Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>ClCCl>[CH3:22][C:21]1[N:3]2[CH2:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[C:2]2=[N:25][N:24]=1
Reactant: CC(=O)NN
Reactant: CCOC(=O)C1CCNC1=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(#N)C.C(=O)(O)[O-].[Na+].[CH3:55][O:56][C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([O:68][CH3:69])[C:65]=1[O:66][CH3:67])[C:60](Cl)=[O:61]>O>[CH3:69][O:68][C:64]1[CH:63]=[C:59]([CH:58]=[C:57]([O:56][CH3:55])[C:65]=1[O:66][CH3:67])[C:60]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:61]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15 mL), acetonitrile (6 mL), water (6 mL), and sodium bicarbonate (0.09 g, 1.03 mmol). Cool to 0° C. in an salt-ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.048 g, 0.21 mmol). After 30 minutes, warm to ambient temperature. After 30 minutes at ambient temperature, partition the reaction mixture between ethyl acetate and brine. Extract the organic layer with 1 M hydrochloric acid solution, then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.11 (silica gel, ethyl acetate). [α]2D0=+61.7° (c=1.01, methanol).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:18])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CC(C)=O.O>[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH2:27][CH:26]=[CH2:25])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: C=CCBr
Reactant: Cc1coc2c(C(=O)c3cccs3)ccc(O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12

Procedure:
To a solution of compound 3 (0.50 g, 1.92 mmol) in acetone (10 mL) was added sequentially potassium carbonate (0.53 g, 3.84 mmol) and allyl bromide (0.47 g, 3.84 mmol). The mixture was heated to reflux for two hours, cooled, diluted with water (50 mL), and acidified with 2N HCl. The aqueous mixture was extracted with methylene chloride (3×25 mL) and the combined extracts dried (Na2SO4) and concentrated to an oil. The crude 3-methyl-4-allyloxy-7-(2-thienoyl)benzofuran thus obtained was sufficiently pure for further synthesis. 1H NMR d 2.44 (3H, d, J=2 Hz), 4.74 (2H, d, J=4 Hz), 5.44 (2H, m), 6.12 (1H, m), 6.71 (1H, d, J=8 Hz), 7.15 (1H, m), 7.36 (1H, d, J=2 Hz), 7.68 (3H, m).
Reaction SMILES: C([C:3]1[C:11]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH:14]1([CH2:13][O:12][C:11]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCc1c(OCC2CCCCC2)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
Ethyl 3-cyclohexylmethoxy benzoic acid (1.8 g, 6.7 mmol) was dissolved in ethanol (50 ml) and THF (50 ml), whereupon NaOH (4 N, 10 ml) was added, and the solution was stirred overnight at 20° C. To the reaction mixture was added HCl (2 N, 200 ml), and the resulting solution was extracted with DCM (3×100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSO4) and evaporated to give 1.6 g of the title compound. LC-MS (m/z): 236 (M+2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[S:34][CH:35]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccccc4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-phenyl-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 149 mg (97% theory) of product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])[CH:2]=[CH2:3].ClC1C=C(C(OO)=[O:19])C=CC=1.S(=O)(O)[O-]>C(Cl)Cl>[O:19]1[CH2:3][CH:2]1[CH2:1][N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10]
Reactant: C=CCN1CC(=O)NC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Solvent: ClCCl
Product: O=C1CN(CC2CO2)C(=O)N1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol) and 3-chlorobenzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml) was stirred for 2 hours at room temperature. An aqueous solution of bisulfite was added (to remove excess 3-chlorobenzenecarboperoxoic acid) and the mixture was stirred for 10 minutes. Na2CO3 was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 5 g (89%) of (±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (interm. 1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: CCCCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C2CCC(CCc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Yield: 50.1 %

Procedure:
0.08 g of Pd/C was added to 1.65 g of the compound 1-3-3-10 having been dissolved in 12.5 mL of toluene and 12.5 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 0.83 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-pentylcyclohexyl)cyclohexyl)ethane (Compound 1-3-3-2) as colorless crystals.
Reaction SMILES: [C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].P(Cl)(Cl)[Cl:22]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([Cl:22])=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: O=C(O)c1ccccc1-[c-]1cccc1
Reactant: ClP(Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1-[c-]1cccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of o-ferrocenylbenzoic acid (1.75 g) and pyridine (3 drops) in 10 cm3 of dry benzene was slowly added 5 cm3 of phosphorous trichloride. The resulting mixture was then stirred for 3 hours at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The residue was twice more evaporated from dry benzene and then taken up in light petroleum (40° to 60° ). Removal of the solvent under vacuum afforded 1.54 g (83%) of o-ferrocenylbenzoyl chloride, a dark-red, viscous oil.
Reaction SMILES: C(O)C.[H-].[Na+].C([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][C:18]3[C:24](=[O:25])[C:23]([C:26]([O:28]CC)=[O:27])=[CH:22][N:21]([CH2:31][CH2:32][Cl:33])[C:19]=3[N:20]=2)[CH2:11][CH2:10]1)(=O)C>O>[ClH:33].[N:12]1([C:15]2[N:16]=[CH:17][C:18]3[C:24](=[O:25])[C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]([CH:31]=[CH2:32])[C:19]=3[N:20]=2)[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: Cl
Yield: 67.6 %

