Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH3:6][C:7]1[C:8]([CH2:16][S:17][C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[N:9][CH:10]=[CH:11][C:12]=1[N+]([O-])=O>C(O)(=O)C>[CH2:3]([O:5][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:16][S:17][C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:21]=3[N:22]=2)[C:7]=1[CH3:6])[CH3:4]
Reactant: CCO
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Reaction time: 1 h

Procedure:
600 mg of sodium hydride dispersion (55-60% in oil) were dissolved in 50 ml of abs. ethanol under argon. 3.68 g of 2-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole were added thereto and the solution was left to stir at 70° for 1 hour. The solution was neutralized with glacial acetic acid and the mixture was then evaporated in a vacuum. The residue was treated with aqueous sodium bicarbonate solution and methylene chloride. The organic phase was separated and the aqueous phase was extracted several times with methylene chloride. The combined organic phases were dried and concentrated The residue was chromatographed on silica gel with methylene chloride/methanol (9:1), using the medium pressure flash chromatography method, pressure was produced with nitrogen gas. There was obtained 2-[[(4-ethoxy-3-methyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole. After recrystallization from ethyl acetate/ether the product melts at 173°-177°.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[CH:6][CH:5]=1>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH2:25][CH3:26])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)cc2)c1C#Cc1ccc(N)nc1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 120 mg (0.32 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoic acid methyl ester using 0.48 mL (0.48 mmol) 1 N NaOH in 3 mL THF.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.Cl.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1ccc(-c2nccs2)cc1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Yield: 79.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (495 mg, 2.79 mmol), and using 4-(thiazol-2-yl)benzylamine hydrochloride (687 mg, 2.61 mmol) obtained in Reference Example 4-(d) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (689 mg) as a white solid. (Yield: 80%)
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:14]3[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:28])=[CH:26][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>C(Cl)Cl.CO>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]3[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:28])=[CH:26][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCCn1c(-c2ccc(C(=N)N)cc2)nc2cc(C(=O)NCCC(=O)OC)ccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCC(=O)O

Procedure:
Obtained as a by-product in (120) Rf value: 0.19 (silica gel; methylene chloride/methanol=8:2)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[S:15]1[C:19]([C:20](=O)[CH3:21])=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:15]1[C:19]([CH:20]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:21])=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: CC(=O)c1cc2ccccc2s1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-benzo[b]thiophen-2-yl-ethanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[CH:33]1.C(=O)=O>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cn1cncc1C=O
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (3.0 g, 6.97 mmol, Intermediate 5: step d) was added THF (40 mL) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 2.8 mL, 7 mmol) was then added dropwise. After 2 minutes, 1-methyl-1H-imidazole-5-carbaldehyde (1.2 g, 9 mmol, in 10 mL THF) was introduced. After 15 minutes, the dry-ice bath was replaced with a 0° C. bath. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc:THF (10:2, 5×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Chromatography on silica gel (30% acetone-DCM increasing to 5% MeOH) provided the title compound.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9]COC)=[CH:6][C:5]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:3]=1[Cl:41].C([O-])(=O)C.[K+].[B:47]1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:48]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:41][C:3]1[C:2]2[B:47]([OH:48])[O:9][CH2:8][C:7]=2[CH:6]=[C:5]([N:13]([C:18]2[C:37]([CH:38]3[CH2:39][CH2:40]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:15])=[O:16])[CH:4]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c4c(c3)COB4O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 90 °C

