Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:13]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH2:1]([NH:5][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:18](=[O:20])(=[O:19])[NH:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNCc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 3.9 mL (2.9 g, 39.5 mmole) of n-butylamine and 1.3 mL (0.95 g, 9.4 mmole) of triethylamine in 40 mL of dry methylene chloride was added 3.39 g (7.9 mmole, based on 89% purity) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (prepared as in Step D). The mixture was stirred under N2 at room temperature overnight and then concentrated to dryness. The viscous oil was dissolved in some fresh methylene chloride and evaporated onto silica gel (the minimum amount required to give a dry powder). This was layered on top of a silica gel flash column, which was eluted initially with 1:1 hexane-EtOAc and then with a larger volume of EtOAc alone. The fractions containing pure product were combined and concentrated in vacuo to yield 2.1 g (70%) of the title compound as a white solid, mp 98°-99° C., homogeneous by TLC (EtOAc); FAB-MS m/e 375 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21](O)=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:21][OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.9 %

Procedure:
To 4-(Carboxy-phenyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (351) (10.7 g, 33.43 mmol) in THF (120 mL) at 0° C. was slowly added BH3—SMe2 (6.69 mL, 66.86 mmol). The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 96 h. The reaction mixture was then quenched with sat. NaHCO3 (120 mL) at 0° C. and diluted with Et2O. The organic phase was dried with MgSO4 and then concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 50% EtOAc/50% hexanes); yielding 3.78 g (86%) pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11]([CH3:13])=O>>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]=[C:11]([CH3:13])[CH3:10])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: CC(C)=O
Reactant: Nc1ccc(O)c(Cl)c1
Product: CC(C)=Nc1ccc(O)c(Cl)c1

Procedure:
4-amino-2-chloro-phenol Compound 13a was refluxed with acetone to provide 2-chloro-4-isopropylideneamino-phenol Compound 13b in quantitative yield. MS (ESI) m/z: 185 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: COC(=O)c1cnc2occ(Br)c2c1
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1cnc2occ(-c3ccccc3Cl)c2c1
Yield: 77 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromofuro[2,3-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chlorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 77%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:26]=1)[CH3:2].ClC(Cl)(Cl)C([N:34]=C=O)=O>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:34])[C:8]=2[N:26]=1)[CH3:2]
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCc4cccnc4)cc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4cccnc4)cc3c21
Reaction time: 0.5 h

Procedure:
The crude 2-ethoxymethyl-5-oxido-1-propyl-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinoline from Part A was dissolved in 50 mL of dichloromethane and trichloroacetyl isocyanate (540 mg, 2.85 mmol) was added dropwise. The reaction was monitored by thin layer chromatography and once the starting material was consumed, 2 mL of concentrated ammonium hydroxide was added. The reaction was stirred for 30 minutes and then passed through a column containing cation-exchange resin. The column was washed with methanol to remove impurities followed by elution of the desired product from the column with 2M ammonia in methanol. The volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane and purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-8% methanol in dichloromethane. The solid was further purified by recrystallization from acetonitrile to give 2-ethoxymethyl-1-propyl-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine as light amber crystals, mp 190.0-191.0° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19].Cl>>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)[CH:18]([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(C)CBr
Agent: Cl
Product: CC(C)CN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and i-butylbromide; m.p. 212° C. (HCl); MS m/z (rel. intensity, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N+:5]([O-:22])=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc2ccccc2cn1
Solvent: ClCCl
Product: CCOc1cc2ccccc2c[n+]1[O-]
Yield: 69.9 %

Procedure:
3-Ethoxyisoquinoline (1.5 g, 8.7 mmol) was taken up in DCM (45 mL) at 0° C. mCPBA (77%, 4.1 g, 18.3 mmol) was added slowly and the resulting solution allowed to warm to it overnight. The reaction volume was doubled with additional DCM and washed with 1M NaOH. Following separation and extraction with DCM, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 3-ethoxyisoquinoline N-oxide (1.15 g, 69%) as a white low melting solid that was used without further purification. LCMS found 190.05 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCCC1.ClCCl.C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:9])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
In tetrahydrofuran (100 ml ) and dichloromethane (100 ml), 3-nitrobenzoic acid (7.58 g) was dissolved. Then 1-hydroxybenzotriazole (6.74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.57 g), and morpholine (9.47 g) were added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, chloroform was added to the solution. The mixture was washed with 1N-HCl aqueous solution, 1N-NaOH aqueous solution, and distilled water. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=160 g, ethyl acetate) to obtain the above-captioned compound ([13]-(132)-158) (9.62 g) as white crystals.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COCCN
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: COCCNC(N)=Nc1ccccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was stirred at ambient temperature for 14 days to give 1-(2-methoxyethyl)-2-(2-morpholinophenyl)guanidine (m.p. 125°-128° C.) which was recrystallised from 1,2-dimethoxyethane and converted into its fumarate salt (m.p. 136°-138° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:19][C:20]3[C:21](=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(Cc3ccccc3)CC1)c1cccn1-2

