Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[C:21]([C:33]([NH:35][C:36]3[S:40][N:39]=[C:38]([CH3:41])[N:37]=3)=[O:34])=[N:22][C:23]([S:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][N:28]=3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:5][O:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][C:20]2[C:21]([C:33]([NH:35][C:36]3[S:40][N:39]=[C:38]([CH3:41])[N:37]=3)=[O:34])=[N:22][C:23]([S:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][N:28]=3)=[CH:24][CH:25]=2)=[CH:17][CH:18]=1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(O)cc2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Sc2ccc(Sc3nncn3C)nc2C(=O)Nc2nc(C)ns2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.43 ml of 1-bromo-2-methoxyethane and 4.99 g of cesium carbonate were added to a dimethylformamide (20 ml) solution of 2 g of 3-[(4-hydroxyphenyl)thio]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Reference Example (step 3), and stirred at 60° C. for 1 hour. At room temperature, aqueous saturated ammonium chloride solution was added to it, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol) and crystallized from ethanol to obtain 1.43 g of the entitled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[Br:1][C:2]1[C:3]([O:14][CH2:21][O:22][CH3:23])=[C:4]([CH:7]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C=O
Reaction time: 72 h
Yield: 102.8 %

Procedure:
To a stirred solution of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (5.80 g, 22.6 mmol) (Intermediate 8) and potassium carbonate (4.10 g, 29.4 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added chloromethyl methyl ether (2.01 mL, 27.1 mmol) and the reaction mixture stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give 3-bromo-5-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (7.00 g, 100%+DMF) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH2:17][O:18][CH3:19])[NH:11][C:10](=[O:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:31]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29][NH:30][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:20])[NH:11][C:12]=2[CH2:17][O:18][CH3:19])=[O:16])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COCC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (0.438 mmol) of 4-(3-chlorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 139 mg (0.657 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of DMF. 126 mg (0.657 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: CCC1OC(=O)c2ccsc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (440 mg, 2.9 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (328 mg, 1.94 mmol) in THF (4 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (190 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].C(Cl)(=O)C(Cl)=O.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[O:15])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)O)c(=O)n1C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in Example 1(7) (2.66 g, 11.6 mmol) in dichloromethane (30 mL) were added oxalyl chloride (4.41 g, 34.8 mmol) and a drop of N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature for 2 h. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (80 mL). To the resulting solution were added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (3.72 g, 17.4 mmol, prepared according to Carceller, Elena et al., J. Med. Chem., 1996, 39, 487), N,N-diisopropylethylamine (2.25 g, 17.4 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (100 mL), and extracted with dichloromethane (100 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=1/1) to give 5.27 g (99%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:29]1[C:21]([NH:18][C@H:16]([C:8]2[N:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: Cc1cccc(-n2c([C@H](C)N)nc3cccnc32)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc(-n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3cccnc32)c1
Temperature: 90 °C
Yield: 30.9 %

Procedure:
A mixture of (S)-1-(3-m-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (420 mg, 1.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (550 mg, 2.33 mmol) and DIPEA (0.52 mL, 3.00 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 177 as a white solid (190 mg, 31%). LCMS (Method K): RT 2.84 min [M+H]+ 371.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.33-7.77 (5H, m), 7.45-7.14 (5H, m), 5.56 (1H, br), 2.25 (3H, s), 1.58 (3H, d, J=6.81 Hz). Broad signals due to presence of rotamers/tautomers
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21

Procedure:
In analogy to the procedure described in example 3 b], [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester was treated with tetrabutylammonium fluoride hydrate to obtain (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: O.II.[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][CH:16]=[CH2:17].C(OC(=O)C)(=[O:24])C>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C.O1CCCC1>[C:19]([N:18]1[CH2:17][CH:16]([OH:24])[CH2:15][CH:14]1[C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[F:4])(=[O:21])[CH3:20]
Reactant: C=CCC(NC(C)=O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: II
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CC(O)CC1c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 ml of water and 600 mg of iodine were added to a tetrahydrofuran (4 ml) solution of 200 mg of N-(1-(2-fluoro-4-nitro-phenyl)-3-butenyl)-acetamide, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate, aqueous saturated sodium thiosulfate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain a crude product. 0.25 ml of triethylamine, 0.13 ml of acetic anhydride and 10 mg of 4-dimethylaminopyridine were added to a chloroform (5 ml) solution of the crude product, and the reaction liquid was stirred at room temperature for 15 minutes. The solvent was evaporated away under reduced pressure, 20 mg of potassium carbonate was added to a methanol (5 ml) solution of the resulting residue, and the reaction liquid was stirred at room temperature for 15 minutes. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=30/1) to obtain the entitled compound as a colorless solid diastereomer mixture.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Mg]Cl)CCC.[C:21]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22].Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][CH2:3][CH2:2][CH2:1][CH2:26][CH2:25][O:24][C:21]([CH3:22])=[O:23]
Reactant: C=CCCC=CCCC=CCCCC
Reactant: CC(=O)OCCBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCCC[Mg]Cl
Agent: Cl
Product: CCCC/C=C\CC/C=C\CCCCCCOC(C)=O
Temperature: 0 °C
Yield: 11 %

