Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[N:3]=1.[IH:20].[Na+].[I-]>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[N:3]=[C:2]([I:20])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCCC2
Reactant: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (534 mg, 1.89 mmol, 1 eq) in a 57% HI solution in water (10 ml) at r.t. was added NaI (1.42 g, 9.47 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,6,7,8-tetrahydroquinazoline which was not further purified.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]([O:24][C:25]([NH:27][C@H:28]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]C1C([N+]([O-])=O)=NC=C(OC2C=CC=CC=2)C=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:46]([O:48][CH3:49])=[O:47])[CH2:29][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reactant: COC(=O)[C@H](Cc1cc(Oc2ccccc2)cnc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C

Procedure:
Methyl N-(tert-butoxycarbonyl)-2-nitro-5-(phenylsulfonyl)-L-phenylalaninate (70) Compound 70 was prepared from 2-bromo-1-nitro-4-(phenylsulfonyl)benzene (69) according to the general procedure for the synthesis of methyl N-(tert-butoxycarbonyl)-3-(2-nitro-5-phenoxypyridin-3-yl)-L-alaninate (65) in Example 66. The product was obtained as an off-white foam (250 mg, 37%). LCMS m/z 463.1 (M−1).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O.N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=[CH:3][CH:4]=1
Reactant: Nc1cnccn1
Reactant: O=C(O)Cc1ccnc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1ccnc2ccccc12)Nc1cnccn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62 %

Procedure:
A solution of 200 mg (0.89 mmol) of quinolin-4-yl-acetic acid hydrochloride salt and 145 mg (0.89 mmol) of N,N-carboyl diimidazole was stirred in 3 ml of dimethylformamide at RT for 2 h. 2-Aminopyrazine (63 mg, 0.66 mmol) in 2 ml of pyridine was added dropwise over 10 mins and stirred at 80° C. for a further 9 h. The solution was allowed to cool, concentrated in vacuo, and partitioned between dichloromethane and water. The organic layer was washed 3 times with water, concentrated in vacuo and the material purified by chromatography. White solid. Amount 108 mg. Yield 62%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:19].B(Br)(Br)Br>C(Cl)Cl>[I:19][C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(-c2nc3ccc(O)cc3s2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
To a solution of 2-(4′-Amino-3′-iodophenyl)-6-methoxy benzothiazole (5) (8.0 mg, 0.02 mmol) in CH2Cl2 (2.0 mL) was injected 1 M BBr3 solution in CH2Cl2 (0.20 ml, 0.20 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 18 hrs. After the reaction was quenched with water, the mixture was neutralized with NaHCO3. The aqueous layer was extracted with ethyl acetate (3×3 mL). The organic layers were combined and dried over MgSO4. The solvent was then evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:ethyl acetate=7:3) to give 2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole (4.5 mg, 58%) as a brown solid. 1HNMR (300 MHz, acetone-d6) δ (ppm): 8.69 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.77 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.02 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.47 (br., 2H). HRMS m/z 367.9483 calcd for C13H9N2OSI 367.9480).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:13]1[C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][S:16][C:12]1=[N:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC(C)C

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14]C)[CH:9]=2)=[N:6][CH:7]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cc(-c2ccc(Cl)cn2)ccn1
Agent: Cl
Product: O=c1cc(-c2ccc(Cl)cn2)cc[nH]1
Yield: 81.4 %

