Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1.C([O-])(=O)C.[K+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3].[O-2].[Ba+2]>C1(C)C=C(C)C=C(C)C=1.[Cu]>[C:26]1([CH:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:14]2=[O:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Ic1ccccc1
Reactant: COc1ccccc1N1Sc2ccccc2CC1=O
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Al+3]
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccccc1N1Sc2ccccc2C(c2ccccc2)C1=O
Yield: 75.2 %

Procedure:
2.7 g of 2,3-dihydro-2-(2-methoxyphenyl)benzothiazin-3-one, together with 1.2 g of potassium acetate, 6 g of iodobenzene and copper on an aluminum oxide support as the catalyst, in 80 ml of mesitylene are heated at 160° C. for 6 hours under a water separator which is charged with 2 g of barium oxide and 5 g of silica gel. After filtration, the residue is washed with dilute ammonia, and the filtrate is concentrated and chromatographed on 100 g of silica gel using ispropyl ether. 2.6 g of crude product are obtained, and this crystallizes from isopropyl ether/a little acetone, melting point 133° C.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([CH2:29][C@@H:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:1]([N:8]([C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH2:10][OH:11])[CH2:32][C@H:30]([OH:31])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.15 g) and (2S)-2-(phenoxymethyl)oxirane (661 mg) in ethanol (9.2 ml) was heated to reflux for 3 hours. After allowed to cool to room temperature, the mixture was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give (2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-3-(4-nitrophenyl)-1-propanol (1.17 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCCN
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCO
Product: CCCNc1cc(C)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.12 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 20 mL (0.24 mole) of n-propylamine was stirred, and 25 mL of ethanol was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. After this time, the reaction mixture was heated to reflux where it stirred for 2.5 hours. An additional five mL of n-propylamine was added to the reaction mixture, then it was allowed to stir at ambient temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 250 mL of 10% methanol in methylene chloride. The cloudy solution was filtered through 300 grams of basic alumina (deactivated with 18 mL of water) using 10% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 21 grams of 2-amino-4-propylamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH:17]=4)[C:11]1([CH3:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@@H:20]([CH:21]=[O:22])[CH3:23])[CH2:18][CH:17]=4)[C:11]1([CH3:33])[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
—Pyridinium chlorochromate (8.79 g) was added to a solution of (3β,5α,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol 3-benzoate (Example 7, step ii; 12.6 g) in dry dichloromethane (130 ml). The reaction mixture was stirred at room temperature for 1.5 h. Another portion of pyridinium chlorochromate (1.50 g) was added and stirring was continued for another 1.5 h. The reaction mixture was filtered and the filtrate was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into dichloromethane and the combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure, to afford (3β,5α,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-carboxaldehyde (10.3 g). The product was used in the following step without further purification.
Reaction SMILES: C(C1[O:6][C:7]2[C:13]([S:14]([N:17]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])=[C:12]([Cl:24])[CH:11]=[CH:10][C:8]=2[N:9]=1)(C)(C)C.O.OS(O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[NH2:9][C:8]1[C:7]([OH:6])=[C:13]([S:14]([N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:12]([Cl:24])=[CH:11][CH:10]=1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)N3CCCNCC3)c2o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCCNCC2)c1O
Temperature: 100 °C
Yield: 80.2 %

Procedure:
To a solution of 2-tert-Butyl-6-chloro-7-(homopiperazine-1-sulfonyl)-benzooxazole (2.0 g, 4.24 mmol) in 1,4-dioxane (56 mL) was treated with water (3.5 mL) and conc. H2SO4 (3.5 mL). The mixture was heated to 100° C. for 16 h. The reaction was cooled to room temperature, and then basified to pH=14 with 25% aq NaOH. washed. The mixture was extracted with ethyl acetate (3 times), dried with MgSO4, filtered, and concentrated to afford the title compound (1.04 g, 80%). EI-MS m/z 306.2(M+).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:6]([CH2:25][CH:26]=[CH2:27])[CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:6]([CH2:25][CH2:26][CH3:27])[CH:5]=1
Reactant: C=CCc1cc([N+](=O)[O-])ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Solvent: CO
Product: CCCc1cc(N)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.1 %

