Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9][C:10]([C:12]1[C:21]2[C:16](=[C:17]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl>[CH2:43]([O:42][C:40]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][S:22]([C:17]2[C:16]3[C:21](=[C:12]([C:10](=[O:11])[NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]4[CH3:2])[CH:13]=[CH:14][CH:15]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:31])=[O:30])[CH2:29][CH2:28]1)=[O:41])[CH3:44]
Reactant: CCOC(=O)Cl
Reactant: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCNCC3)cccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)NC4CCCCC4C)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (2-methyl-cyclohexyl)-amide hydrochloride 48 (190 mg, 0.41 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (0.13 g, 0.18 mL, 1.28 mmol) was added followed by ethyl chloroformate (65 mg, 0.068 mL, 0.60 mmol). The reaction was stirred overnight at room temperature. The crude reaction mixture was charged to a flash column. Elution with 99:1 dichloromethane:methanol afforded H-24 (66 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3) (1:1 mixture of diastereomers) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.25 (d, 1H), 7.55 (m, 3H), 6.20 (d, 1H), 5.47 (m, 1H), 5.26 (s, 1H), 4.00 (m, 2H), 3.75 (m, 3H), 3.20 (m, 1H), 2.75 (m, 2H), 2.15 (m, 1H), 1.78 (m 3H), 1.57 (m 2H), 1.38 (m, 2H), 1.05 (m, 10H); LC/MS m/z 502 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.[OH-].[K+].CC([OH:35])(C)C>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]([NH2:25])=[O:35])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1
Reactant: N#Cc1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Yield: 99 %

Procedure:
A mixture of 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile (0.072 g, 0.198 mmol), potassium hydroxide (0.111 g, 1.981 mmol, v/w) and t-BuOH (2 mL, Acros) was heated at 80° C. overnight. LCMS showed the product. The mixture was diluted with water and extracted with a mixture of CHCl3:i-PrOH (3:1) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (75 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH3:13])[CH:7]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([N:35]1[CH:36]=[CH:37][C:32]([C:16]2[CH:15]=[CH:14][C:4]([O:5][C:6]3[CH:7]=[C:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH:11]=3)=[CH:3][C:2]=2[F:1])=[C:33]([C:43]#[N:44])[C:34]1=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3cc(C)nc(C)c3)cc2F)c(C#N)c1=O

Procedure:
To a solution of intermediate 18 (1.078 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 6 (0.25 g, 0.979 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.113 mg, 0.098 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and the pad of diatomaceous earth was washed with EtOAc. The combined filtrates were washed with water and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 6 that was precipitated from diethylether (0.220 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 89.7 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (4.24 g, 19.48 mmol) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (6.73 g, 21.41 mmol) in DMF (21 ml) were stirred at 50-55° C. for 24 hours. The reaction mixture was allowed to return to room temperature and poured into water (90 ml), and extracted with ethyl acetate (60 ml). The aqueous layer was extracted with ethyl acetate (60 ml) again. The organic phases were combined, washed with water (90 ml) 3 times and a saturated saline solution (60 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (9.29 g, yield 90%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH:11]1([C:14]2[C:19](=[O:20])[NH:18][C:17]([CH:21]=[O:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1.[Al]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:11]1([C:14]2[CH:15]=[CH:16][C:17]([CH:21]=[O:22])=[N:18][C:19]=2[O:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc(C2CC2)c(=O)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: COc1ccc(COc2nc(C=O)ccc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
p-Methoxybenzyl chloride (329 mg) was added to a solution of 5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (228 mg) in chloroform (10 mL), after which the reaction tube was covered with aluminum foil to provide shading conditions. Silver carbonate (771 mg) was added and the mixture was stirred at room temperature for three hours. The insoluble matter was filtered off and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridine-2-carbaldehyde as a colorless oil (417 mg, 86%).
Reaction SMILES: C[O-].[Na+:3].[CH:4]1[C:17]2[NH:16][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:18]([OH:20])=[O:19])[C:10]=3[O:9][C:8]=2[C:7]([C:21]([OH:23])=[O:22])=[CH:6][CH:5]=1>CO>[Na+:3].[CH:4]1[C:17]2[NH:16][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:18]([O-:20])=[O:19])[C:10]=3[O:9][C:8]=2[C:7]([C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1.[Na+:3]
Reactant: O=C(O)c1cccc2c1Oc1c(cccc1C(=O)O)N2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cccc2c1Oc1c(cccc1C(=O)[O-])N2

