Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@:19]([O:49][Si](C)(C)C)([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:72][CH2:73][O:74][C:75]([CH3:77])=[O:76]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=4)[O:31][CH2:77][C:75]([O:74][CH2:73][CH3:72])=[O:76])([OH:49])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (10 g) in THF (50 ml) was added tetrabutylammonium fluoride (41 ml, 1M solution in THF) at room temperature. After being stirred for 4 hours, the mixture was diluted with EtOAc. The mixture was washed with 1N-HCl solution and brine and evaporated. The residue was dissolved in DMF (50 ml), followed by addition of K2CO3 (5 g) and ethyl bromoacetate (2.0 ml) at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with water and brine and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}-acetate (5.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.O.[C:22](OC(C)=O)([CH3:25])([CH3:24])[CH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromophenylacetic acid (5.00 g, 23.2 mmol) in tBuOAc (75 mL) was added BF3.OEt2 (2.95 mL, 23.2 mmol). The mixture was allowed to stir overnight at room temperature and poured into H2O. The aqueous phase was extracted with EtOAc. The organic phase was washed with sat. aq NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash chromatography on silica gel (0% to 100% EtOAc in hexanes) provided the title compound. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J=8.0 Hz, 2 H), 7.19 (d, J=8.0 Hz, 2 H), 3.52 (s, 2 H), 1.48 (s, 9 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[C:5]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH:23]([CH3:24])[C:3]=1[C:4]=23.C([O-])([O-])=O.[K+].[K+].[CH2:38](I)[CH3:39]>CC(C)=O>[CH2:38]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[C:5]3[CH2:20][CH2:21][NH:22][CH:23]([CH3:24])[C:3]=1[C:4]=23)[CH3:39]
Reactant: CCI
Reactant: CC1c2c(O)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2c3c(cn2S(=O)(=O)c2ccccc2)CCNC(C)c13
Temperature: 62 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
tert-Butyl 7-hydroxy-6-methyl-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 15 (16 mg, 0.036 mmol), acetone (5 mL), K2CO3 (50 mg, 0.36 mmol) and EtI (34 mg, 0.22 mmol) were added into a 16 mm test tube with screw cap and the suspension was stirred at 62° C. over night. The solvent from the filtered mixture was evaporated at reduced pressure and the residue was dissolved in DCM/TFA 50/50 (1 mL) and left in room temperature for two hours. The solvent was evaporated at reduced pressure and the crude was purified by preparative HPLC (Xterra C18, 10 mM NH4CO3 (pH 10)-CH3CN) to give 9.0 mg (67%) of the title compound as a brown oil. MS m/z 371 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17](O)=[O:18].[BH4-].[Na+].Cl>C1COCC1.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:17][OH:18])[CH:20]=[CH:21][N:22]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (CDI, 7.88 g, 46.2 mmol, 1.5 equiv) is added at room temperature to a solution of 2-chloroisonicotinic acid (5.0 g, 30.8 mmol) in THF (70 ml). The reaction mixture is stirred at rt overnight, and then added dropwise to a cold (0° C.) solution of NaBH4 (6.07 g, 154 mmol, 5.0 eq) in water (175 ml). After stirring for 10 minutes at 0° C., HCl (2 M aqueous solution) is carefully added. Volatiles are removed via rotary evaporation, and the residue is dissolved in an aqueous 10% solution of NaHCO3. After five extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. 1H-NMR analysis of the residue indicated adequate purity for direct use of the product (4.40 g, 99%) in the next step. 1H NMR (400 MHz, CDCl3): δ=8.37 (d, J=5.1 Hz, 1H), 7.39 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 4.78 (s, 2H). MS (ES+): 144 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)([CH3:14])[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(C)Oc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isopropoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isopropoxyphenylboronic acid in a manner analogous to Example 2c (0.24 g, 40%). MS=288 