Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@@H:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]([OH:37])=[O:36])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), L-phenylalanine (296 mg, 1.8 mmol) and NaOMe (73 mg, 1.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-60% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as an off-white solid. MS: (+) m/z 469.26 (M+1).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[C:1]12([C:6]3[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:25][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)c1cccc(C2=CCCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(C23CCCC2O3)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (23 mmol) of ethyl 3-cyclopent-1-ylbenzoate (4a) and 100 ml of methylene chloride are introduced into a round-bottomed flask. The solution is cooled to 0° C. and 9 g (28 mmol) of meta-chloroperbenzoic acid are added in portions. The mixture is stirred for 30 minutes at 0° C. and then for 4 hours at room temperature. The mixture is filtered. The filtrate is successively washed with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95:5). The title product is obtained in the form of a colorless oil (4.8 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: COCOc1c(C)cc(O)c(C)c1C
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
6.11 g of sodium hydride (55% by weight) were suspended in 300 ml of N,N-dimethylformamide, followed by the addition of 27.5 g of 4-methoxymethoxy-2,3,5-trimethylphenol. The resulting mixture was stirred at room temperature for one hour. To the reaction mixture, 40.1 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate were added in small portions and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=5/1), whereby 57.0 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:2].[H][H]>CO.[Pd]>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][NH2:2])[N:8]=1
Reactant: Cc1ccnc(C#N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccnc(CN)n1
Yield: 91.9 %

Procedure:
To a nitrogen flushed solution of the title compound from Step A (1 g, 8.39 mmol) in methanol (40 ml) was added 10% palladium on carbon (100 mg) and the resulting mixture stirred under a balloon of hydrogen for 3 h. The mixture was filtered through celite and evaporated to give 950 mg (91%) of the title compound (i-6) as an orange oil. 1HNMR (CDCl3): 2.54 (s, 3H), 4.16 (s, 2H), 7.03 (d, J5.0 Hz, 1H), 8.56 (d, J5.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH3:10]
Reactant: Fc1ccc(Br)c(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
76.61 g of 2-bromo-5-fluorothiophenol were dissolved in 740 ml of DMF and 62.23 g of potassium carbonate were added. A solution of 26.07 ml of iodomethane in 130 ml of DMF was then added dropwise at a temperature between 3° C. and 11° C. The reaction mixture was stirred for 3 h at room temperature, then diluted with 3 l of water and extracted four times with 500 ml each of MTB. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuo. 72.71 g of the title compound were obtained as a pale brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)NCc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCc1ccc(C(C)O)cc1
Temperature: 6 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of N-[(4-acetylphenyl)methyl]acetamide (6.1 g) in methanol (50 ml) was added sodium borohydride (1.2 g) under ice-cooling. This reaction mixture was stirred at 5-7° C. for 2 hr. Thereto was added 2% hydrochloric acid and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (6.3 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (5.98 g) as a pale-brown oil, m.p.=61-62° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][NH:5][C:6]([NH2:8])=[O:7])[CH3:2].[C:13](O)(=[O:18])[CH2:14][C:15](O)=[O:16]>C(O)(=O)C>[CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][N:5]1[C:13](=[O:18])[CH2:14][C:15](=[O:16])[NH:8][C:6]1=[O:7])[CH3:2]
Reactant: CCCCC(CC)CNC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Product: CCCCC(CC)CN1C(=O)CC(=O)NC1=O
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 500 g of N-(2-ethylhexyl)urea and 36 g of malonic acid in 100 ml of acetic acid was heated at 80° C. and stirred for 4 hours. After allowing to cool, the acetic acid was removed under reduced pressure and extracted by adding 100 ml of water and 500 ml of chloroform. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and then washed with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure, the residue was washed with n-hexane and collected by filtration to obtain 64 g of N-(2-ethylhexyl)barbituric acid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CC(C)=O.O1CCOCC1.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:30](=[O:32])[CH3:31])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCN(Cc2ccc(F)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 45 °C
Reaction time: 9.5 h
Yield: 61.1 %

