Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>N.[Ni]>[NH3:1].[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Agent: [Ni]
Agent: N
Product: NCCc1ccc(OCCCN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of [4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile (preparation 104), (1 g, 4.1 mmol) and Raney® nickel (100 mg) in 2M methanolic ammonia (35 mL) was stirred under 60 psi of hydrogen gas at 50° C. for 6 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (200 mg) was added to the reaction mixture and heating continued for 5 hours. Tlc analysis again showed that starting material was still present and so additional Raney® nickel (200 mg) was added and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was then filtered through Arbocel® and was concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography using a 4 g RediSep® silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 85:15:1.5 to 80:20:2, to afford the title compound in 16% yield, 160 mg.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12]/[C:13](=[CH:17]\[C:18]1[S:22][CH:21]=[CH:20][CH:19]=1)/[C:14]([OH:16])=[O:15])=[O:11]>C(O)C.[Pd]>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[S:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11]
Reactant: O=C(O)/C(=C/c1cccs1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1cccs1
Reaction time: 16 h
Yield: 19.9 %

Procedure:
To a suspension of (E)-3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(2-thenylidene)propionic acid (150 mg) in ethanol (20 ml) was added 10% Pd-C (70 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure for 16 hours. After the catalyst was filtered off, the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (mobile phase: dichloromethane/methanol=15/1) to give 30 mg of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(2-thenyl)propionic acid as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[N:45]=[C:46]([CH3:49])[NH:47][CH:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[NH:45][C:46]([CH3:49])=[N:47][CH:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Cc1nc(Br)c[nH]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3cnc(C)[nH]3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 4-bromo-2-methylimidazole.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:3][CH:2]=1)=[O:8].[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C)C=O>[CH3:16][N:9]1[C:7](=[O:8])[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10]1=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C1NC(=O)c2cnccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)c2ccncc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3,4-pyridinedicarboximide (10.0 g, 67.5 mmol) in N,N-dimethylformamide was added sodium hydride (1.55 g, 60% dispersion in mineral oil, 67.5 mmol) at room temperature. The mixture was stirred for about 30 minutes, then methyl iodide (9.58 g, 67.5 mmol) was added, and the reaction was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was extracted once with water, twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (azeotroping excess N,N-dimethylformamide with heptanes) to give crude product. Purification by silica gel chromatography using 0-5% methanol/dichloromethane as eluent afforded the title compound of part 11-A as an off-white solid (5 g, 46%): PB MS (M+1)+ 163; 1H NMR=250 MHz (CDCl3) δ: 9.11 (arom, s, 1H), 9.08 (arom, d, 1H), 7.75 (arom, d, 1H), 3.20 (Me, s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)=[O:22])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:32][CH:28]1[C:29]2[C:25](=[CH:24][C:23]([C:21]([NH:20][C:4]3[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=3[CH2:1][CH3:2])=[O:22])=[CH:31][CH:30]=2)[CH2:26][CH2:27]1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl (5-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-carbamoyl}-2,3-dihydro-1H-inden-1-yl)carbamate (1.3 g) was dissolved in methylene chloride (15 ml), trifluoroacetic acid (1.5 g) was added thereto and then stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Water and potassium carbonate were added to neutralize the residue and extracted twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium bicarbonate aqueous solution and water sequentially, and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 1-amino-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]indane-5-carboxamide as a crude product (0.84 g). The crude product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]CC2C=CC=CC=2)=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:18]1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=2[F:30])=[N:18]1
Reactant: O=C(Nc1ccn(Cc2cc(OCc3ccccc3)ccc2Cl)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Reaction time: 2 h