Procedure:
5-Chloro-2′-methoxy-2,4′-bipyridine (810 mg, 3.67 mmol) was stirred in concentrated hydrochloric acid (10 mL) at 120° C. for 18 h and then concentrated. The residue was adjusted to pH 8 with 6 N NaOH and the solids were filtered off, washed with water and dried under vacuum to provide the title compound (617 mg, 81%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.75 (s, 1H), 8.06 (s, 2H), 7.49 (d, J=6.8 Hz, 1H), 7.00 (s, 1H), 6.85-6.84 (dd, J=6.8, 1.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32])[C:24]([O:26]C)=[O:25].O>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31]([N:6]([CH2:5][C:4]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:33])=[O:32])[C:24]([OH:26])=[O:25]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 8.4 g, 33.4 mmol, 1 eq) in THF (80 ml) was added 60% sodium hydride (2.0 g, 50.2 mmol, 1.5 eq) portionwise. The mixture was stirred for 15 minutes before the addition of methyl 3-chloro-4-(chlorosulfonyl)benzoate (Preparation 5, 9 g, 33.4 mmol, 1 eq) then stirred for a further 30 minutes. The reaction mixture was added to water (20 ml) and the THF evaporated in vacuo. The residue was diluted with water (200 ml), extracted with ethyl acetate (2×200 ml) and DCM (100 ml). The combined organics were dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]1([Sn](C)(C)C)[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3].Cl[B:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][Si:2]([C:5]1([B:15]([C:5]2([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: ClB(Cl)c1ccccc1
Reactant: C[Si](C)(C)C1([Sn](C)(C)C)C=CC=C1
Product: C[Si](C)(C)C1(B(c2ccccc2)C2([Si](C)(C)C)C=CC=C2)C=CC=C1
Temperature: 40 °C

Procedure:
To 2.230 g (7.41 mmol) of (trimethylsilylcyclopentadienyl)-trimethyltin is added 0.59 g (0.48 ml, 3.7 mmol) of dichloro-(phenyl)borane dropwise at room temperature. An intense yellow color immediately appears. The mixture is heated at 40° C. for 2 h whereupon the yellow color intensifies. This is followed by fractional distillation wherein the chlorotrimethylstannane formed can first be separated off. In the distillation, a heavy decomposition occurs from about 120° C. bath temperature to give a dark-red oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1.[C:22](Cl)(=[O:24])[CH3:23]>C(OCC)(=O)C.CCCCCC>[C:22]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)(=[O:24])[CH3:23]
Reactant: N#Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(C#N)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-cyanobenzoyl)indole (Example 127) and acetyl chloride. m.p.: 185-187° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 11.91 (1H, br s), 9.85 (1H, brs), 8.12-8.04 (2H, m), 8.03-7.95 (1H, m), 7.77-7.62 (2H, m), 7.46 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=1.8, 8.8 Hz), 1.64 (3H, s)
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][NH2:11]>>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH:3]([NH:8][CH:9]2[CH2:5][CH2:4][CH2:3][CH2:2][CH:10]2[NH:11][CH:3]2[CH2:4][CH2:5][S:1](=[O:7])(=[O:6])[CH2:2]2)[CH2:2]1
Reactant: O=S1(=O)C=CC=C1
Reactant: NCCN
Product: O=S1(=O)CCC(NC2CCCCC2NC2CCS(=O)(=O)C2)C1

Procedure:
Example 1 was repeated using the thiophene dioxide of Example 1 but substituting 1,2-diaminocyclohexane for 1,2-diaminoethane. The resultant product, N,N'-bis(1,1-dioxotetrahydro-3-thienyl)-1,2-diaminocyclohexane obtained was a viscous liquid that became a semi-solid. The infrared spectrum showed absorptions at 3300 cm-1 (NH), at 1300 cm-1 and 1130 cm-1 (SO2).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[O:9][C:8]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:12][CH:11]=2)=[N:7][CH2:6]1.[CH3:30]I>O1CCCC1>[CH3:30][O:3][CH2:4][CH:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:28][CH:29]=2)=[N:7][CH2:6]1
Reactant: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN=C(c2ccc(OCCCCCCCc3cc(C)no3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 1.08 g of sodium hydride (60% in mineral oil) in 50 ml of dry tetrahydrofuran was added over 33 minutes a solution of 6.6 g of 5-{7-[4-(4,5-dihydro-5-hydroxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 23). The mixture was heated at gentle reflux for one hour, then cooled to room temperature, and 4.30 g of methyl iodide in 25 ml of dry tetrahydrofuran was added over a 15 minute period. The reaction mixture was stirred overnight at room temperature, then filtered and concentrated in vacuo. The residue was washed with n-pentane and dissolved in ethyl acetate and the soluble portion isolated (6.31 g, m.p. 53°-55° C.). The latter was recrystallized from hexane to give 5.1 g of 5-{7-[4-(4,5-dihydro-5-methoxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, m.p. 60°-61° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]=[N+]=[N-])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N
Yield: 98.5 %

