Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22]COC)[CH:9]=1)=[O:5].Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[N:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([OH:22])[CH:9]=1)=[O:5]
Reactant: COCOc1cc(CNC(=O)c2cccnc2N)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ncccc1C(=O)NCc1ccc(OCc2ccccc2)c(O)c1
Yield: 28.8 %

Procedure:
Next, a solution of 2-amino-nicotinic acid (16 mg, 0.116 mmol), 4-benzyloxy-3-methoxymethoxy-benzylamine (15 mg, 0.0549 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (55 mg, 0.124 mmol) and triethylamine (0.08 mL, 0.574 mmol) in dimethylsulfoxide (4 mL) was stirred under nitrogen atmosphere at room temperature for 24 hours. Water (100 mL) and brine (50 mL) were added to the reaction solution, which was then extracted with ethyl acetate (100 mL) twice, and washed with water twice. The organic layer was dried over anhydrous magnesium sulfate, which was then filtered, the filtrate was evaporated in vacuo, and 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide was obtained as a pale yellow oil. This was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then hexane:ethyl acetate=3:7), and 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide) (9.4 mg, 0.0239 mmol, 43.5%) was obtained as a pale yellow oil. A solution of the resulting 2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide (7.8 mg, 0.0198 mmol) and 2M hydrochloric acid (2 mL) in methanol (3 mL) was stirred for 21 hour at room temperature. Sodium bicarbonate (600 mg, 7.14 mmol) was added to the reaction mixture to basify it, which was then filtered, evaporation in vacuo was carried out, then, the obtained residue was purified by thin layer NH silica gel chromatography (methanol:ethyl acetate=5:95), and the title compound (2.0 mg, 0.0057 mmol, 29%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]Cl)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[C:6]([OH:8])=[O:7]
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 109.3 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated. The residue was dissolved in ethanol (50 ml), 2M sodium hydroxide (50 ml) was added and the mixture heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])[CH:11]=[C:10]([CH3:21])[CH:9]=1)(=O)=O.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][N:26]2[C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]3[C:22]2=[O:32])[N:13]=[C:12]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])[CH:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCOS(C)(=O)=O)nc(-n2c(C)ccc2C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: ClCCl
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)nc(-n2c(C)ccc2C)c1
Temperature: 40 °C
Reaction time: 20 h
Yield: 63.3 %

Procedure:
To a stirred solution of 250 mg (0.906 mmol) of 6-(2-methanesulfonyloxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 59, Step A) in 0.70 mL of dry N,N-dimethylformide was added 336 mg (1.81 mmol) of potassium phthalimide and 67 mg (0.18 mmol) of tetrabutylammonium iodide. The mixture was stirred at room temperature for 2 h and at 40° C. for 20 h. The reaction was diluted with 50 mL of dichloromethane, washed with 30 mL of saturated aqueous sodium bicarbonate and 30 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. To remove the contaminating phthalimide, the residue was dissolved in 40 mL of diethyl ether and washed 2×20 mL of 2.5 N aqueous sodium hydroxide, followed by saturated aqueous sodium chloride. The organic phase was dried (sodium sulfate), decanted, and concentrated. Flash column chromatography on 26 g of silica gel, eluting with 200 mL of 7% of ethyl acetate/hexane and 500 mL of 30% of ethyl acetate/hexane furnished 206 mg (63% yield) of 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phthalimidoethyl)pyridine as an amber syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9](N(CC)CC)C.C([Li])CCC.CI>CCCCCC.O1CCCC1>[CH2:1]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[CH3:9]
Reactant: Cc1cccc(C)n1
Reactant: CCN(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCc1cccc(C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
In a 250-ml 3-neck jacketed reactor flask, 4.3 g (40.2 mmol) of 2,6-dimethylpyridine and 4.06 g (40.2 mmol) of triethylamine were dissolved by addition of 50 ml of anhydrous tetrahydrofuran, and the solution was cooled to −40° C., after which 28.7 ml (46 mmol) of 1.6 M n-butyllithium in hexane was added dropwise thereto. At the same time, the solution changed to deep red. Next, the solution was stirred for 1 hour, and then warmed to 0° C., after which 5.7 g (40.2 mmol) of methyl iodide was added dropwise thereto, followed by stirring for 1 hour. Then, the reaction product was concentrated, and the concentrate was dissolved in ethyl acetate, washed with water and saline, dried with anhydrous magnesium sulfate, and then concentrated again, thereby obtaining crude 2-ethyl-6-methylpyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[O:29][CH:30]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:27]=2)=[CH:36][CH:35]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
400 mg (1.222 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 306 mg (1.344 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 410 mg (4.888 mmol) of sodium bicarbonate in 8 ml of DMF are stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 10.4 mg (1.6% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[CH:25]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH:22][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C:5]=23)(=[O:31])=[O:30])[N:26]=[CH:25]1
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4cn(C)cn4)c23)c1

