Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].[Cl-].[NH4+:15].[OH-].[NH4+]>C(OC)(C)(C)C.O.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:4][C:5]([C:7]1[N:8]([NH2:15])[CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: [NH4+]
Reactant: C=CCOC(=O)c1ccc[nH]1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCOC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
1H-Pyrrole-2-carboxylic acid allyl ester (Example 1a, 11.73 g, 78.12 mmol) was dissolved in methyl tert-butyl ether (150 mL) and a solution of sodium hydroxide (37 g, 925 mmol) in water (150 mL) was added. Solid ammonium chloride (25.1 g, 469 mmol), trioctylmethylammonium chloride (“Aliquat® 336”, 1 mL) and 28% aqueous ammonium hydroxide solution (50 mL) were added to the biphasic mixture. Under vigorous stirring, a 6.15% aqueous bleach solution (“Chlorox”, 250 mL) was slowly added over a period of 45 min via addition funnel upon which the color of the solution turned orange. After stirring for 1.5 h at 25° C., mixture was poured into methyl tert-butyl ether (150 mL) and the layers were separated. The organic layer was washed with a solution of sodium thiosulfate (10 g) in water (200 mL) and the organic layer was dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford the desired product, 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (8.03 g, 48.32 mmol, 62% yield) as a brown oil.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][NH:30][CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([N:30]1[CH2:31][CH:28]([N:23]2[CH2:22][C:21]3=[C:20]([C:32]#[N:33])[C:19]([Cl:34])=[CH:18][C:17]([CH:15]([N:11]4[C:7]5=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]5[C:13]([CH3:14])=[N:12]4)[CH3:16])=[C:27]3[O:26][CH2:25][CH2:24]2)[CH2:29]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(N2CCOc3c(C(C)n4nc(C)c5c(N)ncnc54)cc(Cl)c(C#N)c3C2)C1
Reaction time: 1 h
Yield: 29.9 %

Procedure:
The crude 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (0.015 g, 0.0278 mmol) was dissolved in N,N-dimethylformamide (2 mL) and cooled in an ice bath, and then N,N-diisopropylethylamine (0.0142 g, 0.112 mmol) and acetic anhydride (0.0032 mL, 0.033 mmol) were added. After stirring for 1 h, the product was purified without work up, by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give 4-(1-acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile as a white amorphous solid (0.004 g, 33%). LCMS calculated for C23H26ClN8O2 (M+H)+: m/z=481.2; found: 481.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].CN1CC[O:21]CC1>C(#N)C>[CH:11]1([CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:21])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=2)[CH2:13][CH2:12]1
Reactant: CN1CCOCC1
Reactant: O=[N+]([O-])c1cc(OCC2CC2)ccc1CBr
Solvent: CC#N
Product: O=Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 1-(bromomethyl)-4-(cyclopropylmethoxy)-2-nitrobenzene (11.4 g) in acetonitrile (200 mL) were added molecular sieves 4 Å (55 g) and N-methylmorpholine (9.37 g) at room temperature. Under an argon atmosphere, the reaction mixture was stirred at room temperature for 1 hr, and filtered through celite. The obtained filtrate was concentrated under reduced pressure, and the residue was dissolved in diethyl ether and the solution was washed twice with 6N hydrochloric acid and once with water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (6.39 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[N+:35](=[CH2:37])=[N-:36]>C1COCC1.CCOCC.C(O)(=O)C>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[CH:37]=[N+:35]=[N-:36])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)C=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (37 g, 0.136 mmol) in anhydrous THF (300 mL) cooled to −20° C. was added dropwise N-methylmorpholine (16.6 mL, 0.15 mmol), followed by isobutyl chloroformate (20 mL, 0.15 mmol) and the reaction mixture was stirred at −20° C. for 30 min. The mixture was warmed to 0° C., and an etheral solution of CH2N2 (0.8 mol) was added. Stirring was continued overnight at rt. Excess diazomethane was decomposed by addition of acetic acid. The mixture was diluted with ether, washed with brine, satd aq NaHCO3 and brine to give a solution of crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (48 g, 100%), which was used without isolation.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=[C:4]([CH:15]=O)[CH:3]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@@:21](/[N:23]=[CH:15]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)=[O:22])([CH3:20])[CH3:19]
