Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1.ClCCCl.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1
Reactant: OC1CCCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: OC1CCCc2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-4H-cyclohepta thiophene-4,5-diol (197.5 mg, 0.531 mmol) in 1,2-dichloroethane (2.9 mL, 37 mmol) were added triethylsilane (0.848 mL, 5.31 mmol) and trifluoromethanesulfonic acid (47.00 uL, 0.531 mmol). The resulting reddish solution was heated at 50° C. for 16 hr. Then the reaction mixture was allowed to cool to rt, and neutralized to pH 7 by the addition of saturated NaHCO3. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (10 mL) then dried over anhydrous MgSO4. Insoluble materials were removed by filtration and then the filtrate was concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% EA/hexane) to give the title compound as a yellow solid (145.6 mg, 77% yield). LCMS: (AA) ES+ , 356/358. 1H NMR (300 MHz, DMSO) δ, 8.48 (dd, J=4.5, 1.6 Hz, 2H), 7.45 (td, 4.4, 1.7 Hz, 2H), 7.42-7.20 (m, 4H), 5.75 (d, J=1.8 Hz, 1H), 5.03 (d, J=3.6 Hz, 1H), 4.45 (d, J=2.5 Hz, 1H), 4.01 (s, 1H), 3.05-2.61 (m, 2H), 2.02-1.43 (m, 4H).
Reaction SMILES: [C:1]([CH:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH:12]=[CH:11][C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9]3)[C:6]1=O)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:25].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[C:14]([Cl:25])[N:15]=2)[CH:12]=[CH:11][C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9]3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2cnc3c(c2c1)C(=O)C(C(C)(C)C)C=C3
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2nc(Cl)c3ccc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
The above 2,9-di-t-butylphenanthridinone (3.0 g, 9.7 mmole) was added to a reaction flask containing phosphorus pentachloride (3.0 g, 14.6 mmole) and 50 mL of phosphoryl chloride. The reaction mixture was refluxed overnight, cooled to room temperature and diluted with toluene. The excess phosphoryl chloride and toluene were removed by a rotary evaporator. The residue was dissolved into ethyl acetate and washed with distilled water followed by brine. The solvent layer was dried over magnesium sulfate, filtered and concentrated to give the desired 2,9-di-tert-butyl-6-chlorophenanthridine (3.0 grams, 98%) as an off white solid. The product was confirmed by GC Mass Spec and not purified further but used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:5][CH:4]=1
Reactant: CNc1nccc(-c2cc(NCCCN3C(=O)c4ccccc4C3=O)c3cc(OC)ccc3c2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1nccc(-c2cc(NCCCN)c3cc(OC)ccc3c2)n1
Temperature: 80 °C

Procedure:
To a solution of 2-(3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl) amino)propyl)isoindoline-1,3-dione 181 (95 mg) in ethanol (10 ml) was added hydrazine hydrate (0.1 ml) and the mixture stirred at 80° C. 3 hours. After cooling the mixture in an ice bath the precipitate formed was filtered off and washed with ice cold ethanol. The filtrate was evaporated to dryness to yield N1-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl) propane-1,3-diamine 182 as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@H:23]3[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]3)=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:18]=2)=[O:20])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NC4CCN(Cc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Yield: 77.5 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (1.0 g, 1.83 mmol) and 1-benzyl-4-piperidinylamine (2.4 ml, 11 mmol) was heated at 105° C. for 4 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2, by volume) changing to dichloromethane:methanol (95:5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (1.0 g, 80%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)([O-])O.[Na+]>ClCCl>[C:11]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:13])[CH3:12]
Reactant: OCc1csc2cncn12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1csc2cncn12
Yield: 95 %

