Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14].[OH-].[Na+].CO>O>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 25 °C

Procedure:
A mixture of campholenic aldehyde (456 g, 3.0 mol) and freshly distilled propionaldehyde (348 g, 6.0 mol) was slowly added, over a 1.0 hour period, to a stirred refluxing solution of 18 ml of 40% aqueous sodium hydroxide and 800 ml methanol. The mixture was refluxed an additional two hours, cooled to room temperature and poured into 1,000 ml of water. The resultant solution was extracted three times with 300 ml of hexane. The hexane extracts were combined, washed first with 600 ml of water and then with 600 ml of brine. The solvent was removed by distillation and the oil fractionally distilled to yield the 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal. Yield 323 g (56.1% theory); bp 64°-65° C (0.9 mm); mol wt. 192 (ms); ir, 3035, 2710, 1690 (s), 1640 (s), 800 cm-1 ; nmr, 0.8δ and 1.0 (6 H, 2s, geminal dimethyl groups), 1.7 (3H, broad s, olefinic methyl attached to the cyclopentenyl group), 1.9-2.2 (3H, broad multiplet), 2.3-2.6 (3H, broad multiplet), 5.3 (1H, broad multiplet, olefinic H), 6.6 (1H, t, J~7.5 Hz), 9.4 (1H, sharp s, aldehyde H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].O.CC[O:16]CC>C1COCC1.[Cl-].[Na+].O>[OH:16][CH2:4][CH2:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: C=CCCc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCCO)cc1
Temperature: 0 °C

Procedure:
4-(3-Butenyl)benzonitrile (from step (i) above, 10.8 g, 69 mmol) was dissolved in dry THF (140 mL) and was cooled to 0° C. BH3—Me2S complex (20 mL, 2 M) was added dropwise over 45 minutes at 0° C. and, after 7 hours, water (70 mL) and NaBO3-4H2O (25 g) were added and the mixture was stirred overnight before dilution with ether (700 mL) and brine (satd., 250 mL). After separation, the aqueous phase was extracted with ether (2×200 mL) and the combined extracts were dried, filtered and evaporated to give crude sub-title compound. Purification by flash chromatography on SiO2 (300 g) with heptane:EtOAc (3:1 to 1:1) gave the sub-title compound (6.99 g).
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=CC3C(=CC(C=[O:47])=C4C=3C=CC=C4)C=2C=CC=1.C(O)C(N)(CO)CO>CO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][OH:47])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CO
Solvent: CCOCC
Product: OCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reactive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and tris(hydroxymethyl)aminomethane (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol hydrochloride, mp 238°-239° (dec), (CH3OH/Et2O), (C,H,Cl,N).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:8]([O:10]CC(Cl)(Cl)Cl)=O)=O.[C:24]1([C:30]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:24]1([C:30]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([C:8]([NH:7][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:37][CH2:36]3)[S:32][N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cccnc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl)pyridin-3-ylimidodicarbonate (271 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.211 ml, 1.22 mmol) in dimethyl sulfoxide (2 ml) was stirred at 70° C. for 3 hours and further stirred at 80° C. for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 106 mg (47.5%) of the desired product as a solid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:2]2[N:3]=[C:4]([CH3:15])[N:5]([C:8]3[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=3)[C:6]=2[CH3:7])[CH:20]=[CH:21][CH:22]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1

Procedure:
The title compound, light brown crystalline solid, MS: m/e=324.2, 326.1 (M+H+), was prepared in accordance with the general method of example 21a from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1H-pyridin-2-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3].CN(C=O)C.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CS(=O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
To a solution of 4-methanesulfinyl-phenol (1.52 g, 9.7 mmol) in DMF (30 ml) cesium carbonate (4.2 g, 12.9 mmol) was added, followed by addition of 5-bromo-2-nitro pyridine (1.75 g, 8.6 mmol) and the mixture was stirred at 50° C. over night. The suspension was filtered and evaporated+co-evaporated with toluene. The compound was purified by chromatography (0→10% EtOH in Methylene chloride) to give 1.5 g (56%) of 5-(4-Methanesulfinyl-phenoxy)-2-nitro-pyridine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCN1CCCCC1
Solvent: CC#N
Product: Clc1ccc2c(NCCN3CCCCC3)ccnc2c1