Procedure:
510 g (0.027 mole) of 1-benzyl-4-piperidone and 2 ml. of glacial acetic acid are added to a solution of 50 g (0.027 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 80 ml. of absolute ethanol. The solution is refluxed for 43 hours and concentrated to an oil which is washed with water. The oil is recrystallized from isopropanol to give 1'-benzyl-7-methoxy-4,5-dihydrospiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 123°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](C(F)(F)F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([O:26][C:27]([F:30])([F:29])[F:28])=CC=1C(O)=O>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1N
Product: COC(=O)c1cc(OC(F)(F)F)ccc1N

Procedure:
The title compound was prepared as in the method of compound 1 from 2-amino-5-(trifluoromethoxy)benzoic acid to give a pale yellow oil (0.538 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13](C3CCCCO3)[C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1.Cl>CO.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][NH:13][C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.1 g, 3.6 mmol) was stirred in MeOH (5 mL) and 2 N HCl in Et2O (20 mL) was added. After 16 h, the mixture was diluted with Et2O (100 mL), and the solid was filtered off. The solid was stirred in NaHCO3 solution (15 mL) for 15 minutes and then refiltered to provide the title compound (620 mg, 78%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 7.85-7.78 (td, J=8.7, 2.9 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.67-7.63 (dd, J=8.6, 4.5 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]4[CH2:25][C:24]5[C:19](=[CH:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=5)[C@H:18]4O)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.C[O:30]C1C=C2C(=CC=1)C(=O)CC2>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([C@H:17]4[CH2:18][C:19]5[C:24](=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[CH:20]=5)[C@H:25]4[OH:30])[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@@H](N1CCN(c3cccc4c3OCCO4)CC1)C2
Reactant: COc1ccc2c(c1)CCC2=O
Product: COc1ccc2c(c1)C[C@H](N1CCN(c3cccc4c3OCCO4)CC1)[C@@H]2O

Procedure:
Prepared in the same manner as the compound of Example 1, but using 5-methoxyindan-1-one instead of 6-methoxyindan-1-one in Step 1.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].C1CCCCC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CO.[Pd]>[C:26]([NH:1][C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)(=[O:28])[CH3:27]
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of 1,6-anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexopyranose (see Example 13) in methanol (20 ml) was subjected to transfer hydrogenation by heating under reflux with cyclohexene (7 ml) 5% and palladium on charcoal (0.5 g), added in three portions over a period of 6 h. Acetic anhydride (2.5 ml) was then added to the mixture at room temperature. After 2 h, the mixture was filtered, the filtrate was evaporated, and the residue chromatographed on silica gel to yield the title compound as a syrup (0.35 g, 52%), [α]D -28.7°; 13C-nmr data: 101.1 (C-1), 46.4 (C-2), 25.9 (C-3), 74.1 and 73.0 (C-4 and C-5), 65.8 (C-6), 70.5 (PhCH2O), 23.3 (NHCOCH3), 169.2 (NHCOCH3), 137.7 (q-aromatic), 128.5 (×2), 127.9, and 127.5 (×2, aromatic).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(F)cccc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1c(F)cccc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoate (1.40 g, 3.12 mmol) obtained in Example 6-(1) was reacted with anisole (1.4 g, 12.9 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above, oxalyl chloride (1.98 g, 15.6 mmol), and N,N-dimethylformamide (15 μl) were reacted, and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoyl chloride as a crude product.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=O)[CH:7]2[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH:7]2[CH2:6]1
Reactant: COC(=O)C1(C)CC2C(=O)N(Cc3ccccc3)CCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CC2CN(Cc3ccccc3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A solution of 3.33 g (11 mmol) of (7RS,8aSR)-7-methoxycarbonyl-7-methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Jones, R. C. F.; Howard, K. J. J. Chem. Soc., Perkin Trans. 1, 1993, 2391) in 125 mL of dry THF was added dropwise to a stirred suspension of 1.26 g (33 mmol) of lithium aluminum hydride in 125 mL of dry THF. The solution was stirred for 2 h at room temperature, and carefully quenched with 1.26 mL of water, 1.26 mL of 15% NaOH, and 3.78 mL of water. After stirring for 30 min, the mixture was filtered through Celite, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography eluting with 9:1 chloroform:methanol gave 1.67 g (58%) of the title compound. 13C NMR (base, CDCl3): δ 25.3, 39.7, 41.8, 51.1, 51.6, 57.1, 62.3, 62.9, 63.3. 71.3, 127.0, 128.2, 128.7, 129.2, 138.3. m/z (MH+) 261.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CN(C)CCN>ClCCl>[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][N:16]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:15]2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCC1(N2CCOCC2)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(CNC(=O)OC(C)(C)C)(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Propane-1-sulfonyl chloride (0.44 ml, 3.9 mmol) was added to tert-butyl [(3-morpholin-4-ylazetidin-3-yl)methyl]carbamate (0.71 g, 2.6 mmol) and triethylamine (0.91 g, 6.5 mmol) in dichloromethane (9 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness to give crude tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate which was used without further purification m/z (M++H) 378.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]=[CH:6][C:5]2=[O:13]>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:9]([CH3:10])([CH3:4])[CH:8]=[O:12])=[CH:6][C:5]2=[O:13]
Reactant: O=C1C=CC(=O)c2cc(O)ccc21
Solvent: CO
Product: CC(C)(C=O)C1=CC(=O)c2cc(O)ccc2C1=O
Reaction time: 4 h

