Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]2[C:25](=[O:26])[N:8]3[C:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]23)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C1C[O:36]CC1.[OH-].[Na+].O>C(OCC)(=O)C>[C:1]([C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]12)=[O:27])([OH:36])=[O:32]
Reactant: C1CCOC1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A solution of 458 mg. (1 mmol.) of t-butyl 7-phthalimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml. of THF was cooled in an ice water bath, and 1.1 ml. of 1N NaOH were then added. After stirring for 5 min., 10 ml. of water and 30 ml. of ethyl acetate were added. The ethyl acetate layer was separated, and 70 mg. of starting material were recovered therefrom. The aqueous layer was acidified to pH 4.0, and the acidified layer was extracted with ethyl acetate. After workup, 330 mg. (83%) of the desired phthalamic acid were obtained [α] + 26.37 (MeCN); λEtOH 260 mμ (ε 8800)D ; ir (CHCl3) 1785, 1730 and 1685 cm-1 ; nmr (CDCl3) δ 1.55 (s, 9, t-Bu), 2.05 (s, 3, Ac), 3.3 and 3.6 (ABq, 2, J = 17 Hz), 4.72 and 5.2 (ABq, 2, J = 14 Hz), 4.98 (d, 1, J = 4.5 Hz), 5.9 (dd, 1, J = 4.5 and 9 Hz), and 7.5-8 (m, 4, ArH).
Reaction SMILES: C(O[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])C.[C:21](#[N:23])[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>CN(C=O)C>[C:21]([CH2:22][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])#[N:23]
Reactant: CC#N
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)OCC)cc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CC#N)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 1-(6-ethoxycarbonyl-2-benzothiazolyl)-3-ethylurea (1.20 g, 4.09 mmol) in 5 mL of anhydrous DMF was treated with 2 mL of acetonitrile, cooled down to about 0° C., followed by treatment with 1 M LiHMDS in THF (13.1 mL, 13.1 mmol, 3.2 eq). It was stirred at the temperature for about 0.5 hour, then warmed up to room temperature, and stirred for another 4 hours. More LiHMDS (4 mL, 4.0 mmol, 1.0 eq) was added after the first hour. The mixture was quenched with MeOH and water, concentrated, and purified by flash chromatography on SiO2 with MeOH and methylene chloride (1/50) to give the desired compound 0.640 g (54%). LC/MS 288.9 (M+1); LC retention time 2.56 min.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:42])[C@H:18]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])[CH3:19]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C@H:18]([CH3:19])[C:17]([O:16][CH3:15])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[CH:10]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[S:13][CH:12]=1
Reactant: CC1(c2cc(CO)cs2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cc(CCl)cs2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-methanol (280 mg, 1.40 mmol) in dry CH2Cl2 (2.58 mL) was treated at 0° C. with Et3N (0.25 mL, 1.82 mmol) followed by DMAP (17 mg, 0.14 mmol) and Ms-Cl (0.13 mL, 1.68 mmol). The reaction mixture was stirred at rt for 2 h before being quenched with water (5 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(4-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. A solution of the crude material in acetone (3.5 mL) was treated, under inert atmosphere (N2) with K2CO3 (588 mg, 4.25 mmol) followed by 4-nitro-1H-pyrazole (181 mg, 1.42 mmol) and TBA bromide (91 mg, 0.28 mmol). The resulting mixture was stirred overnight at rt and then the solvent was removed under reduced pressure. Water (10 mL) and EA (20 mL) were added. The aq. layer was extracted with EA (80 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow solid. TLC: rf (50:50 hept-EA)=0.45. LC-MS-conditions 02: tR=0.96 min; [M+H]+=296.04.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1>C(#N)C.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1
Yield: 98.1 %

Procedure:
Potassium carbonate (19.2 g) and benzyl bromide (19.0 g) were added to a solution of ethyl 4-hydroxy-2-naphthoate (20 g) in acetonitrile (200 ml) and the mixture was heated to reflux for 2 hours. After being cooled, the reaction solution was diluted with ethyl acetate and insoluble materials were filtered through Celite. The filtrate was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/1) to give ethyl 4-(benzyloxy)-2-naphthoate (27.8 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from acetone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 86.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (217 mg), 239 mg 6-(2-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 348 mg (86%) of the title compound as a brown solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)(=O)=[O:25].C(O)C>C(Cl)Cl>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
3.3 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 50 ml of methylene chloride, the solution cooled to -70° C., and a solution of 1.5 gm of sulfuryl chloride in 5 ml of methylene chloride was added dropwise. After 15 hours, 20 ml of 95% ethanol were added, and the mixture was heated to room temperature by removing the cooling bath, neutralized with an aqueous sodium carbonate solution. The methylene chloride phase was dried with sodium sulfate, and the solvent was evaporated. The residue was recrystallized from toluene.