Procedure:
3.57 g of base from 3.96 g of 4,7-dichloroquinoline and 4.8 g of 1-(2-aminoethyl)-piperidine (reaction duration, 5 hours at 140° C.); yellowish crystals from acetonitrile, m.p.: 148°-151° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].O1CCOCC1>O1CCCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 40 °C
Reaction time: 7 h
Yield: 48.5 %

Procedure:
In a hydrogenator, 8.2 g (0.042 mole) of 5-chlorocarbonylphthalide, 50 ml of dioxane and 0.77 g of 5% Pd/BaSO4 are charged and the mixture is hydrogenated at 4 bar and 70° C. for 7 hours. After this period of time, the reaction no longer proceeds because of the co-precipitation of the formed product; thus, the hydrogenation is stopped, the mixture is diluted with 120 ml of tetrahydrofuran and stirred at 40° C. for 20 minutes. The solid is filtered off and the solution is concentrated to a little volume. The crystalline product is recovered by filtration and dried to give 3.3 g of 5-formylphthalide with a purity (HPLC)=82% (yield 40%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][O-].[Na+]>[Cl-].C1([N+](C)(C)C)C=CC=CC=1.CN(C)C=O>[CH3:9][O:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: C[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxy-6-methylpyridine (2.5 g), sodium methoxide (1.36 g) and phenyltrimethylammonium chloride (4.33 g) in dry dimethylformamide (25 ml) was heated at reflux under argon for 2.5 h. The mixture was allowed to cool then stirred at room temperature overnight. Insoluble material was removed by filtration and washed with ethanol. The filtrate was acidified with 6M hydrochloric acid and the solvent was removed in vacuo. The residue was then diluted with water, basified with 2M sodium hydroxide and extracted with ether. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with 3% ethyl acetate in hexane (1.55 g, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[H-].[Na+].[CH3:15][N:16](C=O)C>>[C:15]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:16]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound 2 (6.46 g, 24.1 mmol) in DMF (30 mL) was treated with sodium hydride (1.94 g of 60% dispersion in mineral oil, 48.6 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours and then partitioned between water (100 mL), and EtOAc (350 mL). The layers were separated, and the organic layer was washed with water (4×150 mL). The organic phase was dried (Na2SO4) and concentrated to a white solid. Compound 3 (5.56 g, 24.0 mmol, quantitative yield) was dried under high vacuum and characterized using 1H NMR. It was used in the following step without further purification.
Reaction SMILES: [K].[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:15](Br)[C:16]#[CH:17]>CN(C)C=O.O>[CH2:17]([N:13]1[C:14]2[CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]#[CH:15]
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Reactant: C#CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c2c(c3ccccc31)CCCC2
Reaction time: 0.75 h

