Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].[CH3:59][N:60]([CH3:68])[CH2:61][CH2:62][S:63][CH2:64][C:65](O)=[O:66].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO.O>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:65](=[O:66])[CH2:64][S:63][CH2:62][CH2:61][N:60]([CH3:68])[CH3:59])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CCSCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CSCCN(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Synthesis of (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt previously described. (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (4.06 g, 6.41 mmol) was stirred in DCM (60 mL) with 10% K2CO3 (30 mL) at 0-5° C. After 30 min, the organic phase was separated and the aqueous phase was further extracted with DCM (30 mL). The combined organic phases were stirred with anhydrous MgSO4 for a period of 30 minutes at 0-5° C., filtered, and washed with DCM (30 mL). To the combined filtrates were added to 2-((2-(dimethylamino)ethyl)thio)acetic acid (1.26 g, 7.70 mmol), EDC HCl salt (1.84 g, 9.62 mmol), DMAP (78.3 mg, 0.64 mmol). The thin suspension was stirred overnight at room temperature; after which a period of time, the solution became clear. Next day, deionized water (60 mL) and methanol (30 mL) were added. After stirring for 10 minutes, the clear organic layer was isolated. The turbid aqueous phase is extracted with DCM. The combined organic extracts were concentrated. Crude material was filtered through a plug of silica and taken up in DCM (40 mL) and PBS (pH=11, 50 mL) was added. The mixture was stirred at room temperature for 10 min. Then, the organic phase was separated and the aqueous phase is extracted again with DCM (15 mL). The combined organic phases were stirred with anhydrous MgSO4 for a period of 30 min. The mixture was then filtered, and washed with DCM. The combined filtrates were concentrated in vacuo to yield (Z)-((2-((2-(dimethylamino)ethyl)thio)acetyl)azanediyl)bis(ethane-2,1-diyl) dioleate (3.44 g).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:12][O:13]C(=O)C2C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=2)=[CH:8][CH2:7]1)([CH3:5])=[CH2:4]>CO>[CH3:5][C:3]([C@@H:6]1[CH2:7][CH:8]=[C:9]([CH2:12][OH:13])[CH2:10][CH2:11]1)=[CH2:4]
Reactant: C=C(C)C1CC=C(COC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)[C@@H]1CC=C(CO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (3.23 g, 80.0 mmol, dissolved in 28 mL of water) was added to an ice cold solution of 3,5-Dinitro-benzoic acid 4-isopropenyl-cyclohex-1-enylmethyl ester (14.0 g, 40.4 mmol) in methanol (140 mL) over a period of 0.25 h. The reaction mixture was allowed to warm to room temperature and then stirred for 3.0 h. The methanol was concentrated under vacuum and the resulting residue was suspended in water (60 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (2×100 mL) followed by brine (15%, 100 mL) and dried over sodium sulphate (30 g). The filtered organic layer was concentrated under vacuum to get pure (S)-perillyl alcohol (Weight: 5.84 g, Yield: 95% Purity: 99.4% by GC).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].[H-].[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3](=[O:4])[CH2:20][C:19]#[N:21])[CH:14]=[CH:13]2
Reactant: CC#N
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(=O)CC#N)ccc2c1
Temperature: 90 °C

Procedure:
To a solution of 6-methoxy-naphthalene-2-carboxylic acid methyl ester (1.0 g, 4.7 mmol) in dry toluene (8 mL), NaH (0.55 mg, 9.4 mmol) were added and the mixture was heated at 90° C. To the hot solution, acetonitrile (1.2 mL) was added dropwise. The reaction was then heated for 18 hours and the product precipitated from the reaction mixture as its sodium salt.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: CNC
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N(C)C)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and dimethylamine. LCMS (Method C): 512 (M+H)+, Retention time 12.1 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]=[C:11]([NH2:18])[CH:10]=1.CO[CH:21](OC)[CH2:22]Br.O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]2[CH:21]=[CH:22][N:18]=[C:11]2[CH:10]=1
Reactant: COC(CBr)OC
Reactant: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
