Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:25].[CH3:26][O:27][NH2:28].C(O)C.Cl>C(OCC)C>[ClH:25].[CH3:26][O:27][N:28]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][O:22][CH2:23][CH3:24])[CH3:19]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOC

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride. The product was dissolved a mixture of ethanol and diethyl ether, and a solution of hydrogen chloride (1 equivalent of a 1.0 M solution in diethyl ether) was added. A precipitate formed, and the solvents were removed under reduced pressure. The resulting solid was recrystallized from a mixture of ethanol and diethyl ether to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime hydrochloride in about a 6.4 to 1 mixture of E and Z isomers as a white solid, mp 189-192° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].Cl>N1C=CC=CC=1>[N:9]#[N:10].[S:11]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH:9][NH2:10])=[O:8])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)c2ccccc2C(=O)NN)cc1
Product: N#N
Temperature: 0 °C
Yield: 141.7 %

Procedure:
Benzhydrazide (4.08 g) was dissolved in pyridine (25 mL) and cooled on ice. Tosyl chloride (5.72 g) was added portionwise over 5 minutes. Stirring was maintained at 0° C. for 15 minutes. Stirring at room temperature for 18 hours was followed by pouring into dilute HCl (650 mL). The resultant precipitate was filtered off, washed with water, and recrystallized from hot ethanol/water to afford 6.76 g of product as fine white needles.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O>CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 63 %

Procedure:
4-fluoro-3-nitrobenzoic acid (2.5 g, 14 mmol, 1.0 eq) was dissolved in MeOH (68 mL) and heated to reflux. 2.0M oxalyl chloride in CH2Cl2 (14 mL) was added to the refluxing solution slowly and stirred for 2 h at reflux. The reaction was concentrated in vacuo, crystallized at 0° C., and filtered to give 1.7 g (63%) of crude methyl 4-fluoro-3-nitrobenzoate as a white solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 4-fluoro-3-nitrobenzoate (1.7 g, 8.4 mmol, 1.0 eq) and 5% palladium on carbon (89 mg, 0.84 mmol, 0.10 eq) were dissolved in EtOH (40 mL) and stirred under H2 atmosphere (1 atm) for 24 h. The mixture was filtered through celite and concentrated in vacuo affording 1.4 g (97%) of crude methyl 3-amino-4-fluorobenzoate as a brown solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 3-amino-4-fluorobenzoate (1.4 g, 8.2 mmol, 1.2 eq), 5-bromopyrimidine (1.1 g, 6.8 mmol, 1.0 eq), cesium carbonate (3.1 g, 9.6 mmol, 1.4 eq), Bis(dibenzylideneacetone)palladium (0.50 g, 0.55 mmol, 0.080 eq), and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.47 g, 0.82 mmol, 0.12 eq) were dissolved in Dioxane (17 mL) and stirred under argon at 100° C. overnight. The mixture cooled to rt and was filtered through celite and washed with 5% MeOH in CH2Cl2. The filtrate was collected, concentrated in vacuo, and purified by flash chromatography on silica gel afforded 1.5 g (90%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (s, 1H), 8.50 (s, 2H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.63 (ddd, J=8.5, 4.7, 2.1 Hz, 1H), 7.42 (dd, J=11.2, 8.6 Hz, 1H), 3.83 (s, 3H); ES-MS [M+1]+:248.1.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]=[O:15].[ClH:16]>C(Cl)(Cl)Cl>[Cl:16][CH2:14][O:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1CCCCC1C1CCCCC1
Reactant: C=O
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: ClCOC1CCCCC1C1CCCCC1
Temperature: 2.5 °C

