Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH3:22])[C:15]=1[CH:23]1[C:28](=[O:29])[CH2:27][CH:26]([CH2:30][CH:31]([S:33][CH2:34][CH3:35])[CH3:32])[CH2:25][C:24]1=[O:36])[CH3:13]>ClCCl>[CH2:21]([C:16]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH2:12][CH3:13])[C:15]=1[CH:23]1[C:24](=[O:36])[CH2:25][CH:26]([CH2:30][CH:31]([S:33]([CH2:34][CH3:35])=[O:6])[CH3:32])[CH2:27][C:28]1=[O:29])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC(C)CC1CC(=O)C(c2c(CC)cc(C)cc2CC)C(=O)C1
Solvent: ClCCl
Product: CCc1cc(C)cc(CC)c1C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 70% 3-chloroperoxybenzoic acid (0.104 g, 0.42 mmol) in dichloromethane (2 ml) is added dropwise to a solution of 2-(2,6-diethyl-4-methylphenyl)-5-[2-(ethylthio)propyl]cyclo-hexane-1,3-dione (0.17 g, 0.47 mmol) in dichloromethane (3 ml) at 0° C. and the reaction mixture is stirred for 1 hour at 0° C. and then left to stand at room temperature overnight. The reaction mixture is diluted with dichloromethane, washed with 15% aqueous sodium metabisulfite solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(2,6-diethyl-4-methylphenyl)-5-[2-(ethylsulfinyl)propyl]cyclohexane-1,3-dione, m.p. 58-61° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH3:18]>C1CCCCC1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:23])[CH3:18]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine and 2,2-dimethyl-malonic acid monoethyl ester (Holmes et al., J. Amer Chem. Soc. 1984, 106, 2353). Yield after flash-chromatography with cyclohexane/ethyl acetate 7:3: 79%. Colorless oil. MS: m/e=359 (M+).
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2N)=[CH:11][CH:10]=1>C(O)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:7]=[C:2]2[CH3:3])=[CH:11][CH:10]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccccc1Nc1ccc(I)cc1
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetimidate hydrochloride (6.757 g, 54.9 mmol) was added to a suspension of N-(4-iodophenyl)-1,2-diaminobenzene (6.812 g, 22.0 mmol) in absolute ethanol (30 ml) at room temperature. After 2 hours, 50 ml of ice cold 2N aqueous sodium hydroxide was added and the product was extracted into ethyl acetate (2×100 ml). The extracts were washed with.water (3×100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1-(4-iodophenyl)-2-methylbenzimidazole, 6.695 g as a white solid, m.p. 136°-7° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Temperature: 50 °C
Yield: 18.5 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.346 g, 3.83 mmol) was heated with anhydrous potassium carbonate (2.118 g, 15.33 mmol) in dry DMF (17 ml) at 60° C. for 1 hour. Phenylmethyl 2-(2-bromoethyl)-1-piperidinecarboxylate (1.500 g, 4.60 mmol) was added and the reaction mixture heated at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 ml) and ethyl acetate (150 ml). The aqueous was further extracted with 2×100 ml ethyl acetate. The combined organic layers were washed with 100 ml brine and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator). The residue was dissolved in DCM and loaded onto a 70 g silica cartridge and purified by chromatography using a gradient 0-100% ethyl acetate in dichloromethane+0-12% MeOH finish on a Flashmaster 2. Appropriate fractions were combined and evaporated in vacuo. The material was re-purified by chromatography on silica (70 g cartridge using a gradient of 0-100% ethyl acetate in dichloromethane over 40 mins. and subsequently a flush of 0-100% ethyl acetate in DCM+0-20% MeOH). Product fractions combined and evaporated in vacuo to give the title compound as a colourless oil (0.342 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:45])([O:28][C:29]([F:44])([F:43])[C:30]([F:42])([F:41])[O:31][C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br)[C:24]([F:27])([F:26])[F:25].BrCCCBr.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:41])([F:42])[C:29]([F:43])([F:44])[O:28][C:23]([F:22])([F:45])[C:24]([F:26])([F:27])[F:25])([F:40])[F:39])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 7.3 mmol), 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (3.38 g, 7.47 mmol; prepared by combining 1,3-dibromopropane with 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol), and potassium carbonate (1.16 g, 8.43 mmol) in acetonitrile (20 mL) and refluxing the resulting mixture under nitrogen overnight. The mixture was cooled and filtered, and the resulting solids were washed with toluene (50 mL). The toluene was then removed under reduced pressure, and the resulting waxy solid was dissolved in toluene (50 mL) and washed with three 30 mL aliquots of perfluorohexane. After removing the toluene under reduced pressure, the resulting crude product was further purified by silica gel chromatography, eluting with 20 volume percent ethyl acetate/hexane, to yield 3.60 g of purified product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][O:24][C:25]12[CH2:32][CH2:31][C:28]([NH2:33])([CH2:29][CH2:30]1)[CH2:27][CH2:26]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:33][C:28]34[CH2:31][CH2:32][C:25]([O:24][CH3:23])([CH2:26][CH2:27]3)[CH2:30][CH2:29]4)[N:10]=2)[CH2:3]1
Reactant: COC12CCC(N)(CC1)CC2
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC12CCC(Nc3ncc(C(N)=O)c(N[C@@H]4CCC[C@H](O)C4)n3)(CC1)CC2
Temperature: 130 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
To a solution of 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (1.2 g, 3.8 mmol; synthesis described herein) and 4-methoxybicyclo[2.2.2]octan-1-amine hydrochloride (600 mg, 3.1 mmol) in NMP (12 mL) was added DIEA (1.03 g, 8 mmol). The resulting mixture was stirred at 130° C. under microwave irradiation for 3 h. The resulting mixture was purified by reverse phase column chromatography to give the desired product (230 mg, 0.6 mmol, 15.5% yield). 1H-NMR (400 MHz, CDCl3) δ ppm 8.70 (brs, 1H), 8.08 (s, 1H), 5.40 (brs, 2H), 5.01 (br. s, 1H), 3.99-3.96 (m, 1H), 3.75-3.70 (m, 1H), 3.19 (s, 3H), 2.37-2.34 (m, 1H), 2.15-2.11 (m, 6H), 1.99-1.97 (m, 2H), 1.90-1.86 (m, 1H), 1.80-1.76 (m, 6H), 1.38-1.22 (m, 4H). MS (ESI) m/z=390.2[M+1]+.
