Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(=O)(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.10 g, 0.26 mmol) in THF (5 ml) at room temperature was added 1.1 equivalent of trifluoromethylsulfonyl chloride loaded TFP resin, and DMAP (0.031 g, 0.26 mmol). The reaction was then stirred at room temperature for 15 hours and filtered. The remaining resin was then washed with THF (2×10 ml for 20 min), and then combined organic fractions were concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.02 g, 15%). 1H NMR (400 MHz, CD3OD) δ 7.40-7.37 (m, 2H), 7.17 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.90-5.60 (br s, 1H), 5.14-5.12 (m, 1H), 4.28-4.25 (m, 2H), 1.88-1.84 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS: Calcd.: 516. Found: [M+H]+ 517.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][N:25]([CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21]
Reactant: CCOC(=O)CNCc1ccccn1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
150 ml (0.46 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 98 mg (1.1 equiv.) of N-(2-pyridylmethyl)-glycine ethyl ester and 0.076 ml (1.2 equiv.) of triethylamine are stirred at reflux in 5 ml of acetonitrile for 20 hours. The mixture is concentrated by evaporation and the residue is suspended in diethyl ether and filtered. After drying, the title compound is obtained in the form of a white powder.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C.[OH-].[Na+]>[OH:15][C:16]1[C:7](=[O:8])[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[O:18][C:17]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12

Procedure:
180 mg of 4'-vinyl, 4-biphenyl aldehyde was mixed with 0.3 ml of 2-hydroxyacetophenone in 30 ml of ethanol. In a separate flask, 2.0 gms of NaOH was dissolved in 10 ml of aq. ethyl alcohol (50%). An NaOH solution was slowly added to the aldehyde solution. The resulting solution slowly changed its color from green to yellow to dark red. The rest of the reaction was carried out according to the method described in Example 1(b) above, producing 4'styryl, 3-hydroxyflavone.
Reaction SMILES: [CH3:1][NH:2][CH:3]([OH:5])[CH3:4].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])O.[Na+].O>C(O)C>[N+:16]([C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[N:2]([CH:3]([OH:5])[CH3:4])[CH3:1])([O-:18])=[O:17]
Reactant: CNC(C)O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
20.3 g of N-methylaminoethanol was dissolved in 100 ml of ethanol and, while stirring, solid 1-chloro-2,4-dinitrobenzene was added to the solution by portions at room temperature. After completion of the addition, 8.4 g of sodium hydrogencarbonate was gradually added to the reaction mixture, followed by stirring for 10-15 minutes at room temperature. Then, the reaction mixture was heated at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into 300 ml of water. Continued stirring of the solution yielded a yellowish oily product. Stirring was then discontinued and, after completion of oil formation, the supernatant was removed. After adding water thereto, the solution obtained was stirred and the oil layer formed was collected by separation, and dried to obtain a yellowish oily product. Chemical structure of the product was confirmed by 1H-NMR. Absorptivity coefficient of the product at 365 nm was measured to be 1.79×104 by UV measurement in ethanol. 1H-NMR(CDCl3), TMS standard (400 MHz): 2.22(s,1H), 3.03(s,3H), 3.62(m,2H), 3.92(m,2H), 7.24(d,1H), 8.18(d,1H), 8.63(s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[CH2:24][NH2:25]>>[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[CH2:24][NH:25][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCC1COc2ccccc2O1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2,3-dihydrobenzo[1,4]dioxin-2-ylmethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 3.69–3.73 (2H, m), 3.97–4.03 (1H, m), 4.32–4.42 (2H, m), 6.77–6.88 (4H, m), 7.10 (1H, s), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=344 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C.Br>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1F
Reaction time: 0.29 h

