Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:10]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:92]([O:93][CH3:94])=[CH:91][C:68]3[C:69](=[O:90])[N:70]4[CH:76]=[C:75]([C:77]5[CH:82]=[CH:81][C:80]([N:83]6[CH2:88][CH2:87][N:86]([CH3:89])[CH2:85][CH2:84]6)=[CH:79][CH:78]=5)[CH2:74][C@H:71]4[CH:72]=[N:73][C:67]=3[CH:66]=2)=[CH:11][C:12]2[N:18]=[CH:17][C@@H:16]3[CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:57])[C@@H:30]([NH:32][C:33](=[O:56])[C@@H:34]([NH:38]C(=O)OCC5C6C=CC=CC=6C6C5=CC=CC=6)[CH:35]([CH3:37])[CH3:36])[CH3:31])=[CH:24][CH:23]=4)=[CH:21][N:15]3[C:14](=[O:58])[C:13]=2[CH:59]=1>CN(C=O)C.C(Cl)Cl>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][C@@H:30]([CH3:31])[C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH2:19][C@H:16]3[N:15]([CH:21]=2)[C:14](=[O:58])[C:13]2[CH:59]=[C:9]([O:8][CH3:7])[C:10]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]4[C:92]([O:93][CH3:94])=[CH:91][C:68]5[C:69](=[O:90])[N:70]6[CH:76]=[C:75]([C:77]7[CH:82]=[CH:81][C:80]([N:83]8[CH2:88][CH2:87][N:86]([CH3:89])[CH2:85][CH2:84]8)=[CH:79][CH:78]=7)[CH2:74][C@@H:71]6[CH:72]=[N:73][C:67]=5[CH:66]=4)=[CH:11][C:12]=2[N:18]=[CH:17]3)=[CH:27][CH:26]=1)=[O:57])=[O:56]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC4c5ccccc5-c5ccccc54)C(C)C)cc3)=CN1C2=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@@H]1C=N3)N=C[C@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Excess piperidine was added (0.1 mL, 1 mmol) to a solution of PBD 26 (36.4 mg, 0.03 mmol) in DMF (0.9 mL). The mixture was allowed to stir at room temperature for 20 min, at which point the reaction had gone to completion (as monitored by LC/MS). The reaction mixture was diluted with CH2Cl2 (50 mL) and the organic phase was washed with H2O (3×50 mL) until complete piperidine removal. The organic phase was dried over MgSO4, filtered and excess solvent removed by rotary evaporation under reduced pressure to afford crude product 27 which was used as such in the next step. LC/MS 2.20 min (ES+) m/z (relative intensity) 964 ([M+H]+, 5%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:32][Li]>C1COCC1.C(OCC)C>[OH:3][C:1]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)([CH3:32])[CH3:2]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)=O)c1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (−78°) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-acetyl-pyridin-4-yl)-propyl]-amide (32 mg, 0.08 mmol) in anhydrous THF (2 mL) was added a solution of 1.6 N methyl lithium (0.29 mL, 0.46 mmol) in diethyl ether. The reaction mixture was slowly warmed to room temperature. After 18 hours, the mixture was cooled to −78° C., quenched with saturated aqueous ammonium chloride and extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 μM 30×150 mm column) using a gradient of 15-65% acetonitrile in water with 0.1% TFA. Fractions from the chromatography were concentrated, made basic by saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The solid was triturated with EtOAc-hexanes to afford the title.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>C1COCC1.O1CCOCC1>[ClH:37].[ClH:37].[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:16]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate (4 g, 7.87 mmol) in 20 mL of THF was added 20 mL of 4 N HCl in dioxane. After being stirred at room temperature for 1 hour, the solvents were removed in vacuo to give 3.9 g (99%) of the desired product {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride, which was used for the next reaction. LC-MS: [M+H]+=409.3.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][OH:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:53].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([OH:53])=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1j (0.36 g, 0.51 mmol, obtained from the synthetic method described in step 9 of example 1) in tetrahydrofuran (7 mL) were added saturated aqueous sodium bicarbonate (7.4 mL), potassium bromide (12 mg, 0.10 mmol) and 2,2,6,6-tetramethylpiperidinooxy (8 mg, 0.05 mmol) in turn at 0° C., and then sodium hypochlorite (6.7 mL, available chlorine ≧5.5%) was added dropwise over a period of 10 min. The mixture was stirred at 0° C. for 2 hours and acidified with aqueous HCl(1N) till pH becomes 4. The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 2a (0.38 g, 100%) as yellow oil. The crude product was used in next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.92 (s, 1H), 7.52 (s, 1H), 7.45 (dd, 2H), 7.30 (dd, 10H), 7.19 (t, 3H), 7.05 (d, 2H), 6.82 (d, 2H), 6.75 (d, 2H), 4.75 (m, 3H), 4.68 (d, 1H), 4.36 (d, 1H), 4.29 (d, 1H), 4.09 (d, 1H), 4.02 (m, 3H), 3.93 (m, 2H), 3.89-3.82 (m, 2H), 3.76 (d, 1H), 1.28 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([NH:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:17])[F:1])(=[O:27])[CH3:26]
