Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C(O)(=O)C(O)=O.[OH:26][C@@H:27]([CH3:36])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29].C([O-])(=O)C.[Na+].C(O)(=O)C.COC(OC)OC.[B].CC1N=CC=CC=1.C1COCC1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@@H:27]([OH:26])[CH3:36])[CH2:35][CH2:34]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C[C@H](O)C(=O)N1CCNCC1
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [B]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (14.9 g, 50.0 mmol.) was charged to a suitably sized reactor, followed by methanol (298 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.6 g, 74.9 mmol), sodium acetate (12.3 g, 150 mmol), glacial acetic acid (3.0 g, 50.0 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hr. A 30% solution of 2-picoline-borane in THF (21.4 g, 60.0 mmol) was slowly added and the slurry was stirred for 1-2 h. The reaction mixture was partially concentrated under reduced pressure. Toluene (230 mL) was added and the reaction mixture was concentrated under reduced pressure. Toluene (114 mL) was added and the reaction mixture was again partially concentrated under reduced pressure. To the residue was added toluene (218 mL) and the mixture was cooled to 20-30° C. Water (431 mL) was added and the pH was adjusted to 7.5-8.5 with 10% aqueous sodium carbonate solution (162 mL). The organic phase was separated, cooled to 0-5° C. and extracted with a mixture of water (180 mL) and 96% sulfuric acid (6.1 g). The aqueous phase was separated and toluene (118 mL) was added. The pH was adjusted to 7.5-8.5 with 10% aqueous sodium carbonate solution (110 mL) at 0-5° C. The mixture was warmed to 20° C. and the organic phase was separated. The organic phase was diluted with toluene (100 mL) and concentrated under reduced pressure to its original volume (approximately 150 mL). The solution was warmed to 53-57° C., and n-heptane (26 mL) was added. The solution was seeded with (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II and the suspension was stirred at 53-57° C. for 30 min. Heptane (82 mL) was slowly added and the resulting slurry was cooled to 0-5° C., filtered and washed with a mixture of toluene and n-heptane and subsequently with n-heptane. The cake was dried at 30-45° C. under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (18.6 g, 84% yield)
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCOCC>CCCCCC>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccccc1CC)C(=O)OCC
Temperature: 80 °C
Yield: 94.9 %

Procedure:
A mixture of 2-ethylaniline (11.7 g) and diethyl ethoxymethylene malonate (25.0 g) were warmed together at 80° C. for one hour. After cooling, the mixture was poured with stirring into a mixture of 150 ml of ether and 75 ml of hexane. After cooling the solution in an ice bath colorless needles precipitated and were collected by filtration. There was obtained 26.7 g (95%) of the title product; tlc, Rf =0.73, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Yield: 38.8 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (119.5 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100 mg, 0.32 mmol) in TFE (2.39 mL, 32.8 mmol) was treated with TFA (90.1 mg, 0.790 mmol) and irradiated on the microwave at 105° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to a solid. The material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc] to afford 74 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.46 (br. s., 1 H), 8.35 (s, 1 H), 7.89 (d, J=8.08 Hz, 1 H), 7.26 (d, J=8.84 Hz, 1 H), 7.08 (t, J=2.02 Hz, 1 H), 6.94 (dt, 1 H), 4.52 (s, 2 H), 4.26 (q, J=7.07 Hz, 2 H), 4.11 (quin, J=7.26 Hz, 4 H), 3.92 (s, 3 H), 3.36 (br. s., 1 H), 3.30 (br. s., 1 H), 3.20 (s, 3 H), 2.79 (br. s., 1 H), 2.68 (br. s., 1 H), 2.28-2.33 (m, 2 H), 2.30 (d, J=6.82 Hz, 2 H), 1.77 (d, J=5.81 Hz, 6 H), 1.27-1.37 (m, 9 H). MS (ES+): m/z=734.23 [MH+]. HPLC: tR=1.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[F-].[K+]>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>[CH:26]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1)=[CH2:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [F-]
Solvent: Cc1ccccc1
Product: C=Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A suspension of Intermediate 6 (8.00 g), tri(n-butyl)vinyltin (8.63 ml), tetrakis(triphenylphosphine)palladium(0) (455 mg), and 2,6-di-tert-butyl-p-cresol (8.7 mg) in toluene (120 ml) was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with 10% aqueous potassium fluoride (120 ml), and stirred for 15 hours. After the precipitates were removed by filtration, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (6.72 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].C(O)(=[O:13])C=C.OO.[Na]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:13])=[O:5].[Na+:9].[Na+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [Na]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous sodium maleate solution was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this solution and an aqueous acrylic acid solution was effected in the presence of hydrogen peroxide and sodium hydroxide at 100° C. for 6 h. After neutralization with an aqueous sodium hydroxide solution, a dye-ability-improving agent comprising sodium salt of the copolymer was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.8 %

