Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:10]=2[N:11]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A suspension of 6-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g; prepared according to WO 01/30782) in DMF (40 mL) was treated with 4-methoxybenzyl chloride (1.18 mL) and Cs2CO3 (8.5 g) and stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org. layer was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with Hept, affording a beige solid (2.8 g, 92% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:17][C:14]1([F:18])[CH2:15][CH2:16][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12][CH2:13]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCC(F)(F)CC2)C3)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
In a 20 mL vial was placed 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-one (35 mg, 0.111 mmol), 3-cyanobenzeneboronic acid (23 mg, 0.157 mmol), PdCl2(PPh3)2 (8 mg, 0.011 mmol) and cesium carbonate (91 mg, 0.279 mmol). This solid mixture was dissolved in a Dioxane/water mixture (1.1 mL, 6:1 ratio, respectively). The reaction vial was capped and allowed to stir at 90° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (5 mL) and water (5 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (3 mL/each). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4,4-difluoro-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (30 mg, 0.089 mmol, 80% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][OH:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCC(O)=O.[Br:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>>[CH2:1]([O:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][O:26][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Br:37])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCCCCCBr
Reactant: C=C(CO)COC(=O)OCCCCCCCCCCCCCCCCCC
Agent: O=C(O)CCCCCBr
Product: C=C(COC(=O)CCCCCCBr)COC(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-octadecyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoic acid with 7-bromoheptanoic acid, the desired product was obtained.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:30][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:31](Cl)(=O)[CH2:32][CH2:33][CH3:34]>>[CH3:29][S:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][CH:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:31]([CH2:32][CH2:33][CH3:34])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:30][C:14]3=[CH:15][N:16]=2)=[CH:20][CH:21]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from N-hydroxy-4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.52 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1
Reaction time: 8 h

Procedure:
A mixture of (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (144.8 mg, 0.478 mmol), 2-amino-6-chloropurine (89.1 mg, 0.525 mmol) and N,N-diiso-propylethylamine, redestilled, 99.5% (0.166 mL, 0.955 mmol) in 1-butanol, anhydrous, 99.8% (5.24 mL) was heated to reflux and stirred overnight. The reaction was cooled solvents removed and subjected to chromatography, 89:9:1(DCM/MeOH,NH4OH)gradient,
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][C:14]2([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:15]2)=[C:10]([O:30][CH3:31])[CH:9]=1)(=[O:7])[CH3:6]>CC(OC(C)=O)=O>[C:5]([C:8]1[C:29]([N+:1]([O-:4])=[O:2])=[CH:28][C:11]([O:12][CH2:13][C:14]2([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:15]2)=[C:10]([O:30][CH3:31])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1cc(C(C)=O)ccc1OCC1(NC(=O)OCc2ccccc2)CC1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of HNO3 (65%, 3 mL) in Ac2O (2 mL) at 0° C. was slowly added with a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in Ac2O (3 mL). After stirring at 0° C. for 2 h, the reaction mixture was poured into 50 mL of ice/water and the precipitate was recovered by filtration. The resulting yellow solid was recrystallized with 95% EtOH (5 mL) to give 1-[(4-acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (0.69 g, yield: 56%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-][C:57]#N.[Na+]>CC#N.CC(O)=O.C=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C@H:10]([N:31]([CH3:57])[CH2:32][CH2:33][NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)NCCN[C@@H]1CN(Cc2ccccc2)C[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)NCCN(C)[C@@H]1CN(Cc2ccccc2)C[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-{[(3R,4R)-1-benzyl-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]amino}ethyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (see Example 1, Step 12) (200 mg, 0.259 mmol) was dissolved in 20:1 MeCN—AcOH (3.5 mL) and 37% aqueous formaldehyde was added (0.68 mL) following by addition of NaBH3CN (49 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours and quenched with water (50 mL). The mixture was extracted with CHCl3, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was passed through silica gel layer eluting with 1% MeOH in CHCl3. The solvent was evaporated giving the desired compound. LC-MS APCI: m/z 785.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CCCNCCC
Reactant: O=C1CCc2cccc(Br)c2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1=Cc2c(Br)cccc2CC1

