Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Mg].[C:11](#N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O:21]CC)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccccc1
Reactant: CCOCC
Agent: [Mg]
Product: O=C(Cc1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5.27 ml. (42 mmoles) of 4-fluorobenzyl bromide (Compound CI) is slowly added to 928 mg. (38 mmoles) of magnesium turnings stirred in 38 ml. of anhydrous diethyl ether under nitrogen over a period of 45 minutes at a rate such that the reaction mixture gently refluxes. The reaction mixture is allowed to cool to 20°-25° C., 2.96 ml. (29 mmoles) of benzonitrile in 5 ml. of anhydrous diethyl ether is added over a period of 5 minutes, and the reaction mixture is stirred at 20°-25° C. for 3 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is slowly poured into ice cold 10% hydrochloric acid, and the organic phase is separated. The aqueous phase is extracted five times with diethyl ether and twice with ethyl acetate, and the organic phases are combined, washed once with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The residue is dissolved in 450 ml. of hot petroleum ether, and the solution is filtered and cooled to obtain the product as an off-white solid (3.5 g.), m.p. 109°-110° C. A second crop is also obtained (0.39 g.).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[O:11][CH2:10]2)=[O:6].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:36][C:2]([F:1])([F:35])[C:3]([CH2:40][N+:37]([O-:39])=[O:38])([C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([Cl:33])=[C:30]([Cl:32])[CH:31]=1)[CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)[O:11][CH2:10]2)=[O:6]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.4 %

Procedure:
To the stirred solution of tert-butyl 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 2, 8.6 g, 15.33mmol) in DMF (215 mL) was added nitro methane (8.20 mL, 153.29mmol) and DBU (2.22 mL, 14.87 mmol) at room temperature. Reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with addition of water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with LiCl Solution (2×400 mL) and brine (500 mL). Organic layer was dried over sodium sulfate and concentrated to get crude compound sticky solid (11.23 g). Purification was done by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (5.10 g, impure-used as such in next step). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 3.95 (d, J=18.72 Hz, 1H), 4.13-4.18 (m, 3H), 4.33-4.36 (m, 2H), 5.17-5.18 (m, 2H), 5.42 (d, J=12.2 Hz, 1H), 5.58 (d, J=12.16 Hz, 1H), 7.20 (s, 1H), 7.31 (s, 1H), 7.60-7.65 (m 1H), 7.78 (d, J=16.92 Hz, 1H), 7.98-8.00 (m, 1H). LC-MS (m/z): 622.9 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9](C1C2C=CC=C(N)C=2C=CC=1)[C:10]1([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]1.[Cl-].[NH4+:29].[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>C(OCC)C.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:30]1[CH:34]=[CH:6][C:5]2[C:32](=[CH:7][CH:8]=[CH:3][CH:4]=2)[C:31]=1[NH2:29])[C:10]1([C:13]([F:16])([F:14])[F:15])[CH2:12][O:11]1
Reactant: C1CCOC1
Reactant: COc1ccccc1C(c1cccc2c(N)cccc12)C1(C(F)(F)F)CO1
Reactant: [NH4+]
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccccc1C(c1ccc2ccccc2c1N)C1(C(F)(F)F)CO1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To 30 mg (0.16 mmol) copper(I) iodide in 2 ml THF at −30° C. are added 0.71 ml of a 3-Methyl magnesium bromid in diethyl ether. After 30 minutes at −30° C. 200 mg (0.54 mmol) {[2-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}naphthalene-5-amine in 0.5 ml THF are added. The reaction mixture is stirred for 2 hours while warmed to −10° C. and then poured into a saturated ammonium chloride solution. Phases are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic phases are washed with brine, died over sodium sulphate and evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 10% to 50%) yields 12 mg of the title compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12]O>>[C:2]1([C:1]2[O:9][CH2:12][CH2:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCO
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][C@@H:18]1[O:24][C@:23](/[CH:29]=[CH:30]/[CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23](/[CH:29]=[CH:30]/[CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borohydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed.with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS: Calcd. for C17H16NO2F3Cl (M+H)+: 358.082166. Found: 358.081658.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C[O-].[Na+].[CH2:13](Cl)[C:14]#[CH:15]>CO.C(Cl)Cl>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[C:14]#[CH:13]
Reactant: C#CCCl