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (1.0 g) in acetic acid (30 ml) was treated dropwise with a solution of bromine (0.736 g) in acetic acid (4.5 ml) at 50° in the presence of a few drops of 48% hydrogen bromide in acetic acid. After stirring for 15-20 minutes, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with 8% sodium bicarbonate (50 ml) and water (50 ml). The organic layer was then dried (MgSO4) and concentrated to give a pale brown oil which crystallised from benzene/acetone, 1.2 g, m.p. 129-132°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[C:16]1=[O:28])[C:11]([O:13][CH3:14])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO>[Pd]>[NH2:25][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH:23]=[CH:24][N:15]([C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:11]([O:13][CH3:14])=[O:12])[C:16]2=[O:28]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
A round bottom flask was charged with (R)-methyl 3-(tert-butyldimethylsilyloxy)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (5.5 g, 0.014 mol), methanol (100 mL, 2 mol); palladium, 10% weight on charcoal (0.3 g, 0.003 mol) was added and the reaction stirred under hydrogen atmosphere (1 atm) for 2 h. The reaction was filtered over celite and the solvent removed under reduced pressure and the residue purified by flash chromatography (40 g, 0-10% MeOH/DCM) to yield the product as a yellow sticky mass. MS m/z=377.5 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([Cl:22])([Cl:21])[Cl:20])[O:15][C:16]2=[O:18].Cl>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([Cl:22])([Cl:20])[Cl:21])[O:15][C@@H:16]2[OH:18]
Reactant: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2[C@H]1[C@@H](O)O[C@H]2C(Cl)(Cl)Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
75 ml of a toluene solution of 20% of diisobutyl-aluminum hydride were slowly added at -60° C. to a solution of 20 g of (1R,4R,5S) 6,6-dimethyl-4-trichloromethyl-3-oxa-bicyclo (3,1,0)-hexane-2-one in 200 ml of toluene and the mixture was stirred at -60° C. for one hour and was poured into an ice-water mixture. Aqueous N hydrochloric acid was added to the mixture to adjust the pH to 3 to 4 and the mixture was filtered. The decanted benzene phase was washed with aqueous sodium bicarbonate solution, with water and evaporated to dryness under reduced pressure. The residue was added to petroleum ether (b.p.=35°-70° C.) and the mixture was filtered to obtain 14.5 g of (1R,2S,4R,5S) 6,6-dimethyl-4-trichloromethyl-3-oxa-bicyclo (3,1,0) hexan-2-ol melting at 140° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccc(Cl)cc1
Solvent: CO
Product: CN(CCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 164°-5° C. (methanol), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propanoate by a procedure analogous to that described in Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.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>[CH3:15][Si:16]([C:19]#[C:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2ccc(C#C[Si](C)(C)C)cc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][S:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:30][CH2:29][CH2:28][S:27][CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CSCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 56.4 %

Procedure:
2-Chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.200 g, Example 29c), 2-(methylthio)ethylamine (0.478 g), triethylamine (0.7 ml) and tetrahydrofuran (4 ml) were heated together in a sealed tube at 80° C. for 24 h. The mixture was cooled, poured into saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (eluant 19:1/dichloromethane:methanol) to afford the title compound as a gum (0.129 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH3:26]>CO>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: N
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Solvent: CO
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.016 g, 0.040 mmol) in MeOH (0.50 mL) was added ammonia (0.006 mL, 0.040 mmol, 7 M solution in MeOH). After stirring for 2 hours at room temperature, the reaction mixture was heated to 40° C. for 8 hours. The resulting white precipitate was filtered to yield clean desired product (0.005 g, 46%). MS ESI (+) m/z 303 (M+1) detected; 1H NMR (400 MHz, DMSO) δ 8.16 (br s, 1H), 8.04 (br s, 1H), 6.81-6.94 (m, 3H), 4.33 (s, 2H), 3.45 (s, 3H), 2.33 (s, 3H), 1.63 (s, 3H). 19F (376 MHz, DMSO) −127.1 (s, 1F).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[NH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[N:14]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[C:12]=1[Cl:29]>ClCCl>[NH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][F:7])=[CH:19][CH:18]=2)[N:14]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[C:12]=1[Cl:29]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1nc(-c2ccc(CO)cc2)cc(N)c1Cl
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(CF)cc2)cc(N)c1Cl
Reaction time: 0.25 h
Yield: 32 %

