Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH-:7].[Na+]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: [OH-]
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
(Comparison) 1600 kg of water glass with an SiO2/Na2O ratio of 2.06 and an active substance content of 45.5% were admixed with 36.8 kg of sodium hydroxide solution (48% strength) and spray-dried in a spray tower from Kestner to give an amorphous sodium silicate having an active substance content of 83%. 15 kg of the amorphous sodium silicate are heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). A second batch is treated identically. The chilled materials (about 24 kg) are pulverized using a jaw crusher and a disk mill.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]=1[OH:15])[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[C:8]2[CH3:24])(=[O:4])[CH3:3].[C:25](OCC)(=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>C(O)C>[CH3:24][C:8]1[C:7]2[C:12](=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]3[O:15][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2](=[O:4])[C:5]=3[CH:6]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)OCC)nc12
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCc1c2nc(C(=O)OCC)cc(C)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Sodium (2.925 g) was dissolved in dry ethanol (380 ml) and the product of step (b) (8 g) was added together with diethyl oxalate (8.7 ml). After 2 hours at reflux, the mixture was cooled and acidified with gaseous HCl, until the suspension was yellow and the pH about 2. The mixture was then refluxed 30 minutes, cooled and evaporated. The residue obtained was washed with dilute sodium bicarbonate solution, dried to give the sub-title compound, 7.8 g from ethanol, mp 183°-4°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([OH:11])[N:10]=2)[N:7]=1.[H-].[Na+].[CH3:14]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([O:11][CH3:14])[N:10]=2)[N:7]=1
Reactant: CI
Reactant: Oc1cn2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.69 g of 6-chloro-2-hydroxyimidazo[1,2-b]pyridazine was suspended in 30 ml of N,N-dimethylformamide; 838 mg of a 60% sodium hydride dispersion in mineral oil was added little by little, followed by stirring at room temperature for 30 minutes. Under ice water cooling conditions, 1.2 ml of methyl iodide was added, followed by stirring at room temperature for 3 days. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and concentrated to yield 1.05 g of the title compound.
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2nc[nH]c12
Product: Clc1ncnc2nc[nH]c12

Procedure:
reacting hypoxanthine and phosphorus oxychloride in the presence of an organic base to form 6-chloropurine;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14])#[N:2].[OH-:35].[Na+].OO>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14])(=[O:35])[NH2:2]
Reactant: [OH-]
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(C#N)cccc32)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(C(N)=O)cccc32)cc1

Procedure:
8-Cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.9 g) was dissolved in acetone (12.8 mL), and 1 mol/L-aqueous sodium hydroxide solution (6.4 mL) and 30% aqueous hydrogen peroxide (3.8 mL) were added. The mixture was heated under reflux for 2 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 8-carbamoyl-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (21 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](SC)=[N:19][C:18]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(O)C>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[N:25][NH:26][C:27](=[S:28])[NH2:29])[NH:19][C:18]2=[O:24])[CH:6]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Reactant: NNC(N)=S
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=NNC(N)=S)NC2=O)cc(C(C)(C)C)c1O
Reaction time: 7 h
Yield: 84.1 %

Procedure:
A mixture of 5-[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-thiazolone (6.13 g, 0.0169 mole) and thiosemicarbazide (1.53 g, 0.0169 mole) in ethanol (300 mL) is refluxed with stirring for 7 hours. After standing overnight at room temperature, the product is separated by filtration, washed with ethanol to give 5.78 g of a solid. It is recrystallized from DMF-methanol to give 3.4 g (47%) of pure 2-[5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-oxo-2-thiazolidinylidene]hydrazinecarbothiamide, (Z)-, mp 200°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 1-(2-chloro-4-pyridyl)ethanone (1.0 g, 6.42 mmol) in MeOH was added NaBH4 (0.73 g, 19.21 mmol) and the solution stirred at RT for 30 min. The reaction was then quenched with saturated NH4Cl solution followed by extraction with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to obtain i (0.61 g, 60%). MS 158.10 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]2[C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][CH:13]=[C:9]2[CH:8]=[C:7]([Cl:17])[N:6]=1>>[Cl:17][C:7]1[N:6]=[C:5]([O:2][CH3:1])[N:10]2[C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][CH:13]=[C:9]2[CH:8]=1
Reactant: CC(C)c1ncc2cc(Cl)nc(Cl)n12
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(Cl)cc2cnc(C(C)C)n12

