Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]2.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][NH:16][C:11]=2[N:12]=[C:13]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]3)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CN1C(=O)CCc2cc(Nc3nc(NCc4ccccc4)c4c(C#N)c[nH]c4n3)ccc21

Procedure:
A solution of 4-(benzylamino)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg, 0.12 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (43 mg, 0.24 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2.5 mL) and dioxane (1.5 mL) was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 424.3 (M+H); UV 207.7, 273.1 nm.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:20][C:19]([O:21]C)=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.O>O1CCOCC1>[Cl:1][C:2]1[C:3]2[S:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1
Reactant: COc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Temperature: 40 °C
Yield: 72.8 %

Procedure:
The product from example 31 step (b) (2.0 g) was dissolved in dioxan (150 ml) followed by addition of concentrated hydrochloric acid (1 ml) and water (1 ml) and the whole heated at 40° C. for 67 hours. The mixture was evaporated to dryness and purified by column chromatography (silica-dichloromethane) to give a white solid (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:35])[C@H:26]([NH2:34])[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46]>ClCCl.C(OC)(OC)OC>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:25](=[O:35])[C@@H:26]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:34]([C:45](=[O:47])[CH3:46])[C@@H:37]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7]
Reactant: O=Cc1ccccc1
Reactant: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(NC(=O)[C@H](N)Cc2cccnc2)cc1)C(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(N2C(=O)[C@@H](Cc3cccnc3)N(C(C)=O)[C@@H]2c2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.8 %

Procedure:
To a solution of 4-[[(2R)-2-amino-1-oxo-3-(pyridin-3-yl)propyl]amino]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester (0.224 mmol, 113 mg) in dichloromethane (0.75 mL) and trimethyl orthoformate (0.75 mL), was added benzaldehyde (0.25 mmol, 27.5 mg). After the resulting light yellow solution was stirred for 3 days at room temperature, it was heated to 90° C. (oil bath temperature) and excess acetic anhydride (2.0 mmol, 0.21 mL) was introduced via a syringe. The solution was stirred at 110-120° C. (oil bath temperature) for 6 h, then was cooled to room temperature and the solvents were removed in vacuo. The crude residue was purified by RP-HPLC to obtain 95 mg (67%) of 4-[(2S,4R)-3-acetyl-5-oxo-2-phenyl-4-[(pyridin-3-yl)methyl]imidazolidin-1-yl]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HR MS: Obs. mass, 635.2672. Calcd. mass, 635.2692 (M+H). Another isomer was formed in very minor amount by HPLC (<5%) and not attempted to isolate it.
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[N:1]1([C:7](=[S:21])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#CCC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: N#CCC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 131.2 %

Procedure:
To a solution of 3-morpholin-4-yl-3-oxopropanenitrile (3.0 g, 19.5 mmol) in anhydrous THF (45 mL) was added Lawesson's reagent (4.2 g, 10.3 mmol). The reaction mixture was allowed to stir at rt for 16 h and was then concentrated to small volume. A solid precipitated and was filtered. The solid was washed with diethyl ether to give 3-morpholin-4-yl-3-thioxopropanenitrile (2.3 g, 70%). LCMS: (AA) ES+ 171.2. 1H NMR (400 MHz, CDCl3) δ: 4.27-4.29 (m, 2H), 4.00 (s, 2H) and 3.81-3.83 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH3:23])[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])(=[O:9])=[O:10])=[C:15]([CH3:23])[CH:16]=2)=[O:21])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(C)cc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carboxylic acid (150 mg, 0.393 mmol), ethyl 4-aminobenzoate (130 mg, 0.786 mmol), 4-methylmorpholine (199 mg, 1.96 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (224 mg, 0.589 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (49 mg, 0.39 mmol) was added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (190 mg, 91%). White solid, MS (ISP): m/e 529.2 (M+H).
