Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:7][C:8]([CH2:15][CH2:16][CH2:17][O:18][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[CH:9][C:10]=1[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(CCCO)cc1C(C)(C)C
Reactant: ClCc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc(CCCOCc2cccnc2)cc1C(C)(C)C
Reaction time: 5 h
Yield: 66 %

Procedure:
A solution of 19.74 g (64.42 mmol) of 3-(4-acetoxy -3,5-di-tert-butylphenyl)propanol, 12.68 g (77.3 mmol) of 3-picolylchloride hydrochloride and 5 g of tetrabutylammonium hydrogen sulphate in 250 ml of toluene is treated with 250 ml of 50% aqueous sodium hydroxide with vigorous stirring (>400 rpm) under a nitrogen atmosphere and external cooling with a watdr-bath. Stirring of the dark reaction mixture is continued for an additional 5 hours at room temperature. After usual extractive work-up, the crude product (26.3 g) is purified by flash-chromatography over silica gel with AcOEt/H 2:1 as the eluent, yielding 16.9 g (66%) of 2,6-di-tert-butyl-4-[5-(3-pyridyl)-4-oxapentyl]phenyl acetate as a colourless oil, which is dissolved in 100 ml of dry tetrahydrofuran and added dropwise at -78° C. (acetone/dry ice) under inert conditions to a stirred suspension of 1.77 g (46.76 mmol) lithium aluminium hydride in 100 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred overnight in the gradually-warming cooling bath, maintained for 2 hours at 400C, and quenched under vigorous stirring and external cooling with ice-water by sequential, careful addition of 1.77 g of water, 1.77 g of 15% aqueous sodium hydroxide and a f inal portaionn of 5.31 g of water. After 1 hour, the resulting suspension is diluted with 200 ml of THF, dried with 20 g of Na2SO4 and the aluminate precipitate is removed by filtration through a fritted glass funnel and the solvent evaporated at reduced pressure, to give 12.9 g of crude 2,6-di-tert-buty -1-4-[5-(3-pyridyl)-4-oxapentyl)phenol as a yellow solid, leaving 11.49 g (76% for the deprotection step) of pure product, m.p. 105*C, after recrystallization with n-hexane/ethyl acetate. (C23H33NO2 ; F.W. 355.5).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH3:28])[CH2:17][CH:16]2[CH:18]([CH3:27])[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:23])[C:21]([CH3:22])=[C:15]2[O:14]1.Cl>C(Cl)Cl.C(N(CC)CC)C>[CH3:28][C:13]1([CH:12]=[O:11])[CH2:17][CH:16]2[CH:18]([CH3:27])[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:23])[C:21]([CH3:22])=[C:15]2[O:14]1
Reactant: CC1=C2OC(C)(CO)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Under an argon atmosphere, 0.57 ml of oxalic acid dichloride was dissolved in 12 ml of methylene chloride, followed by cooling to −78° C. To this solution, a solution prepared by dissolving 1.1 ml of DMSO in 2 ml of methylene chloride was added dropwise at −65 C or lower, followed by stirring for 10 minutes. Furthermore, a solution prepared by dissolving 1.34 g of 2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran in 4 ml of methylene chloride was added dropwise, followed by stirring at −78° C. for 3 hours. After the completion of the reaction, 4.2 ml of triethylamine was added dropwise and the reaction solution was heated to room temperature and then 1N-hydrochloric acid was added. The organic layer was extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate, and then solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to obtain 0.86 g of the objective product.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:47]3[C:42](=[CH:43][C:44]([C:48](O)=[O:49])=[CH:45][CH:46]=3)[C:41]([CH3:51])=[C:40]2[CH3:52])=[CH:34][CH:33]=1)=[O:25])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:18][C:48]([C:44]2[CH:43]=[C:42]3[C:47](=[CH:46][CH:45]=2)[N:39]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:27]4[C:26]([C:24]([OH:25])=[O:23])=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:37][CH:36]=2)[C:40]([CH3:52])=[C:41]3[CH3:51])=[O:49])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@@H](N)Cc2ccccc2)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](Cc3ccccc3)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)-2-phenylethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)=[N:7]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[CH3:64][S:65]([CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)(=[O:67])=[O:66].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:28]=[CH:29][CH:30]=[C:2]([N:71]3[CH2:72][CH2:73][CH:68]([S:65]([CH3:64])(=[O:67])=[O:66])[CH2:69][CH2:70]3)[CH:3]=2)[N:7]=[C:8]([C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[N:9]=1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1cccc(Br)c1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1cccc(N2CCC(S(C)(=O)=O)CC2)c1
Temperature: 100 °C
Reaction time: 0.3 h

Procedure:
To a solution of 3-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (100 mg, 0.21 mmol) in toluene (3 mL) were added 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (10 mg, 0.021 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 0.021 mmol), 4-(methylsulfonyl)piperidine (70 mg, 0.42 mmol) and sodium tert-butoxide (40 mg, 0.42 mmol). The mixture was heated at 100° C. under inert atmosphere for 5 h. The mixture was concentrated under reduced pressure, diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (Mobile phase: A=10 mM ammonium bicarbonate/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford the title compound as a yellow solid; MS (ES+) C26H26F3N5O4S requires: 561. found: 562 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.24 (m, 1H), 7.04 (s, 1H), 6.88 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (m, 1H), 6.72 (d, J=7.6 Hz, 1H), 5.34 (s, 2H), 3.81 (bd, J=12.6 Hz, 2H), 2.96 (m, 1H), 2.86 (s, 3H), 2.77 (m, 2H), 2.49 (s, 3H), 2.23 (bd, J=12.7 Hz, 2H), 1.97-1.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Cl:7])[N:6]=1.CCN(CC)CC.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:8]([N:32]=[N+:33]=[N-:34])=[O:10])=[C:5]([Cl:7])[N:6]=1
Reactant: O=C(O)c1sc(Cl)nc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dichloro-thiazole-5-carboxylic acid (1.98 g, 10 mmol) in toluene (50 mL) was added Et3N (1.01 g, 10 mmol) followed by diphenyl phosphoryl azide (2.75 g, 10 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford product as a brown solid (1.82 g, 82%): 13C NMR (75 MHz, CDCl3) δ 163.33, 156.83, 143.94, 124.02.
Reaction SMILES: C(OC([C:6]1[O:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH3:18])[C:8]=2[C:7]=1[OH:19])=O)C.[OH-].[Na+].Cl>C(O)C>[CH3:18][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[O:17][CH2:6][C:7](=[O:19])[C:8]1=2
Reactant: CCOC(=O)c1oc2c3ccccc3n(C)c2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3ccccc31)OCC2=O
Temperature: 0 °C
Yield: 53.1 %

Procedure:
A mixture of 47.0 g (0.18 mole) of 3-hydroxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic ethyl ester (Prep. described in U.S. Pat. Application Serial Number 369,448) in 450 ml of 95% ethanol was treated with 450 ml of 30% aqueous sodium hydroxide. The mixture was stirred at reflux for two hours, cooled, added to 3.0 kg ice/water, and acidified with 6.0 N hydrochloric acid. The product was filtered, washed with water, and recrystallized from ethanol-water to yield 17.9 g (53% yield) of the product, mp 113°-116° C. An additional recrystallization as above raised the mp to 115.5°-118° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=C[CH:18]=3)C[C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@@H]2C[O:37]C[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[CH2:12][O:20][CH2:18][C@H:19]2[OH:37])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1
Product: CCc1nc(N[C@H]2COC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539, 1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm−1; OAMS supporting ions at: ESI+ 315.9 & ESI− 313.9; MS (EI) m/z 315 (M+); HRMS (FAB) calcd for C12H18BRN3O2+H1 316.0661, found 316.0656; Anal. Calcd for C12H18BrN3O2: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84; N, 13.14.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.I[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30]>[Cu](I)I.C1(C)C=CC=CC=1>[NH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]2=[O:30])=[CH:17][CH:18]=1
Reactant: O=C1CCCCN1
Reactant: NCc1ccc(I)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: NCc1ccc(N2CCCCC2=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of 41 mg of copper iodide, 1.82 g of tripotassium phosphate, 38 mg of N,N′-dimethylethylenediamine, 1.00 g of 1-(4-iodophenyl)methyl amine, and 510 mg of 2-piperidone was added 4.29 mL of toluene, followed by stirring at 80° C. overnight under an argon atmosphere. The reaction liquid was filtered through Celite, the filtrate was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 552 mg of 1-[4-(aminomethyl)phenyl]piperidine-2-one.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([O:15][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Methyl 4-tert-butyl-2-hydroxybenzoate (2.04 g, 9.8 mmol) was placed in a dry 250 ml RBF along with 1-Boc-4-hydroxypiperidine (1.97 g, 9.8 mmol) and triphenylphosphine (2.57 g, 9.8 mmol). The solids were dissolved in 50 ml of dry THF; then the mixture was chilled on ice with stirring under a nitrogen atmosphere. Diisopropyl azodicarboxylate (DIAD) (1.98 g, 1.92 ml, 9.8 mmol) was added dropwise to the chilled solution over 20 min. The mixture was stirred a few minutes on ice, then allowed to warm to room temperature and left stirring overnight. The reaction mixture was concentrated in vacuo, partitioned between 200 ml each water and dichloromethane and the organic layer washed with brine, then dried over sodium sulfate and reconcentrated in vacuo. The yellow residue was dissolved in 70 ml of ether, then chilled (−10° C.) to precipitate most of the triphenylphosphine oxide. The mixture was filtered, reconcentrated and then purified on a Waters Prep 500 chromatograph (two cartridges, hexanes through 7:3 hexanes:EtOAc) to give the title product (2.41 g, 63%) as a colorless oil.