Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.I.CS[C:23](=[NH:36])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>N1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]2[NH:36][C:13]([C:12]3[CH:17]=[CH:18][C:9]([O:8][C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:19])[CH:5]=4)=[CH:10][CH:11]=3)=[N:15][N:16]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: NNC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
4-[(2,6-diaminopyrimidin-4-yl)oxy]benzohydrazide (1.48 g, 5.68 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (2.33 g, 5.89 mmol) were suspended in 30 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. The formed yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow foamy solid was re-dissolved in 50 mL of 5:1 EtOAc/MeOH; ca. 15 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was packed into ISCO column and the product was purified using ISCO system (80 g pre-packed column, 50 min run, 0% to 10% gradient of solvent B in solvent A [Solvent A—4 mL of MeOH, 4 ml, of Et3N in 4 L of CH2Cl2; Solvent B—4 mL of Et3N in 4 L of MeOH]). Solvent was removed in vacuo to give the title product as a white solid (1.33 g). Yield 50.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH3:14].C([Li])CCC.[O:20]1[C:22]([CH3:39])([CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]1.O>O1CCCC1>[CH3:12][O:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[C:4]([CH3:14])[C:5]=1[CH2:13][CH2:39][C:22]([CH3:21])([OH:20])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
1.8 g (9 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 100 ml of tetrahydrofuran, treated with 1 g (9 mmol) of potassium tert.butylate and subsequently 6 ml (9.5 mmol) of n-butyllithium (1.6 molar) were added dropwise at room temperature. Thereafter, the mixture was stirred at room temperature for 30 minutes, treated dropwise with 2.7 g (9 mmol) of (2RS,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane and stirred at room temperature for 16 hours. Thereupon, HYFLO and 200 ml of water were added, the mixture was then filtered and washed with water. The residue was stirred up with diethyl ether and sodium sulphate, filtered, washed with diethyl ether and concentrated. There were obtained 3.8 g of (3RS,7RS,11RS)-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3,7,11,15-tetramethyl-3-hexadecanol.
Reaction SMILES: O/[N:2]=[C:3]1\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[NH:11][C:12](=[O:19])[C:13]3[N:14]([CH:16]=[CH:17][N:18]=3)[C:15]\1=2.C.[C:21](O)(=[O:23])[CH3:22]>O.CN(C)C=O.[Zn]>[C:21]([NH:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)(=[O:23])[CH3:22]
Reactant: O=c1[nH]c2c(n3ccnc13)/C(=N/O)c1ccccc1-2
Reactant: CC(=O)O
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 4 h

Procedure:
A suspension of 5.25 g of 10-(E-hydroxy-imino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 2.9 g of zinc powder in 100 ml of acetic acid is heated for 2 hours at a temperature between 80° C. and 90° C. After addition of 100 ml of acetic acid, the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (10 mmHg; 2 kPa) at 65° C. The product obtained (3.8 g) is suspended in 100 ml of distilled water, filtered, washed with 10 ml of distilled water and with 10 ml of acetone and then dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (2 g) is dissolved in 60 ml of boiling dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered while hot. The filter is washed with 10 ml of boiling dimethylformamide and the filtrate and the combined washings are then stored for 4 hours at a temperature in the region of 20° C. The crystals formed are separated out by filtration, washed successively with 10 ml of dimethylformamide, 10 ml of distilled water and 10 ml of acetone and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.43 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting at 330° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 2.00 (s, 3H: --CO--CH3); 6.13 (d, J=8.5 Hz, 1H: CH--N); 7.35 and 7.48 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.48 and 7.85 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.58 and 7.65 (2s broad, 1H each: --H of the imidazole); 8.58 (d, J=8.5 Hz, 1H: --NH--COCH3); 12.50 (cplx, 1H: --NH--)].
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH:26]1([CH2:25][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:28][CH2:27]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
55 g of 4-(difluoromethoxy)-3-hydroxybenzaldehyde, 42.42 g of K2CO3 (1.05 eq), 4.86 g of KI (0.1 eq) and 220 mL of dimethylsulphoxide (DMSO) were loaded in a reactor. The mixture was heated at 70° C. and kept for 1 h. A mixture previously prepared of 42.65 g of bromomethyl cyclopropane (1.08 eq) and 110 mL of DMSO was added for 1 hour. The reaction was kept for 3 h at 70° C., and then cooled at room temperature. Once the temperature was reached, 375 mL of toluene was added. The suspension was filtered to remove the remaining K2CO3, and then it was cooled at 0-5° C., and 375 mL of deionised water were loaded. The phases were separated and the organic phase was washed twice with 55 mL of deionised water. The solvent was removed at reduced pressure, obtaining 70 g (yield 99%) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde as a viscous yellowish fluid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:30])[C:11]([CH:28]=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4].[O-:31]Cl=O.[Na+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:30])[C:11]([C:28]([OH:31])=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C=O)c(=O)n21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C(=O)O)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2 (100 mg, 0.239 mmol) in dimethylsulfoxide (2.40 mL), NaH2PO4 (66.0 mg, 0.478 mmol), dissolved in water (0.960 mL), was added dropwise at room temperature. The mixture was then kept on ice and NaClO2 (86.0 mg, 0.956 mmol) dissolved in water (0.480 mL), was added dropwise during 30 min. A white precipitate formed. The reaction mixture was stirred in room temperature for 1 h and then poured into a separation funnel containing ice-cooled 1M HCl. The aqueous phase was extracted with CH2Cl2 and the combined organic phases concentrated. The residue was dissolved in H2O:MeCN, 8:2 and freeze dried to yield 5 as a white powder (102 mg, yield: 98%). 1H-NMR (400 Mhz, CDCl3) δ 14.60 (s, 1H, CO2H), 8.21 (d, J=8.32 Hz, 1H, ArH), 7.85 (d, J=7.68 Hz 1H, ArH), 7.67 (d, J=8.14 Hz, 1H, ArH) 7.61-7.45 (m, 2H, ArH) 7.30-7.21 (m, 1H, ArH), 6.69 (d, J=6.72 Hz, 1H, ArH), 5.78 (d, J=8.42 Hz, 1H, ArH), 5.51 (d, J=14.55 Hz, 1H, Nph-CH2) 5.37 (d, J=14.55 Hz, 1H, Nph-CH2) 3.87 (s, 3H, CH3) 3.82-3.72 (m, 1H, SCH2) 3.63-3.54 (m, 1H, SCH2) 1.44-1.32 (m, 1H, CH-cyclopropyl) 0.81-0.64 (m, 2H) 0.56 (sd, 2H, CH2-cyclopropyl) 13C-NMR (100 Mhz, CDCl3) δ 167.59, 165.24, 165.09, 163.75, 154.33, 134.92, 133.84, 132.16, 128.83, 126.78, 126.15, 125.76, 125.51, 123.40, 123.23, 118.68, 112.72, 64.10, 53.84, 33.35, 31.58, 12.10, 8.35, 7.67.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>>[CH3:10][N:11]([CH:12]=[O:13])[CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: CNC=O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C=O)Cc1ccncc1
Yield: 76.5 %

