Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:3]=1.[Na].C(=O)([O-])[OH:26].[K+]>ClC1C=C(C=CC=1)C(OO)=O.O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
In step 3, m-chloroperoxybenzoic acid is dissolved in an water immiscible organic solvent such as methylene chloride or toluene. The m-chloroperoxybenzoic acid is charged to the obtained pyrmetazole in a buffered two phase system, consisting of the water immiscible solvent, such as methylene chloride or toluene, and aqueous base, such as sodium or potassium hydrogencarbonate. The organic solvent may optionally be diluted with an alcohol to enhance the solubility of the m-chloroperoxybenzoic acid. The oxidation with m-chloroperoxybenzoic acid is preferably performed between 0° and 25° C. The obtained product is extracted into an alkaline, aqueous phase and the formed product is precipitated from the aqueous phase by lowering the pH of the solution to approximately 9 at ambient temperature. Omeprazole is isolated and washed. The overall yield in the process is usually higher than 75%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[C:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:33]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:34]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (50 mg, 0.142 mmol) and a drop of DMF in dichloromethane (2 ml) was added oxalyl chloride (2M in dichloromethane) (84.91 μL, 0.170 mmol) at ambient temperature. Gas evolution was observed. The mixture was stirred for 1 hour at ambient temperature. Biphenyl-3-amine (28.74 mg, 0.170 mmol) in dichloromethane (1 ml) and triethylamine (59.172 μL, 0.424 mmol) were added to the activated acid. The mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 55.6 mg of the title compound as a thin film (78%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH2:44])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CN(C=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH:44][C:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)=[O:8])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(O)c1cscn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cscn2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.3 %

Procedure:
To a solution of thiazole-4-carboxylic acid (2.25 g, 17.6 mmol) and HOBt (2.60 g, 19.2 mmol) in anhydrous DMF (80 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.69 g, 19.2 mmol) followed by the dropwise addition of a solution of Example 17D (5.07 g, 16 mmol) in anhydrous DMF (50 mL) over 10 minutes, after which anhydrous triethylamine (4.45 mL, 32 mmol) was added to the mixture via syringe. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and H2O (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The yellow solid was crystallized from ethyl acetate (30 mL). The white crystals were dried under vacuum at 40° C. for 12 hours to provide a white powder (4.8 g) as the titled compound. MS (ESI) m/e 427 (M+H)+, 425 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.41 (s, 5 H) 1.44 (s, 4 H), 1.66 (m, 1 H), 2.49 (m, 1 H), 2.59 (m, 1 H), 3.03 (m, 1 H), 3.13 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 2 H) 3.75 (m, 2 H) 3.85 (m, 1 H) 4.53 (m, 2 H) 4.66 (m, 1 H), 8.25 (s, 1 H), 8.99 (s, 1 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[O:17]=[C:18]1[CH:27]([NH:28][C:29](=[O:31])[CH3:30])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1.C(OC(C)C)(C)C>C(O)(=O)C>[N+:1]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[NH:19][C:18](=[O:17])[CH:27]([NH:28][C:29](=[O:31])[CH3:30])[CH2:26]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC1Cc2ccccc2NC1=O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1Cc2cccc([N+](=O)[O-])c2NC1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Fuming nitric acid (2 mL) was added dropwise to acetic anhydride (81 mL) at an internal temperature of 8° C. or lower, and sulfuric acid (81 μL) and a solution of N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (8.1 g) in acetic acid (81 mL) were sequentially added thereto, followed by stirring at room temperature for 3.5 hours. Diisopropyl ether (162 mL) was added to the mixture, and stirring was performed under cooling on ice for 30 minutes. The formed precipitates were recovered through filtration, washed with diisopropyl ether, and dried under reduced pressure, whereby a mixture of the title compound (A) and N-(8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (B) (A:B=1:1) (7.15 g) was yielded.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)CCC.Br[C:24]1[N:28]2[N:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Cu]I>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:6]3[O:14][C:9]4=[CH:10][N:11]=[CH:12][CH:13]=[C:8]4[CH:7]=3)=[CH:25][N:26]=2)[N:29]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2o1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2ncc(-c3cc4ccncc4o3)n2n1
Yield: 43.7 %