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.49 g, 2.35 mmol) and MnO2 (0.80 g, 9.20 mmol) in chloroform (5 mL) is stirred at RT for 4 days. The mixture is filtered through Celite; the Celite is washed with copious amounts of EtOAc. The filtrate is concentrated and purified by flash chromatography to yield the title compound (0.29 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:17][C:18]([NH2:20])=[NH:19]>CO>[NH2:19][C:18]([NH2:20])=[N:17][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]([Br:12])=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Solvent: CO
Product: Cc1cc(Br)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
A solution of 1.8 g of methyl 2-methyl-4-bromo-5-methylsulphonylbenzoate [obtainable in accordance with Ex. 1] and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours, and the solvent is subsequently removed. The residue is treated with water and the remaining crystalline crop is filtered off with suction and treated with dil. sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-bromo-5-methylsulphonylbenzamide is obtained, m.p. 207°-208°.
Reaction SMILES: [Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31]([C:9]3[CH:8]=[N:7][C:6]([NH:11][CH3:12])=[C:5]4[O:13][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CNc1ncc(I)c2cc(Cl)oc12
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(Cl)oc12
Temperature: 85 °C

Procedure:
A mixture of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine (34.0 mg, 0.110 mmol), 1-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55.1 mg, 0.136 mmol), (1,1′-bis-(diphenylphosphino)-ferrocene)palladium dichloride (8.6 mg, 0.012 mmol), and potassium carbonate (41.4 mg, 0.300 mmol) in 1,4-dioxane (2.3 mL) and water (0.9 mL) was irradiated under microwave heating at 85° C. for 30 min. Purification by ISCO chromatography (20 to 50% ethyl acetate:heptane) afforded 42.6 mg (82%) of the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.36 (s, 1H), 6.88 (q, J=4.55 Hz, 1H), 4.17 (tt, J=3.85, 11.31 Hz, 1H), 3.73 (tt, J=4.01, 10.52 Hz, 1H), 2.91 (d, J=4.55 Hz, 3H), 1.99-2.10 (m, 2H), 1.82-1.97 (m, 4H), 1.38-1.53 (m, 2H), 0.88 (s, 9H), 0.08 (s, 6H); MS (ESI): 461.31, 463.30 [M+H]+; HPLC tR=4.28 min (ZQ3, nonpolar—5 min).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=1)=[O:5].[CH3:19][C:20]1[NH:21][C:22]2[C:27]([C:28]=1[CH2:29][NH:30][CH3:31])=[CH:26][CH:25]=[CH:24][CH:23]=2.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C.C(Cl)Cl>[CH3:2][O:3][C:4]([CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:30]([CH3:31])[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:19])=[O:18])=[CH:10][CH:9]=1)=[O:5]
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a stirred solution of (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic acid hydrochloride salt (2.0 g, 7.3 mmole) in 1:1 DMF/CH2Cl2 (100 mL) was added 2-methyl-3-(methylaminomethyl)indole (1.3 g, 7.5 mmole), Et3N (2.1 mL, 15 mmole), and HOBt H2O (1.0 g, 7.4 mmole), followed by EDC (1.4 g, 7.3 mmole). After stirring at room temperature for 18 h the reaction was concentrated to dryness. The residue was taken up in EtOAc, and the solution was washed with H2O then brine, dried (Na2SO4), and concentrated under vacuum. The remaining residue was purified by flash chromatography on silica gel (4% MeOH/CHCl3) to give the title compound (2.08 g, 73%) as an off-white solid: MS (ES) m/e 393.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:27]([O:29][CH2:30][C:31](Cl)=O)[CH3:28]>ClCCl>[CH2:27]([O:29][CH2:30][C:31]1[N:12]([CH2:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:28]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopentanol (approximately 28.8 mmol, prepared as described above) in dichloromethane (200 mL) at 0° C. was added triethylamine (4.41 mL, 31.6 mmol) and ethoxyacetyl chloride (88%, 3.96 g, 30.2 mmol). After 3 h at rt, the solution was concentrated and ethanol (260 mL) and triethylamine (14 mL) were added. The resulting solution was heated at reflux for 18 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed with brine twice and dried over MgSO4, filtered, and concentrated to an oil that formed a white solid when acetonitrile was added. The mixture was sonicated briefly and filtered. The white powder was dried under vacuum to provide pure 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (4.55 g, 49% for three steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cc(C)cc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)cc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 82 %