Procedure:
To a stirring, argon-purged solution of 4-picolyl chloride-HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml of TBF at room temperature was added portionwise over a 20 minute period a suspension of 80% NaH (5.48 g, 183 mmol). The reaction was quenched 18 h later by the addition of ice, partitioned between methylene chloride and water, washed with water and brine, dried over MgSO4, and evaporated to dryness to afford a dark oil. Flash chromatography on silica gel provided 10.5 g (76%) of the titled compounds a pale yellow oil. TLC; silica gel (9:1 CHCl/MeOH) Rf=0.54.
Reaction SMILES: CO[CH:3](O)[C:4]([O:6][CH3:7])=[O:5].[CH:9](=[O:12])[CH2:10][CH3:11]>C(NCCCC)CCC>[CH:9](/[C:10](/[CH3:11])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:12]
Reactant: COC(=O)C(O)OC
Reactant: CCC=O
Solvent: CCCCNCCCC
Product: COC(=O)/C=C(/C)C=O
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
3 g (0.025 mol) of di-n-butylamine were added at 20° C. to a stirred mixture of 120 g (1 mol) of methyl 2-methoxy-2-hydroxyacetate and 58 g (1 mol) of propionaldehyde. An exothermic reaction started immediately and the temperature of the reaction mixture rose to about 90° C., and it boiled vigorously. After about 10 min the temperature started to fall again and reached room temperature after about 1.5 h. Distillation of the reaction mixture yielded 66.4 g of methyl 3-formylcrotonate of b.p. 45°-58° C./8-9 mbar, corresponding to a yield of 52%. The trans/cis ratio was determined by gas chromatography to be 91/9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1(=O)[CH:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH2:17]2)[C:12](=[O:19])[CH:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[OH:19][C:12]1[CH:11]=[C:10]2[C:9]([NH:1][C:2]3[C:3]([S:8]2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:18]2[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=12
Reactant: O=C1C=CC(=O)C2CC=CCC12
Reactant: Nc1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cc2c(c3c1CC=CC3)Nc1ccccc1S2
Reaction time: 1 h

Procedure:
A solution of 2-aminothiophenol (385 mg) in methanol (3 ml) was added to a solution of 4a, 5, 8, 8a-tetrahydro-1,4-naphtoquinone (Ref.: Ber. 62, 2361 (1929)) (500 mg) in methanol (10 ml) and stirred for 1 hour. Then conc. HCl (2 ml) was added and the mixture was stirred for another 2 hours. Ethyl acetate was added to the reaction mixture followed by a solution of NaHCO3. The organic layer was decanted, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (CH2Cl2) to afford the title compound.
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>CO>[Cl:1][C:5]1[C:4]([OH:3])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(O)c1
Reactant: ClCl
Solvent: CO
Product: O=C(O)c1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
Chlorine gas (10.3 g; 147 mmol) was slowly bubbled through a cold solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, while maintaining the temperature below -60° C. After approximately thirty minutes, the chlorine gas was flushed out with nitrogen and the reaction mixture was allowed to warm to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recyrstallization from 50 mL of water followed by recrystallization from 130 mL of benzene containing 10 mL of acetone to provide the desired titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OC2CCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 ml) was heated at 80° C. for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O.C(N(S(F)(F)[F:17])CC)C.C(=O)(O)[O-].[Na+].CCOCC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][F:17]
Reactant: OCCCCCCCCBr
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: FCCCCCCCCBr
Temperature: -78 °C
Yield: 61.3 %

