Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C([O-])([O-])=O.[K+].[K+].[CH:36]1(Br)[CH2:40]C[CH2:38][CH2:37]1>C(#N)C>[CH:17]1([N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:29])[CH:7]=4)[O:24]3)[CH2:12][CH2:13]2)[CH2:38][CH2:37][CH2:36][CH2:40]1
Reactant: BrC1CCCC1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C3CCCC3)CC1)O2
Temperature: 75 °C
Yield: 95.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (500 mg, 1.48 mmol, Intermediate 1, hydrochloride salt) was suspended in acetonitrile (65 ml). K2CO3 (818 mg, 5.92 mmol) and cyclopentyl bromide (882 mg, 5.92 mmol) were subsequently added and the mixture was heated at 75° C. for 14 h. The solvent was then evaporated and the residue was diluted with water and extracted with ethyl acetate, which was dried and evaporated. The crude orange solid (540 mg) was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (500 mg) as a light brown solid. The acid was suspended in DCM (16 ml), TEA (0.30 ml) was added and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as an orange solid (360 mg). The protected hydroxamic acid was dissolved in DCM (4 ml) and treated with 1 M HCl in diethyl ether (4 ml, 4 mmol) as described in Example 2, Step D, giving a light pink solid (247 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][C:6]2[C:8]([F:15])=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:5]=2[N:4]2[N:16]=[N:17][N:18]=[C:3]12>CCO.[Pd]>[CH3:1][C:2]1([CH3:19])[O:7][C:6]2[C:8]([F:15])=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[N:4]2[N:16]=[N:17][N:18]=[C:3]12
Reactant: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2-n2nnnc21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2c(F)cc(N)cc2-n2nnnc21
Yield: 72 %

Procedure:
4,4-Dimethyl-6-fluoro-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine (0.82 g, 3.1 mmol) is dissolved in EtOH (20 ml). The clear solution is transferred to a Parr hydrogenation flask and placed under nitrogen. 10% Pd—C (0.25 g) was added to the Parr flask under nitrogen. The mixture was then transferred to a Parr hydrogenation apparatus, evacuated and filled with hydrogen (×3). The mixture was hydrogenated at 30 psi (optionally topping-up hydrogen) until LC/MS and TLC indicated complete reaction to the amine. After complete reaction, the mixture was placed under nitrogen and filtered through a small pad of Celite. The filter cake was washed with EtOH (×1) and the filtrate was concentrated in vacuo to leave the 4,4-dimethyl-6-fluoro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-amine in 72% yield (0.53 g). LCMS (m/z): 236 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Cl)cc1Br
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: Cn1cc(Cl)cc(Br)c1=O
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-chloro-1H-2-pyridone (930 mg, 4.46 mmol), potassium carbonate (1.25 g, 9.1 mmol) and iodomethane (2.8 mL, 45 mmol) in 10 mL of DME was heated to reflux for 18 hr. The mixture was filtered hot and concentrated. The residue was recrystallized from ethyl acetate to give 3-bromo-5-chloro-1-methyl-2-pyridone (740 mg, 74%), mp 162-163° C. HRMS (C6H5BrClNO): Obs. Mass 220.9249. Calcd. Mass 220.9243 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>O=S(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 473.8 %

Procedure:
A mixture of 3-(4-bromophenyl)propanoic acid (26 g, 12 mmol) in SOCl2 (50 mL) was refluxed overnight, the mixture was concentrated, then added to AlCl3 (80 g, 61 mmol) in DCM (100 mL), the mixture was stirred at room temperature overnight. The mixture was quenched with HCl aqueous, extracted with DCM, washed with brine, dried over Na2SO4, concentrated to give 6-bromo-indan-1-one (12 g, 48%). 1H-NMR (CD3OD): 2.65 (m, 2H), 3.06 (m, 2H), 7.31 (m, 1H), 7.62 (m, 1H), 7.80 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:13][CH2:12][CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: N#Cc1ccc(-c2ccc([C@H]3C[C@@H]3CCO)cc2)cc1

Procedure:
A solution of the product of Example 28E (2-[(1R,2S)-2-(4-bromophenyl)cycloprop-1-yl]ethanol), 4-cyanophenylboronic acid [CAS 126747-14-6] (2 equivalents), Pd(PPh3)2Cl2, and Cs2CO3 in isopropanol under N2 was stirred at reflux overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous NaHCO3 and then with brine. The organic layer was then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: C(=[N:8][N:9]1[C:14]([S:15][CH2:16][CH3:17])=[N:13][C:12](=[O:18])[N:11]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1=[O:24])C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:8][N:9]1[C:14]([S:15][CH2:16][CH3:17])=[N:13][C:12](=[O:18])[N:11]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1=[O:24]
Reactant: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
5.2 g (0.015 mol) of 1-benzylideneamino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (V-1), 3 g (0.015 mol) of S-ethyl-isothiosemicarbazide hydrobromide (VI-1, X=Br) and a spatula-tip of p-toluenesulphonic acid in 80 ml of toluene are stirred at 50°-55° C. for 12 hours. After the mixture has cooled, 0.6 g (0.015 mol) of sodium hydroxide in 5.4 g of water is added dropwise and the mixture is stirred at room temperature for 1 hour. The solid which has precipitated is filtered off and dried. 3.75 g (=95% of theory) of 1-amino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (I-1) of melting point 204°-205° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([SH:24])=[N:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][CH:17]=1)=[O:11].II>>[C:18]1([C:15]2[N:14]=[C:13]3[S:24][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:10](=[O:11])[C:12]3=[CH:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCCc1ccccn1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1CCc1ccccn1
Yield: 91.3 %