Procedure:
To a sired solution of 2.0 g (4.8 nmnol) of the product of Example 135 in 20 mL of DMF was added 1.0 g (10 mmol) of K2CO3 and 1.1 g (7.2 mmol) of 3-picolyl chloride hydrochloride. The reaction niixture was stirred for 48 h at room tempera and then diluted with water. The resulting mixture was extracted with chloroform and the combined organic layers were washed with water, dried over MgSO4, filtered and concentraed in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate. hexane (1:1) to provide 2.90 g (82%) of the desired product as a brown oil. Electrospray Mass Spec: 508 (M+H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)(=O)=O.[NH:28]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:31][N:30]=[N:29]1.[Na]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C@@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C@H:7]([CH2:6][N:29]3[N:30]=[N:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:28]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: COc1cccc([C@H]2[C@H](COS(C)(=O)=O)OC(=O)N2c2ccc(Cl)cc2)c1
Reactant: CCOC(=O)c1nnn[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cccc(OC)c2)n1
Temperature: 70 °C

Procedure:
A small reaction tube fitted with a screw cap is charged with ((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50 mg, 0.12 mmol) and DMF (1 mL). Ethyl 1H-tetrazole-5-carboxylate, sodium salt (39 mg, 0.24 mmol) is added and the mixture is heated to 70° C. overnight. The cooled reaction is quenched with water, extracted with EtOAc, combined organics are washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (12 g Redisep cartridge, 30-50% EtOAc/hexanes) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.53-7.43 (m, 2H), 7.34-7.28 (m, 3H), 7.10-7.08 (m, 1H), 7.06-7.00 (m, 2H), 6.92-6.90 (m, 1H), 5.67 (d, J=5.3 Hz, 1H), 5.52 (dd, J=(ddd, J=14.6, 6.5 Hz, 1H), 5.47-5.41 (m, 1H), 5.11-4.99 (m, 1H), 4.46-4.41 (m, 2H), 3.76 (s, 3H), 1.39-1.35 (m, 3H); HPLC-MS calculated C21H20ClN5O5 (M+H+) 458.1, found 458.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[C:17]([C:21]([O-])=O)[C:18]([O-])=[O:19])[O:14]CC)[CH3:11]>>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[N:7][C:6]=1[CH3:8])[N:1]=[CH:21][C:17]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:18]2[OH:19]
Reactant: CCOC(OCC)=C(C(=O)[O-])C(=O)[O-]
Reactant: Cc1nc(N)ccc1Br
Product: CCOC(=O)c1cnc2nc(C)c(Br)cc2c1O
Temperature: 250 °C
Yield: 34.2 %