Procedure:
Potassium tert.-buroxide, 3.6 g (33 mmol), was added to a solution of 5 g (30 mmol) of 1,2,3,4-tetrahydro-9H-carbazole in 50 ml of dimethylformamide. After stirring for 45 minutes under nitrogen, 3.9 g or 2.9 ml (33 mmol) of propargyl bromide was added and stirring was continued for 30 minutes at room temperature followed by 45 minutes on the steam bath. The cooled reaction mixture was diluted with water and the product was extracted with ether. The extracts were washed with water, dried over sodium sulfate and evaporated. The residue was passed over a plug of silica gel using methylene chloride/hexane 1:1. The fractions containing the least polar product were combined and evaporated. The residue was crystallized from hexane to give colorless crystals of 1,2,3,4-tetrahydro-9-(2-propynyl)-9H-carbazole with m.p. 74°-76°.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>CCO>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:7][CH:8]=1
Reactant: OCCC[n+]1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: OCCCN1CC=C(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-hydroxypropyl)-4-[pyrid-2-yl]pyridinium bromide (8 g) in 100 mL EtOH was added NaBH4 (1.41 g, 37.2 mmol) in small portions. The reaction mixture was stirred at room temperature for 12 h and then quenched with drops of water. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:4 MeOH/EtOAc followed by 1:4 (2M NH3 in MeOH)/EtOAc as the eluting system (Rf =0.6, (2M NH3 in MeOH)/EtOAc=1:4) to obtain 3-(3',6'-dihydro-2'-H-(2,4']bipyridinyl-1'-yl)-propanol as an oil (1.58 g, 39% over two steps).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH:12](C(OCC)=O)[CH2:13][CH2:14][CH2:15][C:7]3=[N:6][C:5]=2[S:4][CH:3]=1.[CH2:21]([OH:23])C.[OH-:24].[Na+].Cl>CCCCCC.O>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][CH2:14][CH2:15][C:7]3=[N:6][C:5]=2[S:4][C:3]=1[C:21]([OH:23])=[O:24]
Reactant: CCO
Reactant: CCOC(=O)C1CCCc2nc3scc(C)c3c(=O)n21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1c(C(=O)O)sc2nc3n(c(=O)c12)CCCC3
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
75 Milligrams of ethyl 3-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-6-carboxylate was suspended in a liquid mixture of 0.5 mL of ethanol, 1 mL of water and 1 mL of 1N aqueous sodium hydroxide solution, and stirred at about 100° C. for 2 hours. Thereafter 0.35 mL of 3N hydrochloric acid was added to the reaction mixture, to adjust the pH to 5. Distilling the mixture under reduced pressure, adequate amounts of chloroform and methanol were added to the residue to precipitate inorganic salts. The precipitated inorganic salts were removed by filtration and the filtrate was condensed under reduced pressure. Solidifying the residue by addition of hexane, 50 mg (74%) of the title compound was obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CC([Si](Cl)(C)C)(C)C>CCOCC>[OH:18][CH:12]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC=O
Reactant: Brc1nccs1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCC(O)c1nccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
n-BuLi (4.0 mL, 6.4 mmol, 1.6M) was added dropwise to a -78° C. solution of 2-bromothiazole (1.0 g, 6.1 mmol) in dry Et2O (12 mL). After stirring at -78° C. for 1 h, hexanal (0.77 mL, 6.4 mmol) was added and the solution stirred for 30 min. before a solution of TBDMSCl (1.1 g, 7.3 mmol) in dry Et2O (5 mL) was added. The solution was allowed to warm to rt while stirring for 16 h. The reaction was quenched with water, the layers separated and the aqueous extracted with EtOAc. The combined extracts were dried (MgSO4) and condensed. The crude material was purified by flash chromatography using 30% EtOAc/hexane to give 0.70 g (62%) of 2-(1-hydroxyhexyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:23])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cnc(NC(C)=O)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C=O)cn1
Reaction time: 4 h

Procedure:
To a stirred solution of N-(4-chloro-5-vinylpyridin-2-yl)acetamide (6 g, 30.5 mmol) and 2,6-lutidine (7.11 mL, 61.0 mmol) in a mixture of 1,4-dioxane (110 mL) and water (25 mL) at 0° C. was added osmium tetroxide (2.5% in 2-methyl-2-propanol, 9.58 mL, 30.5 mmol) followed by the addition of sodium periodate (19.58 g, 92 mmol) and the reaction was stirred for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, concentrated under reduced pressure and residue so obtained was purified by comb flash column 120 g silica column using hexane/EtOAc as eluant. The desired product was isolated at 30% EtOAc in hexane. The required fractions were concentrated under reduced pressure to yield N-(4-chloro-5-formylpyridin-2-yl)acetamide as a off-white solid (5.8 g, 28.1 mmol, 92% yield). LC/MS (ESI) m/e 197.0 [(M)−, calcd for C8H6ClN2O2 197.04] LC/MS retention time (method A): tR=1.21 min; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.18 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[NH3:5].[C:6](=[O:9])([O-])[O-:7].[NH4+].[NH4+].[NH2:12][C:13]([NH:15][C:16]([NH2:18])=[O:17])=[O:14]>>[NH2:12][C:13]([NH:15][C:16]([NH2:18])=[O:17])=[O:14].[NH:1]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[NH:4][C:2]1=[O:3].[C:13]1([O:3][C:2](=[NH:4])[O:9][C:6](=[NH:5])[O:7]1)=[NH:12]
Reactant: N
Reactant: O=C([O-])[O-]
Reactant: NC(N)=O
Agent: NC(=O)NC(N)=O
Agent: [NH4+]
Product: N=c1oc(=N)oc(=N)o1
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
Two-three heated moles of ammonia to one mol of heated carbon dioxide, heated at 160 to 210 degree C. is forced through a reactor which has an aqueous solution or oil-water slurry of ammonia and carbon dioxide which is being circulated at 160° to 210° C. and under 2-6000 psi to form ammonium carbamate which when heated lose 1 mol of water thereby producing an aqueous urea. The aqueous urea contains small amounts of ammonia, ammonium carbonate and biuret. The aqueous urea is concentrated and the urea crystalizes out. The urea may be heated to above the boiling point of urea to produce biuret or cyanuric acid and cyamelide. When urea is heated with a small amount of water it condensates to for a partially hydrolyzed urea condensate.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)SS[CH2:2]1.C1N=CN(C(N2C=[N:23][CH:22]=[CH:21]2)=O)C=1.C[O:26]COC1C(CCN)=C2C(=C(C)C=1C)OC(C)(C)CC2.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[O:12]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:1][CH2:2][CH:21]1[C:22]([NH2:23])=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCOc1c(C)c(C)c2c(c1CCN)CCC(C)(C)O2
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)C1CCc2ccccc2O1
Reaction time: 0.75 h