Procedure:
0.15 g of the 3-hydroxymethylimidazo[5,1-b]thiazole prepared in Preparation 55 was dissolved in 4 ml of dichloromethane, and the solution was stirred. To this was added 0.1 ml of acetic anhydride, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 5 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (5 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.181 g (yield 95%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of the title compound from Example 263 (0.34 grams) and glacial acetic acid (10 mL) was added a 0.7M bromine-acetic acid solution (4 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (Yield 0.31 grams, 67%, MH+ 527).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>COCCOC>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:16]=[C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]3[CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reactant: Cc1cccnc1N
Solvent: COCCOC
Product: CCOC(=O)c1nc(N)sc1-c1cn2cccc(C)c2n1
Yield: 79.4 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (2.93 g) and 2-amino-3-methyl-pyridine (3.24 g) in 1,2-dimethoxyethane (100 ml) was refluxed for 3 hours. The resulting mixture was evaporated in vacuo. To the residue was added water and ethyl acetate, and the resulting mixture was acidified to pH 0.5 with conc. hydrochloric acid. The separated aqueous layer was adjusted to pH 7.0 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(2-amino-4-ethoxycarbonyl-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (2.4 g). mp 243°-245° C. (dec.)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6](/[CH:10]=[CH:11]/[C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].[H][H]>C1COCC1.[Pt](=O)=O>[CH:4]1([CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[CH2:21][CH2:22]2)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8])[CH2:25][CH2:26][CH2:27][CH2:2][CH2:3]1
Reactant: COc1ccc(C[C@@H](/C=C/[C@H](Cc2cccc(Cl)c2)C(=O)O)C(=O)O)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COC1CCC(C[C@@H](CC[C@H](CC2CCCCC2)C(=O)O)C(=O)O)CC1
Yield: 98.6 %

Procedure:
To a solution of (2S,5S,E)-2-(3-chlorobenzyl)-5-(4-methoxybenzyl)hex-3-enedioic acid (113 mg, 0.291 mmol) in THF (5 mL) was added platinum(IV) oxide (60 mg, 0.26 mmol). The reaction was stirred at 1 atm of hydrogen (balloon) for 16 h. The reaction was filtered through CELITE® and washed with MeOH. The combined filtrate and MeOH washing was concentrated to give (2R,5R)-2-(cyclohexylmethyl)-5-((4-methoxycyclohexyl)methyl)hexanedioic acid (105 mg, 0.287 mmol, 98.5 yield) as an oil. Anal. Calcd. for C20H27ClO4 m/z 366.4. found: 365.3 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][C:14]#[N:15])=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH:3]=1.C(=O)([O-])O.[Na+].[ClH:26]>C(O)(=O)C.CN(C)C=O.C(OCC)(=O)C.O1CCOCC1.[Fe]>[ClH:26].[ClH:26].[NH2:15][C:14]1[CH:13]=[CH:12][C:11]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)=[CH:17][CH:16]=2)[N:18]=1
Reactant: Cc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2ccc3ccc(N)nc3c2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(4-methylpyridin-2-yl)-2-nitrocinnamonitrile (1.32 g) in acetic acid (5 ml) and N,N-dimethylformamide (5 ml) was added iron powder (1.63 g), and the mixture was stirred at 100° C. for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 5-10% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 2-amino-7-(4-methylpyridin-2-yl)quinoline dihydrochloride (482 mg).
Reaction SMILES: C(OC([N:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=2)[CH:20]=[N:21][CH:22]=1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=2)[CH:20]=[N:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1COc1cncc(-c2cccc(CCO)c2)c1
Agent: [Pd]
Solvent: CO
Product: OCCc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1

