Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:18])[C:3]=1[C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:1][C:2]1[C:11]2[CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:18])[C:3]=1[C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1c(O)c2cc([N+](=O)[O-])cc3c2n(c1=O)CCO3)N1CCc2ccccc21
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(=O)N2CCc3ccccc32)c(=O)n2c3c(cc(N)cc13)OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-nitro-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.7 g) and acetic anhydride (0.79 g) in pyridine (4 ml) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue containing 2,3-dihydro-7-acetoxy-9-nitro-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine was reduced catalytically in a similar manner to that of Example 22 to give crystals of 2,3-dihydro-7-acetoxy-9-amino-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.7 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].Br[CH2:30][CH2:31][C:32]#[N:33]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[N:26]([CH2:30][CH2:31][C:32]#[N:33])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: N#CCCBr
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCC#N
Temperature: 10 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)—N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to ˜10° C. with an ice bath and 3-bromopropionitrile (0.813 mmol, 109 mg) was slowly added. The reaction mixture was allowed to warm to RT and it was stirred overnight. The liquids were, evaporated. DCM was added and washed twice with water. The separated organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 73.1 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 2.38 (s, 3H), 3.02 (t, 2H), 4.22 (t, 2H), 4.24-4.47 (m, 3H), 6.95 (d, 1H), 7.61 (s, 1H), 7.83 (d, 1H), 7.96-8.02 (m, 2H), 8.07-8.13 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].C(OCC)(=O)C>CC(C)=O>[CH:2]([C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])=[O:1]
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CO)CS(=O)[C@H]12
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1

Procedure:
To a solution of 0.843 g (1.7 mmole) of 2,2,2-trichloroethyl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 50 ml of acetone at 0° is added over the period of about 2 min. 0.450 ml of 8N CrO3 in H2SO3 and the mixture is stirred at 0° for 5 min., then poured into a mixture of 300 ml ethyl acetate - 300 ml water and the ethyl acetate layer washed with water, dried (MgSO4), and evaporated in vacuo. The residue when chromatographed on silica gel with CHCl3 gives 2,2,2-trichloroethyl 3-formyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH:18]=[O:19])=[CH:8][CH:7]=1.[NH4+].[Cl-]>CCOCC.O>[OH:19][CH:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[S:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=1)[CH3:1]
Reactant: COc1ccc(Sc2sccc2C=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Sc2sccc2C(C)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a stirred solution of methylmagnesium bromide (20.7 ml, 0.06 mol of 2.9M solution in ether) in anhydrous ether (50 ml) cooled to -5° C. was added 2-(4-methoxyphenylthio)thiophene 3-carboxaldehyde (10.0 g, 0.04 mol) in anhydrous ether (40 ml) over a 1/2 hour period under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours and was decomposed by adding a solution of NH4Cl (5.3 g, 0.1 mol) in water (50 ml) over a 20 minute period at 0° to 15° C. The ether layer was separated, washed with 3NHCl, saturated, NaHCO3 and water. It was dried, filtered and concentrated in vacuo at room temperature to obtain an amber oil. The product was purified by silica gel column chromatography using 50/50 hexane-ethyl acetate. This procedure gave 8.8 g of amber oil. Yield was 83%.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][CH2:22][NH:23]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(OCCCCCOc3cccc4ncccc34)cccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2c(c(OCCCCCOc3cccc4ccccc34)c1)CCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of 5-[5-(naphthalen-1-yloxy)-pentyloxy]-quinoline (0.83 g, 2.32 mmol) in 10 mL methanol and 1 mL THF was added sodium borohydride (0.35 g, 9.29 mmol) and nickel (II) chloride hexahydrate (0.28 g, 1.16 mmol). The reaction mixture was stirred overnight at room temperature and then 20 mL saturated aqueous ammonium chloride solution was added. The solution was extracted with ethyl acetate (3×20 mL), and the combined organic phases were washed with brine, dried over MgSO4, and concentrated to give a white solid. The crude product was purified by silica gel chromatography to give 5-[5-(naphthalen-1-yloxy)-pentyloxy]-1,2,3,4-tetrahydro-quinoline (335 mg, 0.93 mmol, 40%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[CH2:12](Cl)[CH:13]=[CH2:14]>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:14][CH:13]=[CH2:12])[NH:8][C:4]=2[CH:3]=1
Reactant: C=CCCl
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Solvent: CCO
Product: C=CCSc1nc2ccc(C)cc2[nH]1
Yield: 64.66 %