Procedure:
Using the method of Example 48, sodium methoxide was reacted with 5,7-dichloro-3-isopropylimidazo[1,5-c]pyrimidine (from Example 37) to provide 7-chloro-3-isopropyl-5-methoxyimidazo[1,5-c]pyrimidine. This free base was a white solid which was converted into its white solid dihydrogen sulfate salt, m.p. 155° C. (dec.). Analysis: Calculated for C10H12ClN3O.H2SO4 : %C, 37.1; %H, 4.4; %N, 13.0; Found; %C, 36.7; %H, 4.2; %N, 12.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)(C)O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (85 mg, 0.220 mmol) in 2 mL of THF at 0° C. was treated with methylmagnesium bromide (0.73 mL of 3.0 M solution in ether, 2.20 mmol) and stirred at this temperature for 15 min. It was quenched with ice cold saturated NH4Cl solution and extracted twice with EtOAc. The combined organic solution was concentrated and the residue was purified on a silica gel column and eluted with 50 to 100% EtOAc in DCM to give the title compound (23 mg, 26% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (br., 1H), 8.97 (d, J=2.6 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 5.21 (s, 1H), 3.94 (s, 3H), 2.47 (s, 3H), 1.49 (s, 6H). m/z (ESI, positive ion) 402.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:17])[N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=1.Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[C:20]([CH2:19][N:5]1[C:4]([CH3:3])=[CH:8][N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:6]1=[O:17])#[N:21]
Reactant: N#CCCl
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N=Cc2cccnc2)c(=O)n1CC#N
Reaction time: 0.5 h

Procedure:
0.72 g of sodium hydride are added to a suspension of 4.1 g of 2,3-dihydro-4-methyl-2-oxo-1-pyrid-3-ylmethyleneamino-1H-imidazole in 80 ml of N,N-dimethylformamide. The mixture is heated to 50°, treated with a solution of 1.89 g of chloroacetonitrile in 20 ml of N,N-dimethylformamide, and stirred for 30 minutes. The N,N-dimethylformamide is then removed on a rotary evaporator. In a mixer, the residue is mixed intimately with water. The crystals are filtered off, yielding the title compound melting at 195°-198°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:8]([CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(C)c1
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (5.1 g, 21.96 mmol) in tetrahydrofuran (70 mL) and dimethylsulfoxide (15 mL) cooled in a ice-water bath, NaH (0.96 g, 24.15 mmol) and methyl iodide (1.5 mL, 24.15 mmol) were added. The reaction was continued at room temperature for 12 h, the tetrahydrofuran was removed under vacuo, then dichloromethane (200 mL) were added and the organic phase washed with water (100 mL). The acqueous fraction was extracted with dichloromethane (1×100 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/ethanol 95/5) provided 4.45 g (82%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 80.2 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 27.9 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of N,N-dimethylaniline chloride was removed by filtration and the filtrate was subjected to distillation to recover toluene, whereby 19.8 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[C:7]([NH2:11])[CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[C:7]([NH2:11])[CH:8]=2)[N:3]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCl
Reactant: Nc1cc2c(cc1Cl)NC(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)Cc2cc(N)c(Cl)cc21
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a mixture of 2-oxo-5-amino-6-chloroindoline (3.2 g), potassium carbonate (4.8 g) and acetone (60 ml) was added dropwise ethyl chloroacetate (3.2 g) at ambient temperature. The reaction mixture was refluxed with stirring for 4 hours and then filtered under warm condition. The filter cake was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel to give crystalline ethyl 2-oxo-5-amino-6-chloro-1-indolineacetate (0.9 g).
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39])C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2Cl)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a stirred solution of 1 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-{1(R)-hydroxyethyl}-azetidin-2-on-1-yl]-3-(4-methylthiophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -40° was added a solution of 1.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the reaction was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound as a pale yellow foam (0.66 g, 68%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:19])[CH3:18].CN>C1COCC1.O>[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:3][CH3:1])=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cccc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.04 mL) followed by isobutylchloroformate (0.033 g) were added to a solution of 3-[7-isobutyl-5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.08 g) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Methylamine (2M, 2 mL) was added and the mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. Reaction was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on preparative HPLC to give the title compound (0.027 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccc(N2CCOCC2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol), sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated at 80° C. for 1 h then heated under reflux for 18 h. The hot reaction mixture was poured into warm ethanol. Upon cooling to 25° C., a precipitate formed. The precipitate was filtered to provide a tan solid (4.16 g). This crude tan solid was then treated with concentrated acetic acid (16 mL), concentrated sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction mixture was heated under reflux for 4 h and then poured into water. The water was removed in vacuo to provide crude (4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in methanol (100 mL) and then slowly treated with concentrated sulfuric acid (1 mL). The reaction mixture was heated under reflux for 66 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with water (200 mL) and then treated with a 10% aqueous sodium hydroxide solution until pH=9. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22 g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for C13H17NO3 (M+) 235.1208, found 235.1214.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[CH:9]=[CH:10][CH:11]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(C)(C)C.F.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:7][C@H:8]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH2:23][OH:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=CC(CO[Si](C)(C)C(C)(C)C)Cc1ccc2ccccc2c1)Cc1ccc2ccccc2c1
Agent: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N[C@@H](/C=C/C(CO)Cc1ccc2ccccc2c1)Cc1ccc2ccccc2c1
Reaction time: 3 h

