Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>C(Cl)(Cl)Cl>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][O:1][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2occc21
Solvent: ClC(Cl)Cl
Product: Clc1ccnc2ccoc12
Yield: 50 %

Procedure:
To a solution of Furo[3,2-b]pyridine 4-oxide in CHCl3 (5 mL) was added POCl3 (5 g, 33 mmol). The mixture was refluxed for 2 hours. After cooling, the mixture was quenched with ice water and neutralized with NaHCO3. Extracted with CHCl3 (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography to afford 7-Chloro-furo[3,2-b]pyridine (0.74 g, 50%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (m, 1H), 7.92 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H).
Reaction SMILES: C[C:2]1(C)[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3Br)[CH:11]=C[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:24]([O-])(=O)[CH3:25].[K+].[CH3:29]N(C=O)C.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:29][C:24]1([CH3:25])[C:11]2[C:12]([N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:13][C:14]2[CH:2]=[C:3]3[C:8]([C:9]1=2)=[CH:7][CH2:6][CH:5]=[CH:4]3
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccccc3Br)cc21
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C2=C(C=C3C=CCC=C32)C=C2N=c3ccccc3=C21
Temperature: 100 °C
Reaction time: 11 h
Yield: 55.2 %

Procedure:
N-(9,9-dimethyl-9H-fluorene-2-yl)-2-bromo-aniline (18.5 g), potassium acetate (6.98 g), and DMF (95 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 1 hour. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (1.18 g) and stirred at 100° C. for 11 hours. After the mixture was cooled to a room temperature, the reaction liquid was added to water (300 ml) and extraction was performed with toluene (300 ml). An organic layer obtained was washed with water (200 ml) twice, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel; eluent: toluene/n-hexane) to obtain a pale yellow powder of 12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (7.9 g; yield 55.2%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13]Br.[CH:15]1[N:20]=[C:19](Cl)[C:18]2[N:22]=[CH:23][N:24]([C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[C:17]=2[N:16]=1>>[C:1]1([C:7]2([CH2:8][NH2:9])[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]2([CH2:8][NH:9][C:19]3[C:18]4[N:22]=[CH:23][N:24]([C:17]=4[N:16]=[CH:15][N:20]=3)[C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: BrCCCBr
Product: NCC1(c2ccccc2)CCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 58.3 %
Yield: 62 %

Procedure:
(1-Phenylcyclobutyl)methylamine is prepared from phenylacetonitrile (2.93 g, 25 mmol) and 1,3-dibromopropane (7.57 g, 37.5 mmol) as described in Example 1 in 62% yield. The above amine (1.61 g, 10 mmol) is reacted with 6-chloropurine riboside (2.87 g, 10 mmol) as described in Example 1. As the compound did not crystallize it is purified by removal of the solvent under reduced pressure, followed by dissolving the residual gum in ethyl acetate (50 mL) and washing it with water (2×25 mL) and saturated brine (25 mL) and drying (MgSO4). The solvent is removed under reduced pressure and the residual gum is subjected to flash chromatography on silica gel, eluting with 5% CH3OH in CHCl3. N6-((1-phenylcyclobutyl)methyl)adenosine (2.40 g, 58%) is obtained as a white solid foam m.p. 95°-118° C. Found: C, 61.21; H, 6.23; N, 17.24%. C21H25N5O4 calculated requires: C, 61.31; H, 6.08; N, 17.03%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[Br:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]([Cl:10])[CH:9]=1
Reactant: Oc1c(Cl)cc(CCBr)cc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(Cl)cc(CCBr)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-bromoethyl)-2,6-dichlorophenol (104 mg) in acetone (1.2 ml) were added potassium carbonate (133 mg) and methyl bromoacetate (73 μl), and the mixture was stirred for 3 hours at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=12/1) gave methyl 2-[4-(2-bromoethyl)-2,6-dichlorophenoxy]acetate (82 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[C:12](O)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: C=CCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCCCCCC(=O)NC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 46 h
Yield: 23 %