Procedure:
A solution of 6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.25 g, 0.38 mmol), potassium acetate (0.15 g, 1.50 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.031 g, 0.038 mmol), bis(pinacolato)diboron (0.29 g, 1.13 mmol) in 1,4-Dioxane (3.75 ml) was degassed, purged with nitrogen and heated at 90° C. for 15 h. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in THF (5 mL), and 1M HCl (5 mL) and the solution was heated at 70° C. for 4 h. MeOH (2 mL) was added and the solution was heated at 70° C. for another 15 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (100% EtOAc to 10% MeOH/CH2Cl2) to obtain the title compound as a clear oil. MeOH was added and the precipitate was collected by vacuum filtration, washed with MeOH and dried to afford the title compound (0.0831 g, 39%) as a light tan solid. The filtrate was purified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid)) to afford an additional batch of the title compound (0.0146 g, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1H), 8.50 (d, J=4.68 Hz, 1H), 8.09 (s, 1H), 7.94-8.02 (m, 2H), 7.37-7.46 (m, 3H), 7.28 (d, J=1.56 Hz, 1H), 7.22 (s, 1H), 4.96 (s, 2H), 3.47 (s, 3H), 2.84 (d, J=4.59 Hz, 3H), 2.02-2.14 (m, 1H), 0.98 (br. s., 1H), 0.82 (br. s., 2H), 0.49 (br. s., 1H). LCMS (m/z, ES+)=569.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:58]1[N:63]=[C:62]([CH:64]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH2:65][OH:66])[CH:61]=[CH:60][CH:59]=1>C(OCC)(=O)C.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]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:58]3[CH:59]=[CH:60][CH:61]=[C:62]([CH:64]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)[CH2:65][OH:66])[N:63]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1N
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (Example 1, Step 1) (247 mg, 0.97 mmol), Pd2(dba)3 (54 mg, 0.058 mmol), X-PHOS (139 mg, 0.29 mmol), and potassium carbonate (148 mg, 1.07 mmol). The tube was evacuated, and backfilled with argon three times. A second vial was charged with racemic 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (280 mg, 0.97 mmol) and evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (2.3 mL) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol and the resulting solution was transferred by syringe to the tube containing the rest of the reagents. This vial was sealed and left to stir at 100° C. overnight. The reaction vessel was cooled to room temperature, and the crude reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (silica, 0-3% methanol/ethyl acetate) afforded the title compound. 1H NMR (600 MHz, d6-DMSO): δ 11.28 (s, 1H), 7.94 (d, 2H), 7.79 (s, 1H), 7.69 (t, 1H), 7.61 (s, 1H), 7.54 (d, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 4.51 (t, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.65 (t, 1H), 3.52 (m, 4H), 2.48 (m, 4H). LRMS (APCI) calcd for C21H22ClN5O3S [M+H]+: 460.1, found 460.0
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH:15]([C:22]([OH:24])=[O:23])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C=O
Reactant: COCc1cccc2c1Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCc1cccc2c1C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
A solution of 1-methoxymethylfluorene (4.5 g, 21.4 mmol) in 100 mL of THF at -78° C. was charged with butyl lithium (10.0 mL, 23.5 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced via cannula over a period 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until colorless, diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated, the water layer was washed with ethyl acetate (3×50 mL), then acidified with conc. HCl. The resulting precipitate was collected, washed with water and dried to give 1-methoxymethyl-9-fluorenecarboxylic acid (1.8 g, 33.1%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1[CH:13]=[O:14].O>CCO>[Cl:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1[CH2:13][OH:14]
Reactant: O=Cc1c(Cl)nc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1c(Cl)nc2ccccn12
Reaction time: 1 h
Yield: 77.5 %