Reaction SMILES: [CH2:1]([O:10][C:11]1[N:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:20]N.[CH3:22][CH2:23]O>C(Cl)Cl>[NH2:20][CH2:23][CH2:22][C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[N:12][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:19][CH:18]=2
Reactant: CCO
Reactant: NN
Reactant: CCCCCCCCCOc1ccc2[nH]ccc2n1
Solvent: ClCCl
Product: CCCCCCCCCOc1ccc2[nH]c(CCN)cc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
N-phthaloyl protected 5-nonyloxy-4-azaindole (20 mg, 0.05 mmole) and hydrazine (3 mg, 0.09 mmole) was dissolved in CH2Cl2 (0.5 mL) in a 25 mL round bottom flask. EtOH (1 mL) was added to the reaction mixture and allowed to stir overnight at 25° C. for 12 h, after which it was cooled to 0° C., and filtered, and the white solid material was washed with 3 mL of cold CH2Cl2. The filtrate was evaporated under reduced pressure to afford 7 mg (50%) of 2-aminoethyl-5-nonyloxy-4-azaindole as a yellow solid. LRMS (ESI): M+1 for C18H29N3O calcd 304.4. found 304.4.
Reaction SMILES: C(OC(=NNC(N)=O)C[CH:8]([NH:11][C:12](=[O:48])[C@@H:13]1[CH2:17][CH:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][N:14]1[C:26](=[O:47])[C@H:27]([CH:44]([CH3:46])[CH3:45])[NH:28][C:29](=[O:43])[C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[NH:31][C:32](=[O:34])[CH3:33])[CH:9]=[O:10])(C)(C)C.F[C:55](F)(F)[C:56]([OH:58])=[O:57].CO.C=O>ClCCl.C(O)(=O)C>[C:32]([NH:31][C@H:30]([C:29]([NH:28][C@H:27]([C:26]([N:14]1[CH2:15][CH:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][C@H:13]1[C:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:55][C:56]([OH:58])=[O:57])=[O:48])=[O:47])[CH:44]([CH3:45])[CH3:46])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)(=[O:34])[CH3:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C)C(C)C
Agent: C=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(N-Acetyl-tyrosinyl-valinyl-(4-benzyloxyprolinyl))-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone (270 mg) was dissolved into 10 ml of 25% trifluoroacetic acid in dichloromethane and stirred at room temperature for 3 hours. The mixture was concentrated to give a solid residue. The residue was dissolved into a 10 ml mixture of methanol:acetic acid:37% formaldehyde (3:1:1) and stirred at room temperature for 1 hour. The mixture was concentrated and the resulting residue purified by flash chromatography (SiO2) eluting with dichloromethane/methanol/formic acid (100:5:0.5) to give 37 mg of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH3:4].[CH2:5]=O.[S:7]1[C:11]2[S:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1>C(OC(=O)C)(=O)C>[ClH:1].[CH3:2][N:3]([CH2:5][CH:14]1[CH2:13][S:12][C:11]2[S:7][CH:8]=[CH:9][C:10]=2[C:15]1=[O:16])[CH3:4]
Reactant: O=C1CCSc2sccc21
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)CC1CSc2sccc2C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of 18 g of dimethylamine hydrochloride and 18 g of 37% formalin is stirred for 30 minutes and the temperature of the mixture is raised to 70° C. To the mixture is added 80 ml of acetic anhydride dropwise for 20 minutes at 70°-80° C. and kept for about 20 minutes at the same temperature. To the mixture is added 32.6 g of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one. The mixture is kept for 4 hours at the same temperature and then the solvent is distilled off under reduced pressure. To the residue is added acetone, and the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of ethanol and isopropyl ether to give 35 g of 5-dimethylaminomethyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one hydrochloride as white crystals, melting at 163°-166° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(Cc3ccccc3OC(F)(F)F)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2-(trifluoromethoxy)benzyl bromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C17H11F3N4O, 345. Found, 345.