Procedure:
To a mixture, containing 400 ml of absolute ethanol and 2.0 g of 65% sodium hydride, which was held at 60°C was added with stirring 5.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-8-(2-chloroethyl)-5,8-dihydro-5oxopyrido[2,3-d]pyrimidine-6-carboxylate. The resulting mixture was heated to reflux for 2 hours and at the end of the period 200 ml of water was added. The mixture was refluxed for an additional 30 minutes. The ethanol was distilled off under reduced pressure and the resulting residue was acidified with concentrated hydrochloric acid to pH 1.0. The resulting precipitate was collected and recrystallized from water to yield 2.8 g of the product, m.p 298° - 301°C with decomposition.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[C:18]([O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26]C(O)=O)([CH3:21])([CH3:20])[CH3:19].[N:31]1[CH:36]=CC=CC=1>>[C:18]([O:22][C:23]([CH2:24][CH2:25][CH2:26][N:31]=[C:36]=[O:8])=[O:30])([CH3:19])([CH3:20])[CH3:21]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCCC(=O)O
Reactant: c1ccncc1
Product: CC(C)(C)OC(=O)CCCN=C=O
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Diphenylphosphoryl azide (12.25 g.) was added dropwise to a solution of glutaric acid mono-tert-butyl ester (8.38 g.) in dry pyridine (37 ml.) and stirred at 90° C. for 40 minutes to give 3-tert-butoxycarbonylpropyl isocyanate (I.R.: 2270 cm-1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[C:23]3[C:22]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=4[CH:16]=[N:15][C:14]=3[NH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].C1(C)C=CC=CC=1>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([O-:35])=[O:34].[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[C:23]3[C:22]4[CH2:21][CH2:20][NH2+:19][CH2:18][C:17]=4[CH:16]=[N:15][C:14]=3[NH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Nc1cccc(-c2n[nH]c3ncc4c(c23)CCN(C(=O)OC(C)(C)C)C4)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2n[nH]c3ncc4c(c23)CC[NH2+]C4)c1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of tert-butyl 1-(3-acetamidophenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.108 g, 0.26 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL). The reaction was shaken overnight at room temperature. On completion, toluene (1 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC (C-18 using TFA as a modifier) to give the desired product, 1-(3-acetamidophenyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.042 g, 37%) as an off-white solid; M.p.=245° C. decomposition; 400 MHz 1H NMR (DMSO-d6) δ: 13.89 (br s, 1H), 10.13 (s, 1H), 9.16 (s, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.56-7.5 (m, 1H), 7.48-7.4 (m, 1H), 7.28-7.22 (m, 1H), 4.43 (s, 2H), 3.4-3.3 (m, 2H), 3.1-3.0 (m, 2H), 2.08 (s, 3H); LCMS [M+H]: 308.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:29])=[N-]>C1COCC1>[CH3:29][O:19][C:18](=[O:20])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirring solution of compound 90 (1.281 g, 3.62 mmol) in THF (40 mL) was added an excess of diazomethane at room temperature and the reaction mixture was stirred for 15 minutes. Nitrogen was bubbled into the reaction mixture for 15 minutes then it was concentrated to afford compound 91 (1.032 g, 77%) as a colorless oil after purification by ISCO (0 to 50% EtOAc in hexanes). LRMS (ESI): (calc) 367.44 (found) 368.16 (MH)+. 1H NMR (CD3OD-d4) δ (ppm):7.33-7.23 (m, 10H), 5.09 (s, 2H), 4.18-4.14 (m, 1H), 4.05-4.01 (m, 1H), 3.63 (s, 3H), 3.33-3.30 (m, 1H), 2.86-2.72 (m, 2H), 2.21 (qt, J=11.3, 3.5 Hz, 1H), 1.78 (d, J=12.7 Hz, 1H), 1.28-1.18 (m, 2H), 0.96 (qd, J=12.5, 4.3 Hz, 1H).
Reaction SMILES: [CH:1]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.[CH:25]1([CH2:29][Mg]Br)[CH2:28][CH2:27][CH2:26]1.C1COCC1.[NH4+].[Cl-]>[Cu]I>[C:11]([O:10][C:8]([NH:7][C@H:1]1[C@H:6]([CH2:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: Br[Mg]CC1CCC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1CC1CCC1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 19 %

