Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH:48]([N:53]([CH3:70])[C:54](=[O:69])[CH:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[C:49](=[O:52])[NH:50][CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[N:67]([CH:55]([C:54](=[O:69])[N:53]([CH:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.19 g; 0.783 mmol) was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazole (0.12 g; 0.861 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.900 mmol) was added and the reaction mixture was stirred 15 min at room temperature. N-[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.33 g; 0.783 mmol) and diisopropyl ethylamine (0.15 ml; 0.861 mmol) was added and the reaction mixture was stirred 12 hours at room temperature. Methylene chloride (50 ml) was added and the reaction mixture was washed with water (50 ml), sodium hydrogen sulfate (10%; 50 ml), sodium hydrogen carbonate (sat; 50 ml), water (50 ml) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.366 g of {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester. {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylene chloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reaction mixture was stirred 5 min at room temperature. Methylene chloride (25 ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodium hydrogen carbonate (s) was added until pH=8. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was lyophylised to afford 0.237 9 of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCO)ccc(C(C)=O)c1O
Reaction time: 64 h
Yield: 28 %

Procedure:
A mixture of 5.80 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.6 ml of 3-bromo-1-propanol and 8.3 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethyl formamide was stirred at 75° for 64 hours. The reaction mixture was concentrated in vacuo, the residue was acidifed and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo to 8.7 g of an oil which was chromatographed on 150 g of silica gel. Elution with 40% ethyl acetate-toluene gave 2.84 g which was crystallized from ether-hexane to yield 2.14 g, mp 57°-59°, (28% yield) of 1-[2-hydroxy-4-(3-hydroxypropoxy)-3-propylphenyl]ethanone, the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][O:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
3-hydroxy-4-methoxybenzaldehyde (15 g, 98.6 mmol) was dissolved in acetonitrile (200 mL). 1-Methoxy-3-bromopropane (16.6 g, 108 mmol) and potassium carbonate (34 g, 247 mmol) were added and the mixture was brought to reflux and stirred for 3 hrs. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 22 g (quantitative yield) of the desired product as a yellow oil, used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 4-nitro aniline (1.01 g, 7.23 mmol) in anhydrous CH2Cl2 (20 mL) was added NMM (0.95 mL, 8.68 mmol). To the reaction mixture was added dropwise butyryl chloride (1.00 mL, 8.68 mmol) at 0° C. After stirring for 0.5 h, the reaction was extracted with CH2Cl2 (20 mL), washed with H2O (30 mL), dried over Na2SO4, and evaporated in vacuo to give N-(4-Nitrophenyl)butyramide (1.50 g, 100%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:18]3[C:13](=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:16]=4[CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:2]1=[O:22].CC(C)=O.Br[CH2:28][C:29]1[O:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=1.BrCC1CCCCO1>CC(=O)CC>[F:35][C:34]([F:37])([F:36])[C:31]1[O:30][C:29]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:18]4[C:13](=[CH:14][C:15]5[O:21][CH2:20][CH2:19][C:16]=5[CH:17]=4)[O:12][CH2:11][CH2:10]3)[C:2]2=[O:22])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12CCOc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12CCOc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, acetone to replace butanone, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-6.93 (m, 4H), 6.76-6.70 (m, 1H), 6.38 (d, J=3.5 Hz, 1H), 6.36 (s, 1H), 6.21 (s, 1H), 4.98 (ABq, 2H), 4.80-4.69 (m, 1H), 4.45 (t, J=8.6 Hz, 2H), 4.36-4.28 (m, 1H), 2.92 (t, J=8.5 Hz, 2H), 2.23-2.16 (m, 2H); 13C NMR (75 MHz, CDCl3) δ179.3, 160.6, 155.5, 152.2, 152.1, 141.8, 141.6, 141.3, 135.2, 128.3, 124.1, 123.5, 123.5, 120.6, 120.4, 117.0, 112.6 (2C), 112.5 (2C), 112.1, 109.1, 108.6, 98.6, 71.8, 62.0, 47.8, 36.7, 32.4, 28.8; MS (ES+) m/z 441.7 (M+1).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8]
Reactant: [H][H]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 79.3 %

