Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:24][C@@H:25]([CH2:29][O:30][CH3:31])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:26]([C@@H:25]([NH2:24])[CH2:29][O:30][CH3:31])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1[CH3:16]
Reactant: Cc1c(F)ccc(N)c1Nc1ccccc1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC[C@H](N)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (560 mg, 2.59 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (624 mg, 2.85 mmol), HOAt (388 mg, 2.85 mmol), 4-methylmorpholine (626 μL, 5.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (547 mg, 2.85 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and the mixture heated at 70° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (545 mg, 70%). LCMS (Method C): RT 3.95 min [M+H]+ 300.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=O)[CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[CH:7]1([CH2:10][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9][CH2:8]1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1CN(CC2CC2)CCN1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Lithium aluminium hydride (770 mg, 20.3 mmol) was suspended in tetrahydrofuran (150 mL), 1-(cyclopropylcarbonyl)piperazine (1.56 g, 10.1 mmol) was gradually added thereto, and the reaction mixture was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and 0.8 mL of water, 0.8 mL of a 15% aqueous solution of sodium hydroxide and 2.3 mL of water were sequentially gradually added thereto. The precipitated insoluble matter was removed by filtration through Celite, and the filtrate was evaporated to give the title compound (1.40 g) as a colorless oil. The product was used for the synthesis of (8E,12E,14E)-7-((4-cyclopropylmethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (the compound of Example 27) without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[O:5][CH2:6][CH2:7][NH:8][CH3:9].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].[F-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:9])[CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CNCCOc1cc(F)cc(F)c1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCN1C(=O)c2ccccc2C1=O)CCOc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 78.6 %

Procedure:
A mixture of [2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amine (0.63 g, 3.4 mmol), 2-(3-bromo-propyl)-isoindole-1,3-dione (1.03 g, 3.8 mmol), 30% potassium fluoride on Celite® (1.35 g, 7 mmol) and acetonitrile (30 ml) was stirred for 20 hours at 50° C. The solvent was concentrated and the residue was dissolved in ethyl acetate. The Celite was filtered off, the solution was washed with water, then the organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (97-3) to give 2-(3-{[2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino}-propyl)-isoindole-1,3-dione (1 g, 78.6%).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:24]1[CH2:25][O:26][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:1]1
Reactant: CCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCC1(CC(=O)OCC)OCCO1
Yield: 61.4 %

Procedure:
26(a) A solution of 42.57 g of ethyl 3-oxostearate (prepared as described in Preparation 25). 9.71 g of ethylene glycol and 1 g of camphorsulfonic acid in 200 ml of toluene was heated under reflux for 24 hours, and the water produced was removed through a side arm attached to a water separator. The mixture was allowed to cool, and then washed, in turn, with a saturated aqueous solution of sodium bicarbonate and with water. It was then dried and concentrated by evaporation under reduced pressure, to give 29.66 g of crude ethyl 3,3-ethylenedioxystearate.
Reaction SMILES: [CH3:1][NH2:2].CC1C=CC(S(O[CH2:14][C@H:15]2[O:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][N:22]=3)[CH2:16]2)(=O)=O)=CC=1>CO>[Br:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:17]2[CH2:18][CH2:19][O:20][C@H:15]([CH2:14][NH:2][CH3:1])[CH2:16]2)[CH:26]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(c3cc(Br)ccn3)CCO2)cc1
Solvent: CO
Product: CNC[C@@H]1CN(c2cc(Br)ccn2)CCO1
Temperature: 80 °C

Procedure:
To a 2 M solution of methylamine in methanol was added (S)-(4-(4-bromopyridin-2-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate (1.0 eq). This solution was microwave heated at 80° C. After 1 h the solution was then concentrated in vacuo and water was added. The resulting suspension was sonicated and centrifuged. The water soluble portion was separated from the solids. The resulting aqueous solution of (R)-1-(4-(4-bromopyridin-2-yl)morpholin-2-yl)-N-methylmethanamine was used in the next step without further purification. LCMS (m/z) (M+H)=286.0/288.0, Rt=0.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1.CCCCCC.ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(Cl)c(Cl)c1C=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
3,4-Dichloroanisole (12.5 g, 70.6 mmol) was dissolved in tetrahydrofuran (130 ml) and cooled to −76° C. n-Butyllithium (31 ml of 2.5 molar in hexanes, 77.7 mmol) was added dropwise keeping the temperature below −70° C. The solution was stirred at −70° C. for 30 minutes, then dimethylformamide (6.0 ml, 77.7 mmol) was added dropwise. The mixture was allowed to warm up to room temperature and was then poured onto ice (500 ml) and extracted with diethyl ether. The ether extracts were washed with brine then dried over anhydrous Na2SO4, filtered, and the solvent removed in vacuo to give the crude product. This material was stirred and heated to just below the reflux temperature in hexane (100 ml) and dichloromethane (5 ml), then cooled, and the solid filtered off to give the title compound as an off-white powder (10.0 g).
Reaction SMILES: COO[CH:4](OOC)[CH2:5]Br.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[S:27])=[CH:24][CH:23]=1>C(O)C>[S:27]1[CH:5]=[CH:4][N:28]=[C:26]1[C:25]1[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=1
Reactant: COOC(CBr)OOC
Reactant: NC(=S)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Oc1ccc(-c2nccs2)cc1
Yield: 61.3 %

