Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:7]([CH3:19])[N:6]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:19])=[CH:8][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(C)nc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)nc(OC)c1N
Reaction time: 17 h

Procedure:
To an oxygen free solution of the nitro ester 1-2 from step B (2.5 g, 10.4 mmol) in 50 mL of EtOAc was added 520 mg of 10% Pd on charcoal. Hydrogen gas was added and the reaction mixture was stirred for 17 h. The solution was filtered through a pad of Celite, concentrated and chromatographed (2:3 EtOAc/Hexane) to give the desired amine 9-3 as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[BH4-].[Li+].CO.O>O1CCCC1>[CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)COc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of methyl 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylate (44 mg, 0.21 mmol) prepared in the method of US2009/105209 in tetrahydrofuran (1.5 mL) were added lithium borohydride (23 mg, 1.07 mmol) and methanol (43 μL, 1.07 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound (38 mg, 100%) as a colorless and clear oil.
Reaction SMILES: [H-].[Na+].C1COCC1.Cl[CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)(=O)C.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
80 g of 60% NaH are added in portions to 800 ml of anhydrous THF. The medium is cooled to 10° C. and maintained at this temperature. 500 ml of benzyl alcohol are then introduced dropwise. A solution of 65.8 g of ethyl 4-chloroacetoacetate in 200 ml of benzyl alcohol is then added. The mixture is stirred at room temperature for 20 h. It is neutralized by the slow addition of acetic acid (120 ml) while being cooled with an ice bath. The whole is then poured into a mixture of water and ice and extracted with ether. The organic phase is washed with a solution of sodium bicarbonate, dried over MgSO4 and then concentrated to give an orange oil. The product is purified by two successive distillations to give a yellow oil.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:7]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(C(c2ccccc2)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
Diphenylmethyl bromide (211 mg, 0.877 mmol) was added to a solution of morpholine (23.9 μL, 0.274 mmol), triethylamine (130 μL, 0.932 mmol) and chloroform (1.4 mL) and was allowed to stir at room temperature. After 48 hr, the reaction mixture was concentrated in vacuo and the resulting crude mixture was purified by column chromatography (10% ethyl acetate/hexanes) to provide the title compound in 14% yield.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[F:18][C:19]([F:27])([F:26])[C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O>[F:18][C:19]([F:27])([F:26])[C:20]([C:21]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:22]=1[CH3:23])=[O:25]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
To a stirred solution of 50 mg (0.20 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 2) in 2 ml acetic acid was added 0.026 ml (0.20 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 20 mg (27%) 2,2,2-trifluoro-1-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as an orange oil. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCCCc1ccco1
Yield: 89.6 %