Procedure:
Following general method outlined in Example 1, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (60 mg, 0.192 mmol) (Description 21) and 1-methyl-1H-imidazole-4-sulfonyl chloride (69.4 mg, 0.384 mmol), the title compound (37 mg) was isolated as a TFA salt. LCMS (B) m/z: 457 [M+1]+, Rt 2.85 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16]Br)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)/C=C(\CBr)c1cccc(C#N)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\Cn1cccn1)c1cccc(C#N)c1
Yield: 71.1 %

Procedure:
To a solution of ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (103 mg, 0.35 mmol) in 5 ml anhydrous di-methylformamide was added pyrazole (24 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.7 mmol). Reaction mixture was stirred for 1.5 hours at room temperature after which 25 ml ethyl acetate was added. Organic was washed with 3×25 ml water, 3×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give ethyl (Z)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (70 mg, 71%) as a brown residue which was sufficiently pure to be used without further purification. ES-MS (M+H+): 282.1
Reaction SMILES: [N+:1]([C:4]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:5][CH2:6][CH:7]=[O:8])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]([N+:9]([O-:11])=[O:10])([N+:12]([O-:14])=[O:13])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2]
Reactant: O=CCCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])C(CCCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Crude 4,4,4-trinitrobutaldehyde (878 g, 4.24 mol) was dissolved in methanol (1000 ml) and cooled in an ice bath while NaBH4 (130.7 g, 3.44 mol) was added portion-wise. The mixture was stirred at room temperature overnight under a nitrogen purge which removed much of the solvent. The thick suspension was hydrolyzed with 6 N HCl (approx. 41) and the product extracted with CH2Cl2 (3×1000 ml). The extracts were washed with water (1000 ml), saturated NaHCO3 (2×1000 ml), and water (1000 ml). The product solution was dried over anhydrous MgSO4 and concentrated to yield 554 g (63%) of a yellow oil, nD =4735 (19C). The infrared spectrum showed peaks at 3619, 3370, 2950, 2890, 1595, 1305, 1058 and 801 cm-1.
Reaction SMILES: [NH:1]1[C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]1=[O:10].COCCOC.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>C1COCC1>[OH:8][CH2:7][C:6]1[NH:1][C:2](=[O:10])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cccc(=O)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=c1cccc(CO)[nH]1
Temperature: 0 °C
Yield: 31.7 %

Procedure:
1H-Pyridin-2-one-6-carboxylic acid (2.51 g, 18 mmol) was suspended in dry THF (30 ml) and 1,2-dimethoxyethane (10 ml) under argon. Lithium aluminium hydride (1.0 M in diethyl ether) (30 ml, 30 mmol) was added and the mixture heated to reflux. After 67 h heating was stopped, the mixture cooled to 0° C. and acetic acid (7 ml) added. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel, eluting with 20–30% methanol in dichloromethane, to give the title compound as tan needles (0.714 g, 32%); δH (400 MHz; CD3OD) 4.47 (2H, s), 6.38 (1H, d, J 6.8), 6.41 (1H, d, J 9.2), 7.56 (1H, dd, J 6.8, 9.2); m/z (ES+) 126 (100%, [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Br:33]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Br:33])[C:22]([NH2:21])=[C:27]([Br:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NCCNc1cc(Br)c(N)c(Br)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-amino-3,5-dibromophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]1C=CC=CC=1.C(OCC)C>O>[CH2:12]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (21 g, 0.13 mol) in dry benzene (50 mL, 0.6 mol) was added to ethylenetriphenylphosphorane [prepared from dimsyl sodium and methyltriphenylphosphonium bromide (106 g, 0.291 mol) in dimethyl sulfoxide (600 mL, 8 mol)] The mixture was stirred at room temperature overnight and poured into a separating funnel containing ethyl ether (500 mL) and water (500 mL). The organic layer was separated and the aqueous phase was extracted with ethyl ether (2×500 mL). The combined ether layers were washed with water (500 mL) and brine (500 mL), and dried. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product (18.0 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C([O:27][C:28](=O)[CH2:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31])(C)(C)C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:28](=[O:27])[CH2:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31])=[O:4]
Reactant: CC(C)(C)OC(=O)CC(=O)C1CC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192e) was reacted with 3-cyclopropyl-3-oxo-propionic acid tert-butyl ester (CAS Reg. No. 134302-07-1) to give the title compound as brown oil. MS (ESI): m/z=448.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15][N:14]=2)[N:10]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:43])C>CCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:43])=[CH:15][N:14]=2)[N:10]=1
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C#N)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a mixture of 6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinonitrile (6.77 g) and anhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 55.8 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (100 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and the mixture was stirred at room temperature for 30 min. Insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (3.25 g, 47%) of 6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][CH:13]1[CH2:19][C:18](=[O:20])[O:17][C:15](=[O:16])[CH2:14]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:18](=[O:20])[CH2:19][CH:13]([CH3:12])[CH2:14][C:15]([OH:17])=[O:16])=[CH:3][C:4]=1[O:10][CH3:11])#[N:7]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: COc1cc(N)ccc1C#N
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC(C)CC(=O)O)ccc1C#N
Yield: 108.2 %