Procedure:
To a solution of the product of Step B (0.5 g) in methanol (6 mL) was added Pd--C(10%)(0.05 g), and the reaction mixture was stirred at room temperature for 6 h under an atmosphere of hydrogen gas. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the desired methyl α-(4-amino-2-n-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetate (0.5 g) as a solid. This material without further purification was dissolved in dry THF (5 mL) and reacted with N-iso-propylisocyanate (0.1 mL) at room temperature for 12 h. Purification of the crude product by flash chromatography using EtOAc-hexanes (1:2) gave the titled compound as white solid (0.36 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.[CH2:39]([O:41][C:42](=O)[C:43]#[C:44][O:45]CC)[CH3:40].C(OC#C)C.ClC(OCC)=O>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:44](=[O:45])[CH:43]=[C:42]([O:41][CH2:39][CH3:40])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC#CC(=O)OCC
Agent: C#COCC
Agent: CCOC(=O)Cl
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCOc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine (0.98 g, 3.58 mmol) (prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 starting from R-epichlorohydrin and 4-cyclohexylphenol) in 50 ml of ethanol was added freshly prepared 3-ethoxy-propynoic acid ethyl ester (0.65 g, 4.58 mmol), prepared from 6 ml of 50% ethoxyacetylene and 3.3 ml of ethyl chloroformate (Synthesis, 1989, 123-4). The mixture was stirred for 15 min at room temperature after which it was stirred at 60-65 degrees C. for 6h. The reaction mixture was concentrated to a yellow solid, dissolved in dichloromethane and flash chromatographed on silica gel eluting with dichloromethane/ammonia/methanol to provide 0.544 g of the title compound as a white solid. [α]D25 −1.00 (c 0.5, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1>CCO.CC(O)=O.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: COC(=O)CCc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CCc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
23 (310 mg, 0.90 mmol) was dissolved in EtOH/AcOH (4 mL/4 mL). The solution was degassed with Ar for 2 min. PtO2 (61 mg, 0.27 mmol) was added to the mixture and H2 was bubbled in for 2 min. The reaction was stirred under a H2 balloon overnight. The reaction mixture was filtered through Celite and was concentrated to yield tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate. LC/MS RT (5 min method)=2.47 min. Mass observed: 248.21 (M-Boc+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[O:16][C:15](=O)[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[NH:21][C:15](=[O:16])[NH:14][C:13](=[O:19])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(F)c(F)c1
Yield: 100 %

Procedure:
A solution of 7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.05 g, 3.96 mmol) in concentrated ammonium hydroxide (0.154 mL, 3.96 mmol) was stirred at 100° C. in a high-pressure vessel (75 mL) for 6 h. The formation of white precipitate was observed during the heating. The solvent was removed in vacuum to provide 7-(3,4-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (1.046 g, 3.96 mmol, 100% yield) as a off-white solid. LC-MS (M+H)+=265.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(OCC)(O[CH2:15][CH3:16])(=O)=O>>[CH2:15]([O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:16]
Reactant: CCOS(=O)(=O)OCC
Reactant: OCCOC1CCCCC1
Product: CCOCCOC1CCCCC1

Procedure:
The 2-ethoxyethyl-cyclohexyl-ether was prepared in correspondence with the description of Example 1 from 72 g (0.5 mol) of 2-hydroxyethyl-cyclohexyl-ether and 54 g (0.35 mol) of diethyl sulfate.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:41])[CH:18]([O:23][C:24](=[O:40])[CH2:25][N:26]([C:28](=[O:39])[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:31])[CH3:27])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:21][CH:20]([CH3:22])[CH2:19][CH:18]([O:23][C:24](=[O:40])[CH2:25][N:26]([C:28](=[O:39])[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH3:31])[CH3:27])[C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:41]
Reactant: CC(C)CC(OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)C(=O)N1CCNCC1

Procedure:
To 4-[2-(2-{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylic acid benzyl ester (208 mg, 0.49 mmol) in 1.6 mL of methanol was added 70 mg of Pd/C (10% wt Pd on carbon). The reaction mixture was hydrogenated using a balloon of H2 for 4 h at room temperature. The mixture was then filtered through Celite, and the solvent removed to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid 3-methyl-1-(piperazine-1-carbonyl)-butyl ester.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[N:11][CH:10]=[CH:9][N:8]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>C(O)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:12]1[C:7]2[N:8]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:6]=2)[CH:9]=[CH:10][N:11]=1
Reactant: Cc1ccccc1COc1nccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccccc3C)nccn12
Yield: 3.8 %

Procedure:
Sodium bicarbonate (2.73 g) was added to a solution of 2-amino-3-(2-methylbenzyloxy)pyrazine (3.5 g) and 3-mesyloxy-5-hexyn-2-one (6.18 g) in ethanol (35 ml) and the mixture was refluxed for 12 hours. The mixture was poured into an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g) with a mixture of chloroform and methanol (50:1) as an eluent to give 8-(2-methylbenzyloxy)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyrazine (0.182 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH:11](O)[C:12]3[C:18]([Br:19])=[C:17]([Br:20])[S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[SiH](C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]3[C:18]([Br:19])=[C:17]([Br:20])[S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1c2c(sc(Br)c2Br)C2CN(Cc3ccccc3)CC12
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: Brc1sc2c(c1Br)CC1CN(Cc3ccccc3)CC21
Temperature: 60 °C