Reactant: NNC(=O)CCCCCCCCCC=C(F)F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)NNC(=O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A solution of 0.5 gram (0.002 mole) of 12,12-difluoro-11-dodecenoic acid hydrazide and 0.3 gram (0.003 mole) of triethylamine in 20 ml of diethyl ether was stirred, and 0.2 gram (0.003 mole) of acetyl chloride was added. The reaction mixture was stirred at ambient temperature for 30 minutes and was filtered. The filtrate was in turn washed with aqueous 10% hydrochloric acid, aqueous 10% sodium hydroxide, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 0.4 gram of 12,12-difluoro-11-dodecenoic acid 2-acetylhydrazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.O>ClCCl>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -5 °C
Yield: 61.4 %

Procedure:
Dichloromethane (50 mL) and then triethylamine (11.2 mL, 79.6 mmol, 2.0 eq) were added to glycine methyl ester hydrochloride (5.0 g, 39.8 mmol, 1.0 eq). The mixture was stirred and cooled to −5° C. using an ice/methanol bath. A suspension of biphenyl-4-carbonyl chloride (8.26 g, 39.8 mmol, 1.0 eq) in dichloromethane (25 mL) was added over 22 minutes. The mixture was stirred for 3 hours at −5° C., and then left to stir at room temperature overnight (16 hours). Water (75 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with water (75 mL), then evaporated to dryness using a rotary evaporator to give an off-white solid (6.58 g, 62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.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>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
A suspension of Example A1 (0.125 g, 0.497 mmol), Pd(PPh3)4 (0.029 g, 0.025 mmol), K2CO3 (0.275 g, 1.987 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid (0.104 g, 0.546 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and EtOAc and the solids were removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-((6-nitropyridin-3-yl)oxy)-2′-(trifluoromethyl)-2,4′-bipyridine (139 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=5.2 Hz, 1H), 8.78 (m, 1H), 8.64 (m, 1H), 8.53 (s, 1H), 8.44-8.38 (m, 2H), 8.17 (d, J=2.3 Hz, 1H), 8.03 (m, 1H), 7.36 (dd, J=5.5, 2.3 Hz, 1H); MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(CCCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL flask was placed 1-methyl-piperazine (0.52 g, 5.1 mmol), 4-bromobutyronitrile (0.78 g, 5.3 mmol) and potassium carbonate (0.71 g, 5.3 mmol) suspended in acetonitrile (5 mL). The reaction mixture was stirred at rt for 4 h., followed by addition of H2O (20 mL) and extraction with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO4) and evaporated to dryness to produce 0.72 g of crude 14 which was used without further purification in the synthesis of compound 15.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=4)=[C:18]([Cl:34])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:35][S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:34][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:40](=[O:41])[CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg), 1-hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1) and crystallization from ethanol-ethyl acetate-diisopropyl ether to give the title compound (112 mg) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH2:6][C:5]([CH2:20][CH:19]=[CH2:18])([C:12]([O:14][CH3:15])=[O:13])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl 6-fluorochromane-4-carboxylate (2.1 g) in anhydrous N,N-dimethylformamide was added to a suspension of sodium hydride (265 mg) in anhydrous N,N-dimethylformamide under nitrogen. After gas evolution ceased, the mixture was cooled to 0° C., and neat allyl bromide (0.95 mL) was added. After 1 hour, 20 mL of an aqueous saturated ammonium chloride solution was added, and the mixture extracted with ethyl acetate, the extracts washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as a colorless oil, 2.4 g. (HRMS calc'd 250.1004; found 250.1002).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=[C:15]([C:22](O)=[O:23])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[CH3:54][C:55]([NH2:58])([CH3:57])[CH3:56].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[C:55]([NH:58][C:22]([C:15]1[N:14]=[C:13]([C:11]2[CH:10]=[N:9][N:8]([CH:4]([CH:5]3[CH2:6][CH2:7]3)[CH2:3][C:1]#[N:2])[CH:12]=2)[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=1)=[O:23])([CH3:57])([CH3:56])[CH3:54]