Procedure:
NaBH4 (1.52 g, 41.33 mmol, 1.5 eq) is added to a solution of 2-chloroimidazo[1,2-a]pyridine-3-carbaldehyde x173 (4.96 g, 27.56 mmol, 1 eq) in EtOH (100 ml). After 1 hour at room temperature, water (100 ml) is added and the aqueous layer is extracted with CH2Cl2 (3×50 ml). The combined organic layers are dried on anhydrous MgSO4, filtered and evaporated under reduced pressure. The resulting white solid is recrystallized in CH2Cl2/hexane to yield 3.9 g of (2-chloroimidazo[1,2-a]pyridin-3-yl)methanol x174.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[Br:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCBr
Reactant: CNc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCBr)c1ccccc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
N-methylaniline (300 mg, 2.80 mmol), 1,3-dibromopropane (0.568 mL, 5.6 mmol), K2CO3 (1.16 g, 8.40 mmol) and 18-crown-6 (49.8 mg, 0.30 mmol) were dissolved in 20 mL of anhydrous DMF and mixture stirred for 24 hours at 35° C. The reaction mixture was filtered and washed with DCM, and filtrate dissolved in DCM (100 mL) before extraction in water. The organic layer was washed with water (2×50 ml), brine (50 ml), and dried over Na2SO4, followed by evaporation of solvents under reduced pressure and the residue purified by silica gel column chromatography (EtOAc:n-hexane 1:20 to 1:10) to obtain compound 14. Yield: 0.260 g (74%). 1H NMR (500 MHz, CDCl3): δ 2.16 (tt, 2H, J=6.5 and 13.5 Hz, Hc), 2.99 (s, 3H, NCH3, Ha), 3.46-3.55 (m, 4H, Hb and Hd), 6.71-6.79 (m, 2H, He and Hg), 7.24-7.29 (m, 2H, Hf). EI-MS: [M+H]+ C10H15BrN calcd 228.03, obsd 228.04.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>O1CCCC1>[O:24]=[C:21]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH3:13])([CH3:14])[O:11][C:10]1=[O:15])[CH2:22][CH3:23]
Reactant: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC(C)(C)[C@@H]1Cc1ccccc1
Yield: 85.4 %

Procedure:
Reaction of the auxiliary (10) (0.8 g, 3.90 mmol) in solution in tetrahydrofuran (27 ml) at -78° C. with butyllithium (1.3M, 3.03 ml, 3.94 mmol) and propionyl chloride (0.373 ml, 4.29 mmol) for 30 minutes and then at room temperature overnight with work-up and recrystallisation from pentane gave the title compound (20) as a solid (0.870 g, 85%); mp 61° C.; νmax (CHCl3) 1773 and 1702 cm-1 ; [α]D25 (c 1 in CHCl3)=-42.5; (Found: C, 69.06; H, 7.43; N, 5.21. C15H19NO3 requires C, 68.94; H, 7.33; N, 5.36%); δH (CDCl3 ; 200 MHz) 1.13 (3H, t, J=7.36, CH2CH3), 1.35 (3H, s, C(CH3)2), 1.36 (3H, s, C(CH3)2), 2.81-2.98 (2H, m, CH2Ph and CH2CH3), 3.14 (1H, dd, J=4.0 and 14.4, CH2Ph), 4.50 (1H, dd, J=4.0 and 9.6, CHCH2), 7.18-7.34 (5H, m, ArCH); δC (125 MHz; CDCl3) 8.20 (CH3), 22.15 (CH3), 28.43 (CH3), 29.23 (CH2), 35.24 (CH2), 63.46 (CH), 82.20 (C), 126.96 (CH), 128.82 (CH), 129.26 (CH), 137.26 (C), 152.93 (CO), 174.53 (CO); m/z (CI+, NH3) 262 (M+ +1).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:16])[O:8][C:7]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]#[N:15])=[CH:12][C:6]=2[O:5]1.Br[CH2:18][CH2:19]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[F:16][C:4]1([F:3])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]3([C:14]#[N:15])[CH2:19][CH2:18]3)=[CH:12][C:6]=2[O:5]1
Reactant: ClCCBr
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70° C. The mixture was stirred overnight at 70° C. before the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give crude 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.053 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 303(M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.8 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.4 g) in n-BuOH (10 mL) with diisopropylethylamine (2 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.6 g of desired product. MS (electrospray): 402 (M+1) for C18H20FN7O3. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.3 (s, 1H) 11.0 (s, 1H) 8.80 (m, 1H) 8.50 (m, 1H) 8.15 (m, 1H) 7.80 (m, 1H) 7.30 (m, 1H) 6.20 (d, 1H) 5.80 (m, 1H) 5.35 (m, 1H), 4.60 (m, 1H) 1.50 (d, 3H) 1.20 (d, 6H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:22]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NC1CCCCC1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NC1CCCCC1