Reactant: Cc1cc(C=O)ncc1OCCC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@@](=O)C(C)(C)C)ncc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (1.67 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde (1.79 g, 7.68 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.5 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9](=[O:14])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a mixture of 95% dry sodium hydride (834 mg, 33.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at room temperature was added a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (confirmed by LCMS). The reaction mixture was quenched with methanol (40 mL), the mixture concentrated under reduced pressure, then diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), 30% ammonium chloride (100 mL) and brine (100 mL), dried, and concentrated under reduced pressure. Ethyl ether (20 mL) was added, and the mixture sonicated, filtered, washed with ether (20 mL), and dried to afford tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6 mmol, 72%). LCMS mz 285.9 (M−56+H), 363.9 (M+Na), anal HPLC>97% in purity. 1H NMR (400 MHz; CDCl3) δ 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H); 4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:31]([O:37][C:38](=[O:40])[CH3:39])[C@@H:30]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:29][C@H:6]1[O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O)(=[O:3])[CH3:2].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OCCBr)(=O)C.C(S)CCCCCCCCCCCCCCC.C(=O)([O-])[O-].[Cs+].[Cs+]>CCCCCC.C(OC(=O)C)C.O.ClCCl.CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:31]([O:37][C:38](=[O:40])[CH3:39])[C@@H:30]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:29][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCCCCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 64 %

Procedure:
2-(Hexadecylsulfonyl)ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. 2-Bromoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (Dahmen et al. Carbohydr. Res., 116 (1983)) (540 mg, 1.19 mmol), hexadecanethiol (383 mg, 1.49 mmol), cesium carbonate (292 mg, 0.89 mmol) and dimethylformamide (5 ml) was stirred overnight. Dichloromethane (75 ml) and water (40 ml) were added. The aqueous phase was extracted with dichloromethane (2×25 ml), the combined organic phases were dried (Na2SO4) and concentrated. Chromatography (SiO2 ; ethylacetate: hexane) gave pure 2-(hexadecylthio)ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (480 mg, 0.76 mmol, 64%), which was dissolved in ethyl acetate (12 ml) and treated with m-chloroperbenzoic acid (1.71 mmol). After 4 hours the solvents were removed and the residue was dissolved in dichloromethane and filtered through alumina (10 g) to give the pure sulfone lipid (495 mg, 98%). [α]D23 =-8.7° (c=0.9 in CDCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][NH:39][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:19])=[CH:15][CH:14]=2)=[O:10])=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)O)cc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Into a solution of 4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoic acid (1.0 g, 3.19 mmol) and N-methyl morpholine (420 μL, 3.83 mmol) in anhydrous THF (25 mL) at 0° C. was added isobutyl chloroformate (455 μL, 3.51 mmol) then tert-butyl hydrazine carboxylate (1.12 mg, 7.66 mmol). After stirring at 0° C. for 1 hr and overnight at rt, the reaction mixture was quenched with HCl (1N, 25 mL). Extraction with EtOAc (2×25 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (SiO2, EtOAc) gave the title compound (773 mg, 55%) as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=1)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([O:13][Si](C)(C)C)=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.O>O1CCCC1>[CH3:41][Si:2]([CH3:1])([C:3]1[CH:4]=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]([OH:13])=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)[C:22]1[CH:23]=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:25]([OH:32])=[C:26]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH:27]=1
