Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[C:15]1(C)C=CC=CC=1>O1CCOCC1.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[C:7]([CH3:15])[N:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)nc(OC)c1
Agent: [CH3-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)nc(OC)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
Under argon, dimethyl zink (14.26 g, 149 mmol, 124 mL of a 1.2 M solution in toluene) is added dropwise to a solution of 2-chloro-6-methoxy-isonicotinic acid ethyl ester (5.37 g, 24.9 mmol) and Pd(dppf) (203 mg, 0.249 mmol) in dioxane (120 mL). The mixture is heated to 75° C. and stirred for 18 h before it is cooled again to rt. The reaction is quenched by carefully adding water. The mixture is diluted further with water, filtered over celite and the filtrate is extracted with EA (2×250 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-methoxy-6-methyl-isonicotinic acid ethyl ester (4.10 g) as a colourless oil; LC-MS: tR=0.92 min, [M+1]+=195.93. 1H NMR (CDCl3): δ 1.41 (t, J=7.3 Hz, 3H), 2.52 (s, 3H), 3.97 (s, 3H), 4.39 (q, J=7.3 Hz, 2H), 7.12 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:12][CH2:11][C@@H:10]3[CH2:13][C@:7]1([O:8][C:9]3([CH3:15])[CH3:14])[CH:6]=[CH:5][CH2:4][CH2:3]2>C(Cl)(Cl)Cl>[CH3:1][C@:2]12[CH2:12][CH2:11][C@@H:10]3[CH2:13][C@:7]1([O:8][C:9]3([CH3:15])[CH3:14])[C:6]([CH2:5][CH2:6][CH2:7][OH:8])=[CH:5][CH2:4][CH2:3]2
Reactant: CC1(C)O[C@@]23C=CCC[C@@]2(C)CC[C@@H]1C3
Solvent: ClC(Cl)Cl
Product: CC1(C)O[C@]23C[C@H]1CC[C@]2(C)CCC=C3CCCO

Procedure:
Oil, [α]D10+24.6°, (c=0.62, chloroform) MS: 264 (M+, 85), 249 (7), 246 (15), 231 (8), 41 (100). 1H NMR (CDCl3, δ): 0.89 (s, 3 H, 6-CH3), 1.23 (s, 3 H, 10-CH3), 1.34 (s, 3 H, 10-CH3), 3.64 (t, J=7.0 Hz, 2 H, 3′-H/2R), 5.70 (t, J=3.6 Hz, 1 H, 3-H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:26])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
6.2 g (22.6 mmol) of methyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 4.4 g (29.4 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to the General Method 3A. Yield: 7.9 g (97% of theory)
Reaction SMILES: CS(O)(=O)=O.CS(O[CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=O)=O.[I-:31].[Na+]>CC(C)=O>[I:31][CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]
Reactant: Cc1ccc(SC(C)(C)C(Cc2cccc[n+]2[O-])OS(C)(=O)=O)cc1
Reactant: [I-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(SC(C)(C)C(I)Cc2cccc[n+]2[O-])cc1
Yield: 62.1 %

Procedure:
A solution of 3.35 g of 2-[2-methanesulphonyloxy-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide methanesulphonic acid salt and 2.25 g of sodium iodide in 50 ml of acetone was heated under reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane and the organic phase was evaporated. The residue was taken up in 50 ml of acetone and heated under reflux for 2 hours with 2.25 g of sodium iodide. The cooled reaction mixture was then evaporated and the residue was partitioned between water and dichloromethane. The organic phase was evaporated and the residue was crystallized from dichloromethane/ethyl acetate to give 1.8 g of 2-[2-iodo-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide in the form of a pale yellow solid of melting point 191-193° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([I:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cc(I)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(I)ccc2oc1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
DIEA (30.3 μL, 0.17 mmol) was added to 6-iodo-3-carboxy-coumarin (50.0 mg, 0.16 mmol) and HATU (66.2 g, 0.17 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (33.1 mg, 0.16 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 27.4 mg of product in 34% yield: LCMS (ESI) m/z 508 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH2:14][CH2:13]2)O.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH2:14][CH2:13]2)[Cl:21]
Reactant: OC(c1ccc2c(c1)CCC2)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ccccc1C(Cl)c1ccc2c(c1)CCC2
Yield: 98.5 %