Procedure:
The product from step f) (300 mg, 0.69 mmol) in dichloroethane (2.6 ml) was treated with InCl3 (153 mg, 0.69 mmol) and chlorodiphenylsilane (457 mg, 2.08 mmol). The contents were heated to 60° C. for 16 hours. The reaction mixture was cooled to 22° C., poured into sat. NaHCO3 and diluted with EtOAc (75 ml); producing a white emulsion. The emulsion was passed through celite and the organic layer was separated, washed with brine (25 ml) and dried (MgSO4). The crude product was dissolved in 7:3 hexanes:EtOAc and passed through a plug of silica gel to give the subtitle compound. MS calculated for C16H15Br2NS+H 414, observed 412, 414, 416.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC(Cl)C>[C:1]([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Yield: 87.2 %

Procedure:
In a 100 ml-volume stainless steel autoclave whose atmosphere had been displaced with nitrogen was added a solution of 2.5 g (10 mmole) of methyl 2-(N-benzoylamino)methyl-3-oxobutanoate and 184 mg (0.1 mmole) of [Ru((+)BINAP)](CLO4)2 in 18 ml of dichloroethane, and a reaction was conducted at 70° C. under a hydrogen pressure of 100 kg/cm2 for 30 hours. The reaction mixture was concentrated under reduced pressure of 20 mmHg, and the residue was purified by silica gel column chromatography using a 7/3 (by volume) mixture of hexane and isopropanol as an eluent to give 2.19 g (yield: 86.5%) of methyl (2S, 3R)-2-(N-benzoylamino)methyl-3-hydroxybutanoate having an optical purity of 90 %ee.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(OCOC)cc(C(=O)OC)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(C(=O)OC)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
After adding 30.0 ml of trifluoroacetic acid to a solution of 11.8 g (30.9 mmol) of the obtained ester compound in methylene chloride (50.0 ml), the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester =2:1) to obtain 8.86 g of 3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-hydroxybenzoic acid methyl ester (yield: 85%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[I:10][C:7]1[CH:8]=[CH:9][C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 65.9 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (1.2 g, 4.8 mmol) (Aldrich) was reacted with 4-methoxyphenol (0.71 g, 5.76 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-iodo-2-(4-methoxy-phenoxy)-benzaldehyde as a yellow oil (Yield 1.12 g, 66%).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:9]2[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.[H-].[Na+].[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28]Cl)(=[O:22])[CH3:21]>CS(C)=O>[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:7]1[C:8](=[O:15])[C:9]2[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:2]([Br:1])=[N:3][C:4]=2[N:5]([CH3:17])[C:6]1=[O:16])(=[O:22])[CH3:21]
Reactant: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a stirring suspension of 8-bromo-7-ethoxymethyl-3-methylxanthine (1.52 g, 5.0 mmol) in anhydrous dimethylsulfoxide (20 ml) was added sodium hydride (144 mg, 6.0 mmol). The mixture was stirred at room temperature for 30 min and then (R)-5-acetoxy-1-chlorohexane (983 mg, 5.5 mmol) was added and the mixture was stirred at 70-75° C. After 12 hours, the mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (2×25 ml), with saturated aqueous sodium chloride solution (25 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the product was purified by flash chromatography over silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g, 82% yield) as a beige solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:6])[NH2:5])#[N:2].[NH2:7][S:8]([OH:11])(=[O:10])=[O:9]>O>[S:8](=[O:10])(=[O:9])([OH:11])[NH2:7].[C:4]([NH:3][C:1]([NH2:2])=[O:9])(=[NH:6])[NH2:5]
Reactant: N#CN=C(N)N
Agent: NS(=O)(=O)O
Solvent: O
Product: N=C(N)NC(N)=O
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 181.9 %

Procedure:
Dicyandiamide (84 g) was suspended in 80 ml of water and reacted successively with 97 g sulfaminic acid at 80° C. in such manner that the temperature of 95° C. was not exceeded. The reaction mixture was agitated for another 15 minutes at 95° C. Then the solution was rapidly cooled to 0° C.-5° C., and the resultant colorless crystals were drawn off and washed with 100 ml ethanol. After drying, 181 g (91%) guanylurea sulfamate was obtained.
Reaction SMILES: [Na:1].COC1OCC(CO[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH2:31]([C:33]1([CH2:41][CH3:42])[O:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][O:34]1)[CH3:32]>>[Na:1].[CH2:41]([C:33]1([CH2:31][CH3:32])[O:34][CH2:35][CH:36]([CH2:39][O:40][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:37][O:38]1)[CH3:42]
Reactant: CCC1(CC)OCC(CO)CO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: CCC1(CC)OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Yield: 9.7 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using (2,2-diethyl-1,3-dioxan-5-yl)methanol obtained in the step (23a) to obtain the title compound (164 mg, total yield: 9.7%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([NH:17][C:18]([NH:20][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[C:2]([F:9])([F:8])[F:1])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(=O)NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)NCC(C(=O)O)C(F)(F)F
Temperature: 90 °C
Reaction time: 28 h
Yield: 75.8 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmole) and benzylurea (841 mg; 5.6 mmoles) in DMF (3 ml) was heated at 90° C. with stirring for 28 hours. DMF was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetatechloroform to give 1.10 g (yield: 76%) of 1-benzyl-3-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea. m.p.: 183°-183.5° C.