Procedure:
A 500 ml reactor made of glass was substituted by nitrogen, 46.6 g of 2-cyclohexylcyclohexanol and 200 ml of dehydrated chloroform were charged therein, and the resultant solution was stirred by a stirrer, and then 7.70 g of paraformaldehyde was added therein at the time of complete dissolution. Next, the reactor was cooled to 0 to 5° C. by ice bath, and hydrogen chloride was introduced into the solution by a bubbler. When a suspension of the solution caused by paraformaldehyde became clear and the solution became transparent, the introduction of hydrogen chloride was stopped. The lower phase was separately isolated, followed by drying by adding 28.3 g of anhydrous calcium chloride powder. Thereafter, 48.0 g of chloromethyl(2-cyclohexylcyclohexyl)ether was obtained (the purity according to 1H NMR was 87%) after distillation of the solvent.
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: O=C(O)C1Cc2cscc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cscc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene (3.95 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:29][CH:30]([CH3:32])[CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OC
Temperature: 80 °C
Yield: 21.1 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile was added potassium carbonate (110 mg, 0.798 mmol) and isobutyl bromide (146 mg, 1.064 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:27]([Si:31]([CH3:41])([CH3:40])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:12][C@H:36]1[CH2:37][CH2:38][C@@H:33]([O:32][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:41])[CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (2.07 g, 11 mmol) and diisopropyl azodicarboxylate (2.98 g, 14 mmol) (Aldrich) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added a mixture of trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (3.2 g, 14 mmol) and triphenylphosphine (3.64 g, 14 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water, extracted with ethyl acetate (3×). The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (5% EtOAc;hexanes) to give cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 4.0 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].CCOC(C)=O>CCO>[N+:1]([C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
Preparation I5, Step 1: N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (3.6 g) was dissolved in EtOH and heated to 105° C. prior to the addition of 1N NaOH (60 ml) and 50% NaOH (10 ml). After 2.5 h, the reaction was cooled to rt and EtOAc was added. The organic layer was washed with water and brine. Then it was dried and concentrated to give a crude 2-nitro-3-trifluoromethyl-phenylamine (2.79 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 5.0 (s, 2H), 7.02 (d, 1H), 7.10 (d, 1H), 7.38 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH2:24][OH:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 6-bromo-3-hydroxymethyl-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (1.0 g) in DMSO (10 ml) was added triethylamine (4.4 ml), and pyridine sulfur trioxide complex (2.6 g) was added at room temperature, and the mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (940 mg).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]([F:26])([F:25])[C:14]1([C:21]([Cl:24])([F:23])[F:22])[O:18][CH:17]([CH2:19]O)[CH2:16][O:15]1>O>[N+:1]([O-:4])([O:3][CH2:19][CH:17]1[CH2:16][O:15][C:14]([C:13]([Cl:12])([F:25])[F:26])([C:21]([Cl:24])([F:22])[F:23])[O:18]1)=[O:2]
Reactant: O=[N+]([O-])O
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reaction time: 0.5 h

Procedure:
34 ml nitric acid (96%) is added slowly to 43 ml chilled acetic anhydride. Then, 14.8 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane, is added dropwise with magnetic stirring over a 30 minute period to the chilled mixed acid (0° to -10° C.). An additional 25 minutes of stirring is allowed. The reaction mixture is drowned in 250 ml of cold tap water forming a small lower liquid layer. Ether extraction (3 × 75 ml) removed the lower layer and all of the yellow coloration. The ether solution is washed several times with water and then dried over Na2SO4, filtered and evaporated on a rotary evaporator. The cloudy residue is redissolved in ether, treated with Na2SO4, decanted and evaporated as before. The bright yellow liquid is redissolved in ether and treated with activated carbon (DARCO G-60), then filtered (colorless), and reevaporated to yield the above named product.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(O[CH2:17][CH3:18])C>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:18]2[CH:17]=[CH:5][C:1]3[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=3)[C@@H:3]2[OH:4])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: Oc1ccc(F)cc1
Product: O[C@H]1c2ccccc2C=C[C@@H]1Oc1ccc(F)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-fluorophenol (389 mg, 3.47 mmol). The mixture was heated at 80° C. for 5 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10% ethyl acetate in hexanes) giving a white crystalline solid 7 (163 mg, 92%). The ee was determined to be 97% by HPLC analysis on a CHIRALCEL OD column, λ=486 nm). Retention times in 1.5% isopropanol in hexanes were 28.1 min (major) and 29.5 min. Rf=0.39 on silica (20% ethyl acetate in hexanes); mp 127-129° C. (Et2O); [α]25D=+216° (c=9.5, CHCl3). IR (KBr, cm−1) 3309 (b), 3071 (w), 2864 (w), 1504 (s), 1284 (m), 1052 (s), 781 (s), 692 (m); 1H NMR (400 MHz, CDCl3): δ7.63-7.61 (1H, m), 7.31-7.26 (2H, m), 7.12-7.10 (1H, m), 7.00-6.95 (2H, m), 6.92-6.88 (2H, m), 6.51 (1H, dd, J=2.1, 9.9 Hz), 5.98 (1H, dd, J=2.2, 9.9Hz), 5.15 (1H, dd, J=3.6, 10.0 Hz), 5.01 (1H, ddd, J=2.1, 2.1, 10.1 Hz), 2.54 (1H, d, J=3.8 Hz); 13C NMR (400 MHz, CDCl3): δ157.6 (d, JC-F=239 Hz), 156.4, 153.4, 135.4, 131.8, 129.1, 128.2, 126.5, 125.7, 125.2, 117.5 (d, JC-F=8 Hz), 116.1 (d, JC-F=23.5 Hz); HRMS calcd for (M+) (C16H13O2F): 256.0810. Found: 256.0911.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][N:21]1[C:25](=[O:26])[C:24](Br)=[C:23]([Br:28])[C:22]1=[O:29].Cl>O1CCCC1>[Br:28][C:23]1[C:22](=[O:29])[N:21]([CH3:20])[C:25](=[O:26])[C:24]=1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Reaction time: 0.75 h

