Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[CH2:12]([O:14][C:15]([CH2:17][C:18](=N)[O:19][CH2:20][CH3:21])=[O:16])[CH3:13]>C(O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:18]([O:19][CH2:20][CH3:21])[CH2:17][C:15]([O:14][CH2:12][CH3:13])=[O:16]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=Nc1ccc(F)c(F)c1F)OCC
Temperature: 20 °C
Reaction time: 48 h
Yield: 105.5 %

Procedure:
2,3,4-Trifluoroaniline (58.8 g) is added in a single portion with stirring to a solution of 2-ethoxycarbonyl-1-ethoxyethylideneamine hydrochloride (90 g) in ethanol (820 cc). After 48 hours' stirring at a temperature in the region of 20° C., the suspension obtained is filtered; the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50° C. The oily residue is taken up with water (250 cc). The mixture obtained is extracted with ethyl ether (3×200 cc). The combined organic extracts are washed with water (4×150 cc), dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at approximately 30° C. 2,3,4-Trifluoro-N-[1-ethoxy-2-(ethoxycarbonyl)ethylidene]aniline (122 g) is obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:56]1[CH2:61][CH2:60][NH:59][CH2:58][C:57]1=[O:62].ClCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:59]1[CH2:60][CH2:61][NH:56][C:57](=[O:62])[CH2:58]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCN1
Yield: 44 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and piperazinone in DMF. Yield: 44%; C20H17Cl2N5O3 (446.29); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]([CH:15]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12]O)[CH2:10][CH2:9]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+].C(Br)(Br)(Br)Br>CO>[N:37]([CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:15]=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:9][CH2:10]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCc1cn([C@H]2CC[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.8 %

Procedure:
A mixture of 350 mg of 2',3'-dideoxy-5-ethyluridine, 391 mg of triphenylphosphine, 475 mg of sodium azide and 496 mg of carbon tetrabromide was stirred at room temperature for 20 hours. 3 ml of methanol were added, the mixture was stirred for 1 hour and then evaporated. The residue was suspended in 30 ml of water and extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with 20 ml of water and then evaporated. The residue was subjected to flash chromatography on a column of silica gel using ethyl acetate for the elution. The product was crystallized from a mixture of ethyl acetate and hexane to give 200 mg of 5'-azido-2',3',5'-trideoxy-5-ethyluridine in the form of a white solid which was processed directly without further purification.
Reaction SMILES: [C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2>[Co](Br)Br>[CH2:7]1[CH:4]2[C@H:3]3[C@H:7]4[CH:4]5[CH2:3][CH:2]6[CH:6]([C@@H:5]5[C@@H:5]2[C@H:6]2[CH:1]1[C@H:2]23)[C@@H:1]46
Reactant: C1=C2CCC(=C1)C2
Agent: Br[Co]Br
Product: C1C2C3[C