Procedure:
1.16 g (2.46 mmoles) of Z-Glp-Nle-Pro-NH2 are dissolved in 25 ml of methanol. 0.2 g of a 10% palladium-on-carbon catalyst is added to the solution, and hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated, and the solid, amorphous residue is triturated with ether. The resulting 0.72 g of crude product is dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.66 g (79.5%) of Glp-Nle-Pro-NH2 are obtained: Rf4 =0.43, [α]D25 =-77.1° (c=1%, in acetic acid). Amino acid analysis: Glu: 0.96 (1.0), Nle: 1.00 (1.0), Pro: 1.00 (1.0).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH:36]([NH2:39])([CH3:38])[CH3:37].[BH4-].[Na+]>C(Cl)Cl.CO>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNC(C)C)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), isopropylamine (0.654 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 536.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.58 min.
Reaction SMILES: [C:1]1([N:7]2[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:9](=[CH:17]\[C:18](=O)[CH3:19])/[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]1([CH2:28][CH2:29][CH2:30][O:31][NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1C=CC=CC=1>[C:1]1([N:7]2[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:9](=[CH:17]\[C:18](=[N:32][O:31][CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:19])/[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1
Reactant: NOCCCN1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC(/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1)=NOCCCN1CCCCC1
Yield: 36.1 %

Procedure:
A mixture of 1.11 g of (E)-1-phenyl-3-(2-oxopropylidene]-4-phenyl-2-azetidinone, 0.63 g of O-[3-(1piperidyl)propyl]-hydroxylamine, 46.5 mg of 10-camphorsulfonic acid and 40 ml of benzene was heated at reflux for 8 hours, and the solvent was evaporated under reduced pressure. The residue was chromatographed on alumina [eluent; hexane-acetone (7:3)] to give the fractions containing the end compound, and the solvent was evaporated. The residue was recrystallized from hexane to give 0.6 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CO>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:5][C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[O:3][CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CCOC(C)=C(C#N)C#N
Solvent: CO
Product: COC(C=CN(C)C)=C(C#N)C#N
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a mixture of D1 (34 g, 250 mmol) in methanol (300 ml) was added N,N-dimethylformamide dimethyl acetal (44.68 g, 375 mmol). The reaction mixture was heated at reflux for 2 h. The mixture was then cooled to room temperature and a dark red solid precipitated upon cooling. The solid was filtered off, washed with cold methanol and dried in vacuo yielding compound D2 (16.2 g, 38%) as a red solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@H:20]([CH2:24][NH:25]C(=O)OCC3C=CC=CC=3)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=2)[N:9]=1>[Pd].CCO>[NH2:25][CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCC[C@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 3 h

Procedure:
To a mixture of benzyl ((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (855 mg, 1.77 mmol) and EtOH (15 mL) in a round bottom flask was added Pd/C (86 mg, 10% wt Pd on carbon) and the flask was sealed with a septum. The atmosphere in the flask was evacuated, purged with N2, and equipped with a balloon charged with H2. The mixture was stirred under an H2 atmosphere at ambient pressure for 3 h. After filtration through a plug of Celite using MeOH as the eluting solvent, the reaction mixture was concentrated to 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (625 mg) as a yellow solid. LC/MS: m/z 349.3 (M+H)+ at 1.82 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:54][C:48]=1[CH2:49][NH:50][CH:51]1[CH2:53][CH2:52]1>>[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:54][C:48]=1[CH2:49][N:50]([CH:51]1[CH2:52][CH2:53]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:29][CH:28]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: COCCCc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (rac.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (WO 2005/040165) and N-[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropanamine, as for compound L1, and as described for Example 1. MS (ESI, Q+) m/z 697.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:37])([CH3:36])[C:17]([O:19]C1C(C(C2C=CC=CC=2)(C)C)CCC(C)C1)=[O:18].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:37])([CH3:36])[C:17]([OH:19])=[O:18]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C(=O)OC2CC(C)CCC2C(C)(C)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C(=O)O)c1C
Reaction time: 16 h
Yield: 53 %

