Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][F:27].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2cn3ccccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: FCCCOc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 51.9 %

Procedure:
398 mg (corresponding to 1.89 mmol) of 2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine was dissolved in 15 mL of N,N-dimethylformamide, and 788 mg (corresponding to 5.7 mmol) of potassium carbonate was added thereto. 260 μL (corresponding to 2.8 mmol) of 1-bromo-3-fluoropropane was added to the resulting mixture, and the mixture was stirred for 20.5 hours at room temperature. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 264 mg (corresponding to 0.98 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]imidazo[1,2-a]pyridine (hereinafter referred to as Compound 3) (FIG. 4, Step 3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][OH:12])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(CO)c(C)o1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of (5-methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acetic acid ethyl ester (29) (0.5 g) in tetrahydrofuran (3.0 mL) was cooled to 0° C. with stirring and treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 2.82 mL) under argon. After 30 minutes, the resulting solution was concentrated in-vacuo and partitioned between water (30 mL) and ethyl acetate (4×25 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with diethyl ether/petroleum ether (1:1 by volume) to give compound 30 as a clear oil (188 mg). LC/MS System A: Rt=2.34 mins.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:30][S@@:31]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:30][S@@:31]([CH2:33][C:34]([OH:36])=[O:35])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(C[S@](=O)CC(=O)OC(C)(C)C)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(C[S@](=O)CC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-((S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate, 176a, (0.42 g, 0.64 mmol) in THF (10 mL) was added NaOMe (0.21 mL of 25% solution in MeOH, 0.96 mmol). The solution was stirred at room temperature for 30 minutes. Aqueous saturated NH4Cl solution was added and the solvent was removed under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-15% MeOH/CH2Cl2 gradient) to afford 36 mg of the desired product as a white solid: 1H NMR (400 MHz, MeOD) δ 8.60-8.52 (m, 1H), 8.46 (s, 1H), 8.32 (d, J=5.3 Hz, 2H), 5.16 (m, 2H), 4.00 (d, J=14.7 Hz, 1H), 3.80 (d, J=14.7 Hz, 1H), 3.59 (d, J=13.9, 1H), 1.12 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.93 minutes (M+H) 438.25.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:19](I)[CH3:20]>COCCOC>[CH:1]1([CH:6]([CH2:19][CH3:20])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)CC2CCCC2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C(=O)c1ccc(OC)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 2888.9 %

Procedure:
α-Cyclopentyl-p-methoxyacetophenone (13.0 g, 0.06 mol) was added slowly in dry DME (DME=Dimethoxyethane) to the suspension of NaH (8 g, 55-60% dispersion, 0.018 mmol) in dry DME under N2 atmosphere at room temperature. The suspension was stirred over night. Ethyl iodide (27.7 g, 0.18 mmol) was added and stirring continued for another two hours. Ice water was added cautiously and the water layer extracted with toluene. The organic layer was washed with water, dried and evaporated to give 12.7 g (0.0052 mol, 86%) of the product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:32]([O:34][C:35]([C:37]1[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:38]=1[C:44]([OH:46])=O)=[O:36])[CH3:33].[C:47]1([C:53]2[N:54]=[C:55]3[N:60]=[C:59]([NH2:61])[CH:58]=[CH:57][N:56]3[CH:62]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.O>[CH2:32]([O:34][C:35]([C:37]1[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:38]=1[C:44](=[O:46])[NH:61][C:59]1[CH:58]=[CH:57][N:56]2[CH:62]=[C:53]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:54]=[C:55]2[N:60]=1)=[O:36])[CH3:33]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(CC)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
TBTU (1.1 g) and diisopropylethylamine (1.1 g) were added to a solution of 2-ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (610 mg) in DMF (7 ml), and the mixture was stirred for 30 min at RT. 2-Phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 725 mg) was added to the light yellow solution, and the mixture was stirred over the weekend at RT. Water (15 ml) was added, and the mixture was stirred for an additional 15 min. For purification, the precipitate was suspended in DMF (5 ml) and water (10 ml), and filtered; this process was repeated 4 times. The thus obtained title compound (150 mg, 13%) was dried under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[O:21][C:22]=1[CH3:23]>>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 79 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-furyl)-5-methyloxazole to give 2-(2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole. The yield was 79%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 89-90° C.
Reaction SMILES: OO.O.O.O.O.O.O.O.O.O.O.O.O.P(O)([O-])([O-])=O.[Na+].[Na+].[CH2:22]([CH:24]([CH:27]([OH:31])[CH2:28][CH2:29][CH3:30])[CH2:25][OH:26])[CH3:23].CN(C)C(=O)C>[Cl-].[Na+].O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C1(C)C=CC=CC=1>[CH2:22]([CH:24]([C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:25][OH:26])[CH3:23]
Reactant: CCCC(O)C(CC)CO
Agent: O=[W](=O)([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: OO
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCC(=O)C(CC)CO
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into 5.90 g of 35% hydrogen peroxide solution (60.0 mmol), 720 mg of disodium phosphate dodecahydrate (2.0 mmol) and 165 mg of sodium tungstate dihydrate (0.5 mmol) were dissolved to prepare a mixed reagent (pH 6.5). After 7.3 g of 2-ethyl-1,3-hexanediol (50.0 mmol) was dissolved into 100 mL of N,N-dimethylacetamide, the resultant was heated to 90° C., and the above mixed reagent was added. After the reaction was continued at 90° C. for four hours, 100 mL of toluene and 100 g of 10% brine were added for liquid separation. The aqueous layer was extracted three times with 100 mL of toluene, and all the organic layers were combined and concentrated under reduced pressure. The concentrated liquid was separated and purified by silica gel chromatography (developing solvent hexane:ethyl acetate=3:2) to obtain oily 2-ethyl-1-hydroxy-3-hexanone. The yield was 5.33 g (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.C(Cl)(=O)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.Cl.[OH-].[Na+]>>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: c1ccc2ncccc2c1
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 200 °C

