Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([CH3:18])=[N:9]2)[C:5]([F:19])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([CH3:18])=[N:9]2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2nc(Cl)ncc2F)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nn(-c2nc(Cl)ncc2F)cc1CO
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carboxylate 1 (4.9 g, 17.2 mmol) in 60 mL of anhydrous tetrahydrofuran (THF), was slowly added 38 mL (38 mmol) of 1M solution of di-isobutylaluminum hydride (DIBAL) in toluene with ice bath cooling. After being stirred for 2 hours at the same temperature, the reaction was quenched by slow addition of 1N-NaOH solution. It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then partially concentrated in vacou. To this, n-hexanes were added to form pale yellow precipitates. The resulting solids were collected by filtration and rinsed with n-hexanes and then dried with high vacuum to give 3.7 g (90%) of Intermediate No. 2; 1H NMR (300 MHz, CDCl3) δ 8.57 (1H, d, J=3.3 Hz), 8.52 (1H, s), 7.94 (1H, s), 4.72 (2H, s); MS (ESI) m/z 243 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:6]#[CH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:6]#[CH:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#C[C@H](CC[C@H](O)CO)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#C[C@H](CC[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of(3S,6S)-3-acetoxy-6,7-dihydroxy-hept-1-yne 14 (4.3 g, 23.1 mmol) in CH2Cl2 (50 mL) containing pyridine (3.7 mL, 46.2 mmol) was cooled to 0° C. and treated with p-toluene sulfonyl chloride (4.4 g, 23.1 mmol) and stirred at room temperature for 5 h. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with aqueous CuSO4 solution (2×25 mL) followed by water (2×25 n mL). Organic layer was dried (Na2SO4), evaporated and purified by chromatography (Si-gel, 15% EtOAc-hexane); first eluted was (3S,6S)-3-acetoxy-6,7-di-p-toluene sulfonyloxy-hept-1-yne 15a (1.14 g) in 10% yield as a yellow syrup. 1HNMR (CDCl3, 200 MHz): δ1.48-1.8 (m, 4H, H-3,4), 2.0 (s, 3H, OAc), 2.31 (d, 1H, J 2.5 Hz, H-7) 2.4 (s, 3H, Ar—CH3), 3.94 (d, 2H, J 4.5 Hz, H-1), 4.5-4.64 (m, 1H, H-2), 5.06-5.18 (m, 1H, H-5), 7.20-7.3, 7.56-7.7 (m, 4H each, Ar—H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]2[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]12)=[O:4].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]([N:5]3[CH2:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]4[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]34)=[O:4])[CH2:30][CH2:29]2)[CH:34]=[CH:35][CH:36]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1ccccc1
Reactant: COc1cccc(CN2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(CN2CCN(CC(=O)N3CC=C(c4ccccc4)n4ncc(C#N)c43)CC2)c1
Yield: 25.2 %

Procedure:
A mixture of 3.8 g of 4-(chloroacetyl)-4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 2.9 g of 3-methoxybenzyl piperazine and 1.6 g of sodium carbonate in 165 ml of toluene was reacted as described in Example 146. The product was recrystallized from isopropanol, giving 1.5 g of the desired product, mp 98°-100° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:17]=[CH:18][C:19]([O:21]C(C)(C)C)=[O:20])[NH:10][C:9]2=[O:33]>CO>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:17]=[CH:18][C:19]([OH:21])=[O:20])[NH:10][C:9]2=[O:33]
Reactant: CCCOc1ccc(C=CC(=O)OC(C)(C)C)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(C=CC(=O)O)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
2N Aqueous sodium hydroxide solution (2.8 ml) was added to a stirred solution of t-butyl 3-(8-methylquinazolin-4(3H)-on-2-yl)-4n-propoxycinnamate (Example 10; 0.79 g, 0.0018 mol) in methanol (2.8 ml) and the resulting solution heated under reflux for 4 hours. The solvent was removed by evaporation under vacuum, the residue-dissolved in water (25 ml) and this solution washed with ethyl acetate (4×30 ml). The aqueous solution was acidified with 2N hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give the title compound, which crystallized from ethyl acetate to give a white solid (0.41 g, 60%), m.p. 256°-257° C. Found: C,69.46; H,5.57; N,7.75. C21H20N4O4 requires C,69.22; H,5.53; N,7.69%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:20][C:21]1([C:24]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)CC1