Procedure:
In a 100 mL round-bottom flask with magnetic stirrer and H2 balloon, 2-[3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]ethanol (240 mg, 574 μmol) in MeOH (10 mL) was stirred with 10% Pd/C (50 mg; Alfa Aesar #38305, water content 50%) at room temperature for 130 min. H2 was replaced with Ar, and the catalyst was filtered off over a cotton plug and rinsed with MeOH (2 mL). The solution was evaporated and dried (30° C., oil pump vacuum) to yield the free base as a colorless film. [α]D−1.0, [α]546−1.4 (c 7.35 g/L, MeOH). 1H NMR (CDCl3, TMS, 400 MHz) δ 8.41 (d, 1H, J=1.8 Hz), 8.28 (d, 1H, J=2.8 Hz), 7.45-7.40 (m, 3H), 7.39 (dd, 1H, J=1.8, 2.8 Hz), 7.28 (dt, 1H, J=6.4 Hz (d), 2.1 Hz (t)), 4.31 (m, 1H), 4.12, 4.08 (ABq, 2H, J=9.4 Hz, low-field part d with J=6.2 Hz, high-field part d with J=4.8 Hz), 3.92 (t, 2H, J=6.6 Hz), 3.72 (q, 1H, J=7.9 Hz), 3.48 (m, 1H), 2.95 (t, 2H, J=6.6 Hz), 2.41, 2.29 (ABq, 2H, J=11.0 Hz, low-field part m, high-field part q with J=8.2 Hz), 2.08 (br, NH, OH, and H2O). MS (EI) m/z 284 (M+, 1.9%), 254 (2.2%), 229 (36%), 228 (56%), 199 (10%), 56 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:4][C:3]=1[O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1csc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCOc1cc(Nc2nc(CO)cs2)ccc1C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A solution of ethyl 2-(4-methyl-3-(3-methylbut-2-enyloxy)phenylamino)thiazole-4-carboxylate (52 mg, 0.15 mmol) in anhydrous THF (1 mL) was added to a suspension of LiAla4 (9 mg, 0.22 mmol) in dry THF (1 mL) at 0° C. under nitrogen atmosphere. After 1 h 30 min, additional LiAlH4 (9 mg, 0.22 mmol) was added. After 1 h, the reaction mixture was quenched with H2O, filtrated, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel (Hexane:EtOAc 1/1) to obtain the title compound (27 mg, 59% yield).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH3:4][C:2]([Si:5]([CH3:28])([CH3:29])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([NH:25][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1N[C@@H](COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of N2-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-2,3-pyridinediamine (673.1 g, 1.612 mol) in DMF (10 L) was added K2CO3 (490.1 g, 3.546 mol). Ethyl bromoacetate (196.6 ml, 1.77 mol) was added to the mixture over 15 min and the reaction mixture was stirred at room temperature. After 3 h, the reaction was quenched in H2O (10 L) then partitioned with EtOAc (10 L). The layers were separated and the aqueous was extracted with EtOAc (7 L). The organic phases were combined, washed with H2O (7 L) and brine (7 L), dried over MgSO4 (1 kg), filtered and evaporated. The resulting dark oil (853 g) was purified by column chromatography (9 kg silica, mixtures of heptane and EtOAc as eluent) to give ethyl N-[2-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)amino]-6-(methyloxy)-3-pyridinyl]glycinate (672.0 g, 83%) as a dark oil.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22](=O)[NH2:23])[CH3:21])([CH3:16])([CH3:15])[CH3:14].[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22]1[N:34]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:23]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Cn1cc(Nc2cc(F)ccc2N)cn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Yield: 85.7 %

Procedure:
Triethyloxonium tetrafluoroborate (0.35 g, 1.86 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (0.41 g, 2.22 mmol) in DCM (10 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then was concentrated in vacuo. The residue was dissolved in ethanol (10 mL) and 4-fluoro-N2-(1-methyl-1H-pyrazol-4-yl)-benzene-1,2-diamine (0.183 g, 0.89 mmol) added. The resultant solution was stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a brown oil (0.274 g, 86%). LCMS (Method C): RT 2.77 min [M+H]+ 360.2.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH:16]2[C:20](=[O:21])[C:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[C:18]([O:31]C)[CH2:17]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:20](=[O:21])[CH:19]([C:22]3[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[CH3:28])[C:18](=[O:31])[CH2:17]/2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OCc3ccccc3)CC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C/C(=C\C3CCC(OCc4ccccc4)CC3)C2=O)c(C)c1
Yield: 469.2 %

