Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[K+].[Br:6]Br.[CH2:8]([N:11]1[C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:14][C:13]([C:23]#[N:24])=[N:12]1)[CH2:9][CH3:10].S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:6][C:14]1[C:13]([C:23]#[N:24])=[N:12][N:11]([CH2:8][CH2:9][CH3:10])[C:15]=1[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCCn1nc(C#N)cc1CC1CCOCC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: CCCn1nc(C#N)c(Br)c1CC1CCOCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 98.3 %

Procedure:
Potassium acetate (3.93 g, 40.0 mmol) and bromine (3.58 g, 22.4 mmol) were sequentially added to a solution of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (3.98 g, 16 mmol) in acetic acid (32 mL). The reaction was stirred for 40 hours at room temperature. Saturated aqueous sodium hydrogensulfite was added until the reaction became colorless. Most of the acetic acid was removed under reduced pressure, and 2M aqueous sodium carbonate was added. A precipitate formed, was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 4.91 g of 4-bromo-1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[N:15][C:14]=3[CH:26]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:28]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:28]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][CH2:26][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]([CH3:18])[C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[CH:38]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1-c1nc(C=O)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccccc1-c1nc(CNc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 5-(2-adamantan-1-yl-ethyl)-1-methyl-2-o-tolyl-1H-imidazole-4-carbaldehyde (Example 275, step b) (500 mg, 1.38 mmol) and 3-amino-benzoic acid benzyl ester (313 mg, 1.38 mmol) in 1,2-dichloroethane (5 ml) were added sodium triacetoxyborohydride (409 mg, 1.93 mmol) and then acetic acid (79 μl, 1.38 mmol). The suspension was stirred at room temperature for 2 h, then saturated sodium bicarbonate (40 ml) was added. The product was extracted with ethyl acetate (40 ml), the organic phase was washed with brine (40 ml), dried (MgSO4) and the filtrate was evaporated. The residue was purified by flash column chromatography (silica, hexane/ethyl acetate 1:1) to afford the product (725 mg, 92%). 1H NMR (300 MHz, CDCl3) 7.44-7.23 (12H, m), 6.91 (1H, m), 5.36 (2H, s), 4.50 (1H, br s), 4.24 (2H, s), 3.33 (3H, s), 2.61 (2H, m), 2.20 (3H, s), 2.00 (3H, br s), 1.77-1.57 (12H, m), 1.31 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([O:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[CH:18]1([CH2:17][O:16][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[N:9][C:8]=2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 0.423 g (0.0014 mol) 6-cyclopentylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester in 5.5 mL tetrahydrofuran, 1.40 mL methanol and 1.4 mL water was added 2.8 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 4 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was washed with water (2×) and brine, dried over sodium sulfate and evaporated to yield 0.396 g (0.0014 mol) of the title compound as white crystals melting at 204-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[S:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:7]1[S:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1csc(S(N)(=O)=O)c1
Solvent: ClCCl
Product: COc1cc(S(N)(=O)=O)sc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 82.1 %

Procedure:
To a solution of 4-methoxythiophene-2-sulfonamide (240 mg, 1.24 mmol) in CH2Cl2 (40 mL) is added N-bromosuccinimide (287 mg, 1.61 mmol). The reaction mixture is stirred at 0° C. for 7 hr. After 7 hr, the reaction mixture is diluted with CH2Cl2 (150 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (2:1) to afford the title compound (277 mg, 82%).
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(O)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.N1CCCCC1>C(O)(C)C.C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:5]2[NH:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1NC(=O)C(=Cc2cccnc2)N1

Procedure:
0.1 mol of imidazolidine-2,4-dione, 3 ml of glacial acetic acid, 0.12 mol of pyridine-3-carbaldehyde and 30 ml of toluene were introduced into a round-bottomed flask. 5 ml of piperidine were also added to this mixture. The combination was heated at reflux for 17 h. After cooling, isopropanol was added. The precipitate obtained was filtered off and washed with isopropanol. The yield of 5-(3-pyridylmethylene)imidazolidine-2,4-dione was 85%.
Reaction SMILES: O.O.C[O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([NH2:16])=[NH:15])=[CH:8][CH:7]=1.CN(/[CH:21]=[CH:22]/[C:23]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)=O)C.C[O-].[Na+].[OH-].[Na+]>CO.O>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][N:16]=[C:14]([NH:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:4])=[O:17])=[CH:7][CH:8]=2)[N:15]=1
Reactant: COC(=O)c1ccc(CNC(=N)N)cc1
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Yield: 87.6 %

