Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
To a cooled and stirred solution of 3′-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.56 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.39 g, 74%). MS (ISP) 525.2 [(M+H)+]; mp 211° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]CC)=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C)c2nc(Br)cc(C(=O)O)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 6-bromo-1-isopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.6 g, 1.84 mmol) in EtOH (10 mL), aqueous NaOH (0.11 g, 2.76 mmol, in 5 mL water) was added and reaction mixture stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using 5% MeOH/DCM. The combined organic layers were washed with water & dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford target compound (0.35 g., 63.8%), which was not purified further.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[Na].[NH2:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([N:21]3[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)=[CH:15][C:16]=2S(C)=O)[S:11][C:10]=1[C:31]([NH2:33])=[O:32]>O>[NH2:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([N:21]3[CH2:22][CH2:23][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:29][CH2:30]3)=[CH:15][C:16]=2[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[S:11][C:10]=1[C:31]([NH2:33])=[O:32]
Reactant: CS(=O)c1cc(N2CCC3(CC2)OCCO3)nc2sc(C(N)=O)c(N)c12
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: O
Product: NC(=O)c1sc2nc(N3CCC4(CC3)OCCO4)cc(OCC(F)(F)F)c2c1N
Temperature: 25 °C

Procedure:
To 30 mL of 2,2,2-trifluoroethanol cooled to 0° C. was added sodium metal (0.60 g, 15 mmol), cut fresh and washed in hexanes, in small portions. The mixture was allowed to warm up to room temperature and let stir until all of the sodium metal had reacted. To the mixture was added 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (1.30 g, 3.28 mmol) as a solid in one portion. The mixture was heated to 70° C. for 15 h. The mixture was cooled to room temperature and diluted with H2O. The mixture was washed with CH2Cl2 and the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.940 g of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a white powder.
Reaction SMILES: P([O-])([O-])([O-])=O.[OH-].[K+].P(=O)(O)(O)O.[NH2:13][C:14]1[CH:37]=[CH:36][C:17]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]>CCCCCCC.O>[CH2:38]([S:42]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]([O:22][CH3:23])=[O:21])=[CH:36][CH:37]=1)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC(Oc1ccc(N)cc1)C(=O)OC
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCC(Oc1ccc(NS(=O)(=O)CCCC)cc1)C(=O)OC
Reaction time: 4 h
Yield: 91.9 %

Procedure:
A phosphate buffer solution composed of 49 g of water, 66 g of 45% aqueous potassium hydroxide (0.53 moles) and 38 g (0.32 moles) of 85% phosphoric acid was treated at room temperature with a solution of 69 g (0.197 moles) of methyl 2-[4-aminophenoxy]tetradecanoate (the amine) in 172 g of heptane. The temperature was adjusted to 30° C. and 37.1 g (0.237 moles) of butanesulfonyl chloride was added dropwise over 1 hr. The two-phase mixture was stirred for 4 hr while the temperature was maintained at 30° C. to 35° C. The product assayed 96.9% on a solvent-free basis. The bottom water layer was removed, and the upper layer was washed several times with 100 mL of water and was crystallized by cooling to ice temperature. The product was filtered and washed with 200 mL of cold heptane to afford 85 g (90% yield) of white solid, 98.9% assay by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH3:28])[C:8]1[C:13]([N:14](CC3C=CC(OC)=CC=3)[C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH3:28])[C:8]1[C:13]([NH:14][C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1N(Cc1ccc(OC)cc1)C2=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1NC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
A solution of 4 (20.0 mg, 0.050 mmol) in acetonitrile/H2O (9:1, 0.300 mL) was cooled to 0° C. in an ice-water bath and treated with CAN (82.0 mg, 0.150 mmol). The reaction mixture was stirred at ambient temperature for 12 h and quenched with Na2S2O5 to remove anisaldehyde. The resulting suspension was diluted with H2O, extracted with CH2Cl2, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography afforded 5 (12.0 mg, 86%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.55 (br s, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.15 (dd, J=2.2, 9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 4.31 (m, 2H), 2.12 (d, J=6.6 Hz, 1H), 1.55 (s, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl[C:11]([CH3:19])([CH2:13][CH2:14][C:15]([CH3:18])(Cl)[CH3:16])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:1][C:2]1[C:7]2[C:15]([CH3:18])([CH3:16])[CH2:14][CH2:13][C:11]([CH3:19])([CH3:12])[C:6]=2[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: Cc1cc2c(c(C)c1O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a one necked round bottom flask 2,6-dimethylphenol (13.88 g, 113.6 mmol), 2,5-dichloro-dimethylhexane were added followed by 460 mL of nitromethane. A clear light yellow solution was cooled in a water bath. Aluminum chloride (15.2 g, 113.9 mmol) was added in small portions into the flask. The reaction mixture changed color from pale yellow to green then brown during the addition of aluminum chloride. The reaction was stirred overnight at room temperature and quenched with water. The content was extracted with ethyl acetate and washed with sodium bicarbonate and brine. Crude product was purified by plug of silica gel 5:95 ethyl acetate:hexane to obtain 19.3 g of 1,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-ol. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 6H), 1.67(m, 4H), 2.16 (s, 3H), 2.36 (s, 3H), 2.56 (s, 3H), 3.90 (s, 3H), 5.03(d, 1H, J=3.59 Hz), 6.33 (s, 1H), 6.89(d, 1H, J=3.59 Hz), 7.07 (s, 1H), 7.11(d, 1H, J=3.59 Hz), 8.29 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:18][OH:19])[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: O=C(c1ccccc1)c1cc(F)cc(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To 3,5-difluorobenzophenone (2.5 g) in ethanol (30 mL) was added hydroxylamine hydrochloride (3 eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux for 4 hours and then allowed to cool down to room temperature. The precipitate was then isolated by filtration and washed with water to yield the title compound as a white solid (m.p.=91-93° C., Yield=89%), reflux, 4 h
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:41]=[CH:40][C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14](C(OC(C)(C)C)=O)[CH2:15][C@H:16]([O:25][Si](CC)(CC)CC)[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[ClH:42]>C(OCC)(=O)C>[ClH:42].[CH:1]([O:4][C:5]1[CH:41]=[CH:40][C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][C@H:16]([OH:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(OC(C)C)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (79 mg) was added 4N hydrogen chloride in ethyl acetate (3 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was triturated with diisopropyl ether and dried in vacuo to give (2S)-1-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (35 mg)
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=O)(C)(C)C.[ClH:23]>>[ClH:23].[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:20])[N:11]1[CH2:21][CH2:22][NH:8][CH2:9][CH:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Agent: Cl
Product: O=C1c2c(O)cccc2C2CNCCN12
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (24 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, diluted with water, and lyopholized to give the desired product as an off-white solid (8 mg, 42%). MS (ESI) 205.2 (M−Cl).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1O
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Yield: 97 %

