Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=2[CH:46]([CH3:48])[CH3:47])=[O:35])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:38]([CH:46]([CH3:47])[CH3:48])=[CH:39][CH:40]=[CH:41][C:42]=2[CH:43]([CH3:45])[CH3:44])=[O:35])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCOCc3ccccc3)c2)c2cccnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCO)c2)c2cccnc21
Yield: 31.2 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-benzyloxypropoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (316 mg, 0.48 mmol) in methanol (20 ml) were added ammonium formate (91 mg, 1.44 mmol) and 10% palladium-carbon (100 mg), and the mixture was refluxed for 10 hours. After allowed to stand for cooling, the mixture was filtered through a cerite pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the mixture was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from ether/hexane to give the title compound (85 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([C:12]([OH:14])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.CN(C=O)C.[NH2:36][C@H:37]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1>C(N(CC)CC)C>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:11]([C:12]([NH:36][C@H:37]([C:44]([N:46]2[CH2:53][CH2:52][CH2:51][C@H:47]2[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]2[N:43]=[CH:42][NH:41][CH:40]=2)=[O:14])[N:2]1[CH3:1]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CN1C(=O)c2ccccc2C[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 48 h
Yield: 47.6 %

Procedure:
A solution of (3R)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (350 mg), DCC (412 mg) and DMF (8 ml) is stirred at 9° C. for 1.5 hours, and L-histidyl-L-prolinamide.2HBr (702 mg) and triethylamine (0.49 ml) are added thereto. The mixture is stirred for 2 days. Insoluble materials are filtered off, and the filtrate is distilled under reduced pressure to remove DMF. The residue is dissolved in an aqueous sodium bicarbonate solution, and the solution is passed through a column (2.4×21 cm) packed with CHP-20P resin. The column is washed with water (one liter), and the product is eluted with 30% methanol. The fractions positive to Pauly reagent are collected, and the collection solution is distilled to remove methanol. The residue is lyophilized, whereby Nα -[(3S)-1-oxo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl-L-prolinamide (370 mg) is obtained. Yield: 47.6%
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([O:16]CC)=O)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O

Procedure:
Reagents: Comp 39 (0.36 mmols, 0.10 g); dodecanoyl hydrazine (0.39 mmols, 0.08 g). Yield: 0.105 g (65%), white solid, m.p.=165° C.-166° C.
Reaction SMILES: C([O:5]O)(C)(C)C.C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([CH:26]2[CH2:27][O:5]2)=[O:28])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OO
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CO2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.9 %

Procedure:
A solution of anhydrous t-butyl hydroperoxide (5.5M in nonane, 2.07 ml, 11.38 mmol, 1.5 eq) was added to anhydrous THF (50 mL), at −78° C. under argon. To the resulting solution at −78° C. was added butyl lithium (2.3M in n-hexane, 3.36 ml, 8.4 mmol, 1.1 eq) was added and the solution is stirred for a further 5 min at this temperature. A solution of the 4-Acryloyl-piperazine-1-carboxylic acid tert butyl ester (1.96 g, 7.64 mmol, 1 eq) in anhydrous THF (20 ml) was then added dropwise at −78° C. The resulting mixture was then allowed to warm slowly to room temperature and stirred for a further 16 hr. To the mixture was then added sodium sulfite (1.5 g, 12 mmol, 1.55 eq) and this was then stirred for 15 min. The mixture was then diluted with diethylether (50 ml), filtered through celite and the filtrate evaporated. The residue was purified by chromatography (ethyl acetate/n-hexane 4/1) to give the product (0.39 g, 19%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13].[OH-].[Li+].O.Cl>C1COCC1.CCOCC>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CCCCCCOCCC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCOCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 7-(3,3,3-trifluoropropoxy)heptanoate (50 mmol) is dissolved in 500 ml of THF in a round-bottomed flask, and solid lithium hydroxide (65 mmol, 1.3 eq) is added in portions at RT. The mixture is stirred at RT for 1 hr, and 100 ml of water and 200 ml of MTB ether are subsequently added. The mixture is acidified to pH 1 using aqueous HCl, the phases are separated, and the aqueous phase is extracted a number of times with MTB. The combined organic phases are dried over sodium sulfate and evaporated in a rotary evaporator. The carboxylic acid formed in this way is employed directly in the subsequent step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Nc1c(F)cccc1F
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(F)cccc1F)c1cccc(C(C)=Nc2c(F)cccc2F)n1