Procedure:
A solution of 8-bromooctan-1-ol (Hendry et al., J. Chem. Ecol., 1, 317, 1975), (2.50 g, 11.9 mmol) in methylene chloride (about 3 ml) is slowly added to a stirred solution of diethylaminosulfur trifluoride (DAST) (Middleton, J. Org. Chem, 40, 574, 1975) (1.5 mL, 11.9 mmol) in methylene chloride (10 mL), cooled to -78° C. After the addition is completed, the reaction mixture is warmed to 25° C. and saturated aqueous sodium bicarbonate (about 5 mL) is added, followed by dilution with ether (about 200 mL). The organic layer is then separated, and washed with water (20 mL), saturated sodium bicarbonate (20 mL) and then dried (MgSO4). The volatiles are removed in vacuo and the crude product is purified by flash chromatography using hexane/ethyl acetate, (95.5, v/v) to afford 8-bromo-fluoro-octane (1.54 g, 61%) as a clear colorless liquid: Rf=0.70, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.15-2.0 (m, 12H), 3.39 (t, J=6 Hz, 2H), 4.42 (dt, J=48 Hz, 6 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:33])[C:31]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:31]3[C:30]([Cl:33])=[CH:29][N:28]=[CH:27][C:26]=3[Cl:25])[CH2:2][CH2:3]2)=[O:8])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCNCC2)CC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)CC1
Yield: 36.8 %

Procedure:
General procedure C (See Example 1) was followed using benzyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate 12 (0.11 g, 0.33 mmol), 3,4,5-trichloropyridine (61 mg, 0.33 mmol), NMP (2.5 mL) and triethylamine (93 μL, 0.66 mmol). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 1:1) to furnish the title compound 13 as a white solid (58 mg, 36%), umax (CHCl3)/cm−1 3023, 1699, 1635, 1559, 1432, 1285, 1232, 1015; m/z (ESI) C23H27Cl2N4O3 requires 477.1455, found [M+H]+ 477.1457.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:13][CH:14]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(-c3nccs3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.4 %

Procedure:
To the mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol), 2-(tributylstannyl)-1,3-thiazole (122 mg, 0.33 mmol) in toluene (14 mL) was added tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol) under N2. The mixture was refluxed overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified using preparative LCMS to yield the desired product (80 mg, 79%). LCMS calculated for C23H26N7O2S (M+H): 464.2. found 464.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH2:31][O:32][CH3:33])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and 2-bromoethylmethyl ether (44 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 43 as a colorless oil (19 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)=[O:8])[CH:3]=1.I[C:43]1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(OC(F)(F)F)=CC=3)(=O)=O)C=2C=1.C([Mg]Cl)(C)C.CON(C)C(C1C=C(C)NN=1)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)([OH:8])[CH3:43])[CH:3]=1
Reactant: Cc1cc(C(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Agent: CC(C)[Mg]Cl
Agent: CON(C)C(=O)c1cc(C)[nH]n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5-Methyl-1H-pyrazol-3-yl)[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]methanone To a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (950 mg, 1.544 mmol, intermediate 61) in 5 ml of THF was added a solution of isopropyl magnesium chloride (3.47 ml, 6.95 mmol) in THF (2M) at 0° C. The solution was stirred at 0° C. for 30 min, then a mixture of N-methoxy-N,5-dimethyl-1H-pyrazole-3-carboxamide (261 mg, 1.544 mmol) in 3 mL of toluene was added. The reaction mixture was stirred for 2 hr at 0° C. and then allowed to warm to rt overnight. The reaction was quenched by the addition of 4 mL of 0.5 N HCl. The resulting viscous residue was washed with ethyl acetate (30 mL×2) and acetone (20 mL×2). The combined washes were evaporated under reduced pressure and the residue was crystallized from CH2Cl2 to give the title compound as a light yellow solid; Mass Spectrum: m/e=598 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 96.3 %

Procedure:
A solution of 89A (0.36 g, 1.8 mmol) and aqueous sodium hydroxide (1N, 3 mL, 3 mmol) in a mixture of methanol (1.5 mL) and tetrahydrofuran (3 mL) was heated at 80° C. for 1 h and at rt for 2 h. An additional portion of sodium hydroxide solution (1 mL) was added and the mixture was heated at 80° C. for 5 min. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and acidified with hydrochloric acid (1N). The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 89B (0.314 g, 94%) as a white solid. LCMS: 182 (M+1)
Reaction SMILES: [CH2:1]([N:8]([C:35](=[O:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClCCl>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:35](=[O:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)O

Procedure:
A room temperature solution of Example 20D (300 mg, 0.54 mmol) in 1:1 TFA/dichloromethane was stirred for 2 hours and concentrated to provide the desired product.