Procedure:
An oven-dried 50 mL round bottom flask was charged with 3-aminoquinuclidine dihydrochloride (2 mmol), 10-undecenoic acid (2 mmol), N,N-dimethylaminopyridine (0.3 mmol), diisopropylethylamine (4 mmol), and dry DMF (15 mL). The flask was purged with argon and cooled to 0° C. in an ice bath. Dicyclohexycarbodiimide (2.2 mmol) was then add to the solution, the flask repurged with argon, and the mixture warmed to R.T. and stirred for 46 h. The reaction mixture was concentrated in vacuo and 30 ml diethyl ether added to the residue. The solid was filtered off over Celite and the organic phase concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (3:7) to afford the product as a white solid (23%). Rf=0.44. 1HNMR (400 MHz, CDCl3): δ=5.73 (m, 1H), 4.93 (dd, 1H, 3JHH=17.0 Hz, 4JHH=1.5 Hz), 4.87 (d, 1H, 3JHH=10.3 Hz), 3.71 (m, 1H), 2.10 (t, 2H, 3JHH=7.8 Hz), 1.97 (q, 2H, 3JHH=7.3 Hz), 1.85 (m, 2H), 1.54-1.68 (m, 5H), 1.02-1.34 (m, 15H) ppm. 13CNMR (400 MHz, CDCl3): δ=172.2, 139.1, 114.1, 48.6, 48.0, 37.0, 34.0, 33.7, 33.2, 29.3, 29.2, 29.0, 28.8, 25.9, 25.7, 25.5, 25.0, 24.9 ppm. HRMS-ESI: Calculated [M-C2H2]+: 266.2358. found: 266.2474.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=O)[C:19](=[O:22])[C:18]=2[O:23]CC)=[CH:4][CH:3]=1.[NH2:26][C@@H:27]([CH2:29][CH3:30])[CH3:28]>C1COCC1>[C@H:27]([NH:26][C:20]1[C:19](=[O:22])[C:18](=[O:23])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CC[C@@H](C)N
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added (R)-(−)-2-aminobutane (0.52 ml, 5.12 mmol). The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl(aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 418.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.5 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]2[CH2:18][C@@H:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:11])=[C:4]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:3]=1.C(OCC)(=O)C.[ClH:52]>C(O)(=O)C>[ClH:52].[ClH:52].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]3[CH2:18][C@@H:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[CH2:16][NH:15][CH2:14]3)=[O:11])[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:4]=2[CH:3]=1
Reactant: COCCCCNc1cc(F)ccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccc(F)cc21
Temperature: 80 °C
Reaction time: 72 h

Procedure:
tert-Butyl (3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (294 mg) was dissolved in acetic acid (5 ml), and the mixture was stirred at 80° C. for 3 days. The reaction mixture was cooled to room temperature, 4M hydrogen chloride-ethyl acetate (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added, and the mixture was concentrated again to give the object product (113 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.87 mmol) and THF/H2O (3/1, 80 mL) were combined. 4-Phenylpiperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64 mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) were added. The mixture was heated to reflux for 72 h. The mixture was concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The organic phase was extracted with H2O (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (350 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound: Rf =0.12 (silica gel, 6% methanol in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:26]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:27][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCBr
Reactant: BrCCc1cccc2ccccc12
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]([NH:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.[CH:25](OCC)(OCC)OCC>>[Cl-:1].[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:17]1[N:16]=[CH:8][N:7]2[C:25]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=1
Reactant: CCOC(OCC)OCC
Reactant: Cl
Reactant: Cc1ccccc1NNc1nc2ccccc2c2ccccc12
Product: Cc1ccccc1-[n+]1ncn2c3ccccc3c3ccccc3c21
Product: [Cl-]
Temperature: 25 °C

Procedure:
A suspension of N-phenanthridin-6-yl-N′-o-tolylhydrazine hydrochloride (9.0 g, 27 mmol) in triethyl orthoformate (360 ml) is stirred under reflux under argon for 17 h. After cooling to room temperature, the precipitate is filtered off and washed with triethyl orthoformate and cold acetone. Yield: 8.2 g (88%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: COc1cccc(C(C)=O)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cccc(C(C)=O)c1[N+](=O)[O-]
Reaction time: 17 h