Procedure:
A solution of 6-amino-3-bromo-2-methylpyridine (1.89 g) and diethoxymethylenemalonate (2.16 g) is heated at 110° C. for 30 min. The reaction is cooled and the residue is recrystallized from EtOH. To the resulting solid is dissolved in 45 mL of Ph2O. The mixture is heated to 250° C. for 3 h. The solution is then cooled to room temperature and the resulting precipitate is collected and dried. The crude product is chromatographed on silica (Biotage flash 40M, 2% MeOH/CH2Cl2 eluent). Fractions homogeneous by TLC are collected and concentrated to yield 1.075 g (35%) of the desired product as a yellow solid. Physical characteristics are as follows: m.p. 270° C. (dec.); 1H NMR (DMSO-d6) δ 12.73, 8.49, 8.47, 4.21, 2.67, 1.27.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH2:34])[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH:34][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
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
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c2nc(Br)cnc21
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In a 100 mL round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.0 g, 2.69 mmol) was combined with dichloromethane (3 ml) to give a yellow solution. (R)-1-Benzylpyrrolidin-3-amine (710 mg, 4.03 mmol) and then DIEA (1.88 ml, 10.7 mmol) were added. To the clear solution was added HATU (2.04 g, 5.37 mmol) and to this mixture was added DMF (4 ml). The reaction was stirred under nitrogen overnight then concentrated and partioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was washed with EtOAc (50 ml) then the combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude was dissolved in EtOAc, supported on silica gel, and purified by flash chromatography (120 g silicycle) with 0% to 100% EtOAc in hexanes. The appropriate fractions combined and concentrated to yield 1.38 g (97%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a clear viscous semisolid with a slight red/brown tint. LC-MS (M+H)+=530.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:27]=[C:28](C(O)=O)[C:29]3[C:34]([C:35]=2[C:36]=1[O:37][CH3:38])=[CH:33][C:32]([CH3:39])=[CH:31][CH:30]=3.[N-:43]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)C>[NH2:43][C:28]1[C:29]2[C:34]([C:35]3[C:36]([O:37][CH3:38])=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=3[CH:27]=1)=[CH:33][C:32]([CH3:39])=[CH:31][CH:30]=2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2cc(C(=O)O)c3ccc(C)cc3c2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(N)c3ccc(C)cc3c2c1OC
Reaction time: 0.17 h

Procedure:
A mixture of 400 ml (2.87M) of trifluoroacetic anhydride and 400 ml (5.22M) of trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 61.1 g (0.206M) of 3,4-dimethoxy-6-methyl-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. After the mixture has been cooled to -5°, 16.08 g (0.247M) sodium azide are carefully added in solid form. The mixture is stirred for 2 hours at 0°, poured onto ice, extracted three times with methylene chloride and washed with a solution 1N of sodium hydroxide. The aqueous phases are extracted twice with methylene chloride 2-propanol 8:2. The organic phases are combined, dried and evaporated, to give white crystals. 86 g of the resultant mixted anhydride are warmed for 2 hours under reflux in 800 ml of a solution 2N of sodium hydroxide and 800 ml ethanol and the mixture is evaporated. The residue is washed with water/ice and extracted three times with methylene chloride. The organic phases are combined, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:20][CH3:21])=[O:10])[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 99 %

Procedure:
A mixture of 3-nitrocinnamic acid (11.7 g, 60.6 mmol), concentrated sulfuric acid (0.16 mL, 3.03 mmol) and absolute ethanol (120 mL) was refluxed overnight. The reaction mixture was poured into ice water (400 mL). The mixture was extracted with ethyl ether (500 mL×2). The organic layer was washed with saturated sodium bicarbonate solution (100 mL×2), water (100 mL×2), brine (100 mL×2) and dried over magnesium sulfate. Evaporation gave title compound (12.0 g, 99%) as a colorless oil.