Procedure:
A solution of ((R)-4-azido-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (1.25 g, 5.0 mmol) in ethanol (40 mL) was hydrogenated over 10% palladium on carbon (130 mg) under 30 psi in a 150 mL parr bottle at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite® (diatomite filter). The filtrate was collected and concentrated in vacuo to afford ((R)-4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester as an oil (1.10 g, 98%), which was used in the next step without further purification. MS calcd. for C11H17N3O2 223, obsd. (ESI+) [(M+H)+] 224.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:26])[CH:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=2)[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:26])[C@@H:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=2)[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCC(Oc1ccc(C#N)c(Cl)c1)C(=O)NCCc1ccc(O)cc1
Solvent: O
Product: CCC[C@H](Oc1ccc(C#N)c(Cl)c1)C(=O)NCCc1ccc(O)cc1

Procedure:
The product of Example 105 was prepared by chiral HPLC separation of the product of Example 103. MS: 373.1(M+1 for C20H21ClN2O3) LCMS: C-18 column (25% H2O/75% CH3CN. RT=0.91 min. Purity 99.9%
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)=[O:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[BH4-].[Na+]>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CSc1ccc(C(=O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1

Procedure:
This compound was prepared following the general procedure D, using 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid, and 3 equivalent amounts of sodium borohydride;
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]1[CH:2]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=O)=[C:11]([F:19])[C:10]=1[F:20].[C:21]([C:23]1[C:24](=[C:31]([C:34]#[N:35])[C:32]#[N:33])[O:25][C:26]([CH3:30])([CH3:29])[C:27]=1[CH3:28])#[N:22]>C(O)(=O)C.N1C=CC=CC=1>[CH:5]12[CH2:8][CH:1]([CH2:7][CH2:6]1)[CH:2]1[CH:4]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=[CH:28][C:27]2[C:26]([CH3:29])([CH3:30])[O:25][C:24](=[C:31]([C:32]#[N:33])[C:34]#[N:35])[C:23]=2[C:21]#[N:22])=[C:11]([F:19])[C:10]=1[F:20]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: O=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 100-mL round bottom flask with stirbar was added 4-(3-aza-tricyclo[3.2.1.02,4]oct-3-yl)-2,3,5,6-tetrafluoro-benzaldehyde (0.35 g, 1.23 mmol), 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile (0.39 g, 2 mmol), pyridine (5 mL) and acetic acid (several drops). The mixture was stirred under nitrogen at room temperature for 3 days. TLC showed that one red fluorescent product had formed as the main product. The reaction was stopped. The product mixture was poured into ice-water (500 mL) and vigorously stirred for 4 h. The crude products were extracted with CH2Cl2 (100 mL×5). The combined organic layer was dried over anhydrous MgSO4. After removing solvent, the crude organic product was adsorbed on silica gel, placed at the top of a silica column and eluted (hexane/EtOAc=2/1). Fraction containing only the first red fluorescent product were combined and concentrated to give a red solid, which was recrystallized from 1-propanol to give the final product as red needles. Mp 233° C. IR (neat): 2951, 2228, 1573, 1481, 1390, 1366, 1163, 1107, 983, 962 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=16.8 Hz, 1H), 7.23 (d, J=16.8 Hz, 1H), 2.70 (br s, 4H), 1.80 (s, 6H), 1.63-1.51 (m, 3H), 1.34-1.27 (m, 2H), 0.98-0.92 (m, 1H); 13C NMR (100 MHz, CDCl3): 176.4, 173.4, 148-139 (m), 132.5, 118.8 (t), 111.4, 110.6, 109.9, 97.6, 95.3 (m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[CH2:24][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cccc(CCN)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-(2-aminoethyl)benzoate (900 mg) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (600 mg) and tert-butyl bromoacetate (0.600 mL) under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{2-[(2-tert-butoxy-2-oxoethyl)amino]ethyl}benzoate (738 mg).
Reaction SMILES: NCCC[C:5]1[NH:14][C:13]2[C:12](=[O:15])[N:10]([CH3:11])[C:9](=[O:16])[N:8]([CH3:17])[C:7]=2[N:6]=1>C(=O)([O-])[O-]>[N:10]1([C:12](=[O:15])[C:13]2[NH:14][CH:5]=[N:6][C:7]=2[N:8]([CH3:17])[C:9]1=[O:16])[CH3:11]
Reactant: Cn1c(=O)c2[nH]c(CCCN)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
A solution of 5 mM 8-(3-aminopropyl)-theophylline (R.C. Boguslaski et al., 1980) in 0.1 M carbonate buffer, pH 8.0, was incubated with an N-hydroxysuccinimide ester activated dextran surface (according to Example I.3.2) overnight at 25° C., whereupon the surface was washed with water.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:11]([C:17](=[O:20])[NH:18][N:19]=3)[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1.[I-:21].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[I:21][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:11]([C:17](=[O:20])[NH:18][N:19]=3)[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)[nH]c(=O)n1c(=O)[nH]nc21
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3ccc(I)cc3[nH]c(=O)n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
63.8 mg (0.92 mmol) of sodium nitrite were added at 0° C. to a suspension of 210 mg (0.83 mmol) of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione in 10 ml of acetic acid and 10 ml of sulphuric acid. The reaction mixture was stirred at 0° C. for 1 hr. Subsequently, 2.49 g (16.6 mmol) of sodium iodide in 10 ml of water were added dropwise and the mixture was stirred at RT for a further 1 hr. The precipitate was filtered off, the brown crystals were suspended in 10 ml of 5% sodium thiosulphate solution, filtered off and dried in a vacuum. 145 mg (53%) of 8-iodo-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as brownish crystals;
Reaction SMILES: [F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:9]([OH:11])[CH3:10]>S(=O)(=O)(O)O>[F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5]([O:11][CH2:9][CH3:10])=[O:6]
Reactant: CC1(C(=O)Cl)CC1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1F
Yield: 85 %