48.5 g (161.55 mmol) of 6-(2,4-dichlorophenyl)-2-(ethylthio)pyrimidine-4-amine (Example 3A) and 163.84 g (969.32 mmol) of bromoacetaldehyde dimethyl acetal are introduced into a mixture of 1164 ml of dioxane and 291 ml of water and heated under reflux for 16 h. The dioxane is substantially removed in vacuo, and 1000 ml of ethyl acetate and 1000 ml of saturated aqueous sodium bicarbonate solution are cautiously added. The phases are separated and a further extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and then freed of solvent. The residue is purified by silica gel chromatography. 16.6 g (27% of theory) of the product are obtained and are reacted further in this form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:29])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(CSc2cc(N)ncc2Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CSc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
4-(4-methoxybenzylthio)-5-bromopyridin-2-amine (7.45 g, 22.9 mmol) was dissolved in THF (80 mL). Benzoyl isothiocyanate (3.4 ml, 25 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solution was diluted in 9:1 hexanes:EtOAc and stirred for 5 minutes, then filtered and dried to provide the desired product (8.5 g, 76% yield) as a brown solid.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3OC)[CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>O1CCCC1.CC(C)=O>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH2:9][CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:41][CH3:40])[CH:19]=3)[CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1C1CCCN(C(=O)COC(c2ccccc2)c2ccccc2)C1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C2CCCN(CCOC(c3ccccc3)c3ccccc3)C2)c1
Reaction time: 8 h

Procedure:
A solution of 6.6 g (15.9 mmole) of 1-[(diphenylmethoxy)acetyl]-3-(methoxyphenyl)piperidine in 50 cm3 of tetrahydrofuran was added dropwise to a solution of 0.96 g (25.4 mmole) of lithium aluminum hydride in 100 cm3 of tetrahydrofuran. The mixture was brought to reflux for 5 hours, allowed to stand overnight, then hydrolyzed by the addition of 5 cm3 of water. The alkaline residues were separated. The solution was concentrated under reduced pressure. The residue was treated with a solution of 1.5 g (16.7 mmole) of oxalic acid in 100 cm3 of acetone. The 1-[2-(diphenylmethoxy)ethyl]-3-(3-methoxyphenyl)piperidine oxalate precipitate was filtered and recrystallized from acetone.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[C:9]([OH:16])[CH:8]=[C:7]([OH:17])[C:6]=1[C:18](=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=O)C.[OH-].[K+].Cl>CO>[OH:4][C:5]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[C:9]([OH:16])[CH:8]=[C:7]([OH:17])[C:6]=1[C:18](=[O:28])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1
Reactant: CC(=O)Oc1c(CC=C(C)C)c(O)cc(O)c1C(=O)CCc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCc1c(O)cc(O)c(C(=O)CCc2ccc(O)cc2)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
To 10 ml of a methanol solution of 500 mg of the 1-[2-acetoxy-4,6-dihydroxy-3-(3-methyl-2-butenyl)phenyl-]-3-(4-hydroxyphenyl)-1-propanone obtained in Specific Example 24 was added an aqueous solution of potassium hydroxide (1.5 g/5 ml), and the mixture was stirred at room temperature for 45 minutes. After the reaction, the reaction mixture was carefully neutralized wit dilute hydrochloric acid, extracted with 300 ml of ethyl acetate, washed with water (100 ml×4 times), shaken with a saturated aqueous solution of sodium chloride (100 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from a mixed solvent of chloroform and methanol to obtain 325 mg (yield=73.0%) of 1-[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2].[OH-:36].[Na+].Cl>CS(C)=O.O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([C:1]([NH2:2])=[O:36])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:24][CH:23]=2)=[O:27])=[CH:34][CH:33]=1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(N)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