Procedure:
A solution of the compound obtained in Step 1 (670 mg, 4.52 mmol) and 3-methylglutaric anhydride (579 mg, 4.52 mmol) in THF (20 mL) was heated with reflux for 14 hr. The reaction solution was concentrated under reduced pressure to give 5-((4-cyano-3-methoxyphenyl)amino)-3-methyl-5-oxopentanoic acid (1.35 g, 4.89 mmol, quantitative) as a brownish-red oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19].[C:23](O)(=[O:34])[CH2:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(OCC)(=O)C>[CH3:22][CH:17]([NH:16][C:23](=[O:34])[CH2:24][NH:25][C:26](=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(N)C(C)(C)C
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(NC(=O)CNC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
2.2 g of dicyclohexylcarbodiimide were added to 30 ml of an ethyl acetate solution containing 1.0 g of 3-amino-2,2-dimethylbutane and 1.7 g of hippuric acid in an ice bath. The reaction solution was stirred for 2 hours at room temperature and then allowed to stand overnight. The solid material which separated was filtered off, after which the filtrate was washed with a 10% w/v aqueous solution of sodium hydroxide, then with 1N aqueous hydrochloric acid, and finally with a saturated aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 1.65 g (yield 64%) of the title product melting at 124°-126° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a suspension of 5-(hydroxymethyl)-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.853 mmol) in DCM (4 mL) was added thionyl chloride (0.124 mL, 1.705 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water, adjusted pH about 7 and extracted with DCM. The organic layer was separated and concentrated to afford the title compound (250 mg, 0.802 mmol, 94% yield).
Reaction SMILES: Cl[C:2]1(O)[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])([CH3:26])([CH3:24])[CH3:25]
Reactant: OC1(Cl)NC=Nc2cc(-c3ncccc3C(F)(F)F)ccc21
Reactant: CC(C)(C)c1ccc(N)cc1OCCO[Si](C)(C)C(C)(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
Stir 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol (1.85 g, 6 mmol) and 4-tert-butyl-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenylamine (1.94 g, 6 mmol) in acetonitrile (100 mL) at 80° C. for 4 hours. Cool the mixture and collect the precipitate. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=2[N:16]=[CH:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cc1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: Brc1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of N1-benzyl-5-bromobenzene-1,2-diamine (450 mg, 1.63 mmol) in HC(OMe)3 (15 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the crude 1-benzyl-6-bromo-1H-benzo[d]imidazole. The crude product was used in next step without further purification. LCMS (m/z): 287.1/288.1 [M+H]+/[M+2H]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].Cl.[CH3:18][NH:19][CH3:20].C([BH3-])#N.[Na+].CO.C(Cl)Cl>CO>[CH3:18][N:19]([CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])[CH3:20]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde (40.00 mg; 0.16 mmol; 1.00 eq.) in MeOH (1.00 ml) was added dimethylamine hydrochloride (15.89 mg; 0.19 mmol; 1.20 eq.), and sodium cyanoborohydride (5.10 mg; 0.08 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirred at room temperature for 15 min. The desired product was isolated by flash chromatography (KPNH column, 0 to 100% MeOH/DCM, 15CV) to afford (3aR,5R,6S,7R,7aR)-5-[(dimethylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (9.6 mg, 21%) as a white solid (once lyophilized).