Procedure:
4.11 g (25 mmoles) of 5-methyl-benzimidazoline-2-thione and 2.45 ml of allyl chloride are refluxed in ethanol, then the reaction mixture is evaporated. The residue is worked up according to the method described in Example 2. The residue obtained after the dichloromethane extraction is recrystallized from 7 ml acetonitrile. 3.29 g (64.66 %) of 5-methyl-2-(2-propenyl-thio)benzimidazole melting at a temperature of 128° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=O)=[O:4].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[C:10]1[O:12][N:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]3)=[CH:39][CH:40]=2)[N:20]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C(=O)O
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A mixture of 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylic acid (32 mg, 0.130 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (39.7 mg, 0.130 mmol), HOBT (31.8 mg, 0.208 mmol), EDC (58.5 mg, 0.305 mmol) and diisopropylethylamine (0.091 mL, 0.520 mmol) in DMF (1 mL) was stirred at rt for 18 hr. After warming to 60° C. for 3 hr, the reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-90% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-(methylcarbamoyl)-3-phenylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (29 mg, 0.056 mmol, 43.3% yield) as a colorless glassy solid. HPLC retention time=1.50 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=516.27.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.Br[CH2:29][CH2:30][O:31][CH3:32]>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:29][CH2:30][O:31][CH3:32])=[CH:13][CH:12]=3)[N:19]=1
Reactant: COCCBr
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(O)cc12
Product: COCCOc1ccc2oc(-c3cc4ccccc4cn3)cc(=NO)c2c1

Procedure:
2-isoquinolin-3-yl-6-(2-methoxy-ethoxy)-chromen-4-one oxime was prepared in 67% overall yield using the method described in example 42 and 42A, starting from 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 41A) and bromoethylmethylether instead of iodomethane. The title compound was isolated as a yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-80%), and as a 85/15 mixture of Z/E oxime isomers.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]([O-:40])(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:40][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: O=C([O-])c1ccncc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccncc1
Temperature: 25 °C
Yield: 80 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium isonicotinate (0.33 g, 1.301 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 80%. 1H NMR (400 MHz, DMSO-d6): δ 8.78 (d, 2H), 7.82 (d, 2H), 7.36 (d, 1H), 7.30 (t, 1H), 7.18 (d, 1H), 6.02 (dd, 2H), 4.76-4.70 (m, 1H), 4.10-4.05 (m, 2H), 3.89-3.85 (m, 1H), 3.77-3.74 (m, 1H), 3.35-3.26 (m, partially obscured by water, 2H), 3.19-3.11 (m, 1H), 3.07-3.04 (m, 2H), 2.43 (d, partially obscured by DMSO, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H); MS-APCI (m/z+): 341, 564.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=3[CH:18]=[C:19]([F:31])[CH:20]=2)[CH:27]=1
Reactant: CN
Reactant: COc1ccc(Cl)cc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(F)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.62 g, 38%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:32][C:11]3[C:12](=[O:31])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]5)=[C:18]([O:29][CH3:30])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:32][C:11]3[C:12](=[O:31])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][N:25]([CH3:35])[CH2:24]5)=[C:18]([O:29][CH3:30])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[C@@H]1CCCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[C@@H]1CCCN(C)C1
Yield: 34.2 %

Procedure:
Stir a solution of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridine-7-one (446 mg, 0.96 mmol), formaldehyde (0.38 mL, 37% aqueous solution), and acetic acid (0.22 mL, 3.84 mmol) in methanol (34 mL) at room temperature for 5 min. Add sodium cyanoborohydride (150 mg, 2.4 mmol) to this solution and stir the reaction for 2 h. Concentrate the mixture in vacuo and partition the residue between dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×10 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (dichloromethane to 5% 2 M ammonia in methanol/dichloromethane) to afford 158 mg (34%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:25][CH2:24][C:19]5(OCC[O:20]5)[CH2:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29](=[O:32])[O:30][CH3:31].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:25][CH2:24][C:19](=[O:20])[CH2:18][C:17]=4[CH:26]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:27][NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CC3(CO4)OCCO3)n2)ccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CC(=O)CO4)n2)ccc1Cl
Yield: 68 %