Procedure:
Using the procedure of Example 20, 14.0 g (41.6 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide were treated with 10.6 g (41.7 mmol) of iodine to give 12.7 g of the title compound after recrystallization from ethanol, mp 132-1330° C.
Reaction SMILES: C(OC([O:6][C:7]1[CH:22]=[CH:21][C:10]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[O:14])=[CH:9][C:8]=1[O:23][CH3:24])=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:6][C:7]1[CH:22]=[CH:21][C:10]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])=[O:14])=[CH:9][C:8]=1[O:23][CH3:24]
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)OCC=C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)OCC=C(C)C)ccc1O
Reaction time: 4 h
Yield: 73 %

Procedure:
In 60 ml of methanol is dissolved 1.78 g of prenyl 4-ethoxycarbonyloxy-3-methoxycinnamate. To the solution is added 15 ml of water followed by addition of 0.56 g of sodium carbonate. The mixture is stirred for 4 hours followed by addition of 100 ml of water and then 1N hydrochloric acid to acidify the mixture. The resulting mixture is extracted with chloroform, and the organic layer is washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 1.02 g of prenyl 4-hydroxy-3-methoxycinnamate (5). Spectroscopic data of the product support the structure of the formula (5) below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a mixture of methyl 4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}benzoate (1.15 g) synthesized above, tetrahydrofuran (15 mL) and ethanol (15 mL) was added 1N is aqueous sodium hydroxide solution (15 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (30 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.09 g, 98%) as a white solid.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([Si:19]([CH3:32])([CH3:31])[N:20]1[C:24]2=[N:25][CH:26]=[C:27]([CH2:29][OH:30])[CH:28]=[C:23]2[CH2:22][CH2:21]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.P([O-])([O-])([O-])=O>[C:15]([Si:19]([CH3:32])([CH3:31])[N:20]1[C:24]2=[N:25][CH:26]=[C:27]([CH2:29][OH:30])[CH:28]=[C:23]2[CH:22]=[CH:21]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(CO)cnc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(CO)cnc21
Reaction time: 1 h
Yield: 30.5 %

Procedure:
DDQ (53 mg, 0.23 mmol) was added in three equal portions to a stirred solution of alcohol 14 (54 mg, 0.20 mmol) in a mixture of CH2Cl2 (15 mL) and 0.2 M pH 7 phosphate buffer (0.15 mL). When TLC analysis showed complete consumption of the starting material, the mixture was diluted with saturated aqueous NaHCO3 (16 mL) and stirred vigorously for 1 h. Then the mixture was extracted with AcOEt (2×). The combined organic extracts were washed with saturated brine (1×), dried (MgSO4) and concentrated. The residue was purified by PTLC with benzene as eluent to afford alcohol 15 (16 mg, 31%). 1H NMR (400 MHz; CDCl3) δ 0.63 (s, 6H), 0.93 (s, 9H), 4.77 (s, 2H), 6.52 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)=[O:9]
Reactant: Cn1nccc1C(=O)O
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)c2ccnn2C)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 2-methyl-2H-pyrazole-3-carboxylic acid and 2,4-dimethoxy-benzylamine. MS (M+H, 276.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[C:10]([I:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:18]([C:4]2[C:5]3[C:10]([I:11])=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:20])[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(I)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (17 g, 42 mmol) in a mixture of tetrahydrofuran (250 mL) and N,N-dimethylacetamide (40 mL) were added 1-boc-piperazine (8.6 g, 46 mmol), 1-hydroxybenzotriazole (0.56 g, 4.2 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (8.03 g, 42 mmol). The reaction mixture was stirred at room temperature for 20 hours and then the THF was evaporated under vacuum. An aqueous solution of bicarbonate (200 mL) was then added and the mixture stirred for 1 hour. The precipitate was filtered, washed with water, and then dried to afford the title compound as a yellow solid (24 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Br:14])[CH:8]=1)[CH3:6])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[Br:14][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:15])=[O:3])[CH:12]=[C:11]([Cl:13])[CH:10]=1
Reactant: CCOC(=O)C(C)c1cc(Cl)cc(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-5-chloro-phenyl)-propionic acid ethyl ester (2.0 g, 6.9 mmol) in 2:2:1 MeOH:THF:H2O was treated with 1N aqueous LiOH (3 mL) and stirred at room temperature overnight. The mixture was acidified with 10% aqueous HCl (10 mL) and extracted three times with EtOAc. The combined organic layers were concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O.[C:16]([CH:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:22][CH2:21][NH:20]1)(=[O:18])[NH2:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:14][C:2]([F:1])([F:15])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:20]1[CH2:21][CH2:22][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:24][CH:19]1[C:16](=[O:18])[NH2:17])=[O:13]
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: O=C(O)Cc1ccccc1OC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccccc2OC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-trifluoromethoxyphenylacetic acid (0.10 g, 0.48 mmol) from Step 4 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.10 g, 0.46 mmol) from Step 4 of Example 1 in DMF (10 mL) was added HOBT (0.075 g, 0.5 mmol), EDC (0.22 g, 0.75 mmol), and DIEA (0.13 mL, 0.75 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[C:11]([N+:18]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:18])=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc(N2CCN(C)CC2)ncc1N
Temperature: 80 °C
Yield: 97.6 %