Procedure:
Into six 20 ml microwave vials is added the 5-[(4-benzyloxy-cyclohexyl)-hydroxy-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1 g, 2.2 mmol) in a mixture of acetone (7.5 ml) and 2N aqueous hydrochloric acid (7.5 ml). Each vial is therefore heated for 1 hour to 120° C. by microwave irradiation. The reaction mixtures were then combined and diluted with water (100 ml) and extracted with dichloromethane (2×50 m). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow gum. The gum is purified by flash chromatography to give 4-[1-(4-benzyloxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (4.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ncc[nH]2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 80 ml of N,N-dimethylformamide were dissolved 4.00 g of 2-amino-6-chloro-3-nitropyridine and 15.69 g of imidazole, and the solution was stirred at 120° C. overnight. After spontaneous cooling to room temperature, 100 ml of water was added and the resulting crystals were collected by filtration. The crystals were rinsed with a small amount of water and dried under reduced pressure to provide 3.76 g of 2-amino-6-imidazolyl-3-nitropyridine. Physicochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][CH3:19]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc(O)ccc1Br
Yield: 56.7 %

Procedure:
To a solution of 4-bromoresorcinol (1 g, 5.291 mmol) in acetone (10 mL) were added potassium carbonate (732 mg, 5.291 mmol) and 1-iodopropane (1.799 g, 10.58 mmol), respectively. The reaction mixture was heated at gentle reflux for 6 h. The solvent was removed and the residue was taken in diethyl ether (50 mL). The white solid was filtered off, and the filtrated was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 10% ethyl acetate in hexanes yielded 4-bromo-3-propoxy-phenol as a white solid (693 mg, 57%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][N:8]([C@H](C2C=CC=CC=2)C)[C:7](=[O:18])[CH2:6]1)[CH2:2][CH2:3][CH3:4].N.[Na]>O1CCCC1>[CH2:1]([C@H:5]1[CH2:9][NH:8][C:7](=[O:18])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CCCC[C@H]1CNC(=O)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of (R)-4-butyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one (1.4 g, 5.7 mmol) in dry tetrahydrofuran (10 mL) at −78° C. was added condensed liquid ammonia (100 mL). Freshly cut sodium (0.66 g, 28.5 mmol) was added and the resulting mixture was stirred at −78° C. for 2 h. The reaction was quenched with solid ammonium chloride. Ammonia was evaporated by warming up the reaction mixture slowly to room temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 4:1 EtOAc/acetone) to afford 0.7 g (87%) of (R)-4-butylpyrrolidin-2-one as a colorless oil: [α]D=+0.95° (c=0.60, CH2Cl2) {lit. [α]D=−0.67° (c=0.60, CH2Cl2) for (S)-enantiomer, Meyers, A. I. and Snyder, L. 1993, J. Org. Chem. 58, 36-42}; 1H NMR (CDCl3) δ 6.07 (bs, 1 H), 3.48 (t, 1 H), 3.02 (t, 1 H), 2.45 (m, 2 H), 1.99 (m, 1 H), 1.22-1.50 (m, 6 H), 0.90 (t, 3 H). MS(ES) m/e 142 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1.O.[NH2:24][NH2:25].C([O-])([O-])=O.[K+].[K+]>CC1OCCC1>[NH:24]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1)[NH2:25]
Reactant: NN
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 85 °C

Procedure:
Compound 2-2 (900 mg, 2.87 mmol), hydrazine hydrate (431 mg, 8.6 mmol) and K2CO3 (1.2 g, 8.6 mmol) were suspended in 2-MeTHF (8 mL) in a vial that was capped and heated at 85° C. for 16 h. After cooling to room temperature, the reaction was filtered and the collected solids were washed with water and ether and dried over suction to give Intermediate 2 as a white solid. MS: m/z=310.3 (M+H).