Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
4,5-cis-Diphenyl-2-oxooxazolidine (48.6 g, 203 mmol) was suspended in tetrahydrofuran (330 ml) and, under ice-cooling, sodium hydride (8.12 g, 203 mmol) was added carefully. Thereafter, ethyl bromoacetate (33.9 g, 203 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into a mixture of a 10-fold dilution of conc. hydrochloric acid (60 ml) and ice-water (50 ml) and extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4:1)] to give the title compound (40.6 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])O[C:8](=[O:13])[C:7]=2[CH:14]=1.[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][NH:20][CH2:21]C(O)=O>CC1C=CC(C)=CC=1>[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][N:20]1[C:8](=[O:13])[C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:11][C:10](=[O:12])[CH2:21]1
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(OC)cc3C2=O)c(OC)c1
Temperature: 140 °C

Procedure:
6-Methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (23 g, 119 mmol) and (2,4-dimethoxy-benzylamino)-acetic acid 1 (27 g, 120 mmol) were suspended in p-xylene (500 mL) and heated under argon at reflux (140° C.) for 2 h. The hot solution was allowed to cool to rt, while spontaneous crystallization occurred. The crystals were filtered off and washed with p-xylene (50 mL). Yield: 39 g (92%). mp 196° C. m/z 356 (M).
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:38]>O1CCOCC1.O>[ClH:38].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (324b) (1.1 g, 2.16 mmol) in 8 mL of dioxane and 8 mL of water was added LiOH monohydrate (0.45 g, 10.83 mmol) and heated in an oil bath at 110° C. for 18 h. It was concentrated under reduced pressure to half of its volume. The remaining mixture was lyophilized for 24 h to give a yellow solid. m/z (ESI, +ve) 480.2 (M+H)+. To the yellow solid suspended in 5 mL of dioxane at 0° C. was treated with 10 mL of 4 N HCl in dioxane. The resulting orange mixture was stirred at RT for 3 h. The mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×5 mL of ether. The filtrate was discarded. The orange solid was dried in a vacuum oven at 40° C. for 1 h to give 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c), which was used as crude material and based on theoretical yield. m/z (ESI, +ve) 380.2 (M+H)+. A suspension of the above obtained 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c) in 12 mL of DMF and 12 mL of DCM was treated with DIEA (2.25 mL, 12.93 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.40 g, 2.70 mmol). The resulting homogeneous solution was stirred at RT for 2 h. It was diluted with 200 mL of DCM, washed sequentially with 25 mL of water, 25 mL of 1 N NaOH and 25 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (50% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to give 2′-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (324) (540 mg, 1.494 mmol, 69% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (1H, br.), 7.78 (1H, d, J=6.5 Hz), 7.67 (1H, s), 7.60 (1H, m), 7.35 (1H, t, J=7.8 Hz), 6.90 (1H, m), 6.00 (1H, s), 2.56 (3H, s), 1.52 (9H, s), 1.42 (2H, m), 1.33 (2H, m). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([I:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)cc1I
Yield: 96.8 %

Procedure:
A mixture of compound 489B (4.60 g, 16.8 mmol), tetrahydrofuran (75 mL), ethanol (100 mL), ammonium chloride solution (1.51 g, 28.3 mmol, dissolved in 100 mL of water), and iron (325 mesh, 4.21 g, 75.4 mmol) was mechanically stirred. The reaction mixture was heated to reflux for 3 h or until all starting material was consumed. The reaction mixture was cooled, filtered through Celite and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with 1N sodium hydroxide (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 3.97 g (97%) of compound 489C as a dark solid. HPLC: 95% at 1.877 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 245.13 [M+H]+.
Reaction SMILES: [CH2:1]([C@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:26])[CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:38]CC1>C1COCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@@:4]2([CH2:1][CH2:2][CH2:3][OH:38])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=4)=[CH:14][CH:13]=3)[CH3:11])[C:6](=[O:26])[CH2:5]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)C1
Agent: B
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)CC1=O
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 5-(4-((S)-1-((S)-4-allyl-4-(4-fluorophenyl)-2-oxopiperidin-1-yl)ethyl)phenyl)-1-methylpyridin-2(1H)-one (45 mg, 0.10 mmol) in THF (3 mL) was added BH3/THF (0.3 mL, 1 M) at 0° C. under nitrogen atmosphere. The mixture was stirred for 2 h. The reaction was quenched with water. Aqueous NaOH solution (1 M, 0.6 mL) and H2O2 (0.3 mL□30%) were added to the above mixture. The resulting mixture was stirred for 1 h. The mixture was extracted with EtOAc and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give 5-(4-((S)-1-((S)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)-2-oxopiperidin-1-yl)ethyl)phenyl)-1-methylpyridin-2(1H)-one (1.0 mg, 2%). LC-MS Method 2, tR=1.63 min, m/z=463.1. 1H NMR (CDCl3): δ1.42 (t, 3H), 1.69 (m, 2H), 1.92 (m, 1H), 2.01 (m, 1H), 2.22 (m, 2H), 2.44 (d, 2H), 2.99 (m, 3H), 3.36 (m, 1H), 3.42 (t, 2H), 3.59 (s, 3H), 3.60 (m, 1H), 3.84 (m, 1H), 6.01 (q, 1H), 6.61 (d, 1H) □ 6.89 (m, 4H), 7.14 (m, 4H), 7.33 (d, 1H), 7.49 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: O=Cc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccccc1Cl
Yield: 77.6 %