The N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (360 mg, 0.762 mmol) obtained in Example 10 was dissolved in dimethylsulfoxide (4.5 ml), and then 5N aqueous sodium hydroxide (1.5 ml) was added and the mixture was heated at 80° C. while stirring for 60 minutes. The reaction solution was cooled in an ice water bath, 2N hydrochloric acid (3.75 ml) was added for neutralization, and then the mixture was diluted with water (21 ml) and the precipitated crude crystals were filtered out. These were suspended in ethanol (20 ml) and subjected to sonication, and upon filtering out the crystals they were dried under reduced pressure to obtain the title compound (214 mg, 0.436 mmol, 57.3%) as gray crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:46][C:47]1[CH:48]=[C:49]([NH2:60])[CH:50]=[CH:51][C:52]=1[C:53]([N:55]1[CH2:59][CH:58]=[CH:57][CH2:56]1)=[O:54].ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:46][C:47]1[CH:48]=[C:49]([NH:60][C:12](=[O:14])[CH2:11][C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:50]=[CH:51][C:52]=1[C:53]([N:55]1[CH2:56][CH:57]=[CH:58][CH2:59]1)=[O:54]
Reactant: O=C(O)Cc1cc2cc(Cl)ccc2[nH]1
Reactant: Nc1ccc(C(=O)N2CC=CC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cc1cc2cc(Cl)ccc2[nH]1)Nc1ccc(C(=O)N2CC=CC2)c(Cl)c1
Yield: 37 %

Procedure:
Prepared analogously to Example 1g from 2-(5-chloro-1H-indol-2-yl)acetic acid, TBTU, diisopropylethylamine, and 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)phenylamine in tetrahydrofuran. Yield: 37%; Rf value: 0.34 (silica gel: dichloromethane/ethanol=95:5); C21H19Cl2N3O2 (416.306); mass spectrum: (M+H)+=416/418 (chlorine isotope).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].CO>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C2=CCCC2)cn1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1ccc(C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-cyclopentenyl-pyridine-2-carboxylic acid (2.0 g, 11 mmol) and palladium on carbon (10% w/w, 0.5 g) in methanol (20 mL) under a hydrogen atmosphere was stirred at ambient temperature overnight. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound which was used in the next step without further purification (1.4 g, 72%); MS (EI): m/e=192.1 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:38][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:34][CH:35]=1)[CH3:37]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CN(C)CCCN(C)c1ccc(N)cc1
Product: CC/C(Nc1ccc(N(C)CCCN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH:43][C:44]([CH2:46][CH2:47][C:48]([OH:50])=O)=[O:45])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(=[O:53])C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([O:19][CH2:20][CH:21]([N:43]1[C:48](=[O:50])[CH2:47][CH2:46][C:44]1=[O:45])[CH:22]([O:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[OH:53])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CCC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCCCCCOCC(C(O)OC(c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)CCC1=O
Temperature: 100 °C

Procedure:
A mixture of 2.21 g of the carboxyl compound obtained in Example 8 and 0.45 g of sodium acetate in 10 ml of acetic anhydride was heated at 100° C. for 2 hours, and the mixture was concentrated under reduced pressure. n-Hexane was added to the mixture and the insoluble matter was filtered off. The filtrate was concentrated to dryness to give a crude product of 3-octadecyloxy-2-succinimido-1-trityloxypropanol. This crude trityl compound in 20 ml of 70% acetic acid was heated at 100° C. for 2 hours. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography (chloroform-methanol=20:1) to give 1.316 g (95%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:16]([CH3:17])=[N:15][N:14]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1nncc(-c2ccc(F)cc2)n1
Product: Cc1nnc2nc(-c3ccc(F)cc3)cnn12

Procedure:
A mixture of 0.57 g. of 5-(p-fluorophenyl)-3-hydrazino-1,2,4-triazine and 20 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled and filtered. The desired product is recovered as a brown solid, m.p. 227.5°-231° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9](=O)[C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[Br:28]N1C(=O)CCC1=O>C1COCC1.O.C(OCC)(=O)C>[Br:28][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[NH:10][CH2:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=1