Reactant: CC(C)(C)c1cc([Si](C)(C)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([Si](C)(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 9.8 g (16 mmol) of dimethylbis(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)silane in 50 ml of tetrahydrofuran is slowly added 10.6 g (32 mmol) of tetrabutylammonium fluoride trihydrate. The reaction mixture is stirred for 1 hour at room temperature and to it is added 0.8 g (14 mmol) of glacial acetic acid. The reaction mixture is poured into 250 ml of water and the solution is extracted (2×125 ml) with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to give 7.3 g of an orange residue which crystallizes on standing. The residue is recrystallized from heptane to give 1.2 g (17%) of a white solid; mp. 186°-188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:19]4[CH2:18][CH2:17][CH2:16][C:15](=O)[C:14]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:18](=[N:27][NH:26][C:23](=[O:25])[CH3:24])[CH2:17][CH2:16][CH2:15][C:14]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: CC(=O)NN
Reactant: O=C1CCCc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Solvent: CCO
Product: CC(=O)NN=C1CCCc2nc(-c3cnn(-c4cccnc4)c3)ccc21

Procedure:
A solution of 2-(1-pyridin-3-yl-1H-pyrazol-4-yl)-6,7-dihydro-5H-quinolin-8-one (125 mg, 0.43 mmol) and acetic acid hydrazide (47 mg, 0.63 mmol) in ethanol (5 ml) was heated at 75° C. overnight. The reaction mixture was evaporated to dryness, the residue was taken up in ethyl acetate and washed twice with water. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/methanol 19:1 gave the title product as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:14][CH2:13]1)[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=C[CH:3]=1.C1(NCC2CCC[O:22]C2)CC1.C(NCC1CC1)C1C=CC=CC=1>C(Cl)Cl.CO>[CH:12]1([N:8]([CH2:1][CH:2]2[CH2:7][CH2:6][CH2:5][O:22][CH2:3]2)[C:9]([Cl:11])=[O:10])[CH2:14][CH2:13]1
Reactant: O=C(Cl)N(Cc1ccccc1)C1CC1
Reactant: C1COCC(CNC2CC2)C1
Agent: c1ccc(CNCC2CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)N(CC1CCCOC1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropyl-carbamoyl chloride starting from cyclopropyl-(tetrahydro-pyran-3-ylmethyl)-amine (prepared analogously as described for benzyl-cyclopropylmethyl-amine). TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10][CH3:11])=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1COCC1.[OH-].[Na+]>CO>[CH3:11][O:10][C:8]([C:4]12[CH2:7][C:1]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:9]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C12CCC(C(=O)O)(CC1)C2
Temperature: 15 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A 12-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a 250 mL addition funnel. The flask was charged with dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (208 g, 980 mmol) and THF (6.7 L). The resulting solution was cooled to 15° C. using an ice/water bath. Sodium hydroxide pellets (39.2 g, 980 mmol) were dissolved in methanol (400 mL) and slowly added to the stirring solution over 30 min. After the addition was complete, white solids began to precipitate. The reaction mixture was stirred at room temp for 16 h when TLC analysis (100% ethyl acetate) indicated about 90% conversion. The reaction mixture was concentrated to dryness, slurried in hexane (2 L), filtered, and washed with hexane (2×400 mL). The resulting sodium carboxylate salt was transferred to a 3-L, 3-neck, round bottom flask equipped with a mechanical stirrer, dissolved in water (1 L), and slowly treated with 2 N aqueous hydrochloric acid (430 mL) at 10° C. until pH ˜4. The thick suspension was diluted with ethyl acetate (1 L) and transferred to a reparatory funnel. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2×500 mL), washed with brine (200 mL), dried over sodium sulfate, and concentrated to provide 170 g (87%) of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid. 1H NMR (500 Hz, DMSO-d6) δ ppm 12.21 (s, 1H), 3.60 (s, 3H), 1.91 (d, J=6.7 Hz, 4H), 1.75 (s, 2H), 1.56-1.62 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21]N(C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.BrC1C(=[O:39])N(C)C=C(Br)C=1.O1CCN(C2C=CC(N)=NC=2)CC1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][O:39][CH2:21][CH2:22]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Nc1ccc(N2CCOCC2)cn1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCOCC3)cn2)c1=O

Procedure:
Following the procedures as described for 188c and starting with 3,5-dibromo-1-methylpyridin-2(1H)-one (1.15 g, 4.3 mmol) and 5-morpholinopyridin-2-amine (770 mg, 4.3 mmol), 255c was obtained as a yellow solid (986 mg, 63%). MS: [M+H]+ 365
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C.CN(C=O)C>C(Cl)Cl>[OH:29][C:17]1[C:16]([CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:24]([O:25][CH3:26])[C:23]([CH3:27])=[C:22]2[C:18]=1[C:19](=[O:28])[O:20][CH2:21]2