Procedure:
2,6-Diacetylpyridine (1.76 g, 10.8 mmol) and 2,6-difluoroaniline (2.94 g, 22.8 mmol) were dissolved in 50 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 3 days, with addition of more 4 Å molecular sieves the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield of 4:1 g (24%). 1H-NMR (CDCl3) δ 8.44 (d, 2H, Py-Hm), 7.90 (t, 1H, Py-Hp), 7.05 (m, 2H, ArH) 6.96 (m, 4H, ArH), 2.44 (s, 6H, Me). 19F-NMR (CDCl3) δ −123.6
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Agent: NN
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (401) (2.32 g, 2.4 mmol) was dissolved in an mixture of MeOH and dioxane (150 mL, 4:1). Hydrazine monohydrate (100 mL) was added and the mixture was heated to reflux for 10 days. LC-MS indicated complete de-protection at this point. Upon cooling, a white precipitate formed. The mixture was poured into ice water, forcing additional precipitate to form. The solid was collected by filtration under reduced pressure, rinsed with water (100 mL), and dried under high vacuum for 16 h to give the desired product (402) as a white powder (1.48 g, 1.62 mmol, 68% yield). LC-MS (ESI): (exact mass: 919.53) m/e=920.6 [M+1]+ (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](N)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].[OH2:24].C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([OH:24])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: O
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Agent: C=O
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3O
Yield: 80.5 %

Procedure:
To a solution of 4-amino-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (prepared in Example 1) (1.5 g, 0.0047 mol) in THF (5 mL) was added water (5 mL) and paraformaldehyde (0.5 g). The mixture was heated at reflux for 1 hour, then concentrated in vacuo and the residue extracted with ether. The ether extracts were washed with saturated NaHCO3 solution, brine, and dried and concentrated in vacuo. Elution from a silica gel column with a 7:3 hexane:ethyl acetate mixture gave the product (1.2 g, 80.5%), m.p. 117°-118° C. (ether/hexane). Analytical HPLC showed that the product consisted of two diastereomers in a ratio of 19:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:4][CH:3]=1.[CH2:19]([C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:18][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[N:29][C:21]=3[CH2:19][CH3:20])=[C:10]([NH:14][CH:15]3[CH2:16][CH2:17]3)[N:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Reactant: CCc1ncccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
6-(4-Chlorophenyl)-N-cyclopropylpyrimidine-4,5-diamine (1.00 g, 3.83 mmol) was initially charged in a mixture of DCM (3.20 ml) and pyridine (0.93 ml) and cooled to 0° C. Solid 2-ethylnicotinoyl chloride (780 mg, 4.60 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another hour. After addition of semisaturated NaHCO3 solution, the organic phase was separated off and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:8]1[S:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCNC(=O)c1sccc1C
Product: CCNC(=O)c1sc(Br)cc1C
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 19, making variations only as required to use N-ethyl-3-methylthiophene-2-carboxamide in place of N-benzyl-3-methylfuran-2-carboxamide to react with N-bromosuccinimide, 5-bromo-N-ethyl-3-methylthiophene-2-carboxamide was obtained as a colorless oil in 92% yield: 1H NMR (300 MHz, CDCl3) δ 6.85 (s, 1H), 5.65 (br s, 1H), 3.48-3.38 (m, 2H), 2.45 (s, 3H), 1.22 (t, J=7.3 Hz, 3H); MS (ES+) m/z 248.1 (M+1), 250.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5].O1CCOCC1.Br[C:44]1[C:49]([F:50])=[CH:48][CH:47]=[CH:46][N:45]=1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([C:44]2[C:49]([F:50])=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C(=O)NC4CC4)nn3-c3ccccc3)c2)OC1(C)C
Reactant: Fc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1CC1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 110 °C
Yield: 19 %

Procedure:
To the solution of 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-N-cyclopropyl-1-phenyl-1H-pyrazole-3-carboxamide in dioxane (Preparation 10, 0.63 mmol, 15 mL) was added 2-bromo-3-fluoropyridine (58 mg, 0.33 mmol), Na2CO3 (46.6 mg, 0.44 mmol) in water (1 mL) and Pd(dppf)Cl2 (9 mg, 0.01 mmol). The reaction was degassed with nitrogen for 30 minutes and heated to 110° C. for 17 hours. The reaction was cooled and concentrated in vacuo. The residue was eluted through a small plug of silica with EtOAc followed by reverse phase column chromatography eluting with 3-60% MeCN (containing 0.1% NH4OH) in water (containing 0.1% NH4OH) to afford the title compound (20 mg, 19%).
Reaction SMILES: O.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Br[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:14]1([CH:13]=[CH:12][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrC(c1ccccc1)C(Br)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
Hexadecyltributyl phosphonium hectorite (0.050 mmol) was mixed with 2.0 ml of water containing dissolved sodium iodide (0.264 mmol) and sodium thiosulfate (32.0 mmol) and toluene (2.0 ml) containing dissolved 1,2-dibromo-1,2-diphenyl ethane (1.0 mml). After vigorous stirring for a reaction time of 7 hr at 90° C. the emulsion was broken by centrifugation, and 1,2-diphenylethylene was obtained in 98.0% yield.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH:17]=[C:10]1[CH2:1][CH2:2][C:3]2[S:7][CH:6]=[CH:5][C:4]=2[C:8]1=[O:9])[CH3:16]
Reactant: O=C1CCCc2sccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CCc2sccc2C1=O