Procedure:
A solution of 4-(azidomethyl)-2-chlorobenzoic acid (6.82 g, 32.2 mmol), N-hydroxysuccinimide (5.19 g, 45.1 mmol) and dicyclohexylcarbodiimide (9.31 g, 45.1 mmol) in tetrahydrofuran (250 mL) was stirred overnight at room temperature. The dicyclohexylurea (7.70 g, 76%) was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (40-60% ethyl acetate/hexanes) to give 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (9.64 g, 97%) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(Br)cc1
Agent: N
Product: Brc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-bromo-4-ethynylbenzene (Alfa Aesar, 80 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (dd, J=7.7, 5.0 Hz, 1H), 7.75-8.01 (m, 5H), 8.36 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 9.14 (s, 1H) ppm; MS (DCI/NH3) m/z 303 (M+H)+, 301 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:5]([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH:4]=1)[CH3:2].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Si:24]([O:19][CH2:18][CH2:17][NH:16][C:14]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[S:7][C:6]=1[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[O:15])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of ethyl (5-ethyl-3-{[(2-hydroxyethyl)amino]carbonyl}-2-thienyl)carbamate (0.22 g), tert-butyl(chloro)dimethylsilane (0.15 mL), triethylamine (0.1 g), N,N-dimethylpyridin-4-amine (0.012 g) and methylene chloride (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.35 g, 95%).
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].NC1C=CC=CC=1C(OCCCCCCCCCCCC)=O>>[CH2:1]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCCCCCCCCCCOC(=O)c1ccccc1N
Product: CCCCCCCCCCCCS(=O)(=O)c1ccccc1N
Yield: 93.6 %