Procedure:
To a solution of 8-bromo-2-tetralone (3.0 gm, 13.3 mMol) in toluene (25 mL) were added di-n-propylamine (3.5 mL, 26 mMol) and p-toluenesulfonic acid (100 mg, 0.52 mMol). The reaction was heated to reflux, water being collected in a Dean-Stark trap. After four hours the reaction was concentrated in vacuo to give 8-bromo2-dipropylamino-3,4-dihydronaphthalene as a dark liquid which was immediately dissolved in methanol (50 mL) and acetic acid (5 mL). To this solution was then added sodium borohydride (2.0 gm, 52.9 mMol), and the mixture was stirred 18 hours at room temperature.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])[CH3:17]>C(OCC)C.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:24]2([OH:27])[CH2:23][CH2:22][N:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:26][CH2:25]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
A solution of 16.55 g (60.85 mmol) 1,4-dibromo-2,5-difluorobenzene in 400 ml of ethyl ether stirred at -75° C. under an argon atmosphere was treated dropwise with 24.3 ml of 2.5 M n-butyl lithium in hexane. The mixture was let warm to -50° C. and treated dropwise with a solution of 11.00 g (64.33 mmol) 1-ethoxycarbonyl-4-piperidone in 100 ml ethyl ether. After stirring a further 0.25 hour, the mixture was let warm to room temperature and extracted with ammonium chloride solution. The organic layer was dried (MgSO4), evaporated and the crude product chromatographed on a silica gel column and crystallized from toluene hexane to afford the title compound, mp 133°-136° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](/[C:52]1[CH:57]=[N:56][CH:55]=[CH:54][N:53]=1)=[N:50]\[H].ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:13]1([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:50]=[C:49]([C:52]4[CH:57]=[N:56][CH:55]=[CH:54][N:53]=4)[N:48]=3)[C:2]2=[O:1])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H]/N=C(\NO)c1cnccn1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cnccn3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxypyrazine-2-carboximidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.15 (d, J=1.4, 1H), 8.87 (dt, J=2.0, 2.5, 2H), 7.40-7.21 (m, 10H), 5.01 (s, 2H), 3.54 (t, J=6.5, 2H), 2.84 (t, J=6.5, 2H); MS (DCI) m/z 398.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[N:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C1(OC)CCCC1>>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:19][C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(Br)cc1N
Reactant: N#CN1CCOCC1
Agent: Cl
Solvent: COC1CCCC1
Product: O=c1[nH]c(N2CCOCC2)nc2cc(Br)sc12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (200 mg) produced in Example 1, step C, morpholine-4-carbonitrile (0.17 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (3.0 mL) was stirred at 110° C. for 4 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1) to give the title compound (144 mg) as a pale-yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>[Pd].CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:10]([C:11]([CH3:13])=[O:12])[C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Pd]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccnc1)C(C)=O
Reaction time: 22 h

Procedure:
A mixture of pyridine-3-carboxaldehyde (48 g), ethyl acetoacetate (52 g) aqueous piperidine acetate (40% 4.8 g) and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was hydrogenated at 100 p.s.i. at 30° for 22 hours. The mixture was diluted with ether, filtered and the filtrate was evaporated and distilled under reduced pressure to give ethyl α-(3-pyridylmethyl)acetoacetate (b.p. 146°/1 mmHg). This ester was refluxed with thiourea and sodium ethoxide in ethanol, and the mixture was subsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328°-331°.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O>[CH:17]1([C:2]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)nc1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Oc2ccc(C3CC3)cc2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of the compound (3.22 g) obtained in step (1) above, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.89 g), tetrakis(triphenylphosphine)palladium(0) (669 mg), cesium carbonate (11.3 g), toluene (20.0 mL) and water (10.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, the precipitate was removed by filtration through Celite (registered trademark). To the filtrate, water and ethyl acetate were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) and further purified by preparative HPLC. A saturated aqueous solution of sodium hydrogencarbonate was then added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure to give the titled compound as a colorless oil (614 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)C.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N12CCCC=C1CCCCN2>C1(C)C=CC=CC=1>[CH2:25]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCCCCCCI
Agent: C1=C2CCCCNN2CCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1cnc(-c2ccc(CCCCCCCC)cc2)nc1
Yield: 70 %