Procedure:
6-Hydroxynaphthoquinone (compound 2 prepared in step I above) (0.74 g, 2.35 mmol) was dissolved in 75% MeOH (30 mL) and powdered FeCl3·6H2O (1.65 g, 6.1 mmol) was added. The mixture was stirred for 4 h. The solvent was evaporated and the crude product (compound 3) was purified on silica gel with hexane:EtOAc 4:1. Yield: 0.27 g (47%). 1H NMR (400 MHz, Acetone-d6) δ 1.36 (s, 6 H), 6.90 (s, 1 H), 7.24 (dd, 1 H), 7.39 (d, 1 H), 7.94 (d, 1 H), 9.64 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C@H:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@H:23]1[C@H:30]2[C@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]2)[C@@H:25]([CH2:33][F:34])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C@H:9]([NH:12][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@H:23]1[C@H:30]2[C@H:26]([O:27][C:28]([CH3:31])([CH3:32])[O:29]2)[C@@H:25]([CH2:33][F:34])[CH2:24]1)[CH2:10][CH3:11]
Reactant: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: CC[C@@H](N)Cc1sccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Cc1sccc1Cl)Nc1ncnc2c1ncn2[C@@H]1C[C@H](CF)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-1-(3-Chloro-thiophen-2-ylmethyl)-propylamine hydrochloride (1.36 g, 6 mmoles) and 6-chloro-9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro -cyclopenta-1,3-dioxol-4-yl)-9H-purine (1.63 g, 5 mmoles) prepared as described above were combined in nBuOH (40 ml), iPr2NEt (3.5 ml, 20 mmoles) was then added and the resulting solution was stirred at reflux under an argon atmosphere. After 5 h, the reaction mixture was cooled down to room temperature, partitioned between water, brine and EtOAc, the aqueous layer was separated and extracted two times with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate is concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel eluting with 2% MeOH in CH2Cl2 to yield [(R)-1-(3-chloro-thiophen-2-ylmethyl)-propyl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl -tetrahydro-cylopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine
Reaction SMILES: [CH:1]1([C:6]([OH:30])([CH2:20][C:21]2[O:22]C(C)(C)[O:24][C:25](=O)[CH:26]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[C:11]([F:19])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CCC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[C:11]([F:19])[CH:10]=3)[CH2:20][C:21](=[O:22])[CH2:26][C:25](=[O:24])[O:30]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C#N)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Product: CC(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The title compound was prepared analogously to example A(237) substituting 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-propionitrile from step 2 below in place of 1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile. 1H NMR (400 MHz, CDCl3) δ: 1.33-1.50 (m, 3H), 1.56 (d, J=7.33 Hz, 3H), 1.62-1.75 (m, 5H), 1.85-1.93 (m, 2H), 2.15-2.26 (m, 1H), 2.58-2.68 (m, 3H), 2.72 (d, J=6.57 Hz, 2H), 3.38 (d, J=3.54 Hz, 2H), 4.09 (q, J=7.33 Hz, 1H), 6.84 (d, J=11.12 Hz, 1H), 6.93 (d, J=7.83 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]=[CH2:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.[Na+].[I-]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]=[CH2:13])[C:10]([OH:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: C=CC(CO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [I-]
Product: C=CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3 (50 mg, 0.267 mmol) in acetone (5 mL) was added Jones reagent (4 M, 0.2 mL, 0.8 mmol) at 0° C. over 10 min and the reaction mixture was then stirred for 3 h at rt. Excess Jones reagent was quenched by addition of i-PrOH. The acetone and i-PrOH were removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was separated and the product was extracted into saturated aqueous Na2CO3 solution. Acidification of the aqueous phase to pH 4 with acetic acid followed by extraction with ethyl acetate, drying (MgSO4), filtration and evaporation gave Boc-protected vinylglycine (44 mg, 82%): 1H NMR (300 MHz, DMSO-d6) δ1.37 (s, 9H), 4.51 (dd, J=6, 7 Hz, 1H), 5.17 (d, J=10 Hz, 1H), 5.28 (d, J=17 Hz, 1H), 5.87 (ddd, J=6, 10, 17 Hz, 1H), 7.30 (d, J=7 Hz, 1H), 12.65 (br s, 1H); 13C NMR (75 MHZ, CDCl3) δ 28.2, 56.2, 78.2, 117.1, 133.1, 155.2, 172.0; HRMS (FAB, 3-NBA, NaI) calculated for C9H15NO4 Na (M+Na+) 224.0899, observed 224.0893.