Procedure:
To a stirred solution of 56.2 grams (0.40 mole) of 2-chlorobenzaldehyde and 55.6 grams (0.80 mole) of hydroxylamine hydrochloride in 225 ml of ethanol and 111 ml of water was added in portions over a 15 minute period a solution of 24.0 grams (0.60 mole) of sodium hydroxide in 24 ml of water. The addition caused a solid precipitate to form. The reaction mixture was heated to boiling, and water was added until the solid dissolved. Additional water was added until the solution became cloudy. The reaction mixture was allowed to cool, and as it cooled a crystalline solid formed. The solid, collected by filtration, was dissolved in methylene chloride, and the methylene chloride solution was dried with sodium sulfate. The filtrate was concentrated under reduced pressure to remove ethanol, yielding additional solid, which was collected by filtration. This solid, too, was dissolved in methylene chloride, and the solution was dried with sodium sulfate. The two methylene chloride solutions were filtered from the sodium sulfate and the filtrates combined and concentrated under reduced pressure to give a residual solid. The solid was recrystallized from ethanol-water to give 48.3 grams of 2-chlorobenzaldoxime; mp 73.5°-75.5° C. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[NH2:6][C:4]([C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: NC(=O)c1c(N)cccc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of 2-amino-6-fluorobenzamide (3.80 g, 24.7 mmol) and triethylamine (2.99 g, 29.6 mmol) in THF (50 mL) was added dropwise ethyl chloroglyoxylate (3.70 g, 27.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethanol, and the insoluble material was collected by filtration to give ethyl ((2-(aminocarbonyl)-3-fluorophenyl)amino)(oxo)acetate as a white powder (4.95 g, 79%).
Reaction SMILES: [OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37]N(CC3C=CC=CC=3)[CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7].C(OCC)(=[O:52])C>O=[Pt]=O>[OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:33])([CH:35]2[CH2:40][CH2:39][O:52][CH2:37][CH2:36]2)[CH3:34])[NH:9]1)=[O:7]
Reactant: CCOC(C)=O
Reactant: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CCOCC1

Procedure:
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide prepared in Example 127e (0.28 g, 0.45 mmol) was treated with PtO2 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (0.15 g, 54%)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[F:15][C:4]1[C:3]([CH2:2][OH:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ccc(F)c(CO)c2n1
Yield: 97.7 %

Procedure:
A suspension of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (32.03 g, 118.59 mmol) in acetone (460 mL) and water (585 mL) was treated with NaHCO3 (16.32 g, 194.28 mmol). The mixture was heated at reflux for 6 h. The volatiles were removed under reduced pressure and the aq. phase was extracted with EA (2×250 mL). The combined org. layers were washed with brine, dried over MgSO4 and concentrated to afford the title alcohol as a yellow oil (24 g, 97% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CCOCC>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[CH:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=CCCc1cccnc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(NN=CCCc2cccnc2)cc1

Procedure:
3-(3-Pyridyl)propanal (8.50 g) was added to a stirred suspension of 4-nitrophenylhydrazine (9.62 g) in ether 150 ml. After a minute an orange-brown oil formed which solidified on further stirring. The solid was filtered off to give the title compound pure enough for further reaction (14.05 g), m.p. 146°-147° C. (from ethyl acetate/methanol). Found: C,62.12; H,5.02; N,20.36. C14H14 N4O2 requires: C,62.21; H,5.22; N,20.73%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH:15]([CH3:16])[CH3:17])[C:13]=2[C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reaction time: 1 h
Yield: 76 %

