Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]([C:10]=1[NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH2:8][CH2:7]2)=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(#N)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:9]2[N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1=C(NC(C)c2ccccc2)C2CCC1N2C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)C1C(NC(C)c2ccccc2)C2CCC1N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 3-(1-phenyl-ethylamino)-7-aza-bicyclo[2.2.1]hept-2-ene-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.3 g, 0.81 mmol) in acetic acid-acetonitrile (1:1, 20 mL) was treated with sodium triacetoxyborohydride (0.19 g, 0.89 mmol), stirred for 5 h at 0° C. and then neutralized with saturated aqueous sodium bicarbonate (5 mL). The organic layer was washed with brine (3×20 mL), then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate-hexanes, to provide 3-(1-phenyl-ethylamino)-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester as a 3:1 mixture of diastereomers (0.28 g, 93%). MS: 375 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCC(C)(C)CO2)=[CH:18][C:17]=1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(Cl)c(-c3cccnc3)c2)OC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3ccc(Cl)c(-c4cccnc4)c3)cnc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 105.1 %

Procedure:
A mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.05 g, 0.19 mmol), 3-[2-chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]pyridine (84 mg, 0.28 mmol) and 2 M Na2CO3 (0.28 ml) in 1,2-dimethoxyethane (2 ml) was degassed for 10 min with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.011 g) was added and the mixture was stirred under nitrogen at 80° C. for 12 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2), to give 75 mg (61%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.42-7.45 (1H, m), 7.71 (1H, d, J 8.6 Hz), 7.86-7.89 (1H, m), 8.08 (1H, dd, J 8.6, 2.5 Hz), 8.14 (1H, d, J 2.5 Hz), 8.64 (1H, s), 8.70 (1H, dd, J 4.9, 2.3 Hz), 8.68 (1H, s), 8.82 (1H, dd, J 2.3, 1.0 Hz); MS (ES+) m/z 376.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:25][CH3:26])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[CH2:17][NH:18]C(=O)C)[N:8]=1.Cl.CO>CC#N>[NH2:18][CH2:17][C:16]1[CH:15]=[C:14]([NH:13][C:9]2[N:8]=[C:7]([C:6]3[S:5][C:4]([NH:25][CH3:26])=[N:3][C:2]=3[CH3:1])[CH:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1

Procedure:
By treatment of N-{3-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide with HCl/MeOH. Yellow solid. Mp 287-289° C. Anal. RP-HPLC: tR=10.1 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-D6) δ: 2.68 (s, 3H, CH3), 3.17 (s, 3H, CH3), 4.17 (m, 2H, CH2), 7.23 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.27 (d, 1H, J=8.0 Hz, Ph-H), 7.50 (t, 1H, J=8.0 Hz, Ph-H), 7.70 (d, 1H, J=7.5 Hz, Ph-H), 7.75 (s, 1H, Ph-H), 8.44 (d, 1H, J=6.0 Hz, pyrimidinyl-H). MS (ESI+) m/z 327.37 [M+H]+ (C16H18N6S requires 326.42).
Reaction SMILES: O[CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: CCOP(=O)(OCC)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of Compound 19 (1.00 g, 0.0041M) in thionyl chloride (1.63 g, 0.014M) is allowed to stir at room temperature for 16 hours. The thionyl chloride is removed in vacuo and the crude is poured over ice-water. The aqueous is extracted with ether (2 times). The ether layer is washed with sodium bicarbonate (saturated solution) (2 times) and water. The organic layer is dried (Na2SO4), filtered and concentrated to obtain 0.712 g of a clear oil. The crude is chromatographed over flash silica gel (0.040-063 mm, 100 g) and eluted with 1% acetone/CH2Cl2 to obtain 0.516 g (0.0020M, 48%) of the title compound as a clear oil. 1H NMR (CDCl3 /TMS): δ 7.56-7.52 (m, 2H, Ar), 4.40 -7.32 (m, 3H, ArH), 4.90 (d, J=14 Hz, 1H, CHCl), 4.23-4.12 (m, 2H, CH2), 4.10-4.00 (m, 1H, CH2), 3.95-3.84 (m, 1H, CH2), 1.32 (dt, J=7.0, 0.6 Hz, 3H, CH3), 1.17 (dt, J=7.0, 0.6 Hz, 3H, CH3); 13C NMR (CDCl3): δ 134.16 (d, J=3.0 Hz, Ar), 129.01-128.55 (m, Ar), 64.13-63.86 (m, CH2), 53.67 (d, J=53.7 Hz, CHCl), 16.45-16.19 (m, CH3); 31P NMR (CDCl3): δ 17.82. Anal. calc'd. for C11H16O3CIP: C, 50.30; H, 6.14; P, 11.79. Found: C, 50.06; H, 6.24; P, 11.66.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[CH2:34][NH:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=[C:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-1-(4-nitro-phenyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole (2.6 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Reactant: C1CCNCC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1-2