Procedure:
A solution of EXAMPLE 89 (20 mg, 0.08 mmol), 1-methylcyclopropanecarboxylic acid (10 mg, 0.096 mmol), HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (38 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) in dimethylacetamide (2.5 mL) was stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in a 1:1 mixture of dimethylsulfoxide/methanol, and separated by HPLC (Waters Sunfire® C-8 analytical column [Milford, Mass.], 0.1% trifluoroacetic acid/water/CH3CN) to provide the title compound. MS (DCI/NH3) m/z 338 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0.57-0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H), 2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O1CCOCC1>C(OCC)C>[ClH:29].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O[C@@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.26 mmol) in 10 mL diethyl ether was added 4 M HCl in dioxane (1.3 mL, 5.2 mmol) and the resulting mixture was stirred at rt overnight. The solvent was evaporated off and the residue triturated with ether. Yield 80 mg (88%), LCMS (Method J) RT 0.73 min (92% AP), m/z 284.2 (MH+), 1H NMR (300 MHz, DMSO-d6) δ ppm 7.30-7.45 (m, 5H), 7.27 (d, J=8.4, 2H), 6.97 (d, J=8.7, 2H), 5.09 (s, 2H), 4.09 (s, 1H), 3.44 (d, J=12.6, 2H), 3.32-3.29 (m, 1H), 3.08-3.20 (m, 1H), 2.95 (d, J=12.6, 1H), 2.48-2.58 (m, 1H), 1.82 (d, J=13.2, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:29])([OH:28])[OH:27].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][NH:22][CH2:23][CH2:24][CH2:25][P:26](=[O:27])([OH:29])[OH:28])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Reactant: NCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 6-phenyl-5-p-tolylpyridine-2-carbaldehyde (Compound 55, 67 mg, 0.25 mmol), (3-aminopropyl)-phosphonic acid (34 mg, 0.25 mmol), Bu4NOH (0.2 ml, 0.25 mmol, 1 M in MeOH) and NaCNBH3 (15 mg, 0.25 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:32][CH2:31]1
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CN1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)N1CCN(C)CC1

Procedure:
680 mg (3 meq) of myristic acid and 486 mg (3 meq) of carbonyl diimidazole are reacted in a minimum volume of tetrahydrofuran at ambient temperature for 1.5 hours. 1-Methyl-piperazine (0.33 ml, 3 meq) is added and reacted overnight at ambient temperature. The reaction mixture is evaporated under reduced pressure, dried in vacuo and purified on a column of silica gel in the system CH2Cl2 :CH3OH (5:1). The fractions having Rf 0.80 on TLC silica gel CH2Cl2 :CH3OH (5:1)-iodine are combined, evaporated under reduced pressure (<30°) and dried in vacuo to yield 85 mg of title compound.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([OH:24])=O)=[CH:13][CH:12]=1.[CH3:25][CH:26]1[NH:30][CH2:29][C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:31])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([N:30]2[CH:26]([CH3:25])[CH2:27][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([OH:31])[CH2:29]2)=[O:24])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cnoc1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.04 mmol) was added to a solution of 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (8 mg, 0.04 mmol), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was left at rt for 2 h. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z: calcd for C21H19FN2O3: 366.1380, found 366.1391.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([Cl:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>>[ClH:31].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(15.0 mg, 44%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-fluorophenylsulfonyl chloride (20.8 mg, 0.107 mmol). HRMS-FAB+ for C21H18N2O2SF4.HCl, calculated MH+ (--HCl): 439.11035; found: 439.10807.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: Br
Reactant: OCCCCCCCCCCO
Product: OCCCCCCCCCCBr
Temperature: 25 °C

Procedure:
A solution of 50 g of decane-1,10-diol in 300 ml of 48% aqueous hydrobromic acid was heated at 90° C. for 24 hours while the solution was extracted continuously with petroleum ether 100-140. After cooling to room temperature, the petroleum ether solution was evaporated and the residue was purified by distillation. Boiling point 121°-124° C. (0.1 mm Hg).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:16])[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.CN(C)[CH:19]=[O:20]>O1CCCC1>[CH3:6][C:7]1([CH3:16])[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:19]=[O:20])[C:9]=2[O:8]1
Reactant: CC1(C)Cc2ccccc2O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(C=O)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
n-Butyl lithium, 2.7M, (25.04 ml, 0.0676 mole) was added to a stirred solution of 2,3-dihydro-2,2-dimethylbenzofuran (10.0 grams, 0.0676 mole) in tetrahydrofuran (75 ml) at -78° C. The reaction mixture was then stirred at 0° C. for two hours after which it was added to a cooled (-78° C.) solution of dimethylformamide (5.42 ml, 0.07 mole) in tetrahydrofuran (25 ml). Upon completion of addition, the reaction mixture was stirred at -78° C. for ten minutes and then warmed to ambient temperature. The reaction mixture was quenched with aqueous ammonium chloride (1M, 150 ml) and stirred for three hours at ambient temperature. The reaction mixture was extracted with diethyl ether (2×150 ml), and the combined extract was washed with a saturated aqueous solution of sodium chloride. The dried (magnesium sulfate) extract was concentrated under reduced pressure leaving a residue. This residue was distilled, yielding 3.72 grams of 2,3-dihydro-2,2-dimethylbenzofuran-7 -carboxaldehyde, b.p. 80°-83° C./0.2 mmHg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=3[CH3:18])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:29])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=3[CH3:18])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(C)c(C)c1-c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1-c1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 4-({cyclohexyl[2-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)furan-3-yl]methyl}amino)benzoic acid (211 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (214 mg, 85%).
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CCC>CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4]([CH:5]([CH3:7])[CH3:6])=[N:25][N:24]=[C:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCSC(=Nc1ccc(Br)cc1)C(C)C
Solvent: CCCCO
Solvent: CO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccc(Br)cc1
Temperature: 130 °C
Yield: 28 %