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[C@@H:4]([NH:27][C:28](=[O:51])[CH:29]([NH:32][C:33]([C:35]1[C:36]2[CH:43]=[N:42][N:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[C:37]=2[CH:38]=[N:39][CH:40]=1)=[O:34])[CH2:30][CH3:31])[C@H:5]([O:7]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:6].Cl>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:52])[C@@H:4]([NH:27][C:28](=[O:51])[CH:29]([NH:32][C:33]([C:35]1[C:36]2[CH:43]=[N:42][N:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[C:37]=2[CH:38]=[N:39][CH:40]=1)=[O:34])[CH2:30][CH3:31])[C@H:5]([OH:7])[CH3:6]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C(=O)N[C@H](C(=O)OC)[C@@H](C)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C(=O)N[C@H](C(=O)OC)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) solution of (2S,3R)-2-(2-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-butyrylamino)-3-trityloxy-butyric acid methyl ester (1.47 g, 2.10 mmol) in CH2Cl2 (100 mL) was added a 1 M solution of HCl (6.30 mL, 6.30 mmol) in ether. After 30 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and warmed to room temperature. After 30 minutes, the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over MgSO4, filtered and passed through a pad of silica gel eluting with a gradient of 0-10% methanol in methylene chloride to afford (2S,3R)-2-(2-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-butyrylamino)-3-hydroxy-butyric acid methyl ester as white solid. MS m/z 458.76 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:32]1[N:37]=[C:27]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:31]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 42 mg (0.36 mmol, 1.5 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 60 mg (51% of theory)
Reaction SMILES: [Na].[ClH:2].[N:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6](=[N:12]O)[CH2:5][CH2:4]2.O>C(O)CCCC>[ClH:2].[NH2:12][CH:6]1[CH:7]2[CH2:10][CH2:11][N:3]([CH2:9][CH2:8]2)[CH2:4][CH2:5]1
Reactant: ON=C1CCN2CCC1CC2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCO
Product: NC1CCN2CCC1CC2

Procedure:
Sodium (5.6 g) was added portionwise to a suspension of 1-azabicyclo[3.2.2]nonan-4-one oxime hydrochloride (D1) (2.8 g) in amyl alcohol (100 ml) which was heated under reflux. After all the sodium had reacted, the mixture was cooled to 50° and water (20 ml) was added carefully. The aqueous phase was separated and the amyl alcohol was extracted with 5N hydrochloric acid (2×15 ml). The combined acid extract was washed with diethyl ether and the solvent evaporated in vacuo to give 4-amino-1-azabicyclo[3.2.2]nonane hydrochloride. The hydrochloride salt was basified with 40% sodium hydroxide and the aqueous phase was saturated with potassium carbonate, extracted with diethyl ether, dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (1.4 g, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[N:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:32]([CH3:46])[CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:35][CH2:34][CH2:33][CH:32]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[N:25]=2)[C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(C#N)cc2)CC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(C#N)cc2)CC1

Procedure:
Using general procedure C with 4-[(6-chloro-pyridin-2-yloxy)-(4-cyano-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (236 mg, 0.55 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (203 mg, 0.93 mmol) and then using general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-chloro-pyridin-2-yloxy)-methyl]-benzonitrile as a colourless syrup (65 mg, 37% over 3 steps).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[CH:22](O)[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[CH:22]=[CH:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:19]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)N(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)C1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl 3-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-4-hydroxy-2-oxoimidazolidine-1-carboxylate (160 mg, 0.368 mmol) in DCM (5 mL) at 0° C. was added methanesulfonyl chloride (31 μL, 0.41 mmol) followed by TEA (0.15 mL, 1.1 mmol). After stirring for 1 h at 0° C., the solution was concentrated in vacuo and purified via silica gel chromatography (MeOH-DCM, 2-5%), affording the title compound (100 mg, 65%). LCMS: m/z=415.1 (M−1); 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.41-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 1H), 6.61 (d, J=3.2 Hz, 1H), 6.15 (d, J=3.2 Hz, 1H), 5.21-5.09 (m, 3H), 4.30 (dd, J=14.4, 9.6 Hz, 1H), 4.01-3.94 (m, 1H), 3.49 (dd, J=14.8, 3.2 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:25]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