Procedure:
A suspension of 24 (6.2 g, 25.4 mmol) and 23a (3.0 g, 16.9 mmol) in anhydrous methanol (40 mL) was stirred and heated to reflux for 10 min, then a solution of sodium methoxide 95% (3.65 g, 67.6 mmol) in methanol (40 mL) was slowly added. After refluxing for 24 h, 20 mL of 2.5N NaOH in water were added and the refluxing was maintained for additional 24 h. The mixture was allowed to cool to the room temperature methanol was removed under reduced pressure, 100 mL of water were added and the resultant mixture was extracted with AcOEt. The aqueous phase was separated and acidified to pH 5-6 with 2N HCl to form a precipitate which was collected by filtration, rinsed with water and dried to afford the desired carboxylic acid 25a (4.55 g, 14.8 mmol, 87%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]=1[F:22]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(Cl)c(F)c2)C1=O
Yield: 73.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 4-bromo-1-chloro-2-fluoro-benzene (213 mg, 1.0168 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.2542 mmol) and potassium phosphate (449.7 mg, 2.1185 mmol) to afford 190 mg of the product (73% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][OH:1])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)cc(CO)c1

Procedure:
A mixture of the product from step (ii) (23.4 g), ammonium chloride (23 g) and iron powder (23 g) in methanol (200 ml) and water (200 ml) was heated at reflux for 1 hour. The mixture was filtered and concentrated under reduced pressure and the residue treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated. Yield 19.38 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@:6]2([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7]([CH2:9][C@H:3]1[CH2:4][CH2:5]2)=[O:8].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:29]2[CH:28]=[C:27]([CH3:30])[N:26]=[C:25]([NH2:31])[C:24]=2[N:23]=[C:22]1[CH2:32][O:33][CH2:34][CH3:35]>>[NH2:31][C:25]1[C:24]2[N:23]=[C:22]([CH2:32][O:33][CH2:34][CH3:35])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:11]([CH2:10][C@:6]34[C:2]([CH3:15])([CH3:1])[C@H:3]([CH2:4][CH2:5]3)[CH2:9][C:7]4=[O:8])(=[O:13])=[O:12])[C:29]=2[CH:28]=[C:27]([CH3:30])[N:26]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)Cl)C(=O)C2
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNS(=O)(=O)C[C@]12CC[C@H](CC1=O)C2(C)C

Procedure:
Using the method of Examples 32-46, D-(+)-10-camphorsulfonyl chloride was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 565.2720.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=S.ICC.[H-].[Na+].[N:28]#[C:29][NH2:30]>O1CCCC1>[C:29]([NH:30][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=1)=[N:2][CH3:1])#[N:28]
Reactant: CNC(=S)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CN=C(NC#N)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of 120 mg of N-methyl-6-nitro-spiro[2H-1benzopyran-2,1'-cyclohexane]-4-carbothioamide, 150 μl of iodoethane, and 3 ml of dried tetrahydrofuran was added 23 mg of sodium hydride (60%) with stirring and cooling with ice followed by refluxlng for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added thereto, followed by refluxing for 4 hours. Ice-water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: ethyl acetate:hexane=2:3) recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 90 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine having formula shown below.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[C:9]([C:12](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH3:10]>>[Cl:25][C:21]1[CH:20]=[C:19]([CH:18]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:10])[NH:1][C:2]3[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]2=3)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Reactant: CCn1nccc1N
Product: CCOC(=O)C1=C(C)Nc2c(cnn2CC)C1c1cccc(Cl)c1
Temperature: 130 °C
Yield: 34.9 %