Reactant: OCc1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C#CCOc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A 20.0 L flange flask was charged with 3-hydroxybenzyl alcohol (97%, ex. Aldrich, 903 g, 7.28 mol, 1 eq.) in methanol (MeOH)(9.1 L, dried over 3 A molecular sieves) to give a clear solution, into which sodium methoxide (25% in methanol, ex. Aldrich, 1.746 L, 7.63 mol, 1.05 eq.) was slowly added with vigorous stirring. After stirring for 10 min. the propargyl chloride (70 wt % in toluene, ex. Aldrich, 542.6 g, 805 ml, 7.29 mol, 1 eq) was added slowly with vigorous stirring over a period of 30 minutes. The reaction mixture was heated under reflux for 40 h (isomantle set to 76° C. with an internal temp. of 64° C.). TLC-examination (10% MeOH in DCM) showed that the reaction was not complete. The reaction was nevertheless worked-up at this stage. The MeOH was removed by rotary evaporation, and the residue dissolved in DCM (10.2 L) to give a clear solution, which was washed with water (5.82 L×3), and dried over sodium sulfate. The solvent was removed in vacuo, to give the title compound (706 g, 60%) as an orange gum.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[Br:18]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:18][C:13]1[CH:12]=[C:8]([CH:7]=[CH:6][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cc1Br
Yield: 36.5 %

Procedure:
4-tert-butyl benzoic acid (500 mg, 2.8 mmol) was stirred rapidly in acetic acid (11 mL), nitric acid (1.7 mL) and bromine (114 μL, 5.9 mmol). To this was added a solution of silver nitrate (1.01 g, 5.9 mmol) in water (5 mL). A thick yellow precipitate resulted and further acetic acid was added (2 mL) before heating at reflux for 1 h. The hot solution was filtered and water added to the filtrate until a white solid precipitated. The solid was filtered, air dried and recrystallised from acetic acid to give 3-bromo-4-tert-butyl-benzoic acid as a white solid (263 mg, 36%). 1H NMR (CDCl3, 300 MHz) δ 1.85 (s, 9H, (CH3)3), 7.86 (d, 1H, J=8.5 Hz, ArH), 8.26 (dd, 1H, J=2.0, 8.5 Hz, ArH), 8.62 (d, 1H, J=2.0 Hz).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:4]([CH3:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](C)C1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f65) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Br.[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CS(C)=O>[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:10][CH:9]([OH:11])[CH2:7][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:31][CH:32]=2)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CN1CCNCC1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(CC(O)COc2ccc(Nc3ncc(Br)c(Nc4ccccc4)n3)cc2)CC1
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of potassium carbonate (160 mg, 1.1 mmol), epibromohydrin (0.14 ml, 1.7 mmol) and 4-anilino-5-bromo-2-(4-hydroxyanilino)pyrimidine (Method 4, 200 mg, 0.56 mmol) in DMSO (2 ml) was stirred for 12 hours. 1-Methylpiperazine (0.62 ml) was added dropwise and the resulting solution was stirred for a further 12 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was loaded onto a Varian Mega Bond Elut column and the column was eluted with 50:50 iso-hexane: DCM (2×20 ml), DCM (2×20 ml), 2% 2M NH3/MeOH/DCM (2×20 ml), 4% 2M NH3/MeOH/DCM (2×20 ml), 6% 2M NH3/MeOH/DCM (2×20 ml) and 10% 2M NH3/MeOH/DCM (8×20 ml). Concentration of the appropriate fractions gave the product as a yellow gum (87 mg, 30%). MS (MH+): 513, 515; HPLC (RT): 1.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH2:39][C:34]1([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NCC1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: NCC1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (1-((2-bromophenyl)sulfonyl)cyclopentyl)methanamine. MS (ESI): mass calcd. for C22H23FN5O2S, 426.15; m/z found, 427.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J=1.3, 2H), 8.20 (dd, J=7.9, 1.2, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.57-7.46 (m, 2H), 7.35-7.32 (m, 2H), 2.92 (s, 2H), 2.13-1.99 (m, 2H), 1.65-1.42 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.[H-].[Na+].CCOP(Cl)(OCC)=O.[CH2:25]([C:27]1[O:31][N:30]=[C:29]([CH2:32][N+:33]#[C-:34])[N:28]=1)[CH3:26]>CN(C=O)C>[CH2:25]([C:27]1[O:31][N:30]=[C:29]([C:32]2[N:33]=[CH:34][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=23)[N:28]=1)[CH3:26]
Reactant: [C-]#[N+]Cc1noc(CC)n1
Reactant: Cn1c(=O)[nH]c2ccccc2c1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2ncn3c4ccccc4c(=O)n(C)c23)no1

Procedure:
3-methyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline (5 mmol) was dissolved in dry dimethyl formamide DMF (20 ml) and charged with sodium hydride (6 mmol). The resulting solution was cooled under N2 to -20° C., whereafter chlorodiethylphosphate (6 mmol) was added. The reaction mixture was kept under N2 with stirring and was allowed to reach room temperature and was then charged with a -30° C. cold solution of 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole (6 mmol) and K-t-butylate (6 mmol) in dry DMF (15 ml). The resulting mixture was stirred at room temperature for one hour whereafter the reaction mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and 4M sodium hydroxide. The organic phase was dried and evaporated. Yield 120 mg of title compound. M.p. 199.4°-202.2° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][CH2:3]1.[CH3:17][CH2:18][N:19]([CH:23](C)C)[CH:20](C)C.BrCC(Cl)=[O:29].CNC.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([C:17](=[O:29])[CH2:18][N:19]([CH3:23])[CH3:20])[CH2:3]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CBr
