Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C(O)C>O>[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 118.7 %

Procedure:
A solution of sodium acetate (6.64 g, 60.72 mmol) in water (10 mL) was added into a mixture of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde (5.0 g, 20.24 mmol) benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606), hydroxylamine hydrochloride (4.22 g, 60.72 mmol), ethyl alcohol (300 mL), and water (50 mL). The mixture: was stirred at 70° C. for 10 hours, then poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a white solid (6.3 g, 90% yield); mp 151–152° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.63 (m, 4H), 3.35 (m, 4H), 3.90 (s, 4H), 6.96 (m, 2H), 7.40 (m, 2H), 7.96 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 263 (MH+); Anal. Calcd. for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 64.24; H, 6.81; N, 10.64.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[CH3:15][C:16]([Si:19]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1I
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a stirring solution of 2-iodobenzylalcohol (2.34 g, 10 mmol) in 50 mL DMF was added imidazole (1.02 g, 15 mmol, 1.5 equiv) and TBSCl (1.66 g, 11 mmol, 1.1 equiv). The mixture was stirred at room temperature for 5 h, then 40 mL of water was added. The mixture was transferred to a separatory funnel. The aqueous layer was separated and extracted with ether (2×40 mL). The combined organic layers were then washed with water (2×40 mL), dried with MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography and then Kugelrohr distillation to afford the product (3.107 g, 89%) as a clear colorless liquid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4]C1SC=CC=1)[CH3:2].S1C=CC=C1.C([Li])CCC.CCCCCC.CC[Br:32]>O1CCCC1>[CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][Br:32])[CH3:2]
Reactant: CCCCC(CC)Cc1cccs1
Reactant: CCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CCCCC(CC)CBr
Temperature: -78 °C

Procedure:
In FIG. 2A, an exemplary synthesis of 2-(2-ethylhexyl)thiophene is depicted. As shown in FIG. 2A, a 7.4 mL thiophene was dissolved in 100 mL anhydrous tetrahydrofuran (THF). The solution was then cooled to about −78° C. A 30 mL of 2.5 M n-butyllithium (n-BuLi) in hexane (75 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature for about 2 hours, and then cooled to about −15 to about −20° C. 26 mL 2-ethyl bromide was added to the reaction mixture. The reaction mixture was reacted at about 50° C. for about 18 hours, and poured into crushed ice. The organic phase was isolated and washed with water, and extracted with ether three times. After removal of the solvent by rotary evaporator, the residue was distilled under vacuum to get rid of the 2-ethylhexyl bromide. After removal of the 2-ethylhexyl bromide, the residue was purified by elution with hexane by silica gel column chromatography (i.e., about 10 to about 15 cm) to afford 12.6 g 2-(2-ethylhexyl)thiophene as light yellow liquid. The yield was about 85%. The molecular weight was determined by gas chromatography/mass spectrometry (GC-MS) to be 196.3.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH3:30])[C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[C:20]([CH3:30])[C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:28][CH2:29]2)=[N:22][CH:23]=1
Reactant: Cc1cc(Br)cnc1N1CCNCC1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Product: Cc1cc(Br)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Yield: 96.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1.3 g) described in Preparation Example 37 and 1-(5-bromo-3-methylpyridin-2-yl)piperazine (1.5 g), (R)-3-{4-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-methyloxazolidin-2-one (2.6 g) was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][C:24](=[O:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][C:24](=[O:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC(=O)[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
10% Pd/C (900 mg) was added to a solution of compound 1.9a (2.0 g, 4.5 mmol) in EtOAc (150 mL) and the resulting slurry was hydrogenated in a Parr apparatus (50 psi) at 50° C. for 16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, providing compound 2.0a (1.6 g, 80% yield) as a white solid.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>O1CCCC1>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: O=C1CCCO1
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: COC(CNC(=O)CCCO)OC