Procedure:
A solution of 0.907 g (about 1.35 mmol) of (-)-8-phenylmenthyl (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoate in 10 ml of ethanol is treated with 1 ml of 28% sodium hydroxide solution and the mixture is left to stand at room temperature for 16 hours. The mixture is then diluted with 50 ml of water and extracted three times with 50 ml of ether each time. The aqueous phase is acidified (pH 2) with 10% phosphoric acid and extracted three times with 50 ml of ether each time. The combined organic phases are dried over sodium sulphate and the solvent is subsequently removed on a rotary evaporator. There are obtained 212 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]2[CH:10]=[N:9]1
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(I)ccnc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 76A (535 mg, 1.32 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (500 mg, 1.97 mmol), potassium acetate (520 mg, 5.30 mmol), and anhydrous DMSO (10 mL). The reaction mixture was flushed with argon, treated with PdCl2(dppf).CH2Cl2 (60 mg, 0.082 mmol), and heated to 105° C. for 1.25 h to give the desired product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:15][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: NC1CCCC1
Product: N#Cc1ccccc1NC1CCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclopentylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([F:22])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](F)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of (t-butoxy)-N-(4-hydroxycyclohexyl)carboxamide (1 equivalent) in CH2Cl2 (1 M) cooled to −78° C. was added dropwise a solution of DAST (1 equivalent) in CH2Cl2 (0.5 M). The mixture was stirred at −78° C. for 4 hours, and then allowed to rise to room temperature. The solution was poured into saturated NaHCO3 and extracted with chloroform, dried, and evaporated. The resulting crude product was purified on silica gel, eluting with ethyl acetate/hexane 5:95.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:30]([C:25]1[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=1[O:34][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:34][C:24]2[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(C)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, 2,6-di-tert-butyl-4-methylphenol and triethylamine to give the title compound.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([Cl:3])[CH:14]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1ccc(N)cc1Cl
Reaction time: 5 h
Yield: 80 %

Procedure:
Iron powder (pre-reduced with hydrogen, 10.0 g) was suspended in ethanol (80 ml) and water (10 ml) and concentrated hydrochloric acid (4 ml) were added with vigorous stirring. 2-Chloro-4-nitro-N,N-dimethylbenzamide (7.50 g) was added in small portions over 15 minutes and the mixture then heated to 50°-60° C. and stirred for 5 hours. The mixture was filtered through Celite and the ethanol evaporated. Water (200 ml) and concentrated hydrochloric acid (20 ml) were added and the reaction washed with ethyl acetate and then basified to pH8 with sodium bicarbonate and extracted with methylene chloride. The organic extract was dried and evaporated to give 4-amino-2-chloro-N,N-dimethylbenzamide as a grey crystalline solid (5.21 g) which was recrystallised from chloroform/ethyl acetate to give off-white crystals (3.46 g, m.p. 170°-173° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C=C/c1ccccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccccn1
Yield: 97 %

Procedure:
A solution of 11b (2.0 g, 12.3 mmol) in 41 mL dry CH3OH was treated with 10% Pd-C (100.0 mg, 5 wt %) at room temperature under a hydrogen atmosphere (balloon) (10 h). The reaction mixture was then filtered through a Celite plug, washed with EtOAc (150 mL), and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 15-50% EtOAc/hexanes) afforded 12b (1.97 g, 2.03 g theoretical, 97%). For 12b: -1H NMR (CDCl3, 250 MHz) d 8.39 (d, 1H, J=2.1 Hz, Pyr C6-H), 7.46 (m, 1H, Pyr C4-H), 6.90-7.15 (br m, 2H, J=7.7 Hz, Pyr C3-H and C5-H), 3.51, 3.52, and 3.54 (three s, total 3H, OCH3), 2.97 (m, 2H, PyrCH2), 2.69 (m, 2H, CH2 (C=O)); 13C NMR (CDCl3, 125 MHz) d 173.2, 159.7, 149.0, 136.1, 122.7, 121.1, 51.3, 32.8, 32.5; IR (neat) nmax 3009, 2951, 1738, 1593, 1569, 1475, 1437, 1367, 1199, 1168, 1097, 1052, 1027, 992, 841, 755 cm-1. See FIG. 18a.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:41]4[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COCCN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-(2-methoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17].ClCC(=O)C>O1CCCC1.[I-].[K+]>[O:17]=[C:16]([CH3:18])[CH2:15][CH:4]([C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CC(=O)CCl
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)=O)C(=O)C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
36.8 g of ethyl 4,4,4-trifluoroacetoacetate were mixed in 400 ml of tetrahydrofuran and 9.6 g of sodium hydride were added at 15° C. over 30 minutes. The mixture was stirred at 20° C. for 1 hour and 0.4 g of potassium iodide and 100 ml of acetone were added. 21 g of chloroacetone in 75 ml of tetrahydrofuran were added dropwise over 15 minutes and the mixture was refluxed for 96 hours and then distilled to obtain 24.4 g of the expected product with a boiling point of 65° C. (0.2 mbar).