Procedure:
In a 300 mL recovery flask were put 13 g (44 mmol) of N-[1-(ethylsulfanyl)isobutylidene]-4-bromoaniline, 3.9 g (29 mmol) of benzoylhydrazine, and 40 mL of 1-butanol, and the mixture was heated and refluxed at 130° C. for 10 hours. After that, 1-butanol was distilled off to give a solid. A methanol suspension of this solid was irradiated with ultrasonic waves, and a white solid was collected by gravity filtration, so that 2.8 g of white powder of 4-(4-bromophenyl)-5-isopropyl-3-phenyl-4H-1,2,4-triazole was obtained in a yield of 28%. The reaction scheme of Step 4 is shown in (b-4) below.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH3:34][N:35]1[CH:39]=[C:38]([NH2:40])[C:37]([CH3:41])=[N:36]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCOCC1>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:40][C:38]3[C:37]([CH3:41])=[N:36][N:35]([CH3:34])[CH:39]=3)[N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1nn(C)cc1N
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4cn(C)nc4C)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 1,3-dimethyl-1H-pyrazol-4-amine (1 equiv) and sodium tert-butoxide (2 equiv) in 1,4-dioxane (0.15 M) was added chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (0.06 equiv) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (0.06 equiv). The reaction was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (37% yield). MS (ESI) m/z 562.3 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[N:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[CH2:19]([Si:14]([CH2:15][CH3:16])([CH2:17][CH3:18])[O:13][CH2:12][CH2:11][NH:10][C:7]1[CH:6]=[N:5][C:4]([NH2:1])=[CH:9][N:8]=1)[CH3:20]
Reactant: CC[Si](CC)(CC)OCCNc1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)OCCNc1cnc(N)cn1
Reaction time: 4 h
Yield: 96.1 %

Procedure:
A solution of (5-nitro-pyrazin-2-yl)-(2-triethylsilanyloxy-ethyl)-amine (530 mg, 1.78 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon (60 mg). The reaction mixture was then placed on a Parr shaker under a hydrogen atomsphere of 50 psi for 4 h. The catalyst was then filtered off through a pad of celite, and the celite pad was then washed well with ethyl acetate. The filtrate was then concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, ethyl acetate) afforded N-(2-triethylsilanyloxy-ethyl)-pyrazine-2,5-diamine (459 mg, 96%) as an orange-brown solid: (ES)+-HRMS m/e calcd for C12H24N4O2Si (M+H)+ 269.1792, found 269.1794.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:23]=[N:22][C:21](Br)=[CH:20][N:19]=1>CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:22][CH:23]=1
Reactant: Brc1cnc(Br)cn1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2cnc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A solution of alcohol 101 (see Example 2M) (350 mg, 1.76 mmol) in anhydrous DMF (7 mL) under N2 at 0° C. was treated with 60% NaH (104 mg, 2.60 mmol) and 2,5-dibromopyrazine (837 mg, 3.52 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 3 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (80 mL), and extracted with CH2Cl2 (6×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-2% EtOAc/CH2Cl2 gave 2-{[(5-bromo-2-pyrazinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (104) (428 mg, 68%) as a white solid: mp (MeOH/CH2Cl2/hexane) 198-200° C.; 1H NMR [(CD3)2SO] δ 8.44 (d, J=1.3 Hz, 1H), 8.16 (d, J=1.3 Hz, 1H), 8.14 (s, 1H), 4.62 (s, 2H), 4.40 (d, J=11.0 Hz, 1H), 4.19 (d, J=11.0 Hz, 1H), 1.70 (s, 3H). Anal. (C11H10BrN5O4) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]C(C)(C)C)=[O:13])[N:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1
Reactant: CC(C)(C)OC(=O)c1csc(-c2ccccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1csc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(pyridin-2-yl)thiazole-4-carboxylate 7.3 (340 mg, 1.3 mmol) in commercial anhydrous CH2Cl2 (5 mL) at RT was added TFA (0.93 mL, 13 mmol) under N2. The mixture was stirred at RT overnight. The mixture was diluted with CH2Cl2 (25 mL), washed with an aqueous solution of NaHSO3 10% (5×25 mL), brine (25 mL) and then water (25 mL). The organic layer was dried over MgSO4 and evaporated to afford title product as a yellow oil. Yield: 250 mg (94%). LCMS: P=93%, rt=3.03 nm, m/z=207.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:36])([F:35])[CH:30]([OH:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]([OH:34])[C:29]([F:36])([F:35])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, yellow solid (110 mg, 96%), MS (ISP) m/z=457.4 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.