Reaction SMILES: [SH:1][C:2]1[N:3]([NH2:20])[C:4]([C@H:7]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:8])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=S)[CH:25]=[CH:26][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C.CCOCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[S:1][C:2]3=[N:6][N:5]=[C:4]([C@H:7]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:8])[N:3]3[N:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1nnc(S)n1N
Reactant: S=C=Nc1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: CCO
Product: C[C@@H](NC(=O)OCc1ccccc1)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
(Step 8-ii) A mixture of (R)-benzyl 1-(5-mercapto-4-amino-4H-1,2,4-triazol-3-yl)ethylcarbamate (1.32 g, 4.5 mmol) in ethanol (15 mL) was heated to 80° C. and 3-chlorophenylisothiocyanate (1.3 g, 7.65 mmol) and dicyclohexylcarbodiimide (1.11 g, 5.4 mmol) were added. After 4 hours, the reaction was cooled, diluted with an equal volume of ether, and filtered. The filter cake was washed with additional ether and the collected solids dried in vacuo to provide 0.94 g of (R)-benzyl 1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethylcarbamate: ESMS MH+=429.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]3)=[N:14]2)=[CH:25][CH:24]=1
Reactant: CN1CCNCC1=O
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(Br)c32)C1=O
Product: CN1CCN(c2nn(Cc3ccc(F)cc3)c(=O)c3c(O)c4n(c23)CCN(C)C4=O)CC1=O
Temperature: 100 °C

Procedure:
A mixture of 10-(benzyloxy)-4-bromo-2-(4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.10 g, 0.19 mmol; Example 160, Step 1) and 1-methylpiperazin-2-one (2 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The benzyl protecting group was also cleaved in the process. The reaction mixture was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1cccnc1N
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, aniline 0.3 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various kinds of acids 0.03 mmol as shown in the following table 4, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products from various acids and the results are given in Table 4, below.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl-].[Mg+2].[K+].[F:8][C:9]([F:22])([F:21])[S:10]([CH2:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])(=[O:12])=[O:11].[Cl-].[Cl-]>C1COCC1>[F:19][C:17]([F:20])([F:18])[S:14]([CH:13]([S:10]([C:9]([F:8])([F:21])[F:22])(=[O:11])=[O:12])[CH2:3][CH:2]=[CH2:1])(=[O:15])=[O:16]
Reactant: C=CCBr
Reactant: O=S(=O)(CS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C=CCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
Next, 4,4-bis[(trifluoromethyl)sulfonyl]-1-butene was prepared by adding 3 ml of allyl bromide to 31.3 millimoles of the bis[(trifluoromethyl)sulfonyl] methane potassium magnesium chloride in 35 ml of THF. The mixture was stirred at 70° C. under reflux for 8 hours. After removal of solvent by distillation under reduced pressure, 50 ml of 3N hydrochloric acid was added to the residue and the aqueous solution was extracted with ethyl ether. The ethyl ether solution was dried with anhydrous MgSO4. The ethyl ether was removed from the solution and the product was distilled at 0.02 torr.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([NH:41][CH3:40])=[O:24])=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12
Product: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12

Procedure:
3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was prepared from 3-(7-methoxy-1H-indazol-4-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4). Part of the crude 3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was used without further purification for the next step. A second portion of3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide was purified on chiral HPLC by multiple injections onto 20×250 mm Chiralpak AD preparative column using a mixture of 70/30 hexane/EtOH at 7 ml/min in order to separate the enantiomers CXCIX-A and CXCIX-B.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: Cc1cc(C)c(Br)c(C)c1N