Reaction SMILES: [N:1]#CBr.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.[CH3:17][N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4>C(=O)(O)[O-].[Na+]>[C:17]([N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4)#[N:1]
Reactant: N#CBr
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 6.81 g of cyanogen bromide, 4.7 ml of diisopropylethylamine, and 142 ml of chloroform was added, at room temperature with stirring, a solution of 13.7 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 414 ml of chloroform. The mixture was heated at reflux for 2.6 hr, cooled to room temperature, diluted with aqueous sodium bicarbonate solution, and the layers were separated. The organic layer was washed with sodium bicarbonate solution. The combined aqueous layers were extracted with ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, and filtered. Concentration of the filtrate followed by purification by flash chromatography (silica gel, 2% triethylamine/ethyl acetate) afforded 13.5 g (95%) of 3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.CC([O-])(C)C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([O:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and cyclopropylmethanol (970 uL, 12 mmol) in THF (50 ml) was treated with KOtBu (3.3 g, 15 mmol). After stirring at rt for 12 h, the mixture was treated with water (150 ml) and extracted with EtOAc (3×50 ml); the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (1.3 g, 48%) as a yellow solid. LCMS (M+H)+=274.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:24]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:34][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][N:29]=4)[N:24]=[CH:25][CH:26]=3)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)Cl)cc2)[C@H]1c1ccccc1
Reactant: Nc1ccnc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3ccnc4cccnc34)cc2)[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a vessel charged with (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoyl chloride (50 mg, 0.152 mmol) were added DCM (606 μL), 1,5-naphthyridin-4-amine (commercially available from Astatech Inc., Bristol, Pa.) (24 mg, 0.167 mmol), and DIEA (55.6 μL, 0.318 mmol) respectively. The vessel was sealed and shaken overnight at 40° C. The mixture was dried under reduced pressure and purified using a 25 g, 15 m spherical silica column (Interchim) ramping 0-100% EtOAc in heptane from 0-100% to elute product, which was lyophilized from MeOH/H2O to yield (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N-(1,5-naphthyridin-4-yl)benzamide (64 mg, 96%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.63 (s, 1H), 9.01 (dd, J=1.6, 4.2 Hz, 1H), 8.93 (d, J=5.0 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.46 (dd, J=1.6, 8.5 Hz, 1H), 8.01-7.96 (m, 2H), 7.89 (dd, J=4.3, 8.6 Hz, 1H), 7.76-7.70 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.22 (m, 3H), 5.57 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 439.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].C(Cl)Cl.[Cl-].[NH4+]>C(N(CC)CC)C.[Cu](I)I>[CH3:27][Si:26]([C:24]#[C:25][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3)([CH3:29])[CH3:28]
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(Br)cnc12
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-{[1-bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 2 (100 mg, 0.26 mmol), ethynyltrimethylsilane (81 μL, 0.57 mmol) and copper iodide (5 mg, 0.026 mmol) in anhydrous triethylamine (3.5 mL) degassed under argon for 10 minutes was added Pd(dppf)Cl2.DCM (11 mg, 0.013 mmol). The mixture was stirred at 90° C. for 1 h45 and then allowed to cool to room temperature, poured onto a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate/tetrahydrofuran (1:1). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 20/1) to afford the title compound (80 mg, 75%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 57, step C) (5.0 g, 11.6 mmol), methane sulfonyl chloride (1.4 mL, 17.5 mmol) and DCM (200 mL) was added TEA (80.1 mL, 58.2 mmol). The reaction was stirred at rt and monitored by TLC. After complete consumption of the starting material the clear yellow solution was concentrated onto silica gel and purified by chromatography to afford the title compound of step A as a yellow solid (3.54 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.2, 2.6 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.09-4.00 (m, 2H), 3.89 (s, 3H), 3.10-3.03 (m, 4H), 2.99-2.90 (m, 2H), 2.84 (s, 3H), 2.61-2.52 (m, 5H), 1.85-1.77 (m, 2H), 1.50-1.37 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:22][OH:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[CH2:29]([O:23][CH2:22][C:7]1[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]=1[CH:24]([CH3:25])[CH3:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COCc2ccccc2)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