Reactant: Cc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: -30 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (±)-cis tert-butyl 6-methyl-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 19, Part A (0.87 g, 3.0 mmol) in 15 mL of THF and 4 mL of DMF at −30° C. was added N-bromosuccinimide (0.56 g, 3.15 mmol). The reaction was stirred at −30° C. for 1 h and then was diluted with water and ethyl acetate. The organics were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford 0.99 g (90%) of the title compound which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.CC([O-])(C)C.[K+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C[N:33](C=O)C>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH2:33])[CH:3]=1
Reactant: Cc1c[nH]c2cnccc12
Reactant: CN(C)C=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cn(N)c2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.21 g, 9.16 mmol), KOtBu (2.05 g, 18.3 mmol) in DMF (41 mL) is purged with N2 and stirred at rt for 2 h. Chloramine in ether (0.15 M, 92 mL) is added and the mixture is stirred for 20 min. The reaction is cooled to 00 C. and a solution of Na2S2O3 (5 g) in water (80 mL) is added. The mixture is stirred for 10 min, and then concentrated in vacuo. The residue is triturated in DCM and filtered. DCM is added, cooled to 0° C. and charged with BOC2O (541 mg, 2.48 mmol). The resulting mixture is separated by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo[2,3-c]pyridin-1-yl amine (468 mg, 35%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.27 (d, 1H), 7.46 (d, 1H), 7.09 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][CH2:36]Cl>C1COCC1>[CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:34][O:35][CH3:36])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 1.05 g (2.48 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide, 1.71 g of potassium carbonate and 566 μL of methoxymethyl chloride in 7 mL THF using procedure x. Yield: 420 mg of a white solid. LC-MSD, m/z for C17H17ClF3N3O5S [M+Na]+=490.0, 491.9; HPLC retention time: 2.5 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([Cl:15])[CH:6]=1.[CH:17](OC)=[O:18].[Na].CO>CCOCC.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:13])[F:14])[CH:8]=[C:7]([Cl:15])[CH:6]=1)[CH:17]=[O:18]
Reactant: COC=O
Reactant: COC(=O)Cc1cc(Cl)cc(OC(F)F)c1
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)C(C=O)c1cc(Cl)cc(OC(F)F)c1
Temperature: 2 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
3-Chloro-5-difluoromethoxyphenylacetic acid methyl ester (1 g, 4 mmol; see step (vi) above) and methyl formate (1 g, 16 mmol) were dissolved in ether (100 mL) and cooled in an ice-bath (ca. 2° C.). Then, finely cut sodium (180 mg, 7.8 mmol) and methanol (1 mL) were added and the mixture was left in the ice-bath with stirring overnight. Water (100 mL) was added carefully and the phases were separated. The water containing phase was acidified with hydrochloric acid (2 M) to pH 1 and extracted with ether (2×100 mL). The extract was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (hexane:ethyl acetate (1:1)) which gave 400 mg, 1.4 mmol (yield: 36%) of the sub-title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.S(=O)(=O)=O>CS(C)=O.O>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
Boc-leucinol (3) (12.88 g, 58.9 mmol) was flushed with toluene and then purged with argon gas. It was dissolved in dimethylsulfoxide (dehydrated, 200 ml) and, after addition of triethylamine (22 ml, 158 mmol), cooled in a 15° C. water bath. Meanwhile, in another flask, sulfur trioxide-pyridine complex (25.3 g, 159 mmol) was dissolved in dehydrated DMSO (100 ml) and stirred for 10 minutes under argon stream. Cooling at 15° C., the sulfur trioxide solution was added dropwise (4 minutes) to the solution of Boc-leucinol (3), and, after further stirring of 8 minutes, the reaction mixture was poured into 1500 ml of cold water to terminate the reaction. Following extraction with ethyl acetate, the organic layer was washed with 0.1 M hydrochloric acid, water and saturated saline solution in the order, dried with anhydrous sodium sulfate, and concentrated after removal of the drying agent. Purification using a silica gel open column (250 g, ethyl acetate/hexane=1/5) gave the aimed compound, Boc-Leu-H (aldehyde) (4). Yield: 10.9 g (85.8%).