Procedure:
1,5,9-Tetradecatriene (10 g, 0.052 mol), n-butylmagnesium chloride (24.8 mL of 2.5M in tetrahydrofuran; 0.062 mol) and titanium tetrachloride (0.52 g, 0.0027 mol) were stirred under an inert atmosphere at about 65° C. for about 4.5 hours. The reaction mixture was then cooled to 0° C. and cuprous bromide (0.14 g, 1.0 mmol) was added. 2-Bromoethyl acetate (6.9 mL, 0.063 mol) was then added dropwise and the mixture allowed to warm slowly to room temperature and stirred for several hours at room temperature. Reaction temperature was then raised to 60° C. for 4 hours before the mixture was cooled, acidified with aqueous HCl, then extracted with hexane. The hexane extract was washed with saturated sodium bicarbonate solution, dried over MgSO4, filtered and solvent removed on the rotary evaporator. GLC analysis of this crude reaction product indicated an 11% yield of gossyplure. It should be recognized that while this reaction represents successful production of gossyplure from 1,5,9 -tetradecatriene in one reaction vessel, the reaction parameters have not been optimized. Consequently, significantly improved yields of gossyplure can be expected upon optimization of various reaction parameters.
Reaction SMILES: [CH2:1]([C:3]([CH:5]([CH3:13])[CH2:6][CH:7]([CH3:12])[CH:8]([OH:11])[CH2:9][CH3:10])=C)[CH3:2].I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:10][CH2:9][CH:8]([OH:11])[CH:7]([CH2:6][CH:5]([C:3]([CH2:1][CH3:2])=[O:15])[CH3:13])[CH3:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(CC)C(C)CC(C)C(O)CC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)C(C)CC(C)C(O)CC
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
Osmium tetraoxide (80 mg, 0.3 mmol) was added to a solution of [S-(3R*,5R*,6R*)-2-ethyl-3,5-dimethyl-1-octen-6-ol (15a) (0.552 g, 3 mmol) in 36 mL of 1,4-dioxane and 12 mL of water at 20°-25° C. After 15 min, finely powdered sodium periodate (10.0 g, 46.8 mmol) was added in several portions over a period of 1 h, in accord with the literature procedure [Pappo, R. et al., J. Org. Chem., 1956, 21:478-479]. The mixture was stirred for 16 h, then extracted with ether (2∞50 mL). The ether solution was washed with sodium sulfite solution, dried over anhydrous magnesium sulfate (0.5 g), filtered, and concentrated at 50 torr to yield a residue of serricornin (1 and 2) (0.507 g, 91%). The NMR data are consistent with those previously reported [Mori, K. and Watanabe, H., Tetrahedron, 1985, 41:3423-3428]:300 MHz 1H-NMR (C6 D6) (literature data in parentheses) δ0.8-2.4 (m, 23), 3.2 (lit 3.17) (m, 0.75, CH--O of 2), 3.75 (lit 3.82) (ddd, 0.25, CH--O of 1); 75 MHz 13C-NMR (C6D6), assigned to 1:δ8.0, 10.7, 14.0, 16.5, 27.0, 33.9, 36.1, 36.8, 43.6, 76.4, 213.4 (8.0, 10.8, 13.7, 16.4, 27.5, 33.9, 35.8, 36.8, 43.8, 76.4, 213.6); assigned to 2:7.4, 10.7, 11.7, 16.8, 26.2, 30.2, 31.3, 33.1, 36.1, 72.6, 98.5 (7.4, 10.7, 11.7, 16.7, 26.2, 30.2, 31.3, 33.1, 36.2, 72.7, 98.6), HRMS: calcd for C11 H20O [(M-18)+] 168.1514; found, 168.1506.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16]O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[C-:18]#[N:19].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16][C:18]#[N:19])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: [C-]#N
Reactant: OCc1cnn2c(-c3cccnc3)ccnc12
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cnn2c(-c3cccnc3)ccnc12
Temperature: 100 °C