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:18]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (2.0 g, 13 mmol, 1.0 eq, Aldrich) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP (0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resulting solution was stirred for 12 h. The reaction mixture was quenched with 1 N aqueous HCl and the solution was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3×70 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid, which was used without further purification. 1H NMR (DMSO-d6) δ 8.17–8.20 (m, 1H), 8.03–8.05 (m, 1H), 7.38–7.46 (m, 2H), 7.16–7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS(ESI): calcd.: 262.0879, found: 262.0885.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)([C:8](OCC)=[O:9])[C:3](OCC)=[O:4].[NH2:22][NH2:23]>>[CH3:1][C:2]1([CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:8](=[O:9])[NH:23][NH:22][C:3]1=[O:4]
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)C(=O)OCC
Reactant: NN
Product: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Yield: 62 %

Procedure:
A mixture of 120.8 g (0.4 mol) of diethyl 2-methyl-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-propane-1,3-dioate and 150 ml of anhydrous hydrazine was heated under reflux for 64 hours. The excess hydrazine was removed by distillation and the residue was recrystallized from methanol to give 60.28 g (62%) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)-ethyl]-pyrazolidine-3,5-dione having a melting point of 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8]C.[CH3:23]C1C(NC2C3C(=CC=CC=3)CCC2)=NC(C)=CN=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:23]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cnc(C)c(NC2CCCc3ccccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: Cc1nc(NC2CCCc3ccccc32)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.92, 2.08, 2.29, 2.53, 2.86, 4.48, 5.40, 7.21, 7.33; 13C NMR (CDCl3) δ 19.63, 20.32, 23.67, 29.81, 30.00, 49.20, 124.85, 126.66, 127.69, 129.23, 129.63, 137.17, 138.12, 138.25, 148.78, 151.23; MS (ESI+) for C16H18N3Br1 m/Z 333.3 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C.O>[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:6]
Reactant: CCc1ccccc1NC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of nitric acid (4.2 mL) in glacial acetic acid (5.2 mL)) was added drop wise to solution of N-(2-ethylphenyl)acetamide (Example 139f)(1.00 g, 6.13 mmol) in AcOH (22 mL) and acetic anhydride (18 mL) at 0° C. The reaction was stirred at 0° C. for 1 h, diluted with water (50 mL) and neutralized with Na2CO3 (pH˜8). The neutralized mixture was extracted with EtOAc (3×50 mL), the combined extract was washed with water and brine, and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified on HPLC to give 0.62 g (48%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.81 (broad s, 1H), 7.68-7.73 (m, 1H), 7.57-7.62 (m, 1H), 7.39 (t, J=8.0 Hz, 1H), 2.64 (q, J=8.0 Hz, 2H), 2.00 (s, 3H), 1.10 (t, J=8.0 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[OH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:6]([C:4]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid (intermediate 1, step c, 7.62 g, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (12.8 g, 1.3 eq.), morpholine (3.36 mL, 1.3 eq.) and N-ethyldiisopropylamine (25.7 mL, 5 eq.) in dimethylformamide (85 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with hydrochloric acid (1N), water and brine and dried over sodium sulfate, filtered and concentrated in vacuo. The precipitate was filtered, washed with ethyl acetate and dried in vacuo to yield 7.15 g (74%) of the desired product as off-white solid. MS (m/e): 329.5 (MH+, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]#[CH:10]>C1COCC1.C(OCC)(=O)C>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]#[CH:8]
Reactant: C#CCBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.3g of morpholine (84 mmol) in 80 mL of THF was slowly added 3-bromo-propyne (5.0 g, 42 mmol). A precipitate formed. The reaction was stirred at room temperature for 1 hour. The reaction mixture was then diluted with 300 mL of ethyl acetate (“EtOAc”), and washed sequentially with 2×200 mL water, and 1×100 mL brine. The organic layer was then dried over MgSO4, and concentrated to yield 4-prop-2-ynyl-morpholine as a light yellow liquid (yield. 50%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:28])([F:27])[C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O.N1C=CC=CC=1>[Cl:29][C:23]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:17]([F:27])([F:16])[F:28])[N:26]=[CH:25][CH:24]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(Cl)ccnc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a −78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at −78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at −78° C. for 20 minutes, followed by warming to −50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to −15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94%) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].