Procedure:
By the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, and 34.0g (0.4mole) of piperidine were reacted. The solid precipitate was recrystallized twice from methanol and chromatographed on alumina. Evaporation of solvent from the fraction collected gave the desired product. M.P. 124°-127° C, λmaxCHCl3 328, Elcm1% 731.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9](Cl)(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.Cl>O>[C:9]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCCC(=O)O
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1C(=O)NCCC(=O)O
Reaction time: 6 h
Yield: 74.7 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 17.4 g of o-anisoylchloride were added dropwise under freezing conditions. After stirring for six hours, hydrochloric acid was added and the pH was adjusted to 2 or less. After extraction with 500 mL of ethyl acetate, the product was desiccated over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with aqueous ethanol, and 17.0 g of the desired product was obtained (yield of 75%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CSC.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C@H:18]([OH:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CSC
Product: C[C@@H](O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a cooled solution, −78° C., of 1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 52 mg, 0.176 mmol) in toluene was added (R)-(+)-2-methyl-CBS-oxazaborolidine (97 mg, 0.352 mmol) followed by BH3.DMS (2 M in THF, 0.176 mL, 0.352 mmol). The reaction was warmed to −20° C. and stirred for 3 h followed by treatment with MeOH. The resulting mixture was warmed to ambient temperature and sat. NaHCO3 (aq.) solution was added. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (29 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=2.3 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.5, 8.8 Hz, 1H), 7.28 (t, J=9.0 Hz, 2H), 5.44 (d, J=4.3 Hz, 1H), 5.29 (s, 2H), 5.01-4.91 (m, 1H), 1.47 (d, J=6.7 Hz, 3H). [M+H]=298.2.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C[Si](C)(C)C)(C)(C)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: Clc1nccc2ccccc12
Reactant: C[Si](C)(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C[Si](C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)c1ccc(-c2nccc3ccccc23)cc1

Procedure:
15.0 g (0.07727 mol) of 4-trimethylsilyl-phenylboronic acid, 10.11 g (0.0618 mol) 1-chloro-isoquinoline, 15.11 g (0.0464 mol) of cesium carbonate, 0.71 g (0.000775 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.43 g (0.00185 mol) of di-tert-butyl-trimethylsilylmethyl-phosphane and 100 ml of dioxane were stirred at room temperature for 12 hr. The reaction mixture was filtered and the solvent was removed under vacuum. The resulting mixture was purified by chromatography on silica gel using petroleum ether/ethyl ether (10/0.5) as eluent. Yield of 1-(4-trimethylsilanyl-phenyl)-isoquinoline was 10.63 g (62%) as a colorless solid with m.p. 93.45° C. 1H NMR (CDCl3) 0.30 (s, 9H, Me3Si), 7.45-7.70 (m, 7H, arom-H), 7.85 (s, 1H, arom-H), 8.15 (s, 1H, arom-H), 8.51 (s, 1H, arom-H). Anal. Found: C, 77.68; H, 6.95; N, 4.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:16])[CH3:17])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCC(C)(C)OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OCC(C)(C)OC
Temperature: 80 °C
Yield: 77.5 %

Procedure:
Methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (177 mg, 0.660 mmol), dioxane (1.9 mL) and NaOH (1.8 mL of 1.0 M, 1.8 mmol) were combined and the mixture was heated at 80° C. for 15 min. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in water. The mixture was extracted with EtOAc (3×). The aqueous layer was acidified with 1N HCl before it was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoic acid (130 mg, 77%). ESI-MS m/z calc. 254.1. found 255.5 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.54 (dd, J=8.4, 1.9 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15](OCC)=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
Ethyl 7-chloro-6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (820 mg, 2622 μmol) was dissolved in 1,4-dioxane (5244 μL) and N-ethyl-N-isopropylpropan-2-amine (1370 μL, 7866 μmol). tert-Butyl 2-aminoacetate hydrochloride (659 mg, 3933 μmol) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (200 mg) as a white solid after flash chromatography. MS m/e 420 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield by essentially following the procedures outlined in Example 34, Part A, from methyl 4-bromomethyl-3-nitrobenzoate (Part A, above) and pyrrolidine.
Reaction SMILES: [CH2:1]([C:3]1[N:7](C2CCCCO2)[N:6]=[CH:5][C:4]=1[C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[C:17]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[N:16][CH:15]=1)[CH3:2].C(C1C(C2N3N=CN=C3C(NC3C=CC(N4CCOCC4)=CC=3)=NC=2)=CN(C2CCCCO2)N=1)C.Cl>CO>[CH2:1]([C:3]1[NH:7][N:6]=[CH:5][C:4]=1[C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[C:17]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[N:16][CH:15]=1)[CH3:2]
Reactant: CCc1c(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)cnn1C1CCCCO1
Agent: CCc1nn(C2CCCCO2)cc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Agent: Cl
Solvent: CO
Product: CCc1[nH]ncc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Yield: 17 %

