Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=O)[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.B.C1COCC1.C(O)C.[ClH:26]>C1COCC1>[ClH:26].[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(cc1OC)CCNCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
22.13 g (100 mmol) of the product obtained in Step 1, suspended in 250 mL of THF, are cooled to 0° C. There are then added, dropwise, over 15 minutes, 250 mL of borane/THF (1M in the THF) and heating is carried out at 80° C. for 24 hours. Cooling is carried out and there are then added, dropwise, 250 mL of ethanol, and then 2.6N ethanolic HCl. Heating at reflux is carried out for 40 minutes; some light insoluble material is filtered off and evaporation to dryness is carried out. The residue thereby obtained is recrystallised from a mixture of 150 mL of isopropanol and 20 mL of water to yield the desired product.
Reaction SMILES: C(O[C:4](=[O:8])[CH2:5][C:6]#[N:7])C.[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])[CH3:10]>C(O)C>[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH:13][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:10]
Reactant: CCOC(=O)CC#N
Reactant: CCCCC(CC)CN
Solvent: CCO
Product: CCCCC(CC)CNC(=O)CC#N
Temperature: 154 °C

Procedure:
To ethylcyanoacetate (141 g., 1.25 mole) is slowly added 2-ethylhexylamine (129 g., 1.0 mole) over a period of 0.5 hours. The solution is then gradually heated to 154° C. and the ethanol formed is collected over a period of 1.75 hours. The solution is then stripped of all volatiles boiling at or below 88° C./3.0 mm to give N-(2-ethylhexyl)cyanoacetamide, 201.5 g.
Reaction SMILES: [OH-].[Li+].O.[CH2:4]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:12]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:13]([O:15]CC)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>C1COCC1>[CH2:4]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:12]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:13]([OH:15])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CCc1ccc(Cl)c(Cl)c1)N(Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C(CCc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Lithium hydroxide (80 mg 1.8 mmol) and water (2 ml) were added to a solution of the product of step (c) (280 mg, 0.6 mmol) in THF (5 ml) and the mixture was stirred at room temperature for 16 hours. Acetic acid (0.5 ml) was added and the mixture was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (234 mg) m/e (CI+) 438 (MH+).
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](N(OC)C)=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](=[O:15])[CH3:1])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Add a solution of CH3MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to a suspension of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (0.85 g, 3.33 mmol) in dry THF (10 mL) at 0° C. Then stir the mixture for overnight at ambient temperature. Quench the reaction with saturated NH4Cl aqueous solution (15 mL) and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc=6:1) to afford 1-(4-chlorobenzo[b]thiophen-2-yl)ethanone as white solid (0.6 g, 86.9%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:13]O>>[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)([O:5][CH3:13])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1

Procedure:
To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to −5° C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction mixture was allowed to attain room temperature (25° C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50%, 20 ml) at 0° C. and the separated oily layer extracted into ether (15 ml×3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85%, MS (m/z) M+129 (1%), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25° C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1%), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35° C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0° C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5%, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml×2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95% purity, MS (m/z) M+ 111 (5%), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)].
Reaction SMILES: [OH:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21].[CH2:27](N1C(=O)CC(=O)N(CC2C=CC=CC=2)C1=O)CCC.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>C(Cl)(Cl)Cl>[CH2:8]([N:7]1[C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:11])[CH2:9][CH2:10][CH3:27]
Reactant: CCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Reactant: CCCCN1C(=O)CC(=O)N(Cc2ccccc2)C1=O
Agent: CCOC(=O)CN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 3 h
Yield: 63 %

Procedure:
N-{[6-Hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A solution of 1-butyl-3-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (676 mg, 2.46 mmoles) and diisopropylethylamine (826 uL, 4.93 mmoles) in chloroform (12 mL) was treated with ethyl isocyanatoacetate (211 uL, 2.46 mmoles) and stirred for 3 hours under argon. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was dissolved in ethanol (10 mL), treated with 1 molar sodium hydroxide solution (7 mL) and stirred overnight. The mixture was acidified and extracted into ethyl acetate and the organic solution dried and evaporated. Crystallization from ethanol-water gave the title compound (580 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (s, 1 H), 10.11 (s, 1 H), 7.24-7.35 (m, 5 H), 5.01 (s, 2 H), 4.13 (d, J=5.81 Hz, 2 H), 3.79-3.87 (m, 2 H), 1.54 (dq, J=7.58, 7.41 Hz, 2 H), 1.29 (dq, J=14.97, 7.39 Hz, 2 H), 0.89 (t, J=7.45 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccccc2)sc1CCCOC
Yield: 87.7 %

