Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].F[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[N:15][C:16]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[N:15][C:16]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([OH:27])[CH2:25][CH2:26]4)=[N:17]3)=[CH:12][CH:11]=2)[CH2:2]1
Reactant: O[C@H]1CC[C@H](Nc2ncc3ccc(F)cc3n2)CC1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](Nc2ncc3ccc(OC4CCOC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tetrahydrofuran-3-ol (337 mg, 3.83 mmol) in THF (5 mL) was added NaH (153 mg, 60% disp. in oil, 3.83 mmol) and the mix stirred at r.t. for 20 min., forming a pale suspension. To this was added trans-4-[(7-fluoroquinazolin-2-yl)amino]cyclohexanol (100 mg, 0.383 mmol) and a yellow suspension formed almost immediately. The suspension was stirred at r.t. for 30 min then heated to 45° C. for 1 hour, then heated to 65° C. for 30 min then cooled to R.T. overnight. The liquors were concentrated and diluted with water (10 mL) and EtOAc (25 mL) and shaken vigorously. The aq. was removed and the organics washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and stripped to an oil. Purified by prep TLC eluting with EtOAc to yield the title compound as a white foam, 36 mg, 29%. 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.75 (1H, s) 7.53 (1H, d, J=8.84 Hz) 6.62-6.88 (2H, m) 5.18 (1H, d, J=7.83 Hz) 5.05 (1H, s) 3.81-4.08 (5H, m) 3.54-3.79 (2H, m) 2.22-2.43 (1H, m) 2.08-2.21 (3H, m) 1.91-2.07 (2H, m) 1.36-1.51 (4H, m) 1.19-1.38 (4H, m); MS (API+) for C18H23N3O3 m/z 330.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)(O)[O-].[Na+].IC>CN(C=O)C>[CH3:23][O:20][C:19](=[O:21])[C@H:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:22]
Reactant: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
A suspension of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid (Example 4, 18.0 g, 0.061 mol), sodium bicarbonate (15.36 g, 0.183 mol), and iodomethane (11.40 mL, 0.183 mol) in DMF (164 mL) was stirred at rt for 20 h. The reaction was monitored by reverse phase HPLC. Upon completion, the reaction was quenched by pouring into ice/water (300 mL) followed by extracting with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×150 mL) and brine (150 mL) and was dried over anhydrous sodium sulfate. Filtration and concentration to dryness gave a crude oil which was purified by silica gel chromatography using 10-35% ethyl acetate/hexanes to give 16.38 g (87%) of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester as an oil. 1H NMR (DMSO-d6) δ 7.4 (d, 2H), 7.3 (m, 3H), 7.3 (m, 2H), 7.1 (s, 1H), 6.82 (d, 1H), 6.38 (s, 1H), 5.41 (q, 1H), 5.08 (s, 2H), 3.60 (s, 3H), 1.70 (d, 3H); LC/MS (+esi) m/z 310.2 (M+H)+, RT 3.47 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][CH2:18][N:13]4[C:12](=O)[CH2:11][CH2:10]3)[CH:16]=2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][CH2:18][N:13]4[C:12](=[S:29])[CH2:11][CH2:10]3)[CH:16]=2)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(-c3cccnc3)cc3c2N1CC3
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: S=C1CCc2cc(-c3cccnc3)cc3c2N1CC3

Procedure:
A mixture of 8-pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-one (900 mg, 3.60 mmol) and Lawessons reagent (1.45 g, 3.60 mmol) was refluxed in a mixture of 50 ml toluene and 5 ml THF for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate, 1/1, Rf=0.25). 8-Pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-thione was obtained as a yellow solid (155 mg, 0.58 mmol, 26%), mp (HCl salt, THF) 283° C. 1H-NMR (500 MHz, CDCl3): δ=2.96 (t, 3J=7.9 Hz, 2H), 3.25 (t, 3J=7.6 Hz, 2H), 3.29 (t, 3J=8.0 Hz, 2H), 4.42 (t, 3J=8.2 Hz, 2H), 7.23 (s, 1H), 7.33 (s, 1H), 7.34 (ddd, 3J=7.9 Hz, 3J=4.7 Hz, 5J=0.6 Hz, 1H), 7.81 (ddd, 3J=7.9 Hz, 4J=2.5 Hz, 4J=1.9 Hz, 1H), 8.57 (dd, 3J=4.7 Hz, 4J=1.6 Hz, 1H), 8.59 (d, 4J=2.2 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ=23.5, 27.1, 40.3, 52.0, 122.7, 123.0, 123.6, 125.1, 131.7, 134.2, 135.2, 136.4, 139.6, 148.1, 148.5, 192.5. MS m/z 267.10 (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>[Cu]=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:24][C:25]2[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2ccc(Cl)cc2C(=O)O)cn1
Temperature: 100 °C