Procedure:
40 ml of ethanol are added dropwise at 20° C. and with stirring to 20 g (0.12 mol) of 2-fluoro-1-methylcyclopropane-carbonyl chloride (cis/trans mixture). After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for one hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under reduced pressure. In this manner, 18.4 g (85% of theory) of ethyl 2-fluoro-1-methyl-cyclopropanecarboxylate (cis/trans mixture) are obtained in the form of a liquid of boiling point 42-45° C. at 18 mbar.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9](=[O:16])[NH:10][CH:11]=[C:12]([F:15])[C:13]=1[I:14].Br[CH2:18][CH2:19][C@@:20]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.C(O)(C)(C)C>[F:7][C:8]1[C:9](=[O:16])[N:10]([CH2:18][CH2:19][C@@:20]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=[C:12]([F:15])[C:13]=1[I:14]
Reactant: O=c1[nH]cc(F)c(I)c1F
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)c(F)c1=O)S(C)(=O)=O
Reaction time: 72 h
Yield: 32 %

Procedure:
Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro-4-iodopyridin-2(1H)-one (1.0 g, 3.9 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The resulting suspension was heated to reflux and was stirred at this temperature for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography on an Analogix SF15-24 g column using an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (s, 3H) 1.58 (s, 3H) 2.20 (dt, J=13.90, 7.00 Hz, 1H) 2.52-2.62 (m, 1H) 3.14 (s, 3H) 4.00 (t, J=7.61 Hz, 2H) 4.05-4.22 (m, 2H) 7.94 (dd, J=4.20, 2.05 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[Cl:29])=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=568.3 [M+H+].