Procedure:
To a stirred solution of crude 2-(tributylstannyl)furo[2,3-c]pyridine (1.9 g) in THF (20 mL) in an inert atmosphere was added 3-bromo-6-chloroimidazo[1,2-b]pyridazine (676 mg, 2.9 mmol), copper (I) iodide (55 mg, 0.29 mmol) bis(triphenylphosphine) palladium(II)chloride (102 mg, 0.145 mmol) and triphenylphosphine (38 mg, 0.145 mmol). The mixture was heated to reflux for 2 h. The solvent was removed in vacuum. The residue was dissolved in a mixture of dichloromethane and methanol, filtered through an aminophase-silica-gel column and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with a mixture of ethyl acetate and hexane to give 343 mg of the title compound, which was used without further purification.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:30])[CH2:24][N:25]2[CH2:28][CH:27]([F:29])[CH2:26]2)=[CH:19][C:18]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]2[CH2:26][CH:27]([F:29])[CH2:28]2)=[CH:19][C:18]=1[C:31]([F:34])([F:32])[F:33]
Reactant: N[C@H](CN1CC(F)C1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CC(F)C3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 69 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-fluoro-azetidin-1-yl)-ethylamine hydrochloride to give the title compound. LC/MS [469 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (d, 1H), 9.01 (d, 1H), 8.57 (s, 1H), 8.39 (d, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.82 (m, 1H), 7.68 (m, 1H), 5.45 (m, 1H), 5.12 (m, 1H), 3.59 (m, 2H), 3.21 (m, 2H), 2.95 (m, 5.6 Hz, 1H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3,4-dichlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 325, 327, 329 (MH+).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7].[CH2:14]([N:16]([CH2:26][CH3:27])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH3:15]>C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=CC=1>[CH2:26]([N:16]([CH2:14][CH3:15])[CH:17]=[C:18]([C:2](=[S:1])[NH:3][C:6]([O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH3:27]
Reactant: N#C[S-]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(/C=C/C(=O)OCCC#N)CC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(C=C(C(=O)OCCC#N)C(=S)NC(=O)OCC(Cl)(Cl)Cl)CC
Temperature: 50 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
A mixture of 55.4 g (0.57 moles) of potassium thiocyanate, 1 g of 18-crown-6 cyclic ether, 80.5 g (0.38 moles) of 2,2,2-trichloroethyl chloroformate and 300 ml of toluene was heated for 3 hours at 50° C. to prepare the acyl isothiocyanate. The mixture was filtered and 74 g (0.38 moles) of 2-cyanoethyl trans-3-diethylaminoacrylate were added dropwise over one hour. After 24 hours at room temperature, the mixture was filtered to give 108 g of crude material which was recrystallized from toluene to give 63 g of pure adduct, melting point 116° to 118° C.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50]>C(Cl)Cl.O>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-butanoic acid (315.7 mg, 0.866 mmol) in methylene chloride (8.66 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (210 uL, 1.5 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated to afford 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 268.4 mg. LCMS: (M−1) 462.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:13]=[O:14]>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11])=[C:13]=[O:14]
Reactant: N#Cc1ccc(N)c(F)c1Cl
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N=C=O)c(F)c1Cl

Procedure:
4-Isocyanato-3-fluoro-2-chlorobenzonitrile was prepared from 4-amino-3-fluoro-2-chlorobenzonitrile (73B) in a manner similar to that described in Example 2 for the preparation of 2E.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:38])[C:15](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:16][CH2:17][CH3:18])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:38])/[C:15](/[CH2:16][CH2:17][CH3:18])=[CH:9]/[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])[CH3:12]
Reactant: O=Cc1ccccc1C=O
Reactant: CCCC(C(=O)OCC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC/C(=C\c1ccccc1C=O)C(=O)OCC