Procedure:
The 5-(dimethylaminomethylene)-4-oxo-4,5,6,7-tetrahydrobenzo[b]-thiophene starting material was prepared from 4-keto-4,5,6,7-tetrahydrothianaphthene (5.0 g, 33 mmol) and N,N-dimethylformamide diethyl acetal (15 ml, 87.5 mmol) to give the desired product as large yellow crystals (2.3 g) after recrystallisation from ethyl acetate m.p. 106.9°. MS (ES+) 208 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:5]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1I)C(=O)C(F)(F)F)[CH:2]=[CH:3][CH3:4]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]([C:2]1[C:13]2[C:12](=[CH:17][CH:16]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:14]=2)[NH:5][CH:1]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A solution of N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-4-trifluoromethyl-phenyl)-acetamide (12.7 g, 29 mmol) in DMF (60 mL) is treated with n-Bu4NCl (8.8 g, 32 mmol), Pd(OAc)2 (131 mg, 0.58 mmol), and stirred at 100° C. for 2 h. The mixture is cooled to rt, diluted with EtOAc (150 mL), filtered through a pad of silica gel, and washed with 1 M HCl (150 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-30% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-1H-indole (2.6 g, 42%). MS: 214 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.08 (s, NH, 1H), 7.89 (s, 1H), 7.41 (m, 2H), 7.07 (m, 1H), 2.81 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[NH2:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N)nc4ccccc43)nc21
Temperature: 70 °C
Yield: 76 %

Procedure:
To a flask of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (125 mg) in Ethanol (5.4 mL) was added 10% Palladium on Carbon (0.2 g) and Acetic acid (83 uL). The flask was purged with a nitrogen balloon and then placed under a Hydrogen balloon. The reaction was heated at 70° C. for 48 hours. The reaction was filtered thru celite and the celite cake was rinsed with a mixture of 1% acetic acid in methanol several times. The solvent was concentrated to dryness to give 70 mg of crude 2-(1-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol, 70 mg of which was added to HATU (105 mg), DIPEA (0.12 mL) and acetic acid (24 uL) in DMF (0.8 mL). Upon completion, the reaction was diluted with Ethyl acetate and extracted with water. The organic layer was dried, filtered and concentrated to give crude product. The crude was purified via reverse phase HPLC to afford 11.5 mg of 517 as a white solid. MS (Q1) 548.3 (M)+
Reaction SMILES: C1N([N+]([O-])=O)CN([N+]([O-])=O)CN1[N+:13]([O-:15])=[O:14].C(O[N+]([O-])=O)C(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O.[CH3:37][N:38]([CH3:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[CH3:37][N:38]([CH3:45])[C:39]1[CH:44]=[CH:43][C:42]([N+:13]([O-:15])=[O:14])=[CH:41][CH:40]=1
Reactant: CN(C)c1ccccc1
Reactant: O=[N+]([O-])N1CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Agent: O=[N+]([O-])OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Solvent: CC#N
Product: CN(C)c1ccc([N+](=O)[O-])cc1
Yield: 14 %

Procedure:
Considering the electrophilic nature of the NOx species generated by the photofragmentation of RDX and PETN and their resemblance to the active electrophiles in aromatic nitration reactions, reactions between electron-rich tertiary aromatic amines and the photofragments of RDX and PETN were selected. It was found that photolysis (λ=313 nm) of a mixture of N,N-dimethylaniline (DMA) and 2 equivalents of either RDX or PETN for 10 minutes in acetonitrile under anaerobic conditions afforded the formation of N,N-dimethyl-4-nitroaniline (DMNA) in 14% yield (GC yield). Higher yields of DMNA were obtained with longer photolysis times and DMNA was formed in ca. 80% yield after 1 hour. The photoreaction between DMA and either RDX or PETN under anaerobic conditions was observed to produce only a single, yellow-colored product (DMNA) and other side products were not evident by TLC or GC-MS analyses. The 1H-NMR, IR and high-resolution mass spectra of the isolated yellow product matched those obtained for an authentic commercial sample of DMNA. Conducting the photolysis under aerobic conditions resulted in partial demethylation of DMA and yielded a mixture of DMNA and its demethylated analog, N-methyl-4-nitroaniline (13) (see Scheme 1). Photolysis of DMA with ammonium nitrate was also found to produce DMNA, although relatively longer photolysis times (>30 minutes) were required and greater amounts of demethylated side products were observed (possibly due to the presence of water or other nucleophiles in the solutions).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[F:29].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:45]1([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:29][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:2]=1[NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[S:56])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide was dissolved in ethanol (3.0 ml), and then (S)-(+)-10-camphorsulfonic acid (75.5 mg) was added thereto, followed by stirring at room temperature for 15 min. A solution of phenylacetyl isothiocyanate (45.5 mg) in toluene (3.0 ml) was added thereto, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with brine (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, to which diethyl ether (3 ml) and hexane (3 ml) in this order were then added to suspend. The solid was filtered off, washed with diethyl ether (1 ml), and dried under aeration to provide the titled compound (17.8 mg, 18%) as colorless powder.