Procedure:
In a round-bottomed flask, bromoacetaldehyde dimethoxyacetal (123 μl, 1.04 mmol), p-toluenesulfonic acid (199 mg, 1.04 mmol), and 4-hydroxy-thiobenzamide (160 mg, 1.04 mmol) were dissolved in ethanol (10 ml) and the resulting solution was heated to reflux for about twenty-four hours. The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate, and extracted with saturated aqueous sodium carbonate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes) to furnish the title compound as a white solid (113 mg, 61% yield). LRMS ([M+H+])=177.8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([C:11]([CH2:13]Cl)=[O:12])([CH3:10])[CH3:9].[CH2:15]([C:17]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH3:42])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:22][CH:21]=1)[CH2:18][CH3:19])[CH3:16].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:15]([C:17]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:13][C:11](=[O:12])[C:8]([CH3:10])([CH3:9])[CH3:7])=[C:37]([CH3:42])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:27][C:28]([CH3:33])([CH3:34])[C:29]([CH3:31])([CH3:32])[O:30]2)=[CH:22][CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)c(C)c1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 140 °C
Yield: 31.5 %

Procedure:
Potassium carbonate (54.5 mg, 0.395 mmol) and 1-chloropinacolin (71 mg, 0.526 mmol) were added to a solution of 4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 143-(3); 100 mg, 0.263 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred with microwave heating at 140° C. for 15 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to give the target compound as a colorless oil (39.7 mg, 32%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][SH:21]>>[CH3:20][S:21][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: CS
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CSCCCCOc1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and methylmercaptan.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: [O-][n+]1c(Cl)cccc1N1CCCCC1

Procedure:
A solution was prepared by dissolving 10 grams (0.061 mole) of 2,6-dichloropyridine-N-oxide in 100 milliliters of benzene at 35 C. To this solution was added dropwise 10.3 grams (0.122 mole) of piperidine. Upon completion of the piperidine addition, the reaction mixture was refluxed for 2 hours. At the completion of the reaction, the insoluble material contained in the reaction mixture was removed by filtration and benzene thereafter distilled off. The oily residue which remained was taken up in hexane. The 6-chloro-2-(piperidino)pyridine-N-oxide product was recovered by recrystallization from hexane and recovered in a yield of 7.5 grams. The product melted at 38°-41°C. and was found upon analysis to have carbon, hydrogen, chlorine and nitrogen contents of 54.5, 5.9, 19.9 and 12.9 percent, respectively, as compared with the theoretical contents of 56.8, 6.1, 16.7 and 13.2 percent, respectively, calculated for the above named compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C@:11]([NH:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])[CH2:12][CH2:13][OH:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OC(=O)C)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C@:11]([NH:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:15])[CH2:12][CH:13]=[O:14]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CCO)c1cc([N+](=O)[O-])ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 23 °C
Reaction time: 3 h
Yield: 1445.5 %

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(2-fluoro-5-nitro-phenyl)-3-hydroxy-1-methyl-propyl]-amide (intermediate A4C) (1.1 g, 3.3 mmol) in anhydrous CH2Cl2 (35 ml) at 23° C. was added Dess-Martin Periodinan (1.825 g, 4.3 mmol) and the mixture was stirred at 23° C. for 3 h. Reaction mixture was poured into 20 mL of a 1M aqueous NaHCO3 solution containing 2 g of sodium thiosulfate, pentahydrate and the mixture was stirred at 23° C. for 15 min. The two phases were separated, the collected organic phase was dried over Na2SO4 and removal of the solvent in vacuum left a residue. Purification of the residue was performed by chromatography on silica using a mixture of Heptane and a solution of 3% Triethylamine in Ethylacetate which yielded the (R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(2-fluoro-5-nitro-phenyl)-1-methyl-3-oxo-propyl]-amide (970 mg, 47.7 mmol, 88% yield) as a off-white solid. MS (ISP): m/z=331.1 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][N:19]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:23])=[CH:16][C:15]=2[Cl:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1([CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:30][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:39][CH2:38][CH:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:12]1)[C:20](=[O:23])[N:19]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2Cl)CN(C2CCCCC2)C3=O)CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)c(Cl)cc2CN1C1CCCCC1