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c(NC(=O)CN(CC(=O)O)CC(=O)O)c(C)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves) is prepared with the exclusion of moisture (CaSO4 drying tube) and heated to 50° C. Acetic anhydride (5.11 g) is added dropwise. The reaction mixture clears and is heated to 100° C. After maintaining the temperature for 40 minutes, the reaction mixture is cooled to 55° C. and a solution of 10.7 g 3-bromo-2,4,6-trimethylaniline in 25 ml of dry pyridine is added slowly. The reaction is heated to 100° C. and after 1.5 hours at this temperature, the solution is cooled in an ice-bath. The reaction mixture is rotary evaporated to a semisolid which is dissolved in 125 ml of 10% sodium hydroxide w/v. The basic layer is then extracted with two 100 ml portions of methylene chloride. Distilled water (100 ml) is added to the basic layer which is then brought to pH 3 with concentrated hydrochloric acid to give a precipitate. After refrigeration for about 16 hours, the crude product is filtered, washed with cold distilled water and dried under vacuum at 40° C. The crude product is dissolved in 100 ml of 60% aqueous ethanol, treated with 3.0 g of Darco and filtered hot through a Hyflo-bed to give a solution. Crystals precipitate and are filtered, washed with three 25 ml portions of 50% aqueous ethanol and dried under vacuum at 40° C. The reaction yields 9.1 g of the title compound, melting point 198°-200° C., dec.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].C(C(C(C(O)=O)O)O)(O)=O.[CH3:30][C:31]1[CH:35]=[C:34]([CH3:36])[N:33]([CH2:37][CH2:38][CH2:39][NH2:40])[N:32]=1.C(N(CC)CC)C>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:33]2[C:34]([CH3:36])=[CH:35][C:31]([CH3:30])=[N:32]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)n(CCCN)n1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)n(CCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)n1
Temperature: 120 °C
Yield: 93.6 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.5 mmol), 3-(3,5-dimethyl-pyrazol-1-yl)-propylamine tartrate (167 mg, 0.55 mmol) were mixed in MeCN (3 ml). Triethylamine (0.23 ml, 1.65 mmol) was added and the mixture was heated in a microwave reactor at 120° C. for 15 mins. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography (ISOLUTE SI, 20 g/70 ml), eluting with DCM and then MeOH/DCM (1:99), to give the title compound (195 mg, 94%). 1H NMR (400 MHz, CDCl3): δ 1.70 (s, 9H), 1.72-1.79 (m, 2H), 2.05 (s, 3H), 2.18 (s, 3H), 2.81-2.86 (m 2H), 3.79 (t, 2H), 5.71 (bs, 2H), 7.37-7.46 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 10.8, 13.4, 27.5, 29.2, 41.5, 45.4, 61.3, 105.1, 106.8, 125.0, 128.4, 129.4, 131.4, 135.0, 138.5, 147.7, 159.3; Mass Spectrum: M+H+ 417.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[ClH:15].[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[ClH:15].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:18][C:17]([NH2:19])=[NH:16])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2cc(C(=O)NC(=N)N)ccc21
Yield: 68.8 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.00 g (5.29 mmol) of methyl 1-methyl-5-indolecarboxylate, 5.05 g (52.9 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.85 g (52.9 mmol) of sodium methoxide. Thus 0.92 g (68.9%) of 1-methyl-5-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [OH:1]O.[OH-].[Na+].C[C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=O.O>CO.S(=O)(=O)(O)O>[CH3:14][CH:7]1[CH2:6][CH2:11][CH2:10][C:9](=[O:1])[C:8]1([CH3:13])[CH3:12]
Reactant: OO
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCCC(=O)C1(C)C
Reaction time: 0.25 h

Procedure:
110 ml of a solution of 30 % H2O2 followed by 28 ml of a 6N aqueous solution of NaOH were added dropwise, while stirring and within 45 minutes and 15 minutes, respectively, to a cooled solution (0°-5°) of 40 g of β-cyclocitral (0.26 mole) in 300 ml of methanol which had been acidified beforehand with 40 drops of concentrated sulphuric acid. The reaction mixture was then kept at room temperature for 3 days, while stirring. After having added water thereto, the said mixture was extracted three times with ether and the combined organic extracts were subjected to the usual treatments of washing (water), drying (MgSO4) and concentration. There were obtained 21.5 g of trimethyl-cyclohexanone by fractional distillation; b.p. 66°-69°/12 Torr (66 %).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][CH2:33][CH2:34][CH:35]4[O:40][C:39]([CH3:42])([CH3:41])[O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:54])[CH3:53])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][CH2:33][CH2:34][CH:35]4[O:40][C:39]([CH3:41])([CH3:42])[O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
Tert-butyl 2-(6-(2-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Example 78, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC, reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 712 (100%).