Procedure:
50.9 g of light yellow oily 2-dodecylsulfonylaniline was prepared from 59.4 g of the foregoing 2-dodecylsulfonylnitrobenzene in the same manner as dodecyl o-aminobenzoate in Synthesis Example 2. Yield 93.5%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].[C:12](=S)=[S:13].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]([SH:13])=[CH:2][C:1](=[O:3])[C:4]=2[CH:9]=1
Reactant: S=C=S
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=c1cc(S)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-acetyl-4-bromophenol (20 g) and carbon disulfide (7 ml) in toluene (400 ml) was added dropwise to a suspension of potassium tert.-butoxide (31.4 g) in toluene (500 ml) at 10° C. The mixture was stirred at room temperature for 72 hours. Glacial acetic acid (35 ml) was added and the mixture evaporated under reduced pressure. The residue was treated with water (200 ml) and glacial acetic acid (20 ml) to precipitate an oily solid. Light petroleum (b.p. 40-60° C.) was added and the mixture stirred for one hour, filtered and the solid was collected and washed with light petroleum to give 6-bromo-2-mercapto-4H-1-benzopyran-4-one, m.p. 230° C. (compound 1)
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)=[O:4].C(#N)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH:2]([CH3:13])[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C)cc(C(=O)C(C)Br)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc(C)cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
21 g of 2-bromo-3'-,5'-dimethylpropiophenone are introduced into 50 ml of acetonitrile, the mixture is cooled to 0° C., 30.5 g of 4-benzylpiperidine are added and the mixture is stirred for 3 hours. It is diluted with 30 ml of diethyl ether, the precipitated hydrobromide is filtered off and 150 ml of diethyl ether are added to the filtrate, which produces a second crop of precipitate. This is filtered off and the filtrate is treated twice with 200 ml of 3N hydrochloric acid. The diethyl ether phase is separated off. The aqueous phase contains the hydrochloride of the propiophenone formed, as an emulsion. This aqueous phase is extracted with methylene chloride, the organic phase obtained is washed with water, dilute aqueous ammonia solution is added, the organic phase is decanted, washed with water, dried, filtered and treated with 100 g of silica, the mixture is filtered and the filtrate is evaporated. 14.4 g of an oil remain.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30]([OH:32])=O)[CH3:26].C(N(C(C)C)C(C)C)C.[C:43]([C:47]1[O:51][C:50]([C:52]2[C:53]([NH2:71])=[N:54][CH:55]=[C:56]([C:58]3[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]4[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]4)[N:59]=3)[N:57]=2)=[N:49][N:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:71][C:53]1[N:54]=[CH:55][C:56]([C:58]2[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]3[CH2:66][CH2:67][N:68]([C:30](=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:69][CH2:70]3)[N:59]=2)=[N:57][C:52]=1[C:50]1[O:51][C:47]([C:43]([CH3:44])([CH3:45])[CH3:46])=[N:48][N:49]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(CC)n2)CC1
Temperature: 25 °C
Yield: 147 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (474 mg, 1.25 mmol) was added over 30 seconds in portions to a stirred solution of 3-ethoxy-3-oxopropanoic acid (150 mg, 1.13 mmol), N-ethyl-N-isopropylpropan-2-amine (0.394 mL, 2.26 mmol) and 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (450 mg, 1.13 mmol) dissolved in DMF (20 mL) at 50° C. The resulting solution was sampled after 1 min (complete reaction) and immediately allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude ethyl 3-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (850 mg).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:43]=[C:44]([NH2:48])[CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([N:39]4[CH2:40][CH2:41][CH:36]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[CH2:37][CH2:38]4)[CH:43]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(N2CCC(N3CCOCC3)CC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCC(N5CCOCC5)CC4)c3)nn12
Yield: 13.7 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85.0 mg, 0.000296 mol), N,N-Diisopropylethylamine (0.0773 mL, 0.000444 mol) and 3-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine (155 mg, 0.000592 mol) were dissolved in 2-Methoxyethanol (2.08 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 19.65 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=485.25. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.95 (s, 1H), 7.71 (m, 1H), 7.50 (t, 1H, J=6.88 Hz), 7.32 (m, 1H), 7.21 (m, 1H), 7.09 (m, 3H), 6.90 (q, 2H, J=5.65 Hz), 6.53 (m, 1H), 4.02 (m, 2H), 3.76 (s, 3H), 3.68 (t, 2H, J=12.16 Hz), 3.56 (m, 2H), 3.48 (m, 2H), 3.21 (m, 1H), 3.10 (m, 2H), 2.53 (m, 2H), 2.04 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:15]=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([CH:20]=[C:21]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]#[N:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[NH4+].[Cl-].CO>[Zn].C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][CH:15]=2)[N:31]=[C:22]([NH2:23])[C:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:20]3)[CH:10]=[CH:11][CH:12]=1
Reactant: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)ccc1[N+](=O)[O-])CC1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2ccc(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1

Procedure:
In four μwave tubes, 3-[5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-2-nitro-phenyl]-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (0.175 g, 0.375 mmol, each tube), Zn (2.5 g, 0.038 mol, each tube), NH4Cl (0.8 g, 0.015 mol, each tube), CH3OH (3 mL, in each tube) and THF (3 mL, in each tube) was reacted via μwave at 300W, 150° C. for 11 min. The resulting mixtures were combined and then filtered through Celite®. The solvent was removed to yield a residue which was purified by reverse phase column chromatography (10-90% CH3CN/H2O/0.1% TFA) to yield a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[CH2:10][C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([CH2:10][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ncccc1CCl
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
10 g of 4-piperidinemethanol, 13 g of 3-(chloromethyl)-2-methoxypyridine and 24 g of potassium carbonate were suspended in 80 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then the layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 16.1 g of the title compound as a pale brown oil.