Procedure:
102 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 100 g of cyclohexylamine are heated to 137° C. under 4,000 Pa. 59 ml of water and excess cyclohexylamine are distilled off. Distillation of the residue at 162°-163° C. under 10.7 Pa gives 87.6 g (62% of theory) of an oil of nD20 1.5296 and η25 72.8 Pa.s.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH2:20])[C:12]#[CH:13]>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: C#CCOCCOCCN
Product: C#CCOCCOCCNc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 29.6 %

Procedure:
To 1-chloro-2-nitrobenzene (152 mg, 0.97 mmol, 1.0 equiv.) was added neat 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) (900 mg, 6.31 mmol, 6.5 equiv.), and the resulting slurry was heated to 100° C. for 6 hours during which time the solid dissolved. At the end of this period, the heating bath was removed, the reaction content was mixed with water (50 mL), and then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% CH3OH in CH2Cl2, then 10% CH3OH in CH2Cl2) to yield 2-nitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-6) as a dark yellow oil (76 mg, 30%). IR (thin film) 3378 (m), 3286 (m), 3085 (w), 2875 (m), 2114 (w), 1616 (s), 1570 (s), 1508 (s), 1417 (m), 1349 (m), 1228 (s), 1093 (s), 1034 (m), 740 (m), 670 (s); 1H NMR (500 MHz, CDCl3) δ 8.23 (bs, 1H), 8.18 (dd, J=8.6, 1.6 Hz, 1H), 7.43 (ddd, J=8.6, 7.0, 1.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.65 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 4.22 (d, J=2.4 Hz, 2H), 3.80 (t, J=5.5 Hz, 2H), 3.73 (d, J=2.4 Hz, 4H), 3.52 (q, J=5.4 Hz, 2H), 2.43 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 145.45, 136.13, 132.22, 126.94, 115.39, 113.78, 79.56, 74.61, 70.50, 69.20, 69.19, 58.52, 42.75; HRMS (ES+) calc'd for C13H16N2O4 (M+H) m/z 265.1144 Found 265.1181.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[N:12]=1)=O.Cl>O1CCCC1.[Cl-].[Na+].O>[Cl:23][C:19]1[CH:18]=[C:17]([C:13]2[N:12]=[C:11]([CH2:9][OH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
399 mg (10.50 mmol) lithium aluminium hydride were given to 18 ml tetrahydrofuran (THF) and stirred at room temperature (r. t.) for 10 min. A solution of 1.30 g (5.25 mmol) 6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid methyl ester in 18 ml THF was added drop by drop at 0° C. within 15 min., and the mixture stirred for 2 h at 0° C. 32 ml brine were added slowly at 0° C. and stirred continued for 2 h. The mixture was adjusted to pH=5 by slowly addition of conc. HCl. A formed salt precipitate was isolated by filtration and washed with THF. The combined THF-solutions were evaporated, the residue extracted twice with ethyl acetate, the organic phase dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:1) gave 0.45 g (35%) of [6-(3-Chloro-phenyl)-pyridin-2-yl]-methanol
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[I:15])[CH3:2].[CH2:17](N)C#C>>[I:15][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=1[C:4]([NH:3][CH2:1][C:2]#[CH:17])=[O:16]
Reactant: CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Reactant: C#CCN
Product: C#CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Yield: 85 %

Procedure:
The acid chloride prepared in Example 207 was reacted with propargylamine (3 eq) using General Method E1 to afford the title compound. Purification by recrystallization from hexanes gave 0.48 g of the title compound as an off-white solid in 85% yield. m.p. 109°-111° C.