Procedure:
To a pressure reactor charged with a red-orange solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (0.5 g, 1.255 mmol) in acetone (25 mL) and dioxane (25 mL) was added palladium, 10 wt % on activated carbon (0.053 g, 0.502 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.179 mL, 12.55 mmol) was added at 23° C. The mixture was stirred under hydrogen at 45° C. and 310 kPa for 9.5 hr. The reaction mixture was filtered through Celite™, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a 10% to 100% gradient eluant of EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (341 mg, 61.1%) as an off-white foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.14-1.19 (m, 6H), 2.08 (s, 1.2H), 2.09 (s, 1.8H), 2.52-2.65 (m, 5H), 2.70 (t, J=5.9 Hz, 1H), 2.98 (br s, 4H), 3.58 (s, 2H), 3.70 (dt, J=12.0, 5.7 Hz, 2H), 4.00-4.15 (m, 1H), 4.40 (s, 0.8H), 4.43 (s, 1.2H), 5.35 (d, J=7.8 Hz, 0.4H), 5.38 (d, J=8.3 Hz, 0.6H) 7.08 (td, J=8.3, 2.4 Hz, 1H), 7.21 (td, J=10.0, 2.4 Hz, 1H), 7.44-7.51 (m, 1H); ESI-MS m/z [M+H]+ 445.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.ClC(Cl)C.[CH3:13][O:14][C:15]([C:17]1([CH2:23][CH:24]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1([CH2:23][CH2:24][NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:16]
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(CCNc2ccc(Br)cn2)CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 5-bromopyridin-2-amine (0.488 g, 2.82 mmol) in 1-2 dichloroethane (DCE, 10 mL) was added desired 4-(2-oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.529 g, 2.82), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 eq) was then added in one portion and reaction mixture allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with DCM (10 mL), quenched with 2 M of NH4OH in water. The aqueous layer was extracted with DCM (10 mL×2). The combined organic layers were washed with aqueous NaHCO3 (30 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=4)=[CH:18][CH:17]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1csc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 75 mg, 0.2 mmol) in dioxane (4 mL) was added to a reaction tube containing 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.; 100 mg, 0.6 mmol). A solution of potassium carbonate (80 mg, 0.6 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. The solution was acidified, filtered through silica gel, evaporated, and triturated with aqueous methanol to give 2-(4-benzo[1,3]dioxol-5-yl-phenoxymethyl)-thiazole-4-carboxylic acid. Mass spectrum MH+=356.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][N:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:23]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[C:27]=2[OH:34])(=[O:25])=[O:24])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[C:27]([OH:34])=[C:26]([S:23]([N:22]([CH2:21][C:19]2[CH:18]=[C:4]([CH2:5][NH:6][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:3]=[C:2]([Cl:1])[CH:20]=2)[CH2:35][CH:36]([CH3:37])[CH3:38])(=[O:25])=[O:24])[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of tert-butyl 3-chloro-5-((3,5-dichloro-2-hydroxy-N-isobutylphenylsulfonamido)methyl)benzyl(isobutyl)carbamate (0.23 g, 0.38 mmol) in methylene chloride (5 mL) was added TFA (0.87 mL, 11.3 mmol). The reaction mixture was stirred at rt for 2 h., concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the desired product as white solid (0.18 g, 92%). 1H NMR (CD3OD): δ 7.45 (d, J=2.8 Hz, 2H), 7.40 (s, 2H), 7.37 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 4.57 (s, 2H), 4.07 (s, 2H), 3.04 (d, J=7.2 Hz, 2H), 2.80 (d, J=7.2 Hz, 2H), 2.00 (m, 1H), 1.68 (m, 1H), 1.00 (d, J=6.6 Hz, 6H), 0.76 (d, J=6.6 Hz, 6H); MS (ESI): (M+H)+=507.22, 509.21.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O)(=O)C.S(Cl)(Cl)=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.ClCCl.O.O1CCCC1.CO.C(O)(=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:5]([OH:4])[CH:6]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1C
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-hydroxy-4-methylbenzoic acid (10.73 g, 70.5 mmol, Lancaster) in acetic anhydride (25 mL, 265 mmol, Aldrich) was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into an ice-water mixture (600 mL) and stirred overnight. Solid clumps were broken up and collected by filtration. The residue was washed with water and dried in a vacuum oven to give 3-acetoxy-4-methyl-benzoic acid as a tan solid. (Yield 11.82 g). 3-Acetoxy-4-methyl-benzoic acid (1.94 g, 10 mmol) was suspended in thionyl chloride (3 mL, 40 mmol, Aldrich) and N,N-dimethyl-formamide (3 drops) and heated at reflux for 2 hours. After cooling to room temperature, the mixture was diluted with toluene (30 mL) and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (30 mL) and added dropwise to a solution of 4-chloroaniline (1.34 g, 10.5 mmol, Aldrich) and N,N-diisopropylethylamine (1.6 g, 12.5 mmol) in dichloromethane (50 mL). After stirring for another 2 hours, the mixture was diluted with water (50 mL) and stirred for another 30 minutes. The layers were separated. The organic layer was washed with water (50 mL). Aqueous layers were back washed with dichloromethane (50 mL). Organic layers were then combined and concentrated. The residue was dissolved in mixture of tetrahydrofuran (25 mL), methanol (25 mL) and 1 N aqueous sodium hydroxide (10 mL, 10 mmol). After stirring for 16 hours, the mixture was diluted with water (100 mL) and acetic acid (5 mL) and concentrated under reduced pressure to remove most of the organic solvent. Precipitate formed was collected by filtration and washed with water, and dried to give N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide as off-white crystals. (Yield 2.57 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>CS(C)=O>[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]2([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][CH2:4]2)=[CH:12][CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(c3ccc(F)cc3)CO2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.1 mol) and powdered trimethyl oxosulphonium iodide (0.1 mol) in dry dimethyl sulphoxide (100 ml). A solution of 4,4'-difluorobenzophenone (0.08 mol) in dimethyl sulphoxide (40 ml) was added dropwise at room temperature and the solution heated at 50° for 2 hours. After cooling to room temperature the solution was extracted with diethyl ether (400 ml), washed with water (3×250 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1,1-bis-(4-fluorophenyl)-ethylene oxide (95%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22]CN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CC[N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.23 min; MH+ 511
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:4][CH2:5]Br)[CH3:2].[I-:20].[Na+]>CC(C)=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:4][CH2:5][I:20])[CH3:2]
Reactant: [I-]
Reactant: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCI

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 13.8 g. of 3-ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide (Preparation C4) and 9 g. of sodium iodide in 120 ml. of acetone, to give 15 g. of product as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1)#[N:2]>C1COCC1.[Ni].CCOC(C)=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1
Reactant: CNC(=O)Nc1cc(C#N)ccn1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(CN)ccn1
Yield: 233.6 %

Procedure:
A solution of 1-(4-cyano-pyridin-2-yl)-3-methyl-urea (12.0 g, 11.4 mmol) in THF (80 mL) was treated with Raney nickel (0.5 g) placed under a hydrogen atmosphere (atmospheric pressure) for 8 hours at rt. The reaction mixture was diluted with EtOAc, filtered over Celite® and concentrated in vacuo. The residue was purified by chromatography on silica gel (Gradient elution: 100% CH2Cl2 to 85%/15% CH2Cl2/MeOH) to give 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (4.8 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:21])=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrN1[C:28](=O)[CH2:27][CH2:26]C1=O.C1(B(O)O)CC1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:21])=[C:16]([CH:26]3[CH2:27][CH2:28]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c(Cl)cc2N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)C1CC1
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CC3)c(Cl)cc2N)CC1
Temperature: 25 °C

Procedure:
A solution of 3-amino-5-chloro-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.59 g, prepared following procedures described in Example 5 with N-bromosuccinimide instead of N-chlorosuccinimide in Step C), cyclopropyl boronic acid (0.086 g), tetrakis(triphenylphosphine)palladium (0.094 g), potassium carbonate (0.14 g) in 1,2-dimethoxyethane (5 ml) and water (0.2 ml) was irradiated in a microwave at 150° C. for 20 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate (saturated), water then brine. The organic layer was dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 9:1) to afford 3-amino-5-chloro-6-cyclopropyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.30 g) as a yellow solid. MS (ES+) 491/493 (MH+); 1H NMR (400 MHz, CDCl3) 1.0-1.1 (m, 4H), 1.45 (s, 9H), 1.60 (m, 1H), 1.70 (m, 2H), 1.85 (m, 2H), 2.50 (m, 1H), 2.80 (m, 2H), 4.20 (m, 2H), 7.65 (d, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.9 (m, 1H), 8.60 (d, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28]C)=O)[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH3:36][NH2:37]>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([NH:37][CH3:36])=[O:28])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21
Reactant: CN
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)NC)Sc2ccccc21
Reaction time: 26 h

Procedure:
92 mg of 5(S)-Amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 18)) are dissolved in 3 ml of a 5N methylamine solution in dimethylformamide and the solution is left to stand at room temperature for 26 h. After purification of the concentrated crude product by means of FC (mobile phase T) over 50 g of silica gel, the title compound is obtained as a diastereomer mixture: Rf (T)=0.26/0.31; FAB-MS: (M+H)+ =507.