Procedure:
This compound was synthesized from 11-(2-furyl)-10-undecenoic acid (1.25 g, 5 mmol) by a hydrogenation reaction using Pd/BaSO4 (125 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 90%) as white crystals (mp 40°-41° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 12H), 1.65 (m, 4H), 2.34 (t, 2H), 2.60 (t, 2H), 5.95 (d, 1H), 6.28 (d, 1H), 7.30 (s, 1H), 10.10 (bs, 1H). Anal. Calcd. for C15H24O3 : C, 71.39, H, 9.58%; Found: C, 71.21, H, 9.63%.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([NH2:18])=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(#N)C.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17][C:16]([NH:18][C:2](=[O:3])[O:4][CH3:5])=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Methyl chloroformate (0.23 ml) in acetonitrile (1 ml) was added dropwise to a stirred solution of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (1.1 g) and pyridine (0.24 ml) in acetonitrile (8 ml) and tetrahydrofuran (10 ml) at -20° C. The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate, washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (10:1). The product was recrystallized from ethanol to give pale red crystals of methyl N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}carbamate (0.84 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CN.C1C[O:15][CH2:14]C1>C(O)C>[Br:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C1CCOC1
Agent: CN
Solvent: CCO
Product: COc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a cooled (−78° C.) solution of 5-bromo-2,4-dichloropyrimidine (1.7 g, 7.3 mmol) in THF (30 mL) was added dropwise a 25 wt % solution of methylamine in ethanol (1.7 mL). The reaction was allowed to warm to 0° C. and stirred for 1 h. The reaction was then concentrated and re-dissolved in EtOAc. The solution was washed with brine, dried over Na2SO4, filtered and concentrated to give 5-bromo-2-chloro-4-methoxypyrimidine (1.25 g, 76%). 1H-NMR (CDCl3): δ 8.43 (s, 1H), 4.10 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH2:30]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:11]([N+:20]#[C-:21])[C:10]([N+:22]#[C-:23])=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=Cc1ccc(OC)cc1)C(=Cc1ccc(OCc2ccccc2)cc1)[N+]#[C-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16 mg of xanthocillin X monomethyl ether was dissolved in 3 ml of DMF and 48 mg of potassium carbonate was added thereto. Further, 48 μl of benzyl bromide was added thereto and the mixture thus formed was stirred at room temperature for 20 hours. Then the reaction mixture was poured into 50 ml of water and extracted with 30 ml portions of ethyl acetate thrice. The extracts were combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled from the filtrate. Thus 20 mg of 1-(4'-benzyloxy- (5H, m) and 7.80 (4H, d).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Cc1c(-n2ccnc2)n(CCCCCCO)c2ccccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(-n2ccnc2)n(CCCCCCCl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 1-(6-hydroxyhexyl)-3-methyl-2-(1-imidazolyl)indole (1.3 g) at 0°. The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration to dryness and purification by chromatography gives 1-(6-chlorohexyl)-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH2:14])([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:7].C(N(CC)CC)C.Cl>ClCCl>[CH3:7][C:6]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:8])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (46 mL, 0.6 mol) in dichloromethane (100 mL) was added dropwise over 45 minutes to a solution of tert-octylamine (80 mL, 0.5 mol) and triethylamine (84 mL, 0.6 mol) in dichloromethane (400 mL) at 0° C. The mixture was stirred for a further 1 hour at room temperature then 1M HCl (1 L) was added in one portion. The mixture was extracted with dichloromethane (2×1 L). The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford N-(1,1,3,3-tetramethyl-butyl)-methanesulfonamide as a yellow oil (100.8g, 97%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ncccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
Under an atmosphere of nitrogen, Pd/C (10%, 1.36 g) was charged to a round bottome flask. Ethyl 2-(3-nitro-pyridin-2-yl)-acetate (8.6 g, 0.41 mol) was dissolved in ethanol (200 mL) and added to the reaction vessel. The reaction was placed under an atmosphere of hydrogen and stirred at room temperature for 30 min. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the product as a tan solid (6.94 g, 94% yield).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C>[CH:29]1([CH2:28][O:1][C:2]2[N:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(OCC3CC3)n2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Stir tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (0.25 g, 0.90 mmol) in DMF (10 mL) and add cesium carbonate (0.44 g, 1.35 mmol) and (bromomethyl)cyclopropane (0.13 g, 0.99 mmol). Heat the mixture to 30° C. and stir overnight. Quench the reaction with water, and extract three times with EtOAc (20 mL). Combine the organic extracts. Wash the extracts with water then brine; dry over sodium sulphate; collect the filtrate; and concentrate under vacuum to give the crude product. Purify using silica gel normal phase flash column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether to give the title compound (0.28 g, 94%) as a clear oil. MS (m/z): 333 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:14][CH2:15][CH2:16][O:17]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[NH:26][C:25]([C:27]#[N:28])=[CH:24][N:23]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)OCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amide (as prepared in the previous step, 45 mg, 0.088 mmol) in 3 mL of THF was added tetrabutyl ammonium fluoride (TBAF) (69 mg, 0.264 mmol). The reaction was stirred for 14 h at room temperature, at which time the temperature was raised to 60° C. for 15 min and then diluted with EtOAc (25 mL) and washed with water (3×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue using preparative TLC (10% MeOH—CHCl3) afforded 31 mg (93%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.28 (s, 1H), 7.97 (d, 1H, J=8.3 Hz), 7.33 (dd, 1H, J=8.3, 2.0 Hz), 7.21 (s, 1H, J=2.0 Hz), 5.77 (s, 1H), 3.98 (m, 2H), 3.72 (m, 2H), 2.20-2.15 (m, 4H), 1.75-1.66 (m, 4H), 1.56 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O3, 379.1 (M+H), found 379.1.
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[C:10]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:9]=2[NH:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([N:5]1[C:11](=[O:12])[C:10]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:9]=2[N:8]([CH3:24])[C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCN1C(=O)c2c(c(C)nn2C)Nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2c(c(C)nn2C)N(C)c2ncccc21