Procedure:
(±)-3-benzyl 7-tert-butyl 3,7-diaza-bicyclo[4.1.0]heptane-3,7-dicarboxylate (62 mg, 0.187 mmol), CuI (8 mg, 0.2 equiv), and a stirring bar were put in a 100-mL flask. The flask was evacuated and backfilled with N2 gas (3×). Dry THF (5 mL) was added and the mixture was cooled to −40° C. (Cyclobutylmethyl)magnesium bromide in THF (620 μL, 3 equiv., ˜0.89 M) was added slowly. After 8 min, the reaction mixture was allowed to warm slowly to rt. After 20 min, the reaction mixture turned black. After stirring a further 2 h the reaction was complete. Satd aq NH4Cl solution (5 mL) was added to quench the reaction. The reaction mixture was partitioned between EtOAc (50 mL) and satd aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined EtOAc layers were washed with water (15 mL), brine (15 mL), and dried over Na2SO4. After concentration, the residue was purified by Gilson to afford (±)-trans-benzyl 3-(tert-butoxycarbonylamino)-4-(cyclobutylmethyl)piperidine-1-carboxylate (14 mg, 19% yield). MS ESI +ve m/z 425 (M+Na).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:10][C:9](=[O:11])[CH:8]([O:7][C:6]2[CH:14]=[CH:15][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:12][CH3:13])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCc1ccc(OC(CC)C(=O)O)cc1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCc1ccc(OC(CC)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)cc1
Yield: 114.7 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 416 mg of (2RS)-2-(4-ethylphenoxy)butyric acid and 551 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 850 mg of the title compound as a colorless foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]([OH:27])=O)=[CH:17]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>>[ClH:3].[Cl:3][C:25]([C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[C:6]([CH3:5])[CH:15]=2)[CH:17]=1)=[O:27]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-n2cc(C(=O)O)c3cccnc32)c2ccccc2n1
Product: Cc1cc(-n2cc(C(=O)Cl)c3cccnc32)c2ccccc2n1
Product: Cl

Procedure:
15.5 cm3 of thionyl chloride were added, at a temperature in the region of 25° C. under an argon atmosphere, to 1.1 g (3.6 mmol) of 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid. After stirring at reflux for 2 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was twice in succession triturated with 10 cm3 of dichloromethane and the supernatant removed, and then the residue was concentrated to dryness under reduced pressure (2.7 kPa). 1.1 g of 3-chlorocarbonyl-1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were thus obtained in the form of an orange crystalline solid which was used directly in the following stage.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=[CH:9][C:8]=1[S:7]2.Cl[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]1[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=[CH:9][C:8]=1[S:7]2
Reactant: N#Cc1ccc2c(c1)Nc1ccc(Cl)cc1S2
Reactant: CCOC(=O)C(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 2 h

Procedure:
Sodium hydride (1.85 g; in 50% strength dispersion in vaseline) is added slowly in the course of 10 minutes to a solution of 7-chloro-2-phenothiazinecarbonitrile (10 g) in N,N-dimethylformamide (250 cc). The mixture is then brought to 120° C. and treated in the course of 30 minutes with a solution of ethyl (2RS)-2-chloropropionate (18.5 cc) in N,N-dimethylformamide (100 cc). Heating is continued for 2 hours. After cooling, the mixture is diluted in ethyl acetate (1 liter) and washed with distilled water (1.5 liters). The organic phase is dried over magnesium sulphate, treated with charcoal 3S, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is purified by chromatography on a column (height: 25 cm; diameter: 4.0 cm) of silica (0.2-0.06 mm), eluting with a 90:10 (by volume) mixture (1.5 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give ethyl (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propionate (5.3 g) in the form of a pale yellow product of meringue-like consistency.
Reaction SMILES: [CH3:1][N:2]([CH3:16])/[CH:3]=[CH:4]/[C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:15])=[N:9][CH:8]=1)=[O:6].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO>[CH3:16][N:2]([CH3:1])/[CH:3]=[C:4](\[F:18])/[C:5]([C:7]1[N:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:15])=[N:9][CH:8]=1)=[O:6]
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Temperature: 27.5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 5.53 g, 25 mmol) in MeOH (100 ml) at ambient temperature, was added in portions over 5 mins, Selectfluor (14.16 g, 40 mmol). The temperature was maintained at 25-30° C. by slight cooling. After stirring for 90 min the reaction mixture was cooled in ice/acetone and filtered. The filtrate was evaporated under reduced pressure and the residue was taken into DCM. It was washed with aq. ammonia, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The title compound was isolated by MPLC on silica gel using two separate columns (10% EtOH/EtOAc, then 3.5% EtOH/DCM) as a golden viscose oil, which crystallized on standing over several weeks. Yield=2.50 g (42%). NMR (300 Mz): 1.40 (d, 6H), 2.38 (s, 3H), 3.05 (s, 6H), 4.70 (septet, 1H), 6.96 (d, 1H), 7.08 (s, 1H); 19F NMR (376 MHz): −166.7 (d); m/z 240.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[NH4+]>CCO.O.[Fe]>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Temperature: 60 °C
Yield: 57 %

Procedure:
To a suspension of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (1.51 g, 4.87 mmol) in EtOH/H2O (40 mL/10 mL) was added iron (5.43 g, 97.3 mmol) and ammonium chloride (0.260 g, 4.87 mmol). The reaction mixture was heated to reflux for three hours, then cooled to 60° C. and filtered through a pad of Celite®. The filter cake was washed with EtOH/Et3N (20:1, 200 mL) and MeOH/DCM (1:1, 100 mL). The filtrate was concentrated, and the residue was dissolved in EtOAc (200 mL). The ethyl acetate was washed with NaHCO3, dried (Na2SO4), filtered and concentrated to give the desired product (57%).