Procedure:
Sodium methoxide (82 mg) is added to a solution of phenoxazine 4,6-dicarboxylic acid in methanol (5 ml). The solution is then evaporated to dryness to afford phenoxazine 4,6-dicarboxylic acid sodium salt. This compound may be converted to salts such as potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts and the like using similar methods.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:18])(=O)C.Cl>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:18]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1N
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1N

Procedure:
1-Acetamido-2-amino-4-phenoxybenzene is treated with hydrochloric acid in aqueous methanol to afford 1,2-diamino-4-phenoxybenzene which, in turn, is reacted with methoxycarbonyl isothiocyanate in accordance with the technique set forth in the third paragraph of Example XIV to afford 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-phenoxybenzene.
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]2[C:18]([O:26][CH3:27])=[N:19][C:20]([CH3:25])=[C:21]([CH2:23][CH3:24])[CH:22]=2)[CH3:16])C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:23]([C:21]1[CH:22]=[C:17]([CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[CH2:42][CH2:41]2)=[O:28])[C:18]([O:26][CH3:27])=[N:19][C:20]=1[CH3:25])[CH3:24]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(C(C)CCCCCNC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(C(C)CCCCCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 49 %

Procedure:
Phenyl-N-[6-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)heptyl]carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21]C)[CH2:10][CH2:9]1)=O)(C)(C)C.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[F:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: COc1ccc(F)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(F)cc1C1CCNCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a solution of 4-(5-fluoro-2-methoxyphenyl)piperidine-1-carboxylic acid t-butyl ester (2.0 g, 6.46 mmol) produced in Example (106b) in dichloromethane (50 mL) was added boron tribromide (1M solution in tetrahydrofuran, 19.4 mL, 19.4 mmol), followed by stirring for 4 hours at an external temperature of 60° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give 840 mg of a crude product of the title compound as a yellow oil.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:35])[CH2:29][O:30]C(C)(C)C)[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CCOC(C)=O.CC(OC)(C)C.O>[N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:35])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
3-[4-(Azetidine-1-carbonyl)-phenoxy]-5-((S)-2-tert-butoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-benzamide (101.3 μmol; 51.3 mg) was charged to a small screw capped reaction tube. DCM (500.0 μL) was added the reaction mixture followed by TFA (506.3 μmol; 38.3 μL; 57.7 mg), the reaction mixture was stirred at ambient temperature for 18 hours. HPLC analysis showed no reaction after this time. The reaction mixture was heated to 40° C., extra TFA (506.3 μmol; 38.3 μL; 57.7 mg) was added to the reaction tube and the mixture was held at 40° C. for 18 hours. Water (1 mL) was added to the reaction tube followed by sodium hydroxide (2M) (1.0 mmol; 506.3 μL; 526.6 mg). MTBE (4 mL) was added and the mixture was stirred for 5 minutes. An oily gum had formed which was dissolved by addition of EtOAc (2 mL). The two layers were separated and the upper organic layer was retained, the aqueous was extracted again with EtOAc (2×5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to give a colourless oil (35 mg, 75.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:33]=1[N+:42]([O-:44])=[O:43]>C1COCC1.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:38]([C:35]1[CH:36]=[CH:37][C:32]([F:31])=[C:33]([N+:42]([O-:44])=[O:43])[CH:34]=1)(=[O:39])=[O:40]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (851 mg, 3.39 mmol) and THF (10 mL) to give a clear, light yellow solution. The flask was cooled in a dry ice and acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3387 μl, 3.39 mmol) was added dropwise over 1 minute to give a suspension. The flask was removed from the cooling bath for 10 min, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (737.72 mg, 3.08 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 min. The mixture was stirred for another 5 min, then the mixture was warmed to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (0 to 30% EtOAc/heptane) to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (758 mg, 1.668 mmol, 54.2% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.24 (s, 1 H), 8.18 (dd, J=2.4, 6.7 Hz, 1 H), 7.99 (ddd, J=2.4, 3.9, 8.8 Hz, 1 H), 7.33-7.28 (m, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 6.32 (dd, J=2.3, 8.4 Hz, 1 H), 6.21 (d, J=2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m/z (ESI) 477.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH:34]1([C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Yield: 66.9 %