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=4[N:16]=3)[C:9]=2[OH:27])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.O>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=3[N:16]=2)[C:9]([OH:27])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)[CH:13]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(Cl)cc(-c4cccc(N)c4)c3O)nc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cc(Cl)cc(-c3nc4cc(C(=N)N)ccc4[nH]3)c2O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3′-Amino-5-chloro-2-hydroxy-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 73 (0.070 g, 0.15 mmol) and THF/water (1:1, 0.5 mL) is chilled (0° C.) and treated with 2 N NaOH (0.16 mL, 0.32 mmol) and methane sulfonyl chloride (0.013 mL, 0.16 mmol) in alternating portions. The mixture is kept at 0° C. for 1 h and then treated with another portion of 2 N NaOH (0.016 mL, 0.032 mmol) and methane sulfonyl chloride (0.001 mL, 0.013 mmol). After another 1 h, the solvents were reduced in volume under reduced pressure, and the crude material is purified by C18 reversed-phase HPLC (2-65% MeCN/H2O containing 20 mM HCl, over 50 min.). The appropriate fractions were pooled and the solvent is removed under reduced pressure. 2-(5-chloro-2-hydroxy-3′-methanesulfonylamino-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 74 is obtained as a tan powder (0.012 g, 16% yield) (Example 288, Table 2a):
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][CH2:13][C@H:12]1[C:18]([O:20]C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22](C1C=CC(COC(C2C(C)=NC(S)=NC=2C)=O)=CC=1)([O-:24])=[O:23].[C:44](OCC)(=O)C>CO.O1CCOCC1.[C].[Pd]>[OH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:18]([CH3:44])=[O:20])[CH2:13][CH2:14]1
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: Cc1nc(S)nc(C)c1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 5.7 g (19.43 mmol) of (2S,5R)-1-benzyloxycarbonyl-5-hydroxy-2-methoxycarbonylpiperidine, which was prepared by the procedure described in P.D. Bailey et al., Tetrahedron Letters. 29, 2231 (1988), in 250 ml of methanol was added 570 mg of 5% palladium-carbon, and the mixture was hydrogenated at atmospheric pressure and room temperature for 1 hours. The catalyst was removed by filtration, and the solvent was removed. To a solution of this residue in 30 ml of dioxane was dropwise added a solution of 6.85 g (21.45 mmol) of p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 50 ml of dioxane, and the mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added 300 ml of ethyl acetate, the organic layer was washed successively with 50 ml of 1N HCl(×2), 50 ml of water and saturated aqueous sodium chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (Wakogel® C-300, elution with ethyl acetate - hexane system) to give 5.81 g (yield: 88%) of the title compound.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][OH:9].[OH-].[Na+].C[O:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1>O.CO>[C:27]1([S:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][C:14]([NH:8][OH:9])=[O:13])=[CH:18][CH:19]=2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NO
Reactant: COC(=O)C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a mixture, consisting of dioxane (25 ml), methanol (3 ml), and water (1 ml), hydroxylamine hydrochloride (0.834 g, 12 mmol) and NaOH (0.960 g, 24 mmol) followed by 3-(4-benzenesulfonylamino-phenyl)-acrylic acid methyl ester (74) (1.735 g, 4.1 mmol)) were added. The resulting mixture was vigorously stirred at ambient temperature for 24 hours and evaporated under reduced pressure. The residue was mixed with warm (50° C.) water and filtered. The aqueous solution was acidified with hydrochloric acid to pH 4 and filtered. The precipitate was washed with water (2×10 ml), ethyl acetate (10 ml), and crystallised from acetonitrile (15 ml) to give title compound as a yellow solid (0.405 g, 31%). M.p. 189–191° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.30 (d, 1H, J=15.8 Hz); 7.12 (d, 2H, J=8.6 Hz); 7.32 (d, 1H, J=15.8 Hz); 7.45 (d, 2H, J=8.4 Hz); 7.48–7.86 (6H, m); 9.01 (s, 1H); 10.56 (s, 1H); 10.72 (s, 1H). HPLC analysis on Zorbax SB—C18 column: impurities 1.8% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4, gradient from 30:70 to 100:0; sample concentration 1.0 mg/ml; detector UV 220 nm). Anal. Calcd for C15H14N2O4S, %: C, 56.59; H, 4.43; N, 8.80; S, 10.07. Found, %: C, 56.03; H, 4.24; N, 8.66; S, 10.02.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: Cc1cc(=O)[nH][nH]1
Reactant: CCCCCCCCBr
Product: CCCCCCCCN1N=C(C)CC1=O
Temperature: 135 °C
Yield: 41.6 %

Procedure:
A mixture of 19.63 g 3-methyl-3-pyrazolin-5-one and 42.30 g 1-bromooctane was stirred and heated at 135° C. for 50 hour. After cooling, the reaction mixture was triturated with 200 ml water, treated with 17.00 g sodium bicarbonate in small portions, and heated to 100° C. for 1 hour. After cooling, the mixture was extracted with chloroform (3×100 ml portions). The combined extracts were dried over anhydrous calcium chloride and the solvent evaporated to give an oily residue crystallized from hexane (at -5° C.) to give 2,4-dihydro-5-methyl-2-octyl-3H-pyrazol-3-one (17.50 g, 42 yield) as white plates, m.p. 59° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28]OC(OC)N(C)C>>[CH:1]1([N:7]2[C:8]3[C:9]4[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:10]=4[N:11]=[CH:12][C:13]=3[C:14](=[O:16])[CH:15]=[CH:28]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1NC1CCCCC1
Product: C[Si](C)(C)CCOCn1cnc2c1ncc1c(=O)ccn(C3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1-[7-(Cyclohexylamino)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone (88.9 mg, 0.229 mmol) in N,N-dimethylformamide dimethyl acetal (2.0 mL) was stirred at 180° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 M hydrochloric acid (2 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as a yellow solid (57.5 mg, yield 63%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16])[CH2:8][CH2:9][CH3:10].C(OCC)(=O)C.O>COCCOC>[CH2:7]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][NH2:16])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNc1cc(C#N)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred mixture of lithium aluminum hydride (5.0 g) and 1,2-dimethoxyethane (100 ml) a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzonitrile (15 g) in dry 1,2-dimethoxyethane (150 ml) is during about 1 hour at 100° C. dropwise added, and the mixture is stirred and refluxed for a further 16 hours. After cooling, ethyl acetate (10 ml) followed by water (20 ml) are very cautiously added dropwise, whereafter the mixture is stirred for a further 30 minutes. It is then heated on a steam-bath and filtered hot; the filter-cake is carefully washed with hot 2-methoxyethanol (3 portions of 50 ml). The combined filtrates are evaporated in vacuo to yield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. After recrystallization from 2-methoxyethanol it is obtained with a melting point of 197°-198° C. The material (IR, analysis) is identical with the material prepared as in Example 289.
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].Cl.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28]>O1CCCC1.CCCCCC>[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])=[O:20]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCOC(C)=O
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1ccccc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Cyclohexyl isopropylamine (10.6 grams) is dissolved in 80 ml of tetrahydrofuran and the solution is cooled to -78° C. In a nitrogen stream, a solution of n-butyl lithium (about 15%) in hexane solution (26 ml) is added thereto, and the mixture temperature is raised to -40° C. Then it is cooled to -78° C. once again, 3.3 grams of ethyl acetate is gradually added thereto and, ten minutes thereafter, a solution of 10 grams of o-iodobenzoyl chloride in tetrahydrofuran is dropped thereinto gradually. The mixture is stirred at -78° C. for one hour, then gradually warmed up to 0° C. within two to three hours, 20 ml of 20% hydrochloric acid solution is added thereto, the mixture is poured into ice water, and extracted with ether. The extract is washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, ether is evaporated therefrom, and the resulting oil is purified by distilling in vacuo to give 8.5 grams of pale yellow oil, b.p. 142° C./3 mmHg.
Reaction SMILES: [Li][CH2:2]CCC.[I-].C[S+](C)C.[CH2:11]([O:15][C:16](C1C=CC=CC=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:12]1[O:14][CH2:13]1.O.[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1COCC1>[C:16]([O:15][CH2:11][C@@H:12]([OH:14])[CH:13]=[CH2:2])([C:38]1[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCCCC
Reactant: [Li]CCCC
Reactant: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi in hexane (2.6 M; 182 mL) was added dropwise to a solution of trimethylsulfonium iodide (96.8 g) in THF (800 mL) at −30° C. After stirring at −20° C. for 20 minutes, (S)-trityl glycidyl ether (50.0 g) was added at the same temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (52.0 g).