Procedure:
To 5-hydroxy-2-(4-octylphenyl)pyrimidine (5 g, 0.018 mol) were added ethanol (50 ml), octyl iodide (12.6 g, 0.053 mol) and diazabicyclo[5.4.0]undec-7-ene (0.053 mol), followed by refluxing the mixture for 4 hours, dissolving the reaction mixture in toluene, sufficiently washing the solution with 2N-NaOH aqueous solution, further washing it with water, distilling off toluene and recrystallizing the residue from methanol (75 ml) to obtain 5-octyloxy-2-(4-octylphenyl)pyrimidine (5 g). This product exhibited liquid crystalline properties and its phase transition points were as follows: ##STR19##
Reaction SMILES: COC1C=CC([CH:9]2[C:14]3[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[O:17][C:13]=3[CH:12]=[CH:11][N:10]2[CH3:22])=CC=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:17][C:16]1[CH:18]=[CH:19][C:20]([C@@:13]23[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[C@@H:14]2[CH2:9][N:10]([CH3:22])[CH2:11][CH2:12]3)=[CH:21][CH:15]=1
Reactant: COc1ccc(C2c3c(oc4ccccc34)C=CN2C)cc1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CN1CC[C@]2(c3ccc(O)cc3)Oc3ccccc3[C@@H]2C1
Yield: 84.2 %

Procedure:
A mixture of 3.46 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(4-methoxyphenyl-2-methyl-benzofuro[3,2-c]pyridine and 3.57 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated under a drying tube at 140° for 41/2 hours. The reaction mixture was diluted with 350 ml of water, and the pH was adjusted to 7 by slow addition of 2N HCl with stirring. As the pH reached neutral, the product precipitated out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was filtered, washed with water and then with a small amount of ether, and dried to give 2.77 g (84.2%) of crystalline solid, m.p. s 209°, 215°-217°. Recrystallization from ethanol afforded 2.33 g (70.8%) of crystals, m.p. s 215°, 222°-224°.
Reaction SMILES: CC(N=NC(C#N)(C)C)([C:4]#[N:5])C.C1C(=O)N(Br)C(=O)C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:48])=[CH:24][CH:23]=1.CN>C(Cl)(Cl)(Cl)Cl.CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[C:47](=[O:48])[NH:5][CH3:4])=[CH:26][CH:27]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Agent: CN
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)OC)c3)cc12
Reaction time: 0.5 h
Yield: 210.7 %

Procedure:
AIBN (4.6 mg, 0.028 mmol) and NBS (21.6 mg, 0.121 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (35 mg, 0.093 mmol) in CCl4 (5 mL) at 95° C. It was allowed to stir for 30 min and then allowed to cool and was then treated with methanamine (0.466 mL, 0.932 mmol, 2M in THF) and the reaction was allowed to stir for 10 min then diluted with MeOH. A ppt formed which was filtered away and the filtrate was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=320 nm) to give to give the expected product methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol, 64% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.60 (1H, d, J=2.14 Hz), 8.44 (1H, d, J=2.44 Hz), 8.32 (1H, s), 8.10 (1H, d, J=7.93 Hz), 7.95-8.00 (2H, m), 7.84 (1H, d, J=7.63 Hz), 7.59 (1H, t, J=7.78 Hz), 7.22-7.26 (2H, m), 5.91 (1H, br. s.), 3.98 (3H, s), 3.03 (3H, d, J=4.88 Hz). LC-MS retention time: 1.46 min; m/z (MH+): 405. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](Br)[CH:23]=[CH:24][CH:25]=1>C(Cl)Cl>[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccc(C(F)(F)F)c1)O2

Procedure:
This compound was similarly prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-trifluoromethylbromobenzene as described in Example 26. The product was isolated by chromatography over 50 fold amount of silica gel using methylene chloride for elution. Crystallization of the combined clean fractions from petroleum ether gave colorless crystals with m.p. 81°-83°.