Procedure:
79.3 g (0.26 mol) of 2-chlorophenyl-indan-5-yl-carbinol, dissolved in 150 ml of benzene, are added dropwise to a mixture of 21.5 ml (0.26 mol) of thionyl chloride and 150 ml of benzene at 70° C. After heating the reaction mixture under reflux for five hours, it is evaporated. 71 g (98% of theory) of 2-chlorophenyl-indan-5-yl-chloromethane of refractive index nD20 =1.6050 are obtained. ##STR11##
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1>B(Br)(Br)Br.[Cl-].[Na+].O>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(-c2nc3ccc(Br)cc3s2)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2nc3ccc(Br)cc3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
6-Bromo-2-(4-methoxy-phenyl)-benzothiazole (120 mg, 0.375 mmol) was suspended in boron tribromide (1M in methylene chloride, 7.0 mL) and stirred at room temp under nitrogen for 18.0 h. Reaction was poured into saturated brine and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated brine and concentrated in vacuo. Residue was washed with hexane, and dried under vacuum yielding the title compound (115 mg, 100%) as a tan solid. Mass spec: MH+=306
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:20]4[O:19][C:18]([F:22])([F:21])[O:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[N:7]([CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])[C:6]=2[C:5]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:20]4[O:19][C:18]([F:22])([F:21])[O:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:6]=2[C:5]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cccc3c2OC(F)(F)O3)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cccc4c3OC(F)(F)O4)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(2,2-difluoro-1,3-benzodioxol-4-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (900 mg, 1.77 mmol) in tetrahydrofuran (8.0 mL) was added lithium tetrahydroborate (193 mg, 8.86 mmol) at 0° C. The mixture was stirred at room temperature for 19 hr, and the reaction was quenched by methanol. The mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (630 mg, 1.35 mmol, 76%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N12CCCN=C1CCCC[CH2:14]2.IC>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
To a solution of 1H-indole-5-carboxylic acid (1 g, 6.2 mmol, 1.0 equiv) in acetonitrile (40 mL) were added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.1 mL, 7.4 mmol, 1.2 equiv) and iodomethane (2.3 mL, 37.2 mmol, 6 equiv). The solution was stirred under reflux overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt, washed with a 0.5 N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The obtained oil was used in the next step without further purification.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22])(C)C)(C)(C)C.Cl>C1COCC1>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][OH:8]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-[2-(2-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (9 g, 27.5 mmol) in THF (10 mL) was added an aqueous HCl solution (2 N, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-(2-methoxy-4-nitrophenoxy)ethanol as a off white solid (5.5 g, 94%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1Br)(=[O:15])=[O:14].[Cu](C#N)[C:31]#[N:32].N>N1C=CC=CC=1>[CH3:1][N:2]([CH3:29])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1[C:31]#[N:32])(=[O:15])=[O:14]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Agent: N
Solvent: c1ccncc1
Product: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1C#N