Procedure:
A mixture of 5-amino-1-ethylpyrazole (250 mg) and ethyl 2-acetyl-3-(3-chlorophenyl)acrylate (568 mg) was heated at 130° C. for 3 hours. After cooling, the residue was evaporated. The residue was diluted with CHCl3 and washed with saturated NaHCO3, water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:7)-to give ethyl 4-(3-chlorophenyl)-1-ethyl-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (271 mg) as a yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH2:9][S:10][CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.[F:21][C:22]([F:41])([F:40])[CH2:23][N:24]=[C:25]([NH2:39])[NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]=[C:37]=[S:38])[N:31]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]>O1CCCC1.CC(C)=O>[F:41][C:22]([F:21])([F:40])[CH2:23][N:24]=[C:25]([NH2:39])[NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:8]2[NH:7][CH:6]=[N:5][C:4]=2[CH3:3])=[S:38])[N:31]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Reactant: Cc1nc[nH]c1CSCCN
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1nc[nH]c1CSCCNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (0.5 g.), triethylamine (1 ml.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-(4-isothiocyanatobutyl)thiazole (0.5 g.) in tetrahydrofuran (15 ml.) was allowed to stand at room temperature overnight. The solution then was filtered, and the filtrate evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. The appropriate band was isolated and further purified by preparative thin layer chromatography using methanol/chloroform/ammonia 15:85:1 v/v/v as developing solvent. The appropriate band after extraction and evaporation yielded a brown gum. This was treated in acetone with excess maleic acid to give 1-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butyl]-3-[2-([4-methylimidazol-5-yl]methylthio)ethyl]thiourea containing 2.25 equivalents of maleic acid. The n.m.r. spectrum in d6 dimethyl sulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.5 (multiplet, 4H); 2.25 (singlet, 3H); 2.5 (multiplet, 4H); 3.3 (multiplet, 4H); 3.8 (singlet, 2H); 4.1 (quartet, 2H); 6.45 (singlet, 1H); 8.8 (singlet, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH:21][C:22](=O)[CH3:23])[CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[OH-].[Na+].O>C1COCC1>[CH2:22]([NH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)[N:20]=1)[CH3:23]
Reactant: CC(=O)Nc1cccc(OC2CCN(C)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1cccc(OC2CCN(C)CC2)n1
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
Add LiAlH4 (108 mg, 2.85 mmol) to a solution of N-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-acetamide (preparation 73, 238 mg, 0.95 mmol) in THF (10 mL) and heat at reflux for 3 days. Quench the reaction with water, add 1N NaOH and water, stir for 30 min. Extract with methylene dichloride three times, combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4% 2M NH3-methanol in methylene dichloride provides 110 mg (49%) of the title compound as a colorless oil: mass spectrum (ion spray): m/z=236.0 (M+1); 1H NMR (CDCl3, ppm): 7.34 (t, 1H), 6.00 (d, 1H), 5.90 (d, 1H), 4.95 (m, 1H), 4.30 (m, 1H), 3.26 (m, 2H), 2.73 (m, 2H), 2.31 (s, 3H), 2.29 (m, 2H), 2.02 (m, 2H), 1.84 (m, 2H), 1.25 (t, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])(=O)C.CO.C[O-].[Na+].Cl>O.C(Cl)(Cl)Cl>[C@@H:6]1([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=C(O)CCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
1.5 g (3.4 mmol) of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-butyric acid (see Stage 1.1) are taken up in 13 ml f chloroform and, at -10°, 22 ml of methanol containing 17.3 mmol of sodium methoxide (obtained by dissolving 400 mg of sodium) are added thereto. Stirring is carried out for 1 1/2 hours at 0° and for 1 hour at 22°. The mixture is cooled to 0°, 2 ml of water are added and the whole is adjusted to pH 3.0 with 1 molar hydrochloric acid. Concentration is carried out by evaporation in vacuo and the residue is taken up in warm ethanol and the resulting sodium chloride is filtered off. After concentrating the filtrate by evaporation, 4-(β-D-glucopyranosyloxy)butyric acid is obtained.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([CH:26]([OH:28])[CH3:27])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:19][C:20]3[N:25]=[CH:24][N:23]=[C:22]([CH:26]([OH:28])[CH3:27])[CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: CC(O)c1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(O)c1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Temperature: 150 °C
Yield: 17.4 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (133 mg, 0.445 mmol), 1-(6-aminopyrimidin-4-yl)-ethanol (65 mg, 0.467 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and cesium carbonate (290 mg, 0.89 mmol) in dioxane (3.5 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) to afford a yellow solid. This was re-purified by HPLC [gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)], to afford the title compound as a white solid (31 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.53 (d, J=0.9 Hz, 1H), 9.07 (d, J=1.1 Hz, 1H), 8.09 (d, J=7.3 Hz, 1H), 7.88-7.86 (m, 2H), 7.78 (dd, J=9.2, 7.1 Hz, 1H), 7.68-7.61 (m, 2H), 4.83-4.76 (m, 1H), 1.46 (d, J=6.7 Hz, 3H). LCMS (Method B): RT=2.74 min, m/z: 401 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 99.2 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixture, the reaction mixture was refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and then poured into hexane. The precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 63.5 g (0.3 mole) of 4nitrocinnamoyl chloride and 400 g of methylethylketone were placed in a reaction vessel and the reaction mixtures were stirred by heating at 50° C. under a nitrogen current. 15.42 g (0.14 mole) of resorcinol, 32 g of pyridine, and 100 g of methylethylketone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction solution was refluxed with stirring under a nitrogen current for 2 hours. After the reaction, the precipitate was separated by filtration and the filtrated solid was washed by water and dried. 64 g of white colored crystals (1,3-bis(4-nitrocinnamic acid) benzene) was yielded.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[Cl:17][C:18]1[C:19]([CH:26]=O)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:17][C:18]1[C:19]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]3([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]3)[CH:7]=2)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: C[C@@]1(c2cc(N)ccc2F)CCOC(N)=N1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)CCOC(N)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
In a 5 ml-reaction tube a solution of (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (22 mg, 0.1 mmol) in methanol (0.3 ml) was treated at room temperature at under an inert atmosphere with 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol). The tube was closed and the reaction mixture was stirred at 25° C. for 60 minutes. Then decaborane (24.4 mg, 200 μmol) was added in one portion, the tube was closed, and the mixture was warmed to 45° C. for 15 hours. For the workup, the reaction solution was quenched with a solution of sodium carbonate (10%). Methanol was removed at reduced pressure, then the residue was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduce pressure. The crude product was purified by basic preparative HPLC and after evaporation triturated with a mixture of ether and heptane. The (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8 mg, 20% yield) was obtained as a colorless oil. MS (ISP): m/z=388.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4])(=[O:40])=[O:39]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Reactant: CS(=O)(=O)CCN
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CNCCS(C)(=O)=O)cc34)cc2C)cn1
Yield: 28.4 %

Procedure:
The procedure of Example 62 was repeated except for using 0.09 g of the compound obtained in Example 67 and 0.11 g of 2-methanesulfonyl-ethylamine instead of the compound obtained in Example 61 to obtain the title compound (0.03 g, 29%).