Procedure:
Ethyl 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylate (26.1 g, 86.6 mmol) was dissolved in EtOAc (350 mL) and hydrogenated under balloon pressure for four days until LCMS indicated complete reduction of unsaturation. On day three, the catalyst was removed by filtration, fresh catalyst added and the mixtures re-subjected to hydrogenation at balloon pressure. The catalyst was removed by filtration through a pad of celite. The filter pad was rinsed with EtOAc and the filtrate concentrated to dryness. The crude product was purified by MPLC eluting with pentane/EtOAc to give ethyl 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (23.2 g, 88% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:1]([O:4][C@@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(CO)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a suspension of (5)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (prepared as described for synthesis of (R )-1-(5-hydroxyhexyl)-8-aminomethyl-3,7-dimethylxanthine libraries) (10.5 g, 31 mmol) and potassium carbonate (8.6 g, 62 mmol) in dimethylformamide (100 ml) was added benzyl bromide (8.67 g, 39 mmol). After stirring at room temperature overnight, the mixture was poured into ice water (250 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (4x 50 ml) and dried under vacuum to provide (S)-1-(5-acetoxyhexyl)-7-benzyl-8-hydroxymethyl-3-methylxanthine (9.8 g, 74% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-:20].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:20][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH2:4][CH2:3][C:2]3=[O:1])=[O:13])=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: [Cl-]
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C1CCc2c1cccc2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 200 ml. of chlorobenzene are added 17.6 g. of 1-oxoindan-4-carboxylic acid and 23 g. of phosphorous pentachloride. The mixture is stirred at room temperature for 3 hours, after which time 40 g. of aluminum chloride is added. The mixture is stirred at about 65° C. for 3 hours. After cooling, the mixture is poured into ice and hydrochloric acid, followed by extraction with chloroform. The extract is washed with water, a saturated aqueous solution of sodium bicarbonate and water in the order mentioned. After drying, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (200 g. silica gel; eluted with chloroform). Finally, recrystallization from a 20:5 mixture of benzene and hexane gives 4-(p-chlorobenzoyl)indan-1-one as crystals melting at 144.5°-146° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[Cl:24].Cl>N1C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.52 g of 3,4-dichlorobenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol yielded 0.39 g of 3,4-dichloro-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18](OC)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1C2C(=CC=CC=2)CCC1=O>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Agent: O=C1CCc2ccccc2C1
Product: CC1(C)c2ccccc2C(=O)c2c1[nH]c1cc(Br)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1 and Compound A4, the title compound was prepared from 3,4-dihydro-1H-naphthalen-2-one (560 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O>C1(C)C=CC=CC=1>[CH3:27][Si:26]([N:1]([Si:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(N([Si](C)(C)C)[Si](C)(C)C)c1
Yield: 92.4 %

Procedure:
About 8.37 g of ethyl 3-aminobenzoate, 11.80 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.91 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 30 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]benzoate (3-BTMSAEBz) as a yellow oil (14.50 g, 92% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.95 (multiplet, 1 H, aromatic proton), 7.91 (multiplet, 1 H, aromatic proton), 6.98 (multiplet, 1 H, aromatic proton), 6.91 (multiplet, 1 H, aromatic proton), 4.07 (quartet, 2 H, CH2 protons), 0.95 (triplet, 3 H, CH3 protons), 0.04 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1ccc2nc(-c3ccc(F)cc3)oc2c1
Yield: 81 %

Procedure:
4-Aminoresorcinol HCl salt (1.61 g) is dissolved in 10 ml of NMP under nitrogen atmosphere. 4-Fluorobenzoyl chloride (1.91 g) is added all at once and the mixture is heated under reflux for approximately 2 hours. After reflux, the mixture is allowed to cool and is diluted with 60 ml of water. Potassium carbonate (3.5 g) is added and the mixture is stirred. The resulting precipitate is filtered and recrystallized from ethanol and water to yield 1.85 g of the above-named product. The product melts at 225° C.-227° C.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.O.[NH2:28][NH:29][C:30]([NH2:32])=[S:31]>CO>[C:9]1([NH:8][C:7](=[O:19])[O:6][CH2:5][CH2:4][CH2:3][C:2](=[N:28][NH:29][C:30]([NH2:32])=[S:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc2ccccc12)OCCCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCCOC(=O)Nc1cccc2ccccc12)c1ccccc1
Reaction time: 21 h
Yield: 93 %

