4-dichloro-thiazole-sulphonyl chloride from Example 1 in 250 ml of THF, the cold bath was then removed and the temperature was subsequently allowed to rise to room temperature, the mixture was subsequently stirred for 30 minutes, the resulting suspension was evaporated under a waterpump vacuum, and the residue was stirred with 300 ml of water. The solid was filtered off with suction and chromatographed on silica gel (eluent toluene/EtOH 15:1) in order to remove small amounts of starting material and product which is substituted in the 2-position.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](I)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])[CH2:37][CH2:38][CH3:39]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: CCCCI
Product: CCCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 61 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 334.6 mg (0.7 mmol) of Compound 24 was used and butyl iodide was used in place of methyl iodide. As a result, 228.9 mg (yield: 61%) of Compound 4 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]([O:6][Si](C)(C)C)=[CH2:5])[CH3:2].[CH2:11]([O:18][CH2:19][CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.CO>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][CH:20]([OH:21])[CH2:6][C:4](=[O:5])[S:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCOCc1ccccc1
Reactant: C=C(O[Si](C)(C)C)SCC
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCSC(=O)CC(O)COCc1ccccc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 21.5 mg (0.05 mmol) of (R)-1 in 3 ml of toluene were added 176 mg (1 mmol) of 1-ethylthio-1-(trimethylsilyl)oxyethene and 150 mg (1 mmol) of α-benzyloxyacetaldehyde at 0° C. After stirring for 2 hours at that temperature, the resultant mixture was poured into 10 ml of a buffer (pH 7) at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product in a silylated form. The crude product was poured into 10% hydrochloric acid-methanol, and the mixture was purified by silica gel chromatography (eluent: hexane/ethyl acetate=20/1 by volume) to obtain S-ethyl 4-benzyloxy-3-hydroxybutanethioate in a yield of 84%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.O[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:24]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)c1ccc(CCCc2ccccc2O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2cccnc2)cc1
Reaction time: 72 h
Yield: 57 %

Procedure:
Methyl 4-[3-(2-hydroxyphenyl)propyl]benzoate (1.35 g, 5 mmol) was dissolved in 0.2 ml of THF. The solution was treated with 3-hydroxymethylpyridine (0.6 g, 5.5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol). To this mixture was added slowly diethylazodicarboxylate (0.96 g, 5.5 mmol). The reaction mixture was stired for 72 hours and the solvent was evaporated. The amide residue was purified by chromatography (methanol, dichloromethane) to give methyl 4-[3-(2-(3-pyridylmethyloxy)phenyl)propyl]benzoate as a pink oil (1.03 g, 57%) MS (CI+):362 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 179.2 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-(propoxymethyl)benzyl alcohol (502 mg) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.30 g), and the resulting mixture was stirred at room temperature for 68 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([CH2:22][N:23]2[CH2:28][CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(N(CC)CC)C>[C:16]1([CH2:22][N:23]2[CH2:24][CH:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:7]([C:2]4[C:1]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:8])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
[1,1′-Biphenyl]-2-carbonyl chloride (0.05 mole) was added dropwise to a stirring mixture of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.045 mole) in THF (300 ml) and triethylamine (25 ml). The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 18.5 g of N-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 11, melting point 142° C.).