Procedure:
(Diethylamino)sulfur trifluoride (0.73 mL, 5.5 mmol) was added dropwise to a solution of methyl 4-amino-3-chloro-6-(4-hydroxymethylphenyl)pyridine-2-carboxylate (1.46 g, 5.0 mmol) in dichloromethane (35 mL) at 0° C. The reaction mixture was stirred for 15 minutes and then quenched with ice followed by water. The product was extracted with ethyl acetate and the organic phase was washed with brine and concentrated. The residue was purified by column chromatography (dichloromethane/hexane) giving methyl 4-amino-3-chloro-6-(4-fluoromethylphenyl)pyridine-2-carboxylate (480 mg, 1.6 mmol), mp 95-97° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCCC3)c2)[C@@]2(C)CC[C@@H]1C2
Product: CC1(C)C(NC(=O)c2ccc(NCc3ccccc3)c(S(=O)(=O)N3CCCC3)c2)[C@@]2(C)CC[C@@H]1C2

Procedure:
Compound 2N was prepared from 4-bromo-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide 2.4.AiBa and benzylamine Ck following method 2c.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][CH:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)O
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
A solution of 6-chloro-2-fluoro-9H-purine (616 mg, 3.57 mmol) in THF (18 mL) was cooled in an ice water bath under nitrogen and iPrOH (858 mg, 14.3 mmol), triphenylphosphine, polymer-bound (2.38 g, 7.14 mmol, ˜3 mmol/g), and di-tert-butyl azodicarboxylate (1.730 g, 7.14 mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hr. The solid resin was removed and washed well with ethyl acetate (50 mL). The filtrate was concentrated down in vacuo to give a light yellow solid residue. This was then loaded onto silica and purified via flash chromatography (eluting with 30-50% ethyl acetate in heptanes) to give the title product as a white solid (445 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1 H) 4.72-4.92 (m, 1 H) 1.57 (d, J=6.85 Hz, 6 H). m/z (APCI+) for C8H8FN4Cl 217.10, 215.10 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](/[C:29]([OH:31])=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:35]([O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](\[CH3:28])/[C:29]([O:31][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:44][CH:45]=1)=[O:30])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@@H](/C=C(\C)C(=O)OCc1ccc(OCc2ccccc2)cc1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (287 mg, 0.607 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.728 mmol), 4-(benzyloxy)benzyl alcohol (137 mg, 0.638 mmol) and dimethylaminopyridine (0.12 mmol) in anhydrous dichloromethane (12 mL) are stirred under a nitrogen atmosphere at room temperature for 20 hours. The solvent is removed, the residue taken up in methanol, and the product purified by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the title compound as a white gum, 208 mg, MS: m/z 670.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[C:23]([O:30][CH3:31])[CH:22]=1>CC(O)C.CO>[CH3:31][O:30][C:23]1[CH:24]=[C:25](/[C:27](=[CH:15]/[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:13]=2)/[C:28]#[N:29])[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=1
Reactant: O=Cc1ccc(OCCCCCCCCO)cc1
Reactant: COc1cc(CC#N)cc(OC)c1
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(OC)cc(/C(C#N)=C/c2ccc(OCCCCCCCCO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
5.0 g (20.0 mmol) of 4-[(8-hydroxyoctyl)oxy]benzaldehyde, 3.5 g (19.8 mmol) of 3,5-(dimethoxyphenyl)acetonitrile are dissolved in 50 mL of propan-2-ol. The solution is heated to 60° C. and 2.0 mL (2.0 mmol) of a one molar solution of tetrabuthylamoniumhydroxyde in methanol are added drop wise. After 2 h at 60° C., the reaction mixture is cooled to 0° C. The precipitate is filtered off, washed with cold propan-2-ol and recristalized in propan-2-ol. 3.5 g of (2Z)-2-(3,5-dimethoxyphenyl)-3-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile are obtained as a white solid (42% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([CH:34]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]([CH2:27][CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([CH:34]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:36]([O:38][CH3:39])=[O:37])=[CH:44][CH:45]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: COC(=O)C(=Cc1ccc(OCCCl)cc1)C(=O)OC
Reactant: O=C(c1ccc2[nH]c(=O)sc2c1)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
The compound obtained in Step A is dissolved in DMF and 2 equivalents of potassium carbonate are added. After stirring for 20 minutes at 80° C., 1.2 equivalents of dimethyl 2-[4-(2-chloroethoxy)benzylidene]malonate are added and the reaction is heated for 12 hours. The reaction mixture is then hydrolysed in water and filtered, and the resulting precipitate is recrystallised from methanol to yield the title product.