Reactant: N#CCC(C1CC1)n1cc(-c2nc(C(=O)O)cc3nccn23)cn1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cc2nccn2c(-c2cnn(C(CC#N)C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
In a 2 mL flask, 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid (6.5 mg, 0.020 mmol) and HATU (9.2 mg, 0.024 mmol) were dissolved in DMF (101 μL, 0.020 mmol). After 5 minutes, 2-methylpropan-2-amine (4.4 mg, 0.061 mmol) and diisopropylethylamine (11 μL, 0.061 mmol) were added and the reaction mixture stirred at ambient temperature for 45 minutes. The reaction mixture was diluted in EtOAc and washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC using a gradient of 40-100% acetonitrile/water to afford N-tert-butyl-5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxamide (1.0 mg, 0.0026 mmol, 13% yield). MS (apci) m/z=378.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2cc(O)ccc2c1
Temperature: 70 °C

Procedure:
To a mixture of 6-bromonaphthalen-2-ol (3.8 g, 17.04 mmol), ethynyltrimethylsilane (7.08 ml, 51.1 mmol), (PPh3)2PdCl2 (1.79 g, 2.56 mmol), TEA (12 ml, 85 mmol) in THF (12 ml) was added copper(I) iodide (0.324 g, 1.70 mmol). The resulting mixture was heated at 70° C. in oil bath overnight and cooled. To the mixture was added silica gel (40 g) and the resulting mixture was dried on vacuum. The gel powder was loaded on a silica gel column, eluted with DCM to provide compound 110A.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:16][CH:15]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2ccccn2)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To 4-(pyridin-2-yloxy)benzoic acid (20 g, 92.9 mmol) in tetrahydrofuran (300 ml) was added N,N′-carbonyldiimidazole (16.6 g, 102 mmol), and the mixture was heated under reflux for 1 hr. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (21 g, 51.2 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective substance (20.6 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCc2ccccc2)cc1
Reaction time: 10 h
Yield: 50.4 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde is mixed with 35 ml of dimethylformamide, 16.9 g of (2-chloroethyl)benzene and 16.6 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 80°-90° C. for 10 hours and then cooled. The cooled mixture is added to 500 ml of water and then extracted with 500 ml of chloroform. The extract is washed with water until it becomes neutral. The washed extract is dried with anhydrous sodium sulfate and then chloroform is distilled away. The resulting residue is distilled under reduced pressure to obtain 11.4 g of 4-phenethyloxybenzaldehyde. Thus obtained 4-phenethyloxybenzaldehyde has a boiling point of 173°-181° C./2-3 mmHg.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:16])=O>>[Cl:16][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Product: FC1(F)Oc2ccc(CCl)cc2O1
Yield: 89 %

Procedure:
A solution of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (120 g, 0.64 mol) in neat thionyl chloride (500 mL) was stirred for 2 h at 25° C. The excess thionyl chloride was distilled off in vacuo. The residue was partitioned between saturated NaHCO3 (400 mL) and dichloromethane (200 mL). The separated aqueous layer was extracted with dichloromethane (300 mL×3). The combined organic layers were dried, filtered and concentrated in vacuo to give 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole (117.6 g, 89%), which was directly used in the next step.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.CO.O>C1OC1CC>[F:37][C:38]1[CH:45]=[CH:44][C:41](/[CH:42]=[C:15](/[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]3([CH3:13])[CH3:14])\[CH3:16])=[CH:40][CH:39]=1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CCC1CO1
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C/C(=C\c1ccc(F)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 53.9 %

Procedure:
45 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide are suspended in 200 ml of 1,2-butylene oxide. After the addition of 8 g of 4-fluorobenzaldehyde the mixture is boiled at reflux for 16 hours. After cooling the clear, yellowish solution is poured into 1 l of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three times with water and, after drying over sodium sulphate, evaporated. The crystalline residue can be recrystallized from hexane and gives 11.2 g of (E)-6-(p-fluoro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 99°-101°.