Procedure:
To a solution of 19.1 g. of 2,5-dichlorobenzoic acid [Besley & Goldberg, J. Chem. Soc., 2448 (1954)] in 100 ml. of amyl alcohol is added 6.9 g. of anhydrous potassium carbonate and 0.1 g. of copper oxide. The mixture is stirred and heated at 100° C. for 30 minutes, then 13.0 g. of 5-amino-2-methoxypyridine is added and the mixture is heated at reflux and stirred for 3 hours. A small amount of water forms and is collected in a Dean-Stark apparatus. The reaction mixture is cooled, poured into water and made basic with potassium carbonate. The mixture is steam-distilled to remove the amyl alcohol, then filtered and the filtrate is acidified to pH 6. The mixture is again filtered and this pink filtrate is acidified with 6 N hydrochloric acid to pH 4. The solid is collected, giving 5-chloro-2-(6-methoxy-3-pyridylamino)benzoic acid as a pink crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)C>C(N(CC)CC)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([N:28]3[CH2:29][CH2:30][N:31]([C:6]4[N:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)[CH2:32][CH2:33]3)=[O:27])[CH2:22][CH2:21]2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: O=C(N1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1
Yield: 45.7 %

Procedure:
4-Methyl-6-chloropyrimidine (0.51 g) was added to a stirred mixture of 1-(4-bromophenylsulphonyl)-4-(1-piperazinylcarbonyl)piperazine hydrochloride (1.50 g) and ethanol (35 ml). Triethylamine (2.2 ml) was added and the mixture was heated at reflux for 6 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane as eluent to give a foam. This was crystallised from methyl tert-butyl ether to give 1-(4-bromophenylsulphonyl)-4-[1-(4-methylpyrimidin-6-yl)piperazin-4-ylcarbonyl]piperazine as a solid (0.77 g); m.p. 215-216° C.; NMR (CDCl3): 8.5 (s, 1H), 7.7 (m, 2H), 7.6 (m, 2H), 6.35 (s, 1H), 3.6 (m, 4H), 3.4 (m, 4H), 3.3 (m, 4H), 3.05 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=2)[CH:7]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(-c2cc(Cl)ccc2C#C[Si](C)(C)C)ccn1

Procedure:
A solution of 333 mg (1.16 mmol) of [(2-bromo-4-chlorophenyl)ethynyl](trimethyl)silane, 195 mg (1.28 mmol, 1.1 eq.) of (2-methoxypyridin-4-yl)boronic acid, 401 mg (2.9 mmol, 2.5 eq.) of potassium carbonate and 14 mg (0.02 mmol, 0.015 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/monodichloromethane adduct in 18 ml of dioxane was irradiated in a microwave at 130° C. for 15 min. The reaction mixture was then filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the organic phase was concentrated under reduced pressure. Yield: 550 mg (purity 41%, 62% of theory)
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCCOc1cccc2ccccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 10 g. 3-(α-naphthyloxy)propyl bromide and 12.5 g. ethyl 4-aminobenzoate in 100 ml. hexamethylphosphoramide is stirred at 110° for 15 hours. The cooled solution is diluted with 200 ml. water and extracted 3 times with 100 ml. portions of ether. The combined extracts are washed with brine, dried and evaporated to an orange residue. The product is crystallized from ethanol to yield a solid which is crystallized from ethanol to yield white crystals, m.p. 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccsc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride (82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled to room temperature, and concentrated in vacuo. The residue is treated with water for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant solid is purified by flash column chromatography eluting with a gradient of 1% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-[(2,4-dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 198-200° C.; 1H NMR (DMSO-d6) δ 7.47 (d, J=4 Hz, 1H), 7.54 (dd, J=6, 2 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 8.61 (s, 1H), 9.67 (s, 1H); MS 318.1, 320.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:20](=[O:21])[C:19]3[C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[CH:16]=[C:15]([O:26][CH2:27][CH2:28][CH3:29])C=3NC=2)=[CH:7]1.[H-].[Na+].CI>C(OCC)(=O)C.O>[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:20](=[O:21])[C:19]3[C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[CH:16]=[C:15]([O:26][CH2:27][CH2:28][CH3:29])[C:3]=3[N:2]([CH3:1])[CH:4]=2)=[CH:7]1
Reactant: CCCOc1cc2ccccc2c2c(=O)c(-c3ccoc3)c[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccoc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a DMF solution (5 ml) of 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (300 mg, 0.94 mmol) was added sodium hydride (60% oil base, 61 mg, 1.4 mmol), and then the mixture was stirred at room temperature for 5 minutes. Methyl iodide (181 mg, 1.27 mmol) was added thereto and the resulting mixture was stirred at room temperature for 62 hours. Water and ethyl acetate were added to the reaction mixture and the resulting mixture was subjected to separation. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=90:1→80:1). The purified product was concentrated under reduced pressure to recrystallize the residue from ethyl acetate-n-hexane, giving a pale gray powder of 2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (130 mg, yield: 42%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[CH:12]=[O:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a suspension of 1-bromo-2-naphthaldehyde (502 mg, 2.14 mmol), sodium carbonate (270 mg, 2.55 mmol), and phenylboronic acid (339 mg, 2.78 mmol) in 4.2 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (24 mg, 0.11 mmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with diethyl ether, and the solution was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain the title compound as a white powder (416 mg, 84%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[K+]>O.Cl>[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][NH2:1])=[CH:10][N:11]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(F)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Product: NNc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of sodium nitrite (345 mg, 5.00 mmol) in water (2.5 ml) was added dropwise to a vigorously stirred solution of 6-fluoropyridin-3-amine (561 mg, 5 mmol) in 6N hydrochloric acid (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, then a solution of tin (II) chloride dihydrate (2.82 g, 12.5 mmol) in 6N hydrochloric acid (5 ml) was added dropwise whilst adding small pieces of ice to keep the inner temperature below 5° C. The formation of a foamy layer was observed during the addition and stirring was continued at 0° C. for 3 h. The mixture was made alkaline (pH=14) by addition of 40% aqueous solution of potassium hydroxide and extracted with ethyl acetate (5 times 15 ml). The combined organic extracts were dried over sodium sulfate, the drying agent was filtered off and the solvent was removed under reduced pressure to afford 250 mg (39%) of the target compound as a pale-yellow solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[CH2:31]([NH:38][C:18]1[C:19]2[N:20]([CH:21]=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]([C:13]2[CH:14]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:10]=[N:11][CH:12]=2)=[N:16][N:17]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)ccn23)c1
Temperature: 100 °C
Yield: 129.5 %