Procedure:
A solution of {5-[5-ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-(4-morpholin-4-yl-phenyl)-amine and {5-[3-ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-(4-morpholin-4-yl-phenyl)-amine (40 mg, 0.077 mmol) and conc. HCl (0.3 mL) in MeOH (10 mL) is stirred at room temperature for 5 hours. After removing the solvent, the solid residue is partitioned between ethyl acetate and sat. NaHCO3. The undissolved solid is collected by filtration, washed with water, diethyl ether and petroleum ether and dried to afford the title compound (5 mg, 17%). Conversion into the mesylate salt using 0.1M methanesulfonic acid (0.128 mL) affords the title compound (5.6 mg, 89%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:27]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:28]=[C:19]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:8]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (100 mg, 0.363 mmol) and o-phenylene diamine (40 mg, 0.369 mmol) were dissolved in dry THF (8 mL), and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 9.60 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.0 & 9.2 Hz), 7.87 (m, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.47 (m, 1H), 7.28 (m, 2H), 5.77 (dd, 1H, J=2.4 and 8.8 Hz), 4.00 (m, 1H), 3.76 (m, 1H), 2.53 (m, 1H), 2.13 (m, 2H), 1.77 (m, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[C:12]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=[C:10]([CH3:24])[C:9]=1[CH3:25])(=[O:3])[CH3:2].[H][H]>[Pt].C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([CH3:25])=[C:10]([CH3:24])[N:11]=[C:12]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1N

Procedure:
1-[(2,3-Dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]eth-2-yl acetate (11.5 g, 33.30 mmol) was combined with 5% platinum on carbon (5.0 g) in a Parr flask. Toluene was added to the flask (120 mL) and the resulting mixture was pressurized with hydrogen at 310 kPa at room temperature for 1.6 hours. The reaction was complete as determined by LC/MS and HPLC. The resulting reaction mixture was filtered through Celite™ filter agent, and the filter cake was rinsed with more toluene. The volatiles were removed under reduced pressure, and the resulting oil was carried on to the next step.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:27])([CH3:26])[C@@H:10]([NH:12][CH2:13][CH2:14][C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:19])[CH2:16][CH:17]=[CH2:18])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([C:15]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:19][C:36](=[O:38])[N:12]([C@H:10]([C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])([CH3:26])[CH3:27])[CH3:11])[CH2:13][CH2:14]1)[CH:17]=[CH2:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)C(=O)O1
Yield: 52.1 %

Procedure:
To a solution of 1-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-ylamino)-3-phenylhex-5-en-3-ol (550 mg, 1.41 mmol) and Et3N (1.4 g, 14.1 mmol) in CH2Cl2 (5 mL) was added triphosgene (138 mg, 0.46 mmol) at 0° C. The formed mixture was heated to reflux overnight. The mixture was washed with water. The organic phase was separated and concentrated to give the crude product which was purified by TLC to afford 6-allyl-3-((2S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 17%). 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.08 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 2.83 (q, 1H), 4.08 (brs, 1H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C1COCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Benzenethiol (13.2 g) was dissolved in THF (100 ml), and to this solution was added triethylamine (17.1 ml) and then 4-nitrobenzyl bromide (21.6 g). The reaction solution was stirred for 30 minutes at room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate (=10/1), to give 1-nitro-4-[(phenylsulfanyl)methyl]benzene (20.7 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1.COC(=O)CC1C=CC=CC=1CNC(OC(C)(C)C)=O>>[CH3:16][S:13]([NH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:17])=[O:2])=[CH:6][CH:7]=1)(=[O:15])=[O:14]
Reactant: COC(=O)Cc1ccc(CNS(C)(=O)=O)cc1
Agent: COC(=O)Cc1ccccc1CNC(=O)OC(C)(C)C
Product: CS(=O)(=O)NCc1ccc(CC(=O)O)cc1

Procedure:
Compound 12a was prepared by following the procedure of Example 1, Step e, except 11a was substituted for 5a. (54%) Mass Spectral Analysis m/z=242.2 (M−H)− tR=1.47 min (96%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15]I.[OH-].[K+]>CN(C=O)C.O>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.4 %

Procedure:
In a similar manner to Step 1 of Reference Example 12, indole-6-carboxylic acid (200 mg, 1.24 mmol) was dissolved in DMF (2 mL), and the solution was treated with 60% sodium hydride-mineral oil dispersant (109 mg, 2.71 mmol), methyl iodide (0.258 mL, 0.410 mmol) and 4 mol/L aqueous potassium hydroxide solution (2 mL). The reaction mixture was added with water and separated into aqueous layer and organic layer, and the organic layer was removed. The aqueous layer was added with 1 mol/L hydrochloric acid to adjust the pH to 1, followed by stirring at room temperature for 1 hour. The obtained solid was collected by filtration and dried under reduced pressure to obtain 1-methylindole-6-carboxylic acid (154 mg, yield 71%).