Procedure:
A mixture of 4-butyrolactone (54 g) and aminoacetaldehyde dimethylacetal (55 g) in tetrahydrofuran (THF) (500 mL) was refluxed for 4 h. A further portion of aminoacetaldehyde dimethylacetal (27 g) was added followed by reflux for 2 h. Reflux was continued and two further portions of acetal were added at 2 h intervals. Concentration of the reaction mixture in vacuo followed by destillation of the remaining oil gave N-(2,2-dimethoxyethyl)-4-hydroxybutyramide as an oil, bp. 230° C./10 torr, yield 72 g. The oil was dissolved in dry THF (800 mL) and added slowly to a suspension of of lithium aluminium hydride in THF (200 mL). After reflux for 16 h, the reaction mixture was cooled and subsequently quenched with water (88 mL), 15% NaOH solution (44 mL), and water (220 mL). Filtration and removal of solvent in vacuo gave an oil which was dissolved in methylene chloride (500 mL) and dried over magnesium sulfate. Filtration and removal of solvent in vacuo gave 4-(2,2-dimethoxyethylamino)-1-butanol as an oil, yield 62 g. A portion of the oil (20 g) was dissolved in methylene chloride (100 mL) and added dropwise to a solution of cyclohexylisocyanate in methylene chloride (50 mL) at 5° C. Reflux for 3 h and concentration in vacuo gave N-cyclohexyl-N′-(2,2-dimethoxyethyl)-N′-(4-hydroxy-1-butyl)urea as an oil, yield 35 g. The oil was dissolved in a mixture of THF (200 mL) and 2 M hydrochloric acid (200 mL) followed by reflux for 24 h. The reaction mixture was concentrated in vacuo followed by addition of ethyl acetate (300 mL) and 4 M NaOH (300 mL). The organic phase was dried over magnesium sulfate. Removal of solvent gave 1-cyclohexyl-3-(4-hydroxy-1-butyl)-1,3-dihydroimidazol-2-one as an oil, yield 29 g. The oil was dissolved in methylene chloride (250 mL) and triethylamine (13 g) was added followed by cooling to 5° C. A solution of methanesulfonyl chloride (14 g) in methylene chloride (20 mL) was added dropwise followed by stirring for 1.5 h at room temperature. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo giving the title compound as an oil, yield 36 g. 1H NMR (CDCl3): δ 1.05-1.25 (m, 1H), 1.30-1.50 (m, 4H), 1.60-2.00
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][C:34]#[CH:35])[CH:30]=3)[N:25](S(C3C=CC=CC=3)(=O)=O)[CH:24]=2)[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][C:34]#[CH:35])[CH:30]=3)[NH:25][CH:24]=2)[CH:3]=1
Reactant: C#CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#CCOc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3)c2c1

Procedure:
A solution of Example 241a (0.056 g, 0.088 mmol) in dioxane (1.5 mL) was treated with 20% sodium hydroxide (0.10 mL, 0.088 mmol). The mixture was heated at 90 C for an hour. The solvent was evaporated. The residue was treated with 20% brine and twice extracted with dichloromethane. The layers were combined, dried with MgSO4 and concentrated to give 0.037 g of the title compound. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:11]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([O:20]C)[CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([NH:7][C:8]([C:10]2[C:11]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([OH:20])[CH:14]=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2cc(C(=O)Nc3ccccc3)c(Nc3ccccc3Cl)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 120 h

Procedure:
2-(2-Chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acid phenylamide (404 mg, 1.0 mmol) was dissolved in dry CH2Cl2 (5 ml). After cooling to −78° C., 1.0 N BBr3 (5.0 ml, 5.0 mmol) in CH2Cl2 was dropped into the above solution over 5 min. The reaction mixture was allowed to warm to room temperature over 1 hr and stirred for 5 days. CH2Cl2 was added to extract the reaction mixture, and washed with water, saturated brine and then dried with magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on SCX column using MeOH as eluent. At last, 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid phenylamide was obtained as yellow solid after recrystallization from CH2Cl2 and Hexane; 210 mg (54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[NH2:17][C:18]1[C:25]([O:26][CH2:27][CH3:28])=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:29][CH2:30][CH3:31]>>[NH2:17][C:18]1[C:19]([O:29][CH2:30][CH3:31])=[CH:20][C:21]([CH2:22][N:13]2[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]3[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH2:15][CH2:14]2)=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1cc(C=O)cc(OCC)c1N
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(OCC)c1N
Yield: 34 %

Procedure:
The title compound (14 mg, 34%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 4-amino-3,5-diethoxybenzaldehyde. MS: 413.5 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:26].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([NH2:15])=[O:26])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc(Cl)c(CC(N)=O)n2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 50 ml of ethanol was dissolved 3.5 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)-5-cyanomethylimidazole, and 10 ml of 1 N-sodium hydroxide was added to the solution, followed by stirring at 60° C. for 2 hours. The solution was allowed to cool, and the resulted crystals were recrystallized from 70 ml of 90% ethanol, thereby yielding 2.2 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)imidazole-5-acetamide as colorless needles, m.p. 215°-216° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])[N:4]([CH3:16])[N:3]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([O:20][C:18]([NH:15][S:12]([C:5]1[N:4]([CH3:16])[N:3]=[C:2]([Cl:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1c(Cl)nn(C)c1S(N)(=O)=O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1c(C(=O)OCC)c(Cl)nn1C
Yield: 88.4 %

Procedure:
Into 30 ml of dry acetone, there were added 5.35 g of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, 2.5 g of ethyl chloroformate and 4.14 g of anhydrous potassium carbonate and the mixture was refluxed for three hours. After cooling, acetone was evaporated and the residue was added into ice-water. After separation of a trace of water insolubles, the filtrate was made acidic with hydrochloric acid. The reaction mixture was extrated with diethyl ether and organic layer was dried and the solvent was evaporated under reduced pressure to give 6.0 g of N-(ethoxycarbonyl)-3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[S:6][CH:7]=1.Cl.C[O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27]>>[CH3:29][CH:28]([CH3:30])[C@H:26]([NH:27][C:16](=[O:18])[C@H:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:21])[F:20])[N:4]=2)=[CH:14][CH:13]=1)[CH3:19])[C:25]([OH:31])=[O:24]
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)C(=O)O
Yield: 40.4 %