Procedure:
Prepared analogously to Example 6 from 9-(n-butyl)-1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3,2-b][1,4]diazepin-10-one, sodium hydride, and methyl iodide in N,N-dimethylformamide with subsequent chromatographic purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccn1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 1.0 g (3.8 mmol) N-(tert-butoxycarbonyl)-3-pyridin-2-yl-D-alanine in 7 ml DMF was added 0.62 g (3.8 mmol) L-proline methyl ester hydrochloride, 0.52 mL (3.8 mmol) triethylamine, 0.51 g (0.38 mmol) HOAt, and 1.1 g (5.7 mmol) EDC. After 3 h at room temperature, the reaction mixture was diluted with 300 ml EtOAc, washed with 200 ml each of saturated NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by automated flash chromatography (ISCO combiflash, 70 g silica gel, linear gradient 50-100% EtOAc:hexane 30 min then 2-10% MeOH/EtOAc at 60 mL/min) afforded 0.9 g N-(tert-butoxycarbonyl)-3-pyridin-2-yl-D-alanyl-L-proline methyl ester of which 0.44 g (1.2 mmol) was dissolved in 7 mL MeOH. To this was added 1.2 mL (1.2 mmol, 1M aqueous solution) LiOH and the reaction mixture stirred 6 hours, then another 0.12 mL (0.12 mmol, 1M aqueous solution) portion of LiOH was added and the reaction mixture stirred an additional 16 hrs before addition of 0.12 mL conc. HCl (1.44 mmol, 12M aqueous solution) was added and the reaction concentrated to give N-(tert-butoxycarbonyl)-3-pyridin-2-yl-D-alanyl-L-proline as a foam. 1H NMR (CD3OD, 400 MHz) δ 8.47 (m, 1H); 7.78 (m, 1H); 7.34 (m, 2H,); 4.31 (dd, 1H, J=4.21, 8.8 Hz); 3.78 (br m, 1H); 3.54 (br m, 1H); 3.17 (dd, 1H, J=6.23 and 13.5 Hz); 3.02 (m, 2H); 2.3-1.8 (br m, 4H); 1.35 (s, 9H); electrospray mass spectrum 364.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:16])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])([CH3:5])([CH3:4])[CH3:3].[C:17]1([CH2:23][CH:24]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO.ClCCl.O>[C:2]([O:6][C:7](=[O:16])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCNCCc1ccccc1
Reaction time: 8 h

Procedure:
(6-Aminohexyl)carbamic acid tert-butyl ester hydrochloride (5 g, 20 mmol) was dissolved in 50% dichloromethane/methanol (50 mL) and treated at ambient temperature with phenylacetaldehyde (2.3 mL, 20 mmol) for one hour. Sodium cyanoborohydride (1.2 g, 19 mmol) was added and the mixture stirred overnight. Water was added, followed by saturated sodium hydrogencarbonate and additional dichloromethane. The mixture was partitioned, the organics dried over sodium sulfate and the volatiles removed under reduced pressure to give the title intermediate, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]#[N:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1.[OH-:36].[Na+]>CO.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]([NH2:35])=[O:36])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: [OH-]
Reactant: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C(N)=O)CCOCC5)c4)cnc3N)on2)cc1
Temperature: 100 °C

Procedure:
4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carbonitrile (Trifluoroacetic Acid (1)) (18 mg, 0.03002 mmol) was dissolved in methanol (1 mL) and then 1 M sodium hydroxide solution (300.2 μL of 1 M, 0.3002 mmol) was added. The reaction mixture was heated in the microwave to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to a solid. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carboxamide Compound I-13 as a yellow solid (6 mg, 31.37%). 1H NMR (400.0 MHz, DMSO-d6) δ 2.2-2.25 (m, 2H), 2.45-2.5 (m, 2H), 2.65-2.7 (m, 3H), 3.6-3.75 (m, 4H), 4.28-4.33 (m, 2H), 7.18-7.2 (m, 1H), 7.27-7.3 (m, 1H), 7.35-7.39 (m, 1H), 7.7 (d, 2H), 7.85 (s, 1H), 8.05 (d, 1H), 8.1 (s, 1H), 8.18 (d, 2H), 8.7 (d, 1H), 8.88 (br s, 2H), 9.05 (s, 1H); LC/MS m/z 486.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=[N:33]C=2C=1.[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39](O)=[O:40]>CN(C)C=O.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:42]([NH:37][CH2:38][C:39]([NH2:33])=[O:40])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: On1nnc2ccccc21
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(N)=O

Procedure:
Seven-hundred milligrams (1.86 mmols) of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride, 478 mg of WSCI, 375 mg of HOBt.H2O and 486 mg of Boc-Gly were dissolved in 100 ml of N,N-dimethylformamide, and 0.35 ml of triethylamine were added thereto. The mixture was reacted at 50° C. for 3.5 hours. Seven-hundred milliliters of water were added thereto, and the resulting mixture was extracted with ethyl acetate. Subsequently, the ethyl acetate layer was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, ether), and then dissolved in a small amount of dichloromethane. Diethyl ether was added thereto for crystallization to obtain 1.71 mmols of the final product in a yield of 92%.