Triethylamine (14 mL) was added to a chloroform (120 mL) solution of methyl L-tryptophanate hydrochloride (5.0 g) under ice-cooling, and further acrylic acid (1.6 mL) was added thereto. Next, a methylene chloride (30 mL) solution of DCC (4.9 g) was added dropwise to the mixture. The mixture was stirred at room temperature for 24 hours, and thereafter a half the volume of the solvent was distilled off under a reduced pressure, acetone was added to the residual mixture, and the mixture was allowed to stand in a freezer overnight. Triethylamine hydrochloride and DC urea were filtered off, the solvents of the filtrate was distilled off under a reduced pressure, and the residual oily product obtained was purified by silica gel column chromatography (BW-127ZH, chloroform:methanol=19:1), to give the captioned compound (1.5 g, 28%) as an oily product.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH2:17].[Na].C(NC(C=C([C:29]1[C:30]([NH2:39])=[C:31]([CH:35]=[C:36]([Br:38])[CH:37]=1)[C:32]([O-])=[O:33])C)=O)(C)(C)C>CC(O)C>[NH2:39][C:30]1[CH:29]=[CH:37][C:36]([Br:38])=[CH:35][C:31]=1[C:32]([NH:17][C:13]1[NH:14][CH2:15][CH2:16][N:12]=1)=[O:33]
Reactant: CC(=CC(=O)NC(C)(C)C)c1cc(Br)cc(C(=O)[O-])c1N
Reactant: NC1=NCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Nc1ccc(Br)cc1C(=O)NC1=NCCN1

Procedure:
A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (0.523 g; 2.03 mmol) and sodium (37 mg; 1.63 mmol) in 2-propanol (16 ml) is refluxed for 30 min. 1-(tert-Butylcarbamoyl)-prop-1-en-2-yl-2-amino-5-bromobenzoate (example 15) (0.300 g; 0.812 mmol) is added and the mixture is refluxed over night. The precipitate formed is filtered off and discarded. The filtrate is evaporated, and the residue is purified by preparative RP-HPLC (column: Xbridge C18 (Waters); water-ACN; modifier: ammonia) to yield the title compound (C10H11BrN4O).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([C:21]#[CH:22])(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1)#[CH:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmol), trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh3)4 (Aldrich, 29 mg, 0.025 mmol) and Cul (Strem Chemicals, 10 mg, 0.05 mmol) in DMF (10 mL) was stirred at ambient temperature overnight. DMF then was removed under reduced pressure. The residue was treated with tetrabutyl ammonium fluoride (Aldrich, in THF, 1 M, 5 mL) at room temperature for 3 h. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) δ 1.42-1.54 (m, 1H), 1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m, 5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H) ppm. MS (DCI/NH3): m/z 228 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][O:8][C:5]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:4][CH2:3]2.[Li]CCCC.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:1][C:2]12[CH2:3][O:4][C:5]([C:10]3[O:11][C:12]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:8][CH2:9]2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC12COC(c3ccco3)(OC1)OC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
2-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)furan (2.0 g, 10.2 mmol) was dissolved in THF (20 ml) and the solution was cooled to −78° C. n-BuLi (1.6M solution in hexanes, 7.7 ml, 12.32mmol) was added and the mixture stirred at −78° C. for 30 min, allowed to warm to 0° C. for 20 min. and then recooled to −78° C. The tributyltin chloride (3.5 ml, 4.68 g, 14.4 mmol) was added and stirring was continued at −78° C. for 15min. The mixture was allowed to warm gradually to room temperature and stirring continued for three days. The reaction was quenched by the addition of water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (4.7 g, 9.7 mmol, 95%); δH [2H6]DMSO 6.52 (1H,d), 6.38 (1H, d), 3.96 (6H,s), 0.77-1.63 (30H,m).