4.5 g (12.5 mmol) of the compound from Example 4 in 50 ml of dimethylformamide are added dropwise under nitrogen to a suspension of 414 mg (13.8 mmol) of 80% strength sodium hydride in 20 ml of dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at the same temperature. Subsequently, 1.65 ml (13.8 mmol) of benzyl bromide in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for a further 3 h at room temperature. The mixture is poured into 300 ml of water at 0° C. and extracted three times using 150 ml of ether each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 1:10).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1>C(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[C:23]2=[N+:24]([O-:9])[CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mCPBA (1.239 g, 5.53 mmol) was added to the CH2Cl2 (30 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (2.17 g, 5.03 mmol) at rt. The reaction was stirred at room temperature overnight. The solvent was removed via vacuum. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 85%. The product was obtained by flushing the column with 85% ethyl acetate in hexane (1.572 g, 69%). MS (ESI)[M+H+]=448.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (br. s., 1H) 6.94-7.11 (m, 2H) 6.84-6.92 (m, 2H) 6.66-6.72 (m, 1H) 6.42 (t, J=4.28 Hz, 1H) 4.04 (dd, J=14.73, 4.41 Hz, 1H) 3.73-3.88 (m, 1H) 2.96 (dd, J=14.48, 5.41 Hz, 1H) 2.50 (d, J=5.79 Hz, 1H) 2.13-2.25 (m, 2H) 1.80-1.94 (m, 1H) 1.18-1.32 (m, 3H) 1.09 (d, J=7.55 Hz, 9H) 1.00 (d, J=7.55 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:22]N1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@:14]3([CH3:22])[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Reactant: CN1CCCN(C)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@@]3(C)C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of compound 23G (600 mg, 1.96 mmol) in anhydrous THF (10 mL) at rt was added DMPU (4 mL). The resulting clear solution was cooled to −78° C., then a 2.0 M solution of LDA in THF (1.96 mL, 3.92 mmol) was added slowly so that the reaction temperature was maintained below −72° C. The resulting dark brown solution was stirred at −78° C. for 30 min, then iodomethane (0.36 mL, 3.92 mmol) was added dropwise. After addition, the reaction was stirred at −78° C. for 30 min, then at 0° C. for 3 h. The reaction was quenched with 5% aqueous KHSO4 and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 1% MeOH in EtOAc/CH2Cl2 (1:9) to give a mixture of compound 25 and compound 26 (150 mg), which was further purified using preparative HPLC to afford the title compound (20 mg). HPLC: 99% at 4.40, 5.20 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=7.9 min (99%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 320 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:12][C:11]1[C:13]([O:14][CH3:15])=[CH:16][C:6]([CH:5]=[O:17])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
1,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C[O:15][CH2:16][CH2:17]OC>[Cu].C(N(CC)CC)C>[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]([CH2:1][CH3:2])[C:12]([O:15][CH2:16][CH3:17])=[O:13])[CH3:10]
Reactant: COCCOC
Reactant: CCN=C=O
Agent: [Cu]
Agent: OCC#CC#CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC)CC
Yield: 95 %

Procedure:
The monomer 2,4-hexadiyne-1,6-diol-bis-ethylurethane is synthesized in 95% yield by the reaction of 11.0 gm (0.10 mole) 2,4-hexadiyne-1,6-diol with 26.5 gm (0.37 mole) ethyl isocyanate in the presence of 1,2-dimethoxyethane (50 ml), dibutyl-tin-2-ethylhexoate (0.1 gm), and triethylamine (2 ml). The monomer is recrystallized as approximately 3 cm long needles by the slow cooling of a 10:90 acetone/petroleum ether solution (75ml) containing 0.2 gm sample, as described in Example 4. These crystals rapidly turn pink upon exposure to light. Polymerization proceeded quantitatively by 60 Co α -ray irradiation at a dose rate of 1 Mrad/hr and a total dosage of 60 Mrad. The resulting polymer fibers are copper-like in appearance and strongly dichroic, with dichroic axis in the fiber axis direction. The polymer fibers are monoclinic monocrystals in which the polymer chain axis, with repeat length 4.9 A, is in a non-unique axis direction. The polymer fibers are annealed as described in Examples 4 and 5, in order to obtain reversible thermal-dimensional behavior. The annealed polymer fiber has a negative thermal expansion coefficient over the entire temperature range from -50° to 100°C. The average thermal expansion coefficient is -1.46 × 10-5 °C-1 between -50° and +100°C amd -1.31 × 10-5 °C-1 between -50° and +40°C.