Procedure:
In a microwave tube, 390 mg of 1-methyl-4-[5-nitro-4-(propan-2-yloxy)pyridin-2-yl]piperazine are introduced into 12 ml of methanol. 525 mg of ammonium formate and 210 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 340 mg of 6-(4-methylpiperazin-1-yl)-4-(propan-2-yloxy)pyridin-3-amine in the form of a brown oil.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCOc1ccc(CC(C)=O)cc1
Yield: 99.2 %

Procedure:
To a solution of 1-[4-(3-carbomethoxyprop-2-eneoxy)phenyl]propan-2-one (1.1 g) in ethanol (50 ml), was added 10% Pd/C (100 mg) and the mixture hydrogenated at ambient temperature and atmospheric pressure until hydrogen uptake was complete (approx. 10 minutes). The solution was filtered, evaporated to give the title compound (1.1 g) as an oil.
Reaction SMILES: C([BH3-])#N.[Na+].[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1
Reactant: Ic1ccc2cc3n(c2c1)CCNC3
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Sodium cyanoborohydride (95%, 1.6 g, 24 mmol) was added over 3 min to a stirred solution of 7-iodo-1,2,3,4-tetrahydropyrazino[1,2-a]indole (2.2 g, 7.4 mmol) in acetic acid (50 mL) at 10° C. under Ar. After complete addition the reaction was allowed to warm to room temperature and stirred for 18 h. The mixture was cautiously poured into a mixture of saturated aqueous sodium hydrogen carbonate solution (150 mL) and ethyl acetate (100 mL). The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as a yellow oil (1.74 g, 79%) which was used immediately.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].CCCCCC>C1(C)C=CC=CC=1>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 93 %

Procedure:
Suspended in 1 ml of toluene were 200 mg (1.316 mmol) of trimethylhydroquinone (TMH) and 100 mg of Sc-Bent, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 430 mg (1.45 mmol) of isophytol in 1 ml of toluene was added dropwise over 5 minutes under heating and reflux, TMH and isophytol were further reacted each other for 1 hour. The reaction liquid was cooled, to which 20 ml of n-hexane were added. The resulting mixture was filtered and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-ether system), whereby 527 mg of the title compound were obtained in the form of a brown oil. (Yield: 93%, GLC purity: 99%)
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].Cl.O.CCOCC>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
Dissolve 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.47 g.) in hot methanol (25 cc.). Add 3N hydrochloric acid (15 cc.) and keep the mixture at 70° C. under nitrogen for 1 hour. Add water and work up with ether and chromatograph the resulting gum on activated alumina (40 g.). Elute with ether to give a fraction (0.2 g.) which on recrystallization from light petroleum gives 13β-ethyl-17β-hydroxy-gon-4-en-3-one; m.p. 153°-5° C; ultra-violet absorption peak at 240 mμ (ε 16,300).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][CH:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1.[NH4+].[Cl-]>CN(C=O)C>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][CH:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 133.6 %

Procedure:
To a stirred suspension of 60% NaH dispersion in mineral oil (78.8 mg, 2.0 mmol) in DMF (2.5 mL) cooled to 0° C. is added a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 561 mg, 2.1 mmol) in DMF (3 mL). The mixture is stirred for 20 min and a solution of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (450 mg, 1.8 mmol) in DMF (2.5 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and it is warmed to room temperature and stirred for 48 h. Saturated NH4Cl solution is added and the reaction mixture is extracted with EtOAc. The organic layer is separated, washed with water, then brine, dried (MgSO4) and concentrated to afford the title compound (1.04 g, 50% pure) as an oil.