Agent: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2(C)C
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1 H-indole (2.38 g, 10.71 mmol), Hunig's base (9.33 mL, 53.5 mmol) and bromo-acetylchloride (1.159 mL, 13.92 mmol) in tetrahydrofuran (100 mL) was maintained at 0° C. for 2 hours. Dimethylamine (2.0M in THF, 42.8 mL, 86 mmol) was added to the solution and the reaction was warmed to room temperature and maintained for 5 hours. The reaction was poured into saturated sodium bicarbonate, the organic layer was dried over sodium sulfate, filtered, and purified by column chromatography to afford {2-[3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}dimethylamine (2.14 g, 65.0% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 7.35 (s, 1 H), 3.97 (s, 2 H), 3.92 (s, 3 H), 3.21 (s, 2 H), 2.26 (s, 6H), 1.34 (s, 6 H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:25][CH:26]([CH2:38][CH2:39][CH3:40])[C@@H:27]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1)[OH:28]>>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[C:27]([C@@H:26]([NH:25][C:5](=[O:7])[CH:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:38][CH2:39][CH3:40])=[O:28]
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Reactant: CC(C)(Cc1ccccc1)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Product: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC(C)(C)Cc1ccccc1)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15](=[O:28])[CH2:16][CH2:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:35]1C[CH2:38][CH2:37][CH2:36]1>>[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@:15]([C:38]#[C:37][CH2:36][OH:35])([OH:28])[CH2:16][CH2:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)C#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6M, 34 ml, 55.4 mmol) was added dropwise to a stirred solution of O-trimethylsilyl propargyl alcohol (8 ml, 52 mmol) in tetrahydrofuran (40 ml) at −78° C. This solution was added via syringe to a stirred solution of (1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 24; a 3:1 mixture of C6 epimers, 5 g, 12.7 mmol) in tetrahydrofuran (30 ml) at −78° C. over 30 minutes. The reaction mixture was stirred for 1 hour and quenched with acetic acid (3.1 ml), warm up to room temperature and concentrated in vacuo. The residue was treated with tetrahydrofuran (50 ml) followed by 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (75 ml). The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was treated with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (4.05 g, 71%) as a 3:1 mixture of C6 epimers.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26]COCC[Si](C)(C)C)[C:23]4[C:18](=[C:19]([N:37]5[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]5)[CH:20]=[C:21]([O:35][CH3:36])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:35][CH3:36])=[CH:20][C:19]=4[N:37]3[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(N2CCCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A solution of 6-methoxy-8-(4-methyl-[1,4-]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 27d) (0.989 g, 1.59 mmol) in 20 mL methanol was poured into 300 mL 0.05 N hydrochloric acid. The clear dark yellow solution became cloudy within 5 minutes. The mixture was stirred at room temperature for 45 minutes and then adjusted to pH 7 with 10% sodium hydroxide. The resulting yellow precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the desired product as a yellow solid (0.629 g, 80%). 1H NMR (300 MHz, DMSO, d6) δ 9.97 (s, 1H,C(O)NH), 7.67 (d, 2H, Jo=8.8 Hz, ArH2′ & H6′), 7.47 (bs, 1H, ArH5), 7.00 (s, 1H, C═CH), 6.99 (d, 2H, Jo=8.8 Hz, ArH3′ & H5′), 6.71 (bs, 1H, ArH7), 3.85 (s, 3H, OCH3), 3.75 (t, 4H, J=4.6 Hz, OCH2CH2N), 3.70 (bs, 2H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2H, ArNCH2CH2NCH3), 3.09 (t, 4H, J=4.6Hz, OCH2CH2N), 2.95 (bs, 2H, ArNCH2CH2NCH3), 2.73 (bs, 2H, ArNCH2CH2CH2NCH3), 2.36 (s, 3H, NCH3), 2.07 (bs, 2H, ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N5O4+H]+ Theor. m/z=492; Obs.=492. Analysis for C27H33N5O4.1.0eqHCl.0.3eqH2O: Calculated C, 60.79; H, 6.54; N, 13.13. Found C, 60.82; H, 6.53; N, 13.17.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][NH2:23]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][NH:23][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCCC1=O

Procedure:
A mixture of 17.1 g. of ethyl 2-oxo-1-pyrrolidineacetate (U.S. Pat. No. 3,459,738) and 25.4 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine (U.S. Pat. No. 3,446,811) is heated at 95°-100° C. for 16 hours. The excess cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is evaporated at reduced pressure and the residue is fractionated. The product, cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-oxo-1-pyrrolidineacetamide, is obtained as an oil, b.p. 178°-183° C./0.15 mm., which crystallizes on standing; m.p. 93°-94.5° C. after two crystallizations from ethyl acetate-pentane.