Procedure:
A mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-methanol and 0.025 mole of potassium cyanide in N,N-dimethylformamide is heated at 100° C. for 16 hours. The solvent is removed and water is added to the residue to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-acetonitrile. A mixture of 0.001 mole of the preceding compound in a 1:1 mixture of acetic acid and concentrated hydrochloric acid is heated at reflux temperature for 16 hours. The solvent is removed to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid. The preceding compound is heated at 180° C. to give the product of the example.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:4]=[N:3]1.[CH3:21][O:22][CH:23]([O:32][CH3:33])[CH2:24][NH:25][C@@H:26]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:27].C(OCC)(=O)C>CCCC(C)C>[CH3:21][O:22][CH:23]([O:32][CH3:33])[CH2:24][N:25]([C@@H:26]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:27])[C:15](=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]1[CH:18]=[CH:19][CH:20]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:8]=1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: CCCC[C@@H](C)NCC(OC)OC
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C)N(CC(OC)OC)C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1
Reaction time: 2 h

Procedure:
The subtitled compound (234 mg) was prepared using a similar method to that described in Preparation 3 Step iii) from 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] and (R)—N-(2,2-dimethoxyethyl)hexan-2-amine [Preparation 13] and the reaction mixture was stirred for 2 h. The elution gradient used was 30-50% ethyl acetate in isohexane. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (s, 1H), 7.36-7.24 (m, 3H), 7.11-7.05 (m, 1H), 4.69-4.63 and 4.41-4.37 (m, 1H), 4.38-4.31 and 3.85-3.76 (m, 1H), 3.94 (s, 3H), 3.85-3.76 (m, 2H), 3.74-3.65 (m, 2H), 3.43-3.37 (m, 6H), 3.33-3.25 (m, 1H), 3.22-3.14 (m, 1H), 2.94-2.85 (m, 2H), 2.80-2.57 (m, 2H), 1.59-1.12 (m, 9H), 0.93-0.85 (m, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[ClH:11].[NH3:12]>CO.C(O)C>[ClH:11].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]([NH2:12])=[NH:6]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: N
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)c1ccc(F)c(F)c1

Procedure:
3,4-difluorobenzonitrile (4) is reacted with dried HCl gas in anhydrous methanol, followed by reacting the resulting crystals with dried ammonia gas in anhydrous ethanol to obtain 3,4-difluorobenzamidine hydrochloride (5).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(=O)(O)[O-].[Na+].Cl.C([BH3-])#N.[Na+].[H-]>>[NH2:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[O:2]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Product: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Reactions of carboxymethyl cellulose sodium salt (0.5-1.0% w/v) were carried out with glucosamine-hydrochloride (1.5-3.0% w/v) in the presence of equimolar amounts of base, such as a sodium bicarbonate solution (0.55-1.1% w/v) to neutralize the hydrochloride, sodium cyanoborohydride as hydride and as reducing reagent (0.27-0.50% w/v), at room temperature, producing 2-amino-2-deoxy-glucose derivatives of carboxymethyl cellulose with nitrogen incorporation values of 2.60-3.07%, as shown in Table 2, page 17.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:15][CH:14]=1.FC(F)(F)[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH:33]([C:30]1[CH:29]=[C:16]([CH:15]=[CH:14][C:13]=1[O:12][CH3:11])[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18 g of hexamethylene tetramine was added little by little to a mixture of 31 g N-(4-methoxybenzyl)phthalimide and 100 ml trifluoroacetic acid, stirred at room temperature for 1 hr, and then heated under reflux for 4 hr. The reaction solution was cooled to 0° C., and water was added thereto. Potassium carbonate was added thereto and the resulting crystals were collected by filtration. The crystals were dried to give 20 g of N-(3-formyl-4-methoxybenzyl)phthalimide.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc(OC)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5gms. of 3-methoxy-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids, and then is extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(3-methoxy-phenyl)-3-oxo-propionitrile in the amount of 2.0202 gms.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:34][CH3:35])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:40][N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:19])[F:18])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:34][CH3:35])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(N2CCOCC2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
(5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (500 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto is added 3-fluoro-5-(trifluoromethyl)benzylbromide (528 mg) and thereto is added sodium hydride (60%) (82 mg) under ice-cooling, and the mixture is stirred at room temperature for 2 hours and a half. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→22:3) to give (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (440 mg). MS (m/z): 663 [M+H]+