Procedure:
(E)-3-(2-Formylphenyl)-2-propyl 2-propenoic acid ethyl ester as a colourless oil was prepared from o-phthalaldehyde and 2-(triphenylphosphoranylidene)pentanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 10.0 g of ethyl p-{[2-(p-bromophenoxy)-ethyl]amino}benzoate, 10 g of potassium hydroxide and 100 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, chilled and filtered. The solid is washed with water to give crystals, mp 190°-192° C. Recrystallization from ethanol (500 ml) gives white crystals, mp 194°-196° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=[O:9])=CC=1.[N+:13]([CH2:16][C@@H:17]1[CH2:21][C@H:20](CC([O-])=O)[CH:19]=[CH:18]1)([O-:15])=[O:14]>CO>[N+:13]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([OH:9])[CH:19]=[CH:18]1)([O-:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])C[C@@H]1C=C[C@H](C[N+](=O)[O-])C1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C[C@@H]1C=C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a 5 mL round-bottom flask is added at room temperature p-toluenesulphonic acid monohydrate (0.01 g, 0.053 mmol), methanol (8 mL) and (1R-cis)-4-nitromethyl-2-cyclopentene -acetate as prepared in Example 10 (0.20 g, 1.1 mmol) and the resulting solution is stirred overnight. The crude reaction mixture is loaded on a silica column (32 μm-63 μm) and purified by flash chromatography by eluting with 20% ethyl acetate/hexane. The fractions containing the product (Rf=0.3) are combined and are concentrated in vacuo to give (1R-cis)-4-nitromethyl-2-cyclopenten-1-ol as a clear oil which exhibited the following physical data: MS(CI) m/z=126 [C6H8NO2 +, Loss of H2O followed by rapid protonation]; and [α]D20 =+4.8° (c=0.16, CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:5]([NH:1][CH2:2][CH2:3][NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: NCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
60.0 g (998 mmol) of 1,4-diazabutane is dissolved in 750 ml of absolute methanol and cooled to 0° C. At this temperature, the drop-by-drop addition of 20.0 g (188 mmol) of benzaldehyde, dissolved in 100 ml of absolute methanol, is carried out. After a reaction time of 2 hours at 0° C., the addition in portions of a total of 7.13 g (188 mmol) of sodium borohydride is carried out. After 12 hours at 25° C., the reaction solution is suctioned off on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is taken up in 500 ml of dichloromethane and washed three times with 100 ml of water in each case. After the organic phase is dried on sodium sulfate, the solvent is drawn off in a vacuum. The oily residue that is thus obtained is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCSc1cccc2nccn12

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (2,003 g, 9.62 mmoles) and triethylamine (2.01 ml, 14.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.89 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]imidazo[1,2-a]pyridine as a yellow oily product.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[C:5]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].O>C(O)C>[CH3:3][C:4]1[C:5]2[CH:19]=[C:18]([C:20]([NH2:21])=[O:1])[CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: OO
Reactant: Cc1c(Cc2cccnc2)sc2ccc(C#N)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2cccnc2)sc2ccc(C(N)=O)cc12
Reaction time: 2 h

Procedure:
Hydrogen peroxide (1.6 ml of 30% w/v solution) was added to a stirred solution of 3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene-5-carbonitrile (the product of Example 12(ii)) (0.30 g) in ethanol (3.5 ml) followed by 6N sodium hydroxide solution (1.6 ml). The resulting micture was heated at 50°-55° C. with stirring for 2 hours and then cooled and poured into water. The solid was filtered off, washed with water and crystallised from ethanol/water to give 3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene-5-carboxamide (0.21 g), m.p. 194°-195°.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN1CCN(C2C=CC(C(O)=O)=CC=2)CC1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:57]=2)[C:52]([NH2:70])=[N:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:57]=2)[C:52]([NH:70][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([N:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[N:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(OCCOCc3ccccc3)cc21
Agent: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride, prepared from 248 mg (1.13 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoic acid as described above in preparation 3, and DIPEA (0.386 ml, 2.25 mmol) in dry THF (10 ml) was treated dropwise at r.t., under argon atmosphere, with a solution of 3-amino-6-(2-benzyloxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (143 mg, 0.374 mmol) in 10 ml of dry THF. The reaction mixture was heated up to 50° C. and stirred for 12 h. The volatiles were removed under reduced pressure, the residue taken up in DCM (100 ml) and washed with a saturated solution of NaHCO3 (75 ml). The organic layer was separated, dried over sodium sulfate and evaporated to dryness and the crude residue purified by flash chromatography over silica gel eluting with DCM/MeOH 98:2 then 90:10 affording 124 mg (yield: 57%) of the title compound as a white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188c) (50 mg) was dissolved in acetic acid (1 mL). A hydrobromic acid-acetic acid solution (1 ml) was added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0, 10%) to obtain 20 mg of the title compound as a glassy solid (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](C=O)=[C:16]([S:20][C:21]([F:24])([F:23])[F:22])[C:15]([C:25]#[N:26])=[N:14]1.Cl.[NH2:28][OH:29].[C:30](=[O:33])([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH:30]=[O:33])=[C:16]([S:20][C:21]([F:22])([F:24])[F:23])[C:15]([C:25](=[NH:26])[NH:28][OH:29])=[N:14]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Yield: 8.2 %

Procedure:
To a stirred solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-formyl-4-trifluoromethylthio-1H-pyrazole-3-carbonitrile (3.0 g) in ethanol was added a solution of hydroxylamine hydrochloride (0.46 g) and sodium carbonate (0.9 g) in water. After 1 hour the mixture was poured into water, extracted (ethyl ether), dried (sodium sulfate) and evaporated. Purification by column chromatography on silica gel gave 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-formyl-N-hydroxy-4-trifluoromethylthio-1H-pyrazole-3-carboximidamide (0.255 g), m.p. 72-75° C. Compound 22.