Reaction SMILES: [F:1][C:2]([F:16])([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:3][CH2:4][O:5]C(=O)C.[OH-].[Na+]>C(O)C>[F:16][C:2]([F:1])([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:3][CH2:4][OH:5]
Reactant: CC(=O)OCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of acetic acid [3,3-difluoro-3-(4-fluorophenyl)-propyl]ester (5.50 g, 23.7 mmol) in ethanol (70 ml) is added 35% aqueous sodium hydroxide (20 ml) at 0° C. and the reaction mixture is stirred at RT for 1 h. After completion of reaction, the solvent is evaporated and the residue is diluted with water (150 ml) and acidified with aqueous hydrochloric acid before extraction with EtOAc (3×100 ml). The combined organic layers are washed with water (150 ml), brine (150 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 10% EtOAc/hexane) to yield 3,3-difluoro-3-(4-fluorophenyl)-propan-1-ol (4.30 g, 22.6 mmol, 95%).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.CI.[C:11](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br:1][C:2]1[N:3]([CH3:11])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(Br)[nH]c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1c(Br)nc(Cl)c1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4,5-dichloroimidazole (1 g, 4.6 mmol), methyl iodide (346 μL, 5.56 mmol), potassium carbonate (1.27 g, 9.2 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) in acetonitrile (2 mL) was stirred vigorously at 70-80° C. for 1.0 h. After cooling to room temperature, the inorganic salts were filtered off and washed with acetonitrile. The filtrate was evaporated and the residue was purified by flash chromatography (Si) to afford 2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a white solid. LCMS calc.=230.89; found=230.9 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 3.61 (s, 3 H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:36]=[C:37]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[NH2:38]>CN1C(=O)CCC1>[CH3:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[O:18][N:38]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:36]=2)=[CH:14][C:13]=1[NH:12][C:10]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1)=[O:11]
Reactant: NC(=NO)N1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2nc(N3CCOCC3)no2)cc1NC(=O)c1cnc2ccccn12
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A stirring suspension of 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoic acid (4) (41 mg, 0.138 mmol) in anhydrous NMP (1 mL) was heated in the microwave at 105° C. for 2 minutes to dissolve all solid. Then, 1,1′-carbonyldiimidazole (22 mg, 0.138 mmol) was added and the reaction was stirred at room temperature for 15 minutes. N′-hydroxymorpholine-4-carboximidamide (20 mg, 0.138 mmol) was added and the reaction was stirred for 30 minutes. The reaction was heated in the microwave at 130° C. for 15 minutes. The crude product was purified by reverse phase preparative HPLC to give N-(2-methyl-5-(3-morpholino-1,2,4-oxadiazol-5-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F75). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.52-9.48 (m, 1H), 8.68 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.68-7.63 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 3.72-3.69 (m, 4H), 3.41-3.38 (m, 4H), 2.39 (s, 3H). MS m/z 405.16 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[NH:6]2.[OH-].[K+].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]2[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2c(Cl)cc(Cl)cc2n1CCN1CCOCC1

Procedure:
To a solution of 4,6-dichloro-2-methylindole (75 mg, 0.37 mmol) in 0.5 mL DMSO was added pulverized KOH (95 mg, 1.69 mmol), then 2-chloroethylmorpholine HCl (140 mg, 0.75 mmol) and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 91 mg (0.29 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.42-2.55 (m, 4H), 2.44 (s, 3H), 2.60 (t, J=7.0 Hz, 2H), 3.65-3.79 (m, 4H), 4.08 (t, J=7.0 Hz, 2H), 6.31 (s, 1H), 7.09 (s, 1H), 7.16 (s, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.84, 41.59, 54.10, 57.79, 66.91, 98.99, 107.84, 119.47, 125.23, 125.51, 126.17, 137.22, 138.20. MS m/z 313.5 [M+H]+.