Procedure:
In the same manner as in Example 47, the title compound was prepared from 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one obtained in Example 45 and 3,3-diphenylpropyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cc1cccc(O)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using the following starting materials: (3-hydroxy-phenyl)-acetic acid ethyl ester and 2-fluoro-5-nitrobenzaldehyde.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH:7]1([C:9]2([CH:6]3[CH2:5][CH2:4][CH:3]=[CH:2][CH2:7]3)[CH:8]=[CH:12][CH:11]=[CH:10]2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCC=C1
Reactant: BrC1C=CCCC1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C1=CC(C2CC=CCC2)(C2CC=CCC2)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A 1.0 L double-walled reactor, provided with baffles, condenser, top stirrer, thermometer and dropping funnel equipped with a nitrogen inlet was charged with ALIQUAT 336 (7.6 g, 19 mmol), 3-bromocyclohexene (58.8 g, 0.37 mol) and freshly cracked cyclopentadiene (11.9 g, 0.18 mol). A 50 wt. % NaOH aqueous solution (152 g) was then added via the dropping funnel to the, turbulently stirred reaction mixture. The reaction mixture was cooled with water during the addition of the base. After 4 hours of stirring at room temperature, stirring was stopped and the phases separated, the aqueous basic solution was isolated and removed. GC analysis showed that 4 % of mono- and 96% of di-(3-cyclohexenyl)cyclopentadiene were present in the mixture. The product was distilled at reduced pressure and after vacuum distillation, 36.0 g of di-(3-cyclohexenyl)cyclopentadiene were obtained. Characterization of the product took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].Cl.[CH2:31](O)[CH3:32]>>[CH2:31]([O:2][C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:3])[CH3:32]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A boiling solution of 7.5 g. (0.02 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole and 200 ml. of ethanol was saturated with hydrogen chloride, then heated under reflux for 26 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 4.1 g. (51%) of off-white crystals, m.p. 134°-135°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19]CC)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[Li+].[OH-]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([OH:19])=[O:18])(=[O:11])=[O:12])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(N)cc12
Yield: 7 %

Procedure:
The ethyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoate was hydrolyzed with LiOH following the hydrolysis procedure described in Example 46. The title compound was obtained in 7% yield (over two steps, 2.6 mg). MS (ESI+) calcd for C16H14N2O4S2 362.039498, found 362.040938.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([O:14]C)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:14]
Reactant: Nc1ccccn1
Reactant: COC(=O)c1nnc2ccccc2c1O
Product: O=C(Nc1ccccn1)c1nnc2ccccc2c1O
Temperature: 150 °C
Reaction time: 10 h

Procedure:
4-Hydroxy-cinnoline-3-carboxylic acid, methyl ester (6 g), prepared accoring to J. Chem. Soc. 687 (1968), is reacted with 2-aminopyridine (16.6 g, stepwise added) in polyphosphoric acid (300 g:160 g of H3PO4 and 140 g of P2O5) under stirring at 150° C. for 10 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered and washed with water. Crystallization from dimethylformamide gives 4.9 g of 4-hydroxy-N-(2-pyridyl)-cinnoline-3-carboxamide, m.p. 341°-343° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O>[CH2:33]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[CH2:16][CH2:15]1)=[O:13])[CH3:34]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added, followed by stirring at room temperature for 15 min and then iodoethane(39.2 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[C:34]([F:36])[CH:35]=1)[CH2:32][C:31](=O)[CH2:30][CH2:29]2>>[CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH:23][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[C:34]([F:36])[CH:35]=[C:26]([F:25])[CH:27]=3)[CH2:32]2)[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: 13C NMR 14.2, 19.5, 19.6, 28.2, 28.3, 28.5, 28.6, 28.6, 28.7, 28.8, 29.7, 29.8, 30.8, 36.5, 36.6, 39.8, 52.3, 52.7, 54.0, 57.2, 57.3, 60.3, 60.8, 67.1, 100.8, 101.1, 101.3, 104.6, 104.7, 110.5, 110.6, 110.8, 110.9, 130.5, 137.6, 137.7, 139.9, 159.7, 162.3, 172.3, 172.5; MS m/z 504.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1OCCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1cc(N2CCOCC2)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
The methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-(morpholin-4-yl)benzoate (2.34 g, 5.93 mmol) was diluted with ethanol (60 mL) and water (60 mL). Potassium hydroxide pellets (1.64 g, 29.2 mmol) were added, and the resulting mixture was heated to 70° C. After 2 h, the reaction mixture was concentrated in vacuo. The residue was diluted with methylene chloride (200 mL) and extracted with saturated aqueous citric acid (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the acid (2.24 g, 5.90 mmol, 99%).