Procedure:
50.0 g of 3-methoxyacetophenone was added slowly, drop-by-drop, to 250 ml of 70% nitric acid at room temperature. The mixture was allowed to stand for 17 hours, warmed and held at 40° C. for 1 hour, cooled and diluted to three times its volume with water. The resulting mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated sodium chloride solution, dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in ethyl acetate, hexane was added and the mixture was set in dry ice. The solid that formed was collected and dried under reduced pressure to give 3-methoxy-2-nitroacetophenone (4A), as a cream-colored solid, m.p.: 125°-127°C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([O:27][CH2:28][CH2:29][OH:30])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(N(CC)CC)C>CN(C=O)C.O>[C:17]1([S:14]([C:10]2[C:9]3[C:13]4[N:12]([CH2:2][CH2:3][O:4][C:5]=4[CH:6]=[C:7]([O:27][CH2:28][CH2:29][OH:30])[CH:8]=3)[N:11]=2)(=[O:16])=[O:15])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(OCCO)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn2c3c(cc(OCCO)cc13)OCC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 2-[7-(2-chloroethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]ethanol (1.18 g, 2.65 mmoles) and triethylamine (0.4 ml, 2.65 mmoles) in DMF was stirred overnight at 70° C., cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 5% CH3OH/EtOAc to afford the title compound (1.03 g, 2.5 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45](Cl)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43])(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidine-carboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacue. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthyl-sulfonyl)-L-arginyl]-2-piperidinecarboxylate. For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192°-3° C. I.R. (KBr): 3,210, 1,747, 1,638 cm-1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1.C(N(CC)CC)C.C1C=CC(O[C:44](OC2C=CC=CC=2)=[N:45][C:46]#[N:47])=CC=1.[CH3:55][NH2:56]>CC(O)C.CO>[C:55](/[N:47]=[C:46](/[NH:45][CH3:44])\[NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1)#[N:56]
Reactant: CN
Reactant: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(C)O
Product: CN/C(=N/C#N)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one (66 mg, 0.158 mmol) was weighed into a flask, then dissolved in 2.0 mL IPA. Triethylamine (0.055 ml, 0.38 mmol) was then added followed by diphenyl cyanocarbonimidate (75 mg, 0.316 mmol). The reaction was then stirred at room temperature for 1.5 hours. The reaction was then transferred to a scaled tube, followed by addition of 3 mL of methyl amine (2.4 ml, 4.9 mmol) in MeOH. The reaction was then placed in a 60° C. bath for 12 hours. The reaction vas then removed and concentrated, and the residue was purified by flash column chromatography (3-7% MeOH/CH2Cl2) to provide the desired product (32 mg, 41%) as a light orange foam film. MS ESI (+) m/z 499 (M+E) detected; 1H NMR (400 MHz, MeOH) δ 7.48 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.38 (m, 2H), 7.28 (m, 3H), 3.45 (m, 1H), 3.39 (m, 1H), 3.27 (m, 1H), 2.78 (s, 3H), 2.45 (m, 1H), 1.99 (m, 1H), 1.59 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>ClCCl.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[S:11][C:10]=1[C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(OCc2ccccc2)c(C(=O)O)s1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON(C)C(=O)c1sc(C(C)C)cc1OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
860 mg of 3-benzyloxy-5-isopropyl-thiophene-2-carboxylic acid were dissolved in 30 ml of dichloromethane, and 560 mg of N,O-dimethylhydroxylamine hydrochloride and 2.3 of triethylamine were added. After 15 min at 22° C., 2.3 ml of a 50% strength 1-propanephosphonic anhydride solution in acetic acid were added, and the mixture was stirred at 22° C. for a further 18 h. The reaction mixture was washed twice with 20 ml of water each time and once with 70 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnc(Cl)cc1NCc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(Nc2cc(NCc3ccccc3)c(C#N)cn2)c1
Temperature: 120 °C

Procedure:
To ˜10 ml of NMP was added 15.1 (150 mg) and DIEA (˜0.1 mL). To this stirring solution was added benzylamine (1.1 eq in ˜5 mL NMP) dropwise. After stirring for 1 hour, H2O was added to the reaction mixture, followed by EtOAc. HPLC analysis indicated substantial amounts of product in each layer. Both layers were concentrated and the resulting oil was dissolved in a H2O/TFA/ACN mixture. This solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 20% to 60% B mixture over 10 minutes to give 205 mg of 4-(benzylamino)-6-chloronicotinonitrile (11). To 100 mg of 4-(benzylamino)-6-chloronicotinonitrile (11) in ˜3 mL NMP was added 1 ml of 60 mg/ml m-toluidine and 45 mg pTSA.H2O. Reaction heated at 120° C. for 72 hours. Due to inadequate conversion to product, the reaction mixture was transferred to a microwave tube and subsequently heated via microwave irradiation at 220° C. for 20 minutes. Water was added to the crude reaction mixture and a preparative rpHPLC was run in order to isolate pure 4-(benzylamino)-6-(m-tolylamino)nicotinonitrile (12). To 12 in ˜3 mL DMSO was added K2CO3 (˜100 mg) and 1.5 mL H2O2 (50% by wt.). The reaction was heated to 70° C. at which point the reaction mixture bubbled rigorously. Heat was removed until bubbling ceased and then the reaction mixture was again heated at 70° C. for an additional hour. The reaction mixture was cooled and a H2O/TFA mixture was added. The resulting solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 15% to 55% B mixture over 10 minutes. UV: 257 nm. M+H found for C20H20N4O: 333.3. NMR (CD3OD): 8.12 (1H, s), 7.37-7.24 (6H, m), 7.14-7.09 (1H, m), 6.99 (1H, br), 6.92-6.87 (1H, m), 5.88 (1H, s), 4.45 (2H, s), 2.38 (3H, s) ppm.