Procedure:
7.51 Parts of 2,5-di(p-chloroanilino)terephthalic acid obtained in Example 13, 79 parts of nitrobenzene, 6 parts of benzoyl chloride and 1.65 parts of quinoline were charged into a 200-ml flask of stainless steel, and maintained at 200° C. for 5 hours. When the mixture was temperature-increased up to about 180° C., hydrochloric acid gas was generated and the intramolecular-dehydration reaction was initiated. The reaction mixture was cooled to 110° C., and then 2.27 parts of 30% sodium hydroxide was dropwise added to decompose an excess of benzoyl chloride. Then, the reaction mixture was filtered while it was hot, washed with methanol, washed with water and dried to give 6.37 parts (92.8% of the theoretical yield) of 2,9-dichloroquinacridone.
Reaction SMILES: [C:1]([C:3](=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31])[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=O)#[N:2].[CH3:33][NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([N:34]([CH3:33])[C:7](=[O:9])[CH2:6][CH2:5][CH:4]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]([C:1]#[N:2])=[CH:16][C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:18]=2[N+:30]([O-:32])=[O:31])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: N#CC(=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(CCC(=O)O)C1CCOCC1
Reactant: CNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C(=O)CCC(C(C#N)=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCOCC1)C1CCCCC1

Procedure:
A solution of 5-cyano-6-(2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (0.87 g, 2 mmol), N-methylcyclohexylamine (0.26 mL, 2 mmol), HBTU (1.13 g, 3 mmol), DIPEA (1.2 mL, 7 mmol) in DMF (20 mL) was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture. The solution washed with saturated aqueous NaHCO3 solution. The organic phase was separated and dried with MgSO4, and filtered. The solvent was removed in vacuo to yield the title compound as an oil.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.C(OC(Cl)=O)C(C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2([CH2:39][CH2:40][CH2:41][NH:42][CH3:43])[S:38][CH2:37][CH2:36][CH2:35][S:34]2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].ClCCCC1(C2C=CC(OC)=C(OC)C=2)SCCCS1.CN>O1CCCC1.C(N(CC)CC)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:8]=1[O:9][CH3:10])[CH2:2][CH2:1][N:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C:33]1([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)[S:38][CH2:37][CH2:36][CH2:35][S:34]1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CNCCCC1(c2ccc(OC)c(OC)c2)SCCCS1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: COc1ccc(C2(CCCCl)SCCCS2)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)CCCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 1 h

Procedure:
1 g of homoveratric acid is dissolved in 15 ml of absolute tetrahydrofuran and treated with 0.15 g of triethylamine. 0.72 g of chloroformic acid isobutyl ester are then slowly added dropwise at 0°-5° C. and the mixture is stirred for 1 hour at 5°-10° C. There is then added dropwise a solution of 1.63 g of 2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine [prepared in a manner analogous to that described in Example 15 from 2-(γ-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane and methylamine] in 5 ml of tetrahydrofuran. The resulting mixture is left to stand at room temperature overnight. After evaporation of the solvent, the residue is partitioned between 1-M hydrochloric acid and ether. The organic extracts are washed with 5% sodium carbonate solution and water. After drying over magnesium sulphate, the solvent is removed by evaporation. The oily residue (1.5 g) is dissolved in 15 ml of tetrahydrofuran and added dropwise to a suspension of 0.15 g of lithium aluminium hydride under reflux and under argon. The mixture is boiled for 2 hours and then treated slowly with a concentrated sodium sulphate solution in water and then with 10 ml of methylene chloride. The mixture is filtered under suction and then concentrated. The residue is chromatographed on silica gel and there is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine in the form of a thick oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:21]([O:20][C:18](=[O:19])[C:15]([CH3:17])([S:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:16])[CH3:22]
Reactant: CCOC(=O)C(C)(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)SC1CCNCC1
Yield: 105.6 %