Procedure:
A suspension of naphthalen-1-carbamic acid 4-oxo-4-phenyl-butyl ester (4.72 g, 14 mmol), prepared in the previous step, in 100 ml of methanol plus 3.8 ml of 1 N HCl and 3.8 ml of water was warmed to dissolve the solid. While still warm thiosemicarbazide (1.29 g, 14 mmol) was added and the reaction stirred for 21 hours. The solid present was collected by filtration and dried under high vacuum to give the title compound (5.29 g, 92%) as a tan solid, mp 189-192° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O>O[Mo](O)(=O)=O>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=[Mo](=O)(O)O
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A D-glucose solution is added molybdic acid compound thereto and heated at a temperature of 110°-160° C with pH 2.0-4.5 to perform epimerizing reaction of D-glucose, and thereby 30-36%, based on the D-glucose, of D-mannose is formed. To the epimerized mixture thus obtained is further added glucose-isomerase to perform enzymatic isomerizing reaction of D-glucose remaining in the epimerized mixture, thereby 46% based on the remaining D-glucose is converted into D-fructose. The epimerized mixture or enzymatically isomerized mixture is subjected to catalytic hydrogenation under high pressure, and thereby is produced D-mannitol at high yield based on the initial D-glucose.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:4][C:3]=2[O:2]1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) (7.37 g, 25 mmol) in dry DMF (25 mL) was added triethylamine (3.52 mL, 25 mmol) and benzyl bromide (3.00 mL, 25 mmol). The mixture was stirred at ambient temperature overnight and added dropwise to a solution of sodium hydroxide (25 mmol) in water (200 mL). A precipitate was formed, collected by vacuum filtration, washed with water (2×50 mL), and dried in vacuo overnight to yield the product as a freely flowing pale yellow powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Fc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2cccc(F)c2)CC1
Reaction time: 16 h
Yield: 44.8 %

Procedure:
1.28 g (0.0127 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.0159 mol) of 3-fluoro-benzyl bromide and 5.0 ml (0.0349 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.19 g (36%) of 1-(3-fluoro-benzyl)-piperidin-4-ol was obtained as yellow crystals; m.p. 61°-62°.
Reaction SMILES: [C-:1]#[N:2].[Na+].C([O:6][C:7](=[O:13])[CH2:8][C@H:9]([OH:12])[CH2:10]Cl)C.[C-]#N>C(O)(=O)C>[C:1]([CH2:10][C@@H:9]([OH:12])[CH2:8][C:7]([OH:6])=[O:13])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 0.02 h

Procedure:
A first feed tank was charged with a 15% (w/w) aqueous solution of sodium cyanide. A second feed tank was charged with an 80% w/w aqueous solution of acetic acid. A third feed tank was charged with (S)-ethyl-4-chloro-3-hydroxybutyrate. The sodium cyanide and acetic acid solutions were mixed at a molar ratio of 21:1 using a plug flow reactor element with a 1.4-second residence time at ambient temperature. The mixture was continuously fed into a two-stage plug flow reactor element into which (S)-ethyl-4-chloro-3-hydroxybutyrate was continuously fed such that the molar ratio of cyanide to substate was 2:1. The two stage reactor element consisted of an initial pre-mixer with a 4.5 second residence time and a secondary mixer with a 72 second residence time, both mixing elements being contained within a heat transfer medium such that the reaction temperature was maintained at between 105° C. and 110° C. The mixture was then continuously quenched using additional 80% acetic acid in a plug flow reactor element with a residence time of 4.0 seconds at ambient temperature. The quench acid flow rate was adjusted to maintain the crude product flow stream at a pH of between 5.0 and 5.5. The crude product was obtained as an aqueous solution, which was subjected to steam distillation to remove contaminants. The aqueous residue was then extracted with dichloromethane and the product (R)-4-cyano-3-hydroxybutyric acid was isolated in 80% chemical yield after solvent evaporation and simple vacuum distillation.