Procedure:
To a solution of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.100 g, 0.226 mmol) in 1,4-dioxane (10 mL) was added benzylamine (0.124 mL, 1.13 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 12 h in a sealed tube. The reaction mixture was diluted with ice cold water (150 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 50% EtOAc/hexanes) to yield 5-(1-(benzylamino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-N-(tert-butyl)pyridine-3-sulfonamide (0.150 g, 33.0%). LCMS Method B-4: retention time 1.15 min, [M+1]=513.43. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.17 (s, 9H), 4.31 (d, J=5.2 Hz, 2H), 5.65 (t, J=5.2 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 7.22-7.35 (m, 5H), 7.42-7.44 (m, 1H), 7.47-7.50 (m, 2H), 7.55-7.57 (m, 2H), 7.69 (d, J=2.8 Hz, 1H), 7.75 (s, 1H), 8.65 (t, J=2.0 Hz, 1H), 9.12 (d, J=2.0 Hz, 1H), 9.34 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>>[OH:16][CH2:17][C@H:18]1[N:23]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@H:2]([CH3:1])[CH2:11]3)[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1

Procedure:
A solution of (3R)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (325 mg, 1.59 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (345 mg, 1.59 mmol dissolved in EtOH (7 mL)) was heated in a sealed tube to 155° C. for 3 hours in the microwave. The reaction was cooled and concentrated to give crude product which was purified via MPLC (40-100% EtOAc/Hexane) to give the title compound as a mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCCl>[OH:2][C:3]1[CH:34]=[CH:33][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Oc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(OCCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Two g of the compound of Example 12 was added to a suspension of 4.2 g of aluminum chloride and 2.8 g of ethanethiol in 50 ml of 1,2-dichloroethane at 0° C. The mixture was stirred for 2.5 hours at 0° C., and then worked up by the procedure used in Example 13. Thereby there was obtained 2.0 g of crystalline product. The product was recrystallized from acetone to obtain 1.71 g of the desired product, m.p. 216°-217° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=NC=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=C[N:28]=[C:27]([Cl:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][N:28]=[C:27]([Cl:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Clc1cc(Br)ccn1
Product: Cc1ccc(Nc2ccnc(Cl)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 4-Bromo-2-chloropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=343.0, 345.0 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([NH:39][C:40]1[C:41]([CH3:47])=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:48]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57]O)=[CH:52][CH:51]=1)#[N:49]>C1COCC1.O>[C:32]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:57][CH2:56][C:53]2[CH:54]=[CH:55][C:50]([C:48]#[N:49])=[CH:51][CH:52]=2)[C:41]=1[CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1c(O)cccc1NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)OC(C)(C)C)cccc1OCCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Triphenylphosphine (1.31 g, 13.5 mmol) and diethylazodicarboxylate (1.7 mL) were dissolved in THF (20 mL) under nitrogen. After 15 minutes 3-t-butoxycarbonylamino-2-methylphenol (2.48 g; 11.1 mmol; from step (i) above) dissolved in THF (20 mL) and 2-(4-cyanophenyl)ethanol (1.9 g, 13 mmol) were added. After 5 days at room temperature water was added and the stirring continued for 30 minutes. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 2.98 g (77%) of the sub-title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>C(OCC)(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCCn1ccnc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1NCCCn1ccnc1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
1-(3-Aminopropyl)imidazole (4.55 ml) was added to 2-chloronitrobenzene (3.000 g) and stirred for 15 hours at 125° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, and extracted with 1N hydrochloric acid aqueous solution. The extract was alkalified with 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (4.442 g) as orange oil.