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)O)C(=O)OC2
Yield: 36.8 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 μL, 0.55 mmol), and 2,6-lutidine (64 μL, 0.55 mmol) was stirred in CH2Cl2 (1 mL) and DMF (0.5 mL) for 1 hour at ambient temperature. The reaction mixture was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 7.8 mg of the product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16 (s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.57 (s, 2H), 3.81 (s, 3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CD3OD) δ 20.2 ppm; 19F NMR (282.6 MHz, CD3OD) δ -74.0 ppm; MS (m/z) 386.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([SeH])[CH2:11][CH2:10][CH:9](CC=C)[C:8]2=[O:15])C=CC=[CH:3][CH:2]=1.[Cl-].[NH4+].OO>C(Cl)Cl>[CH2:3]=[CH:2][CH2:1][CH:7]1[C:8](=[O:15])[CH:9]=[CH:10][CH2:11]1
Reactant: C=CCC1CCC([SeH])(c2ccccc2)C1=O
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC1CC=CC1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
An ice cold (3° C.) solution of 2-phenylselenyl-5-(propene-3-yl)cyclopentanone, (mixture of isomers, (12.0 g, 43 mmol)) in methylene chloride (200 mL) was stirred in a 1 L round bottomed-flask that was equipped for boil-over containment. To this solution was added saturated aqueous ammonium chloride (45 mL), followed by dropwise addition of a 30% aqueous solution of hydrogen peroxide (22 mL). The reaction mixture was then slowly warmed to room temperature with intermittent cooling, as necessary, to prevent excess bubbling and boil-over. After stirring at room temperature for an additional hour the solution was washed with water (100 mL), followed by stirring with 10% aqueous sodium thiosulfate pentahydrate (75 mL) for 10 min, and the aqueous and organic layers were then allowed to separate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine (75 mL each), dried using Na2SO4 and concentrated to a volume of about 30 mL. Purification of the crude reaction was effected by loading the crude mixture onto a silica gel column (˜400 cc) using methylene chloride as the eluting solvent. Concentration of the appropriate fractions afforded 5-(propene-3-yl)cyclopent-2-enone (3.95 g, 75%) as a very pale yellow oil. NMR (CDCl3): δ 7.61 (m, 1 H), 6.12 (m, 1 H), 5.60-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 2.70-2.80 (m, 1 H), 2.45-2.55 (m, 1 H), 2.30-2.40 (m, 2 H), 2.05-2.15 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OO.C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)[Cl:23]>C(O)(C(F)(F)F)=O.CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:23]
Reactant: COC(=O)c1nc(Cl)ccc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)cc(Cl)c1Br
Temperature: 60 °C
Yield: 49 %

Procedure:
To a stirred solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (1.92 g, 7.67 mmol) in TFA (18 ml) was added hydrogen peroxide (30% w/w aqueous solution, 5.22 ml, 53.7 mmol) and the reaction mixture was heated at 60° C. for 21 h. The reaction mixture was then cooled and slowly poured onto saturated K2CO3 solution (100 ml), followed by extraction of the aqueous layer with EtOAc (3×100 ml), washing of the combined organic phases with brine (2×50 ml), drying (Na2SO4) and evaporation. The desired 3-bromo-6-chloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (2.61 g, ˜75% purity) was used crude in the next stage of the synthesis without any further purification. To the crude 3-bromo-6-chloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (˜75% purity, 2.61 g, 7.35 mmol) was added POCl3 (3.42 ml, 36.7 mmol) and the solution was heated to 100° C. for 4 h. After cooling the POCl3 was remove in vacuo to give a white solid which was columned over silica eluting with 0% to 10% of EtOAc in heptane to afford the title compound as a pale yellow powder (1.07 g, 49% over two steps). LC-MS 99%, 2.02 min (3.5 minute LC-MS method), m/z=283.7/285.7/287.7, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.56 (s, 1H) 4.00 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:24]3[CH2:23][C@H:22]([CH3:26])[NH:21][C@H:20]([CH3:19])[CH2:25]3)=[CH:4][C:5]=2[N:6]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg, 0.43 mmol) in DMF (4 mL) were added (cis)-2,6-dimethyl-piperazine (74 mg, 0.648 mmol) and potassium carbonate (117 mg, 0.847 mmol). The resulting mixture was stirred at RT for 17 h, then concentrated in vacuo. The resulting residue was triturated with water to give the title compound as an off-white solid (127 mg, 77%).