Procedure:
Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) was taken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellow solution was added dropwise to a suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150 mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). After stirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The unpurified residue was dissolved in 2 mL methanol at 40° C. Concentrated HCl (approx. 30 μL) was added to the solution and stirring continued for 1 hr. At the completion of the reaction, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane) afforded the desired chroman amide as a colorless oil, 140 mg. 1H NMR (CDCl3, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q, 2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H), 1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of the intermediate amide using the procedure described above produced 5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide as a yellow oil that was purified by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane). 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m, 1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44 (m, 3H), 1.26 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C@H:6]1[C:17](O)=[O:18])=[O:4].Cl.[CH3:23][C:24]([O:27][C:28]([C@@H:30]1[CH2:46][S:45][S:44][CH2:43][C@H:42]([NH2:47])[C:41](=[O:48])[NH:40][CH2:39][CH2:38][C:33]2([CH2:37][CH2:36][CH2:35][CH2:34]2)[C:32](=[O:49])[NH:31]1)=[O:29])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:26][C:24]([O:27][C:28]([C@@H:30]1[CH2:46][S:45][S:44][CH2:43][C@H:42]([NH:47][C:17]([C@@H:6]2[C@@H:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][N:5]2[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])=[O:18])[C:41](=[O:48])[NH:40][CH2:39][CH2:38][C:33]2([CH2:34][CH2:35][CH2:36][CH2:37]2)[C:32](=[O:49])[NH:31]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)C(=O)N1CC[C@H](c2ccc(O)cc2)[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](N)C(=O)NCCC2(CCCC2)C(=O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H]2[C@@H](c3ccc(O)cc3)CCN2C(=O)C(C)(C)C)C(=O)NCCC2(CCCC2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a mixture of (2S,3R)-1-(2,2-dimethyl-1-oxopropyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid (45 mg, 0.15 mmol) and (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester hydrochloride 70 mg, 0.15 mmol), prepared in Example 6, in 0.5 mL of DMF was added DIPEA (58 mg, 0.45 mmol) and HBTU (59 mg, 0.15 mmol). The solution was stirred at room temperature for 3 hours and was diluted with water to 3 mL. The resulting white precipitate was collected and was dried over night at reduced pressure to give 98 mg of (8R,13R)-13-[[[1-(2,2-dimethyl-1-oxopropyl)-3-(R)-(4-hydroxyphenyl)-2-(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester as a white solid. This dried solid was the dissolved in 1 mL of dichloromethane and the solution was treated with 4 N HCl in dioxane (2 mL). The solution was stirred overnight and was concentrated. The residue was purified by reversed phase HPLC (5-95% of acetonitrile containing 0.75% of TFA in water over 40 min linear gradient) to give (8R,13R)-13-[[[1-(2,2-dimethyl-1-oxopropyl)-3(R)-(4-hydroxyphenyl)-2(S)-pyrrolidinyl]carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid as white solid (9 mg). HRMS (M+H): Obs. 635.2543, Calcd. 635.2573.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C1CCCCCCCCCCC=1.[OH2:29]>>[CH:5]1([OH:29])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O
Reactant: C1CCCCCCCCCCC1
Agent: C1=CCCCCCCCCCC1
Solvent: ClC(Cl)Cl
Product: OC1CCCCCCCCCCC1
Yield: 93 %

Procedure:
The chloroform layer (top layer) was diluted at 5° C. with 200 ml of water and then passed to the heated hydrolysis vessel where chloroform was distilled off. Next, the reaction mixture was heated at 95°-100° C. in this vessel for 60 minutes. The organic layer was separated off and analyzed. It was found to contain 3.52 grams of cyclododecane, 6.80 grams of cyclododecene (conversion 77%) and 23.45 grams of cyclododecanol (0.121 mole; yield 93%, calculated with subtraction of recovered starting material).