Procedure:
A mixture of 4.6 g of 5-dimethylamino-N-(5-bromo-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide and 1.3 g of copper cyanide is heated for 8 hours at 120° in 30 ml of pyridine. The mixture is poured onto aqueous ammonia solution, worked up in the customary manner and 5-dimethylamino- N-(5-cyano-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:16])[C:22](=[O:23])[C:21]2[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNc1cnccc1-c1ccnc(Cl)c1F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccnc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 55, from (2′-chloro-3′-fluoro-[4,4]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (12%). MS (ESI): m/z=478.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc(-c3ccccc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene (0.9 g) obtained by the above-mentioned reaction, methyl 4-aminobenzoate (0.9 g), sodium carbonate (0.6 g) and sodium iodide (1.8 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-{[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methyl]amino}benzoate as an amorphous compound. The obtained methyl 4-{[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methyl]amino}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (2 mL) was added, and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.2 g, 20%) as an amorphous compound.
Reaction SMILES: CO.[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:11]1[C:23](=[O:47])[CH2:24][NH:25][C:26](=[O:46])[NH:27][C:28]1[CH:29]=[C:30]([CH:34]([CH3:45])[C:35]([O:37]CC2C=CC=CC=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O-])=O.[NH4+]>[Pd].[OH-].[Na+]>[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:11]1[C:23](=[O:47])[CH2:24][NH:25][C:26](=[O:46])[NH:27][C:28]1[CH:29]=[C:30]([CH:34]([CH3:45])[C:35]([OH:37])=[O:36])[CH:31]=[CH:32][CH:33]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3cccc(F)c3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3cccc(F)c3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
In an inert atmosphere 20 cm3 of methanol are slowly added to a flask containing 1.38 g of benzyl 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenyl}propionate (B form), 0.85 g of ammonium formate and 1.38 g of 10% palladium on charcoal. The reaction mixture is heated under reflux for 1 hour, then cooled to a temperature in the vicinity of 25° C. The catalyst is then removed by filtration and the filtrate is concentrated to dryness under reduced pressure at 40° C. The residue obtained is dissolved in 20 cm3 of a 0.1N aqueous sodium hydroxide solution and washed with two times 10 cm3 of diethyl ether. The aqueous phase is brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution. The precipitated product is separated by filtration, washed with 2 times 10 cm3 of water and dried in air. 1.0 g of 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenyl}propionic acid (B form), melting at 130° C., is thus obtained. [α]D20 =+82°±2° (C=0.707%; DMF)
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].C(=O)([O-])[O-].[Ca+2:10]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:10].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:10].[Ca+2:10]
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
10% phosphoric acid was added dropwise to a 20% aqueous slurry of calcium carbonate (Super #2000, manufactured by Maruo Calcium Company Limited) at a Ca/P mole ratio=3.33 under stirring aid, thereafter, this was stirred at 50° C. for 3 hours to obtain a white slurry. The white slurry was dehydrated using a filter press to obtain calcium phosphate I. It was confirmed by X-ray diffraction that the resulting white cake is a mixture of hydroxyapatite and calcite type calcium carbonate.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[BH4-].[Na+]>CO>[F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate [van Niel, M. B.; et al.; J. Med: Chem. 1999, 42, 2087-2104] (52.27 g, 241 mmol) was dissolved in anhydrous MeOH (600 mL), cooled to 0° C. and treated in portions with sodium borohydride (37.8 g, 361 mmol) over a 15 minute period. After stirring at 0° C. for 30 minutes, the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated ammonium chloride solution (400 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to provide the desired product as a thick oil that slowly solidified upon standing (52.7 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:20]([OH:38])=[C:21]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[O:28])[CH:22]=[CH:23][C:24]=2[Cl:25])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])=[O:28])=[C:20]([OH:38])[C:19]=1[S:16]([NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(Cl)c3Cl)c2O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCC2CCNCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 44 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-[3-[N″-[(1-tert-butoxycarbonylpiperidin4-yl)methyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea (20 mg, 0.033 mmol) was stirred in trifluoroacetic acid to form the desired product (9 mg, 44%). LC-MS (m/z) 509.0 (M+).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:3][NH:4][C:5]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17](C)[C:18](OCC(Cl)(Cl)Cl)=O)=[CH:14][CH:15]=1.P([O-])(O)(O)=O.[K+].[OH-].[Na+]>O1CCCC1.[Zn]>[OH:1][CH:2]([C:32]1[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=1)[CH2:3][NH:4][C:5]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1
Reactant: CN(Cc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1)C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
In 370 ml of tetrahydrofuran was dissolved 26.9 g of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-[N-methyl-N-(2,2,2trichloroethoxycarbonyl)aminomethyl]-2-furyl]methylthio] -ethyl]guanidine. Thereto were added 320 ml of a 0.5 M aqueous potassium dihydrogen phosphate solution and 42 g of an active zinc powder, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH 9.8 with a 5N aqueous sodium hydroxide solution and extracted with 370 ml of ethyl acetate. The solvent of the extract was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant:chloroform:methanol:aqueous ammonia solution=85:15:1) and then recrystallized from 95% aqueous ethanol solution to obtain 12.6 g (yield: 65%) of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2-furyl]methylthio]ethyl]guanidine having a melting point of 146.5° to 147° C..
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][N:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[CH2:3][CH2:2]1.O.O.Cl[Sn]Cl.O.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.CO>[NH2:29][C:25]1[CH:24]=[C:23]([NH:22][C:13]2[C:12]3[C:17](=[CH:18][N:19]=[C:10]([NH:9][CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A mixture of 6-(2-morpholinoethylamino)-4-(3-nitrophenylamino)-1,7-naphthyridine-3-carbonitrile (120 mg, 0.29 mmol, 1 eq) and SnCl2.2H2O (348 mg, 1.54 mmol, 5.3 eq) in ethyl alcohol (12 mL) was heated to reflux for 2.5 hr. After cooling to room temperature, water (10 mL) was added followed by sodium bicarbonate (500 mg). The mixture was stirred at room temperature for 1 hr. Ethyl acetate extraction followed by column chromatography (3-5% methyl alcohol in dichloromethane) yield 43 mg product (39% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.40-2.48 (m, 4 H) 2.53-2.60 (m, 2 H) 3.34-3.40 (m, 2 H) 3.54-3.63 (m, 4 H) 5.18-5.27 (m, 2 H) 6.39-6.47 (m, 3 H) 6.57 (s, 1 H) 7.01-7.08 (m, 2 H) 8.22 (s, 1 H) 8.81 (s, 1 H) 9.43 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N+:3]=1[O-:13].[OH-:14].[Na+].Cl>>[OH:13][N:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:7][C:2]1=[O:14]
Reactant: COCCOc1cc[n+]([O-])c(Cl)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COCCOc1ccn(O)c(=O)c1
Yield: 29 %

Procedure:
2-Chloro-4-(2'-methoxyethoxy)-pyridine-1-oxide is treated with 10% w/v aqueous NaOH and the mixture is heated on a steam bath for 3 hours. The resulting solution is acidified to pH 2 with concentrated HCl, the reduced in volume by evaporating in vacuo and left to crystallise. The resultant white solid is recrystallised from ethanol to give 1-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one (0.58 g, 29%), m.p. 134° C., δ(CDCl3) 3.42 (s, 3H), 3.7 (t, 1H), 4.08 (t, 1H), 6.05 (d, 1H), 6.05 (q, 1H), 7.62 (t, 1H).