Procedure:
A solution of N-[1-({2-chloro-5-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide (for a preparation see Example 5)(2.44 g, 5.38 mmol) in ethyl acetate (50 ml) was added to 10% palladium on carbon (wet) (0.585 g, 0.275 mmol) under vacuum. The mixture was hydrogenated at ambient temperature for 2 h. A further amount of 10% palladium on carbon wet (0.79 g) was added and the reaction was stirred for a further 2 h. The reaction mixture was filtered using a 10 g celite cartridge. The filtrate was concentrated in vacuo to leave a brown solid (2.01 g). The residue was preabsorbed on florosil and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.24 g); LCMS: (System 4) MH+=364, tRET=2.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.N.C(#[N:13])C>[OH-].[Na+]>[NH2:13][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CC#N
Reactant: ClCc1ccc(Cl)nc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stainless steel autoclave was charged with 14.99 g of 2-chloro-5-(chloromethyl)pyridine, 63.01 g of 25% aqueous ammonia and 60 ml of acetonitrile and the mixture was stirred on an oil bath at 80° C. for 2 hours. The reaction mixture was diluted with 12.3 g of 30% aqueous sodium hydroxide solution and concentrated. The residue was diluted with 200 ml of ethanol, dried over anhydrous magnesium sulfate and filtered to remove the insolubles. Finally, the filtrate was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (4:1)) to give 7.66 g of 5-(aminomethyl)-2-chloropyridine as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[N:4]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([Cl:18])[CH:9]=1)=[N+:5]=[N-:6]>O.O1CCCC1>[N:4]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([Cl:18])[CH:9]=1)=[N+:5]=[N-:6]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of lithium hydroxide monohydrate (7.00 g, 166.8 mmol) in water (100 mL) was added to a solution of 4-(azidomethyl)-2-chlorobenzoic acid, methyl ester (12.17 g, 53.9 mmol) in tetrahydrofuran (100 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated to remove some of the tetrahydrofuran. The solution was extracted with ethyl acetate (200 mL) and the extract was discarded. Then 1 M HCl (100 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to give 4-(azidomethyl)-2-chlorobenzoic acid (6.82 g, 60%) as a white solid, mp 87-88° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(=O)(O)(O)O.O.S(=O)(=O)(O)O.C=CC1C=CC=CC=1>>[CH3:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH2:5]1
Reactant: ClCCc1ccccc1
Reactant: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C=Cc1ccccc1
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to a mixture of 652 parts of 78 per cent strength by weight phosphoric acid and 20 parts of sulfuric acid monohydrate at 30° to 35° C, whilst stirring vigorously. A mixture of 90 parts of styrene, 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is then added at 30° to 35° C over 5 hours. After completion of the addition, the mixture is stirred for a further 2 hours and the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation at 10 mm Hg gives 25 parts of 1-methyl-3-phenylindan, 30 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 28 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=O)[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.Cl.[NH2:28][OH:29].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[N:28][OH:29])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: NO
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 136C (240 mg, 0.5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved into methanol (2 mL) and treated with Na2CO3 (318 mg, 3.0 mmol). The suspension was stirred at room temperature overnight and then heated at 70° C. three days. The mixture was cooled to room temperature and filtered, the solids being rinsed with 50% MeOH/CH2Cl2. The filtrate was concentrated, then partitioned between water and MeOH/CH2Cl2; some clean product remained undissolved and was separated. The organic phase was concentrated, dissolved in a little methanol, and seeded with the previously collected product. After this material had crystallized, both crops of product were rinsed with methanol and permitted to dry to provide the title compound as a white microcrystalline solid (49% yield). 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 3H), 1.4-2.1 (m, 4H), 2.2-2.6 (m, 3H), 2.34 (s, 3H), 3.00-3.12 (m, 2H), 3.20-3.34 (m, 2H), 6.49 (s, 1H), 7.41-7.48 (m, 3H), 7.56-7.63 (m, 2H), 7.68 (dd, 1H), 7.70 (bs, 1H), 7.88 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH:10]1([N:8]([CH3:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: CN(c1cccc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CN(c1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 83.8 %

Procedure:
Following General Procedure D and using (3-bromo-phenyl)-cyclopropyl-methyl-amine (Intermediate 113, 0.056 g, 0.25 mmol), triethyl amine (3 mL), copper(I)iodide (0.025 g, 0.13 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.09 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1.5% ethyl acetate in hexane as the eluent, the title compound (0.051 g, 84%) was obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[N:10]([CH2:21][CH2:22][OH:23])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7])C.CC(C[AlH]CC(C)C)C.O>C1COCC1>[OH:23][CH2:22][CH2:21][N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)[CH:17]=[C:9]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester (700 mg, 2.1 mmol) in THF (25 mL) was added DIBAL-H (1.0 M, 4.2 mL, 4.2 mmol) at −78° C. The mixture was stirred at room temperature for 1 h. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (15% ethyl acetate/petroleum) to afford 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 49%). 1H NMR (300 MHz, d-DMSO) δ 8.42 (d, J=1.5 Hz, 1H), 7.95 (dd, J=1.2, 8.7 Hz, 1H), 6.36 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 5.25 (br s, 1H), 4.46-4.42 (m, 4H), 3.69-3.66 (m, 2H), 3.24-3.21 (m, 2H), 1.42 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[F:31][C:29]([F:30])([F:32])[O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To the product from step 3 (0.23 g, 0.51 mmol) was added 4 M HCl in dioxane (5 mL). The resulting mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. The crude product was triturated with ether and dried under reduced pressure to afford the title product (0.12 g, 61%) as a light green oil; 1H NMR (400 MHz, DMSO-d6) δ 1.74 (m, 1H), 1.94 (m, 2H), 2.12 (m, 1H), 3.22 (m, 2H), 3.89 (m, 1H), 4.15 (m, 1H), 4.25 (dd, J1=3.8 Hz, J2=10.8 Hz, 1H), 7.00-7.10 (m, 6H), 7.36 (d, J=8.4 Hz, 2H), 9.32 (br s, 1H); MS (m/z) 354.5 (M+1); LC (98.4%); HPLC (99.7%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH2:11]([C:8]1[O:7][C:6]([C:4]([OH:5])=[O:3])=[N:10][CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid ethyl ester (0.95 g, 3.5 mmol) and lithiumhydroxide-hydrate (0.73 g, 17.5 mmol) in 20 mL MeOH and 10 mL water was stirred at room temperature for 2 h. The mixture was evaporated in vacuo, extracted with hexane and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4, and evaporated to yield the crude product which was used in the next step without further purification. LCMS (method A) RtA=1.350 min; [M+H]+=203.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][N:9]1C(OC(C)(C)C)=O)=[O:7]>CCOCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][NH:9]1)=[O:7]
Reactant: COCCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)OC(C)(C)C
Solvent: CCOCC
Product: COCCNC(=O)[C@@H]1CC(=NOC)CN1
Reaction time: 0.33 h
Yield: 1393.7 %