Procedure:
((1R)-4-(tert-Butyldimethylsilanyloxymethyl)-1-((2-naphthyl)methyl)-5-(2-naphthyl)pent-2-enyl)carbamic acid tert-butylester (2.20 g; 3.60 mmol) was dissolved in a mixture of acetonitrile (100 ml) and an aqueous solution of hydrogen fluoride (48%, 4.5 ml). After stirring for 3 h a mixture of ethyl acetate (200 ml) and aqueous sodium carbonate (10%, 200 ml) was added. The phases were separated and the organic phase was dried (Magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (4×38 cm) using a mixture of ethyl acetate (85%), ethanol (14%) and conc. aqueous ammonia (1%) as eluent. Two close spots were separated this way. The one that eluted first was clean on HPLC whereas the following contained several isomers. The first fraction had E-geometry and 220 mg of (3E,5R)-5-amino-6-((2-naphthyl)-2-(2-naphthyl)methyl)hex-3-en-1-ol were taken to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate (125) (0.23 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration, light brown foam was obtained. Trituration with hexanes (containing 1% MeOH) afforded compound 126 as a white solid (0.175 g, 82%). mp 155-156° C. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.02 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 383 (M+H)+, m/z 381 (M−H)−. Anal. Calcd for C23H23ClO3.0.25H2O: C, 71.31; H, 6.11; Found: C, 71.26; H, 6.05.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([NH2:14])[CH2:4]1.[O-:15][C:16]#[N:17].[K+]>Cl>[CH3:2][N:3]1[CH2:7][C@@H:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([NH:14][C:16]([NH2:17])=[O:15])[CH2:4]1
Reactant: CN1C[C@@H](N)[C@H](c2ccccc2)C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CN1C[C@@H](NC(N)=O)[C@H](c2ccccc2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(3S,4R)-1-Methyl-4-phenylpyrrolidin-3-amine hydrochloride (556 mg, 2.231 mmol) was dissolved in HCl (2 N, 4 mL) and potassium cyanate (905 mg, 11.16 mmol) was added. The reaction mixture was stirred at 80° C. for 3 h. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc followed by 3:1 chloroform/IPA. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-((3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl)urea, which was carried onto the next step without further purification. MS ESI calc'd. For C12H17N3O [M+1]+ 220. found 220.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])SC)#[N:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:27])[CH2:25][NH2:26])=[CH:20][CH:19]=1>C(O)C>[C:1]([NH:3][C:4]([NH:26][CH2:25][CH:24]([OH:27])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])#[N:2]
Reactant: NCC(O)c1ccccc1
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NCC(O)c1ccccc1
Yield: 20.3 %

Procedure:
With 5 ml of ethanol were mixed 1 g of N-cyano-N'-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}-S-methylisothiourea and 2.6 g of DL-β-hydroxyphenethylamine, and the resulting mixture was subjected to reaction under reflux for 5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was washed with 20 ml of diethyl ether and then purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=10:1 by volume) to obtain 0.27 g (yield 20%) of amorphous N-cyano-N'-(β-hydroxyphenethyl)-N"-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}guanidine.