Procedure:
[(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.6 g, 1.5 mmol) was dissolved in 20% TFA in DCM (10 mL). The resulting solution was stirred for 1 h then the mixture was passed through an SCX column. The column was washed with DCM and MeOH to remove non-basic impurities and the product was then eluted with 2M NH3 in MeOH. The product fractions were concentrated to give a yellow solid (0.34 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 8.77 (1H, d, J=6.1 Hz), 7.85 (1H, td, J=10.5, 2.4 Hz), 7.69 (1H, dd, J=11.4, 6.4 Hz), 7.57 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.8, 6.9 Hz), 7.07 (1H, dd, J=13.7, 11.6 Hz), 4.35 (1H, q, J=8.7 Hz), 4.03 (1H, sept, J=9.3 Hz), 1.60 (3H, d, J=8.8 Hz), 1.40-1.29 (6H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[CH2:4][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: O=Cc1c(Cl)cccc1N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-(pyrrolidin-1-yl)benzaldehyde (1.40 g, 6.68 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.13 g, 6.07 mmol, 1.00 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred 30 min at room temperature. Sodium triacetoxyborohydride (3.85 g, 18.2 mmol, 2.99 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with 1,2-dichloroethane (20 mL). The resulting solution washed with H2O (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3/7) to yield 1.95 g (77% yield) of tert-butyl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25]>C(O)C>[CH2:23]([O:26][N:27]=[CH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[CH:24]=[CH2:25]
Reactant: C=CCON
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 13.1 %

Procedure:
To a solution of 1-benzyl-1H-indole-3-carbaldehyde (1.086 g, 4.61 mmol) in 4:1 ethanol:2.5 M NaOH solution (16 mL) was added O-allyl hydroxylamine hydrochloride hydrate(0.768 g, 7.17 mmol). The reaction mixture was heated to reflux for 30 minutes and allowed to cool back down to room temperature. The reaction mixture was concentrated to a small volume and the pH of the mixture was then adjusted to 7 using 2 M hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90) to give 1-benzyl-1H-indole-3-carbaldehyde O-allyl-oxime (0.176 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.30(s, 1H), 8.15 (m, 1H), 7.24 (m, 7H), 7.10 (d, 2H), 6.10 (m, 1H), 5.30 (m, 4H), 4.68 (d, 2H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH2:6][O:7][C:8](=[O:11])[CH2:9]Br)[CH2:4]1)[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2].[C:27]([O-:32])(=[O:31])[CH:28]([CH3:30])[CH3:29].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH3:4])[C@H:6]1[O:7][C:8](=[O:11])[CH2:9][O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2]
Reactant: CC(C)C(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(COC(=O)CBr)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)C
Yield: 70.8 %

Procedure:
In a mixture of 50 ml of acetone and 10 ml of water are dissolved 1.5 g of 16β-ethyl-bromoacetoxy-4-estren-3-one and 0.8 g of potassium isobutyrate and the solution is refluxed for 6 hours. The acetone is distilled off under reduced pressure and the residue is extracted with 200 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of diisopropyl ether, elution is carried out with 300 ml of ethyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.08 g of the above-identified compound as a viscous oil.
Reaction SMILES: C([NH:5][C:6]1[C:7]2[N:8]([N:16]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)CCC.N>>[NH2:5][C:6]1[C:7]2[N:8]([N:16]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCCNc1nc2ccccc2n2ncc(C(=O)OCC)c12
Agent: N
Product: CCOC(=O)c1cnn2c1c(N)nc1ccccc12

Procedure:
2.76 g. of the chloro compound of Example 1 c is stirred for 10 hours with 25 ml. of saturated alcoholic ammonia solution at room temperature. The product, 4-aminopyrazolo-[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester, is obtained as a white precipitate which is filtered under suction, treated with water and recrystallized from ethanoldimethylformamide; yield 1.76 g., m.p. 235°-237°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.CC(=O)CC.[IH:39].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([I:39])=[N:11][CH:10]=1
Reactant: I
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To a solution of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide in 10 ml 2-butanone 1.1 g (7.2 mmol) sodium iodide and 0.28 ml (2.1 mmol) hydroiodic acid (57% in water) were added at room temperature. The mixture was heated at 80° C. for 2 h. After cooling to room temperature the mixture was diluted with ethyl acetate and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated to give 1.5 g of crude product. Flash column chromatography gave 1.11 g (93.6%) of the title compound as a yellow oil.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:31]([NH:33][CH2:34][CH2:35][C:36]3[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=3)=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(O)(=O)/[CH:45]=[CH:46]/[C:47]1[CH:54]=[CH:53][C:51]([OH:52])=[C:49]([OH:50])[CH:48]=1>>[C:16]([NH:18][C@H:19]([C:31]([NH:33][CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1)=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])(=[O:17])/[CH:45]=[CH:46]/[C:47]1[CH:54]=[CH:53][C:51]([OH:52])=[C:49]([OH:50])[CH:48]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: CCCCOC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Product: CCCCOC(=O)NCCC[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-butoxycarbonyl-L-ornithyl]dopamine (1.0 g, 1.75 mmol) was deprotected following the indications of general procedure G. The free amino groups thus obtained were coupled with caffeic acid (472 mg, 2.6 mmol) following the general procedure D. The crude material was purified by flash chromatography using a solvent gradient from 30% to 90% EtOAc/CH2Cl2/1% AcOH. The desired product was obtained as white crystals (370 mg, 40%).