Procedure:
Deprotection of 6.05 g (18.3 mmol) of 4-(1-ethoxycarbonyl-1-methyl-ethylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester is achieved by treatment with 4M aqueous HCl solution (9.13 mL) in 1,4-dioxane (40 mL) at room temperature for 18 h. The reaction mixture is concentrated to afford 4.47 g of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester as its hydrochloride salt as a brown oil. Yield: 92%; ES-MS: m/z 232 [M+H]
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[C:33](=[O:36])([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:4][C:5]#[C:6][CH2:7][N:9]2[CH2:14][CH2:33][O:36][CH2:11][CH2:10]2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (150 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (63 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (160 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine dihydrochloride (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([C:16](OCC)=[O:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([CH2:16][OH:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(I)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A solution of ethyl 1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6.5 g, 11.40 mmol) in anhydrous DCM (110 mL) was cooled to −55° C. and then DIBAL-H (22.80 mL, 22.80 mmol) (1M/toluene) was added dropwise in ˜20 min and the mixture was allowed to warm to 0° C. in 1 h and kept at 0° C. for 1 h. More DIBAL-H (12 mL, 12 mmol) was added and stirring at 0° C. continued for 1 h. The mixture was cooled to 0° C. and water (1.4 mL) was added slowly followed by 15% NaOH/water (1.4 mL) and water (3.5 mL). The mixture was stirred at RT for 15 min then filtered through a path of celite washing with dichloromethane. The filtrate was concentrated and co-evaporated with MeCN, dried in vacuo to provide (1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (5.0 g, 9.66 mmol, 85% yield) as an orange solid. 1H NMR and LCMS are consistent with proposed structure. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.80 (br s, 1 H), 2.83 (s, 3 H), 5.02 (d, J=2.15 Hz, 2 H), 5.40 (s, 2 H), 6.35 (d, J=3.51 Hz, 1 H), 6.92-7.12 (m, 3 H), 7.13 (d, J=3.51 Hz, 1 H); LCMS (m/z) ES+=415 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCCCN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCCNCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 120 h

Procedure:
To a solution of the aldehyde 6 (132 mg) in 3 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (300 mg), n-pentylamine (0.217 mL), and sodium triacetoxyborohydride (260 mg). After five days, the reaction was poured into EtOAc and washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the amine 7 as a brown oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:5]([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:2][CH2:3][CH3:4].[CH2:16]=[O:17].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>N1C=CC=CC=1>[C:14]([C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][OH:17])#[N:15]
Reactant: C=O
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold stirred solution of α-n-butyl-2,4-dichlorobenzylcyanide (5g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4g., 0.08 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 16 hours. The reaction mixture is poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6g. of a thick oil, which is identified by nmr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(N(C)C)=O.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].O1CCOCC1>[N:26]1([CH2:25][CH2:24][O:23][C:22]2[CH:21]=[C:20]([NH:18][C:16]3[N:17]=[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:14]4[N:15]=3)[CH:33]=[CH:32][CH:31]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: COc1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: Brc1cccc(OCCn2ccnc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cccc3nc(Nc4cccc(OCCn5ccnc5)c4)nn23)cc1
Temperature: 150 °C

Procedure:
In a microwave vial, 5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.05 g, 0.208 mmol), 1-[2-(3-bromo-phenoxy)-ethyl]-1H-imidazole (0.073 g, 0.27 mmol), bis(dibenzylideneacetone)palladium (0.01 g, 0.01 mmol), xantphos (0.012 g, 0.02 mmol) and sodium tert butoxide (0.04 g, 0.416 mmol) were added successively. 1,4-Dioxane (1.2 mL) and dimethylacetamide (4 drops) were added and the vial was sealed and heated in the microwave (150° C., 10 min). The mixture was filtered and purified by preparatory LCMS. LCMS method: 2, RT: 3.36 min; MI: 427 [M+1]. NMR 1H (DMSO): 3.85 (s, 3H), 4.18 (t, 2H), 4.36 (t, 2H), 6.42 (dd, 1H), 6.94 (s, 1H), 7.11-7.15 (m, 5H), 7.26 (s, 1H), 7.46-7.64 (m, 3H), 7.78 (s, 1H), 8.02 (d, 2H), 9.65 (s, 1H).