Procedure:
Following the same procedure described for 16 and starting from (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (3) (0.18 g, 0.57 mmol) and L-valine methyl ester hydrochloride (0.095 g, 0.57 mmol), after workup compound 17 (0.093 g, 0.23 mmol) was isolated as a white solid (69%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:13]1[C:19]2=[C:20]3[C:25](=[N:26][C:27]4=[CH:28][CH:29]=[CH:30][C:17](=[C:18]24)[O:16][CH:15]([CH3:31])[C:14]1=O)[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:12]>O1CCCC1>[CH2:11]([N:13]1[C:19]2=[C:20]3[C:25](=[N:26][C:27]4=[CH:28][CH:29]=[CH:30][C:17](=[C:18]24)[O:16][CH:15]([CH3:31])[CH2:14]1)[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:12]
Reactant: CCN1C(=O)C(C)Oc2cccc3nc4c(c1c23)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN1CC(C)Oc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 14.22 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.90 g) in portions, with stirring. After five mins, 1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.21 g) was added and stirring was continued for 0.5 hr. The reaction mixture was quenched with ethyl acetate (200 ml) and 10% sodium hydroxide solution (200 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. Recrystallized of the residue from diethyl ether/pentane gave 2.17 g (54%) of product, mp 101°-103° C.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[S:36][S:37][C:38](=[S:40])[N:39]=1.O>O1CCCC1>[CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:34][C:35]2[S:36][S:37][C:38](=[S:40])[N:39]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: Nc1nc(=S)ss1
Reactant: CC(C)=CCCC(C)=CCOc1ccc(CC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCOc1ccc(CC(=O)Nc2nc(=S)ss2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
2-{4-[(3,7-Dimethyl-2,6-octadienyl)oxy]phenyl}acetic acid (1.00 g,3.47 mmol) was dissolved in tetrahydrofuran (12 ml), and 1,1′-carbonyldiimidazole (0.68 g, 4.16 mmol) was added thereto. The mixture was stirred for 1 hour at room temperature, and then 3-amino-1,2,4-dithiazole-5-thione (0.42 g, 2.70 mmol) was added thereto. After being stirred for 3 hours at room temperature, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel chromatography (chloroform), to give 2-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}-N-(3thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 2) (0.187 g, 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[N:1]=[C:14]([OH:15])[N:13]=[CH:4]2
Reactant: NC(N)=O
Reactant: COc1cc(N)c(C=O)cc1Br
Product: COc1cc2nc(O)ncc2cc1Br
Temperature: 180 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methoxybenzaldehyde (3 g, 13.1 mmol) and urea (12 g, 196.5 mmol) was stirred at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and washed with water (3×100 mL). The precipitate was collected and dried to give the title compound (3 g, crude) as a yellow solid. MS (ES+) C8H7BrN2O2 requires: 254, 256. found: 255, 257 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH:7]([N:14]1[C:18](=[O:19])[C:17]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[N:16]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCOCC1>[O:19]=[C:18]1[C:17]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:16]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15][N:14]1[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To tert-butyl 3-(5-methoxy-5-oxo-1-phenylpentyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.07 g, 0.13 mmol) was added 4M solution of HCl in dioxane (1.5 mL). After stirring at room temperature for 90 minutes, the reaction mixture was concentrated in vacuo to obtain methyl 5-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:24].CO.[ClH:39]>O1CCOCC1>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]3)[CH2:34]1)[CH2:36]2)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNC2CCNCC2)ccc1Cl

Procedure:
Prepared from 4-[[[4chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.158 g, Example 31b) methanol (3 ml) and 4N hydrochloric acid solution in dioxane (2 ml). Solvents were removed under reduced pressure and the residue was triturated with ethyl acetate, iso-hexane and diethyl ether to give the title compound as a white solid (0.126 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:20]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH2:32][CH2:33]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Yield: 61 %

Procedure:
To a solution of 3-chloro-4-nitro-N-phenyl-benzamide (0.13 g, 0.47 mmol) in N,N-dimethylformamide (10 mL) were added piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.12 g, 0.56 mmol) and potassium carbonate (0.1 g, 0.72 mmol) and the resulting mixture was heated at 50° C. overnight. The reaction mixture was then heated at 80° C. for 8 hours; then more piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.33 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the resulting mixture was heated at 85° C. overnight. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 20/80 to 40/60) to give 0.13 g, (61% yield) of [1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as on orange colored solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCOCC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C#N)CCOCC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(aminocarbonyl)tetrahydro-2H-pyran-4-yl-carbamate (C-25) and triethylamine (2.1 eq.) in dichloromethane was cooled to 0° C. and trifluoroacetic anhydride (1.1 eq.) was added dropwise under nitrogen. Stirring was continued for 1 hour allowing the mixture to reach room temperature. Volatiles were removed in vacuo and residue was taken up in ethyl acetate, washed with HCl 1N, brine and dried over Na2SO4. Evaporation gave a crude which was purified by flash chromatography on silica gel (eluent: petroleum ether: ethyl acetate=7:3) to give the title compound (C-26), colorless oil, as a 8:2 mixture of two rotamers by 1H NMR.