Procedure:
To a solution of methyl N-[[2-chloro-5-(1-spiro[2H-1-benzopyran-3(4H), 2′-[1,3]dioxolan]-6-yl-1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Example 9, Step B) (150 mg, 0.32 mmol) in acetone (15 mL) was added 3N HCl (4.5 mL). The reaction mixture was heated at 85° C. for 16 hrs when TLC analysis (50% ethyl acetate/pet ether) showed completion of reaction. The reaction mixture was cooled and the solvent was concentrated under vacuum. The resultant residue was partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the title compound, a compound of the present invention, (90 mg, 68% yield) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH:43]([CH3:44])[CH3:45])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (218 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (320 mg, 77%).
Reaction SMILES: [F:1][C:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12](O)[N:7]2[N:6]=1)([F:4])[CH3:3].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:12]1[N:7]2[N:6]=[C:5]([C:2]([F:4])([F:1])[CH3:3])[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=1
Reactant: Cc1cc(O)n2nc(C(C)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1

Procedure:
This intermediate was synthesized by suspending Intermediate 2 in phosphorus oxychloride (ALDRICH, 21.98 ml, 236 mmol) was heating the mixture under reflux for 2 h, the starting material dissolved meanwhile. An aliquot of the reaction was partitioned between NaCO3 10% aq. (1 mL) and DCM (1 mL) and the organic phase was checked by TLC (Hexane/AcOEt 6/4) showing the reaction was complete. The reaction mixture was slowly added to a mixture of water and ice. The solution was neutralized with 10% aq. Na2CO3 (800 mL approx.) and product was extracted with DCM (250 mL). The aqueous layer was further extracted with DCM (2×150 mL) and the combined organic layers were washed with water (200 mL), then with brine (200 mL) and dried over MgSO4. Solvent was removed under reduced pressure. The crude product was purified (silica gel column, eluting with Hexane/AcOEt mixtures from 100:0 to 50:50%) and Intermediate 3 was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[S:20]([CH3:22])=O>>[CH2:22]([S:20][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:18])=[O:10])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1O
Product: O=C(c1ccc(SCc2ccccc2)cc1)c1cc(Cl)cc(Cl)c1O
Temperature: 100 °C

Procedure:
The residue is dissolved with 200 ml of dimethyl sulphoxide, 32 g of (3,5-dichloro-2-hydroxyphenyl)-(4-fluorophenyl)methanone are added and the mixture is heated to 100° C. for 8 hours under argon.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH3:10][O:11]C(Cl)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[OH:9])[CH:10]=[O:11])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCc1ccccc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TiCl4 (45.6 g, 238 mmol) was added slowly to a solution of 2-ethylphenol (15 g, 119 mmol) in CH2Cl2 (150 ml) was at 0° C. The mixture was warmed to room temperature and dichloromethyl methyl ether (18.3 ml, 200 mmol) was added (strong HCl evolution). The mixture was stirred for 4 h. at room temperature, subsequently cooled to 0° C. and 1M HCl (119 ml, 119 mmol) was added dropwise. The mixture was stirred for 10 min. and subsequently extracted with diethyl ether. The organic phase was washed with saturated NaHCO3 solution and with NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/MeOH 9:1). 3-Ethyl-4-hydroxy-benzaldehyde was obtained as a brown oil (7.97 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:33][CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole), 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of N,N-diethylethylenediamine (7.32 g, 0.063 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was evaporated to a solid. The solid was triturated with water (50 ml), filtered, and the filter cake was rinsed twice with water, twice with a 5% potassium hydroxide solution and twice with water. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature. Addition of water caused a white solid to form. The solid was collected by filtration and rinsed with water to give 4.21 g (52%) of a white solid. A 1.0-g sample of the solid was dried under high vacuum at room temperature to give a white solid, mp 142°-143° C.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:23])[CH:16]=1)#[N:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[C:17]([F:23])[CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)C(N)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-3-methylbutanoate (8.5 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro-benzyl bromide (FluoroChem Ltd, 9.4 g, 0.044 mol) and NaHCO3 (10.2 g, 0.12 mol). The resulting mixture was stirred at RT for 16 h. Water (70 mL) was added and the desired product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The resulted residue was purified by column chromatography using petroleum ether/ethyl acetate as eluent, affording of the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J=10.2 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 3.85-3.79 (m, 2H), 2.72 (m, 1H), 2.49 (m, 1H), 1.81 (m, 1H), 1.37 (s, 9H), 0.86 (m, 6H).