Procedure:
Preparation of example 33 from the title compound of Example 7 (35 mg, 0.13 mmol), (2S)-[(tert-butoxycarbonyl)amino](cyclohexyl)ethanoic acid (39 mg, 0.15 mmol), triethylamine (0.073 mL, 0.52 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (58 mg, 0.15 mmol) in N,N-dimethylformamide (2.0 mL) was carried out analogously to Example 11 except that after 24 hours additional (2S)-[(tert-butoxycarbonyl)amino](cyclohexyl)ethanoic acid (17 mg, 0.065 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) were added to drive the reaction to completion. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (45 mg, 0.087 mmol) as a yellow powder in 67% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O>O1CCCC1>[CH2:3]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCOCc1ccccc1
Yield: 56.3 %

Procedure:
60% Sodium hydride (1.2 g) was suspended in tetrahydrofuran (30 ml), and benzyl alcohol (3.0 g) was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 min, and again ice-cooled. 1,4-Dibromobutane (6.0 g) was added and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.8 g of 4-benzyloxybutyl bromide.
Reaction SMILES: Cl.CCOC(C)=O.[CH:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CCOC(C)=O>[CH:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24](=[O:25])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCc2ccccc2C1C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C([C@@H]1CCCN1)N1CCc2ccccc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
4 M HCl/EtOAc (4 mL) was added to a solution of tert-butyl (2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidine-1-carboxylate (1.79 g) in EtOAc (4 mL). The mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain 1-cyclohexyl-2-L-prolyl-1,2,3,4-tetrahydroisoquinoline (1.26 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Cl[CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[N:1]1([CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: COC(=O)COCCl
Product: COC(=O)COCn1ccnn1

Procedure:
The title compound was prepared from 1,2,3-triazole and methyl chloromethoxyacetate by a similar method to that of Preparation 40 as a colourless oil which was characterised by NMR. 1H-NMR (300 MHz, CDCl3): δ=3.76 (s,3H), 4.16 (s,2H), 5.84 (s,2H), 7.80 (d,2H) ppm.
Reaction SMILES: C(O[CH:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[CH:6]=O)C.[NH2:11][C:12]([NH2:14])=[O:13].Cl.[OH-].[Na+]>C(O)C>[CH:8]([C:5]1[CH:6]=[N:11][C:12](=[O:13])[NH:14][CH:4]=1)([CH3:9])[CH3:10]
Reactant: CCOC=C(C=O)C(C)C
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cnc(=O)[nH]c1
Yield: 82 %

Procedure:
A mixture of 3-ethoxy-2-isopropylprop-2-enal (ref. Menicagli, R. et al. Tetrahedron 1987, 43, 171–177) (250 mg, 1.76 mmol) and urea (250 mg, 4.16 mmol) in ethanol (2.5 ml) was treated with concentrated HCl (0.5 ml) and heated to reflux for 1 hour. Upon cooling, the reaction mixture was neutralized with 1N NaOH (0.6 ml) and extracted with chloroform. The organic layer was dried over MgSO4 and concentrated to provide 5-isopropylpyrimidin-2(1H)-one as an off-white solid (0.20 g; 82% yield).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[OH:26][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28]>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[O-:28][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:26]
Reactant: CCCCCCCCCC(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CCCCCCCCCC(=O)[O-]

Procedure:
According to the preceding example, 4.5 g of the salt are prepared, starting from 3.36 g (10-2 moles) of apovincamine and 1.72 g (10-2 moles) of capric acid. The product is a semisolid, low melting substance, insoluble in water and alcohol, with an apovincamine content of 50%.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([NH:12][C:8]4[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])[CH:11]=[CH:10][CH:9]=4)=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CCC(=O)O)c4)c23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Initially charge 1000 mg (2.085 mmol) of 3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}phenyl)propanoic acid methyl ester in 30 ml of THF and add 6.3 ml of 1N sodium hydroxide solution at RT. Stir the mixture at 50° C. for 1 h and then, after cooling, acidify slightly with 1N hydrochloric acid. Filter off the precipitated solid with suction, wash repeatedly with water and dry at 40° C. under high vacuum overnight. 934.5 mg (96.3% of theory) of the target product are obtained as a colourless solid.