Procedure:
A solution was made containing the amide compounds from the previous step, e.g. tert-butyl (2S,4EZ)-2-{[(2-methoxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidine-carboxylate (1.5 g, 0.4 mmol), in anhydrous ether (35 ml). HCl gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 20 minutes, the ether was evaporated. The product was concentrated in vacuo from DCM (2–3 times) to remove the HCl. The desired product, e.g. (2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (1.2 g, quant.) was isolated as a yellow oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][CH:5]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH2:7][CH2:8]I.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O1CCCC1>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][CH:5]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH2:7][CH2:8][N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: CN1CCNCC1
Reactant: Clc1ccc(Cl)c(OC(CCCI)c2cccs2)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Product: CN1CCN(CCCC(Oc2cc(Cl)ccc2Cl)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
The product from Example 19 step (c) (0.35 g, 0.83 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and N-methylpiperazine (0.25 g, 2.49 mmol) added and stirred at room temperature for, 18 h. The precipitated white solid was filtered off and discarded. The filtrate was evaporated and the residue dissolved in methanol and placed on a CC SCX resin. After washing with methanol (150 ml), the product was liberated with 7N ammonia in methanol (100 ml). The solvents were evaporated and the residue dissolved in methanol, treated with one equivalent of fumaric acid, and stirred for ten minutes. The solvent was removed in vacuo and the solid residue recrystallised from hot isopropanol to afford the title compound (0.13 g, 30%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[N:5]=2.[CH:23]1(OC2N=C3C(N=CN3C3CCCCO3)=C(N)N=2)CCCC1>>[Br:1][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:14][CH2:15][CH2:23][CH2:16]1)[N:5]=2
Reactant: Nc1nc(OC2CCCC2)nc2c1ncn2C1CCCCO1
Reactant: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Product: Nc1nc(OC2CCCC2)nc2c1nc(Br)n2C1CCCCO1

Procedure:
Prepared similarly to Intermediate 56 from 2-(cyclopentyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][C@@H:20](OS(C)(=O)=O)[CH2:19][N:18]2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[CH2:11][CH2:10]1>C(#N)C>[C:1]([S:3][C@@H:20]1[CH2:19][N:18]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][OH:6])[CH2:10][CH2:11]2)=[O:16])[CH2:21]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
685 mg of potassium thioacetate were added to a solution of 2.0 g of (2S,4R)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described step 54(a)(ii), 54(a)(ii') and 54(a)(ii") above] in 20 ml of dry acetonitrile, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the residue was diluted with 200 ml of ethyl acetate, and the dilute solution was washed with an aqueous solution of sodium chloride; was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 9:1 to 4:1 by volume as the eluent, to give 1.35 g of the title compound, as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:27])=[O:5])[CH3:2].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:29][OH:30])[CH2:8][CH:7]1[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OCc3ccccc3)cc2C(=O)CC1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1c2cc(OC)c(OCc3ccccc3)cc2C(=NO)CC1C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.99 g, 5.39 mmol) in 95% ethanol (20 mL) was added hydroxylamine hydrochloride (1.1 g, 16 mmol) and sodium acetate (1.1 g, 14 mmol), and the mixture was heated at reflux. After 2 h, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 2.05 g of the title compound (99%).