Procedure:
A solution containing 1.445 g of indole, dissolved in 29 ml of dry tetrahydrofuran, is held between −20 and −10° C. under argon, and then 26 ml of LiHMDS (1M in hexane) are added, dropwise, over the course of 15 minutes. After 45 minutes at −10° C., the solution is diluted with 15 ml of additional tetrahydrofuran, and a solution containing 2 g of N-methyl-2,3-dibromomaleimide dissolved in 17 ml of tetrahydrofuran is added dropwise over the course of 30 minutes. After 15 minutes at −10° C. and 15 minutes at 0° C., the reaction is stopped by the addition, at 0° C., of 50 ml of 0.3N hydrochloric acid solution. The reaction mixture is extracted with ethyl acetate, and the organic phases are washed with saturated NaCl solution, dried over MgSO4 and then evaporated under reduced pressure. The desired product is precipitated using methanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16](OCC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:16](=[O:17])[CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:22][CH2:21][C:5]1=2)[CH3:24]
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: CCN
Product: CCNC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and ethyl amine (40% aq, 2.5 ml) was heated at 100-120° C. for 3-4 h to obtain 19 mg of N-ethyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[NH:33]1[CH2:38][CH:37]=[CH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[N:33]1([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:11]([N:9]3[CH2:8][CH2:7][N:6]4[C:2](=[O:1])[O:3][C:4]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:5]4[CH2:10]3)=[O:12])=[CH:14][CH:15]=2)[CH2:34][CH:35]=[CH:36][CH2:37][CH2:38]1
Reactant: O=Cc1ccc(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)cc1
Reactant: C1=CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(CN2CC=CCC2)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 40.5 %

Procedure:
To a solution of 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]benzaldehyde (0.15 g, 0.35 mmol) and 1,2,3,6-tetrahydropyridine (44 mg, 0.53 mmol) in tetrahydrofuran (4 mL) was added sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and the mixture was stirred at room temperature for 27 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=4:1) and crystallized from diisopropyl ether to obtain the title compound (70 mg, yield 41%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[N:17][C:18]([C:31](=[O:33])[NH2:32])=[C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:20]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:31]([C:18]1[N:17]=[N:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]2)=[N:20][C:19]=1[NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:27])=[CH:29][CH:30]=1)(=[O:33])[NH2:32]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nnc(C(N)=O)c(Nc3ccc(C(=O)O)cc3)n2)C1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Reaction time: 0.08 h

Procedure:
Compound 5 (90 mg, 0.20 mmol) was mixed with morpholine (53 μL, 0.60 mmol) in DMF (5 mL). To the mixture were added DIEA (105 μL, 0.60 mmol) and PyBOP (312 mg, 0.60 mmol). The mixture was stirred for 5 min, diluted with 100 mL EtOAc, washed with brine ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 50 to 100% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate in quantitative yield. (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate was treated with DCM (10 mL) and TFA (3 mL) for 1 h at RT. The mixture was concentrated in vacuo to dryness. The residue was subjected to reverse phase prep HPLC to isolate the (R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (6) as HCl salt. MS found for C20H26N8O3 as (M+H)+ 427.1, (M−H)− 425.2. UV: λ=270 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCCCC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (50 mg, 0.165 mmol) and valeric acid (36 mg, 0.247 mmol) in DMF (5 ml) were added N-methyl morpholine (51 mg, 0.5 mmol) and HBTU (94 mg, 0.247 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was poured into water and extracted with ethyl acetate (3×20 ml). The combined ethyl acetate part was dried over Na2SO4 and evaporated to furnish the crude material (60 mg). The crude was purified by prep. HPLC and the desired product (30 mg, 47%) was obtained as sticky white solid. MS (LC/MS): 387.2 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[NH:16]1C=CN=[CH:17]1>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]2[CH:14]=[CH:17][N:16]=[CH:13]2)=[CH:7][CH:8]=1
Reactant: CN(C)CC(=O)Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Cc1ccc(F)cc1)Cn1ccnc1
Yield: 54.1 %

Procedure:
A solution of product from step B (7.80 g, 36.6 mmol) in ethanol (30 ml) and water (30 ml) containing imidazole (12.4 g, 183.0 mmol) was heated under reflux for 6 hrs. The mixture was allowed to cool and partitioned between dichloromethane (100 ml) and water (100 ml), the organic phase was washed with brine (5×100 ml) separated and dried (MgSO4). Evaporation of the residue left a yellow oil. This was purified by chromatography (Biotage flash 40, 90 g, SiO2 cartridge) eluting with a gradient of 0-5% methanol/dichloromethane to give 1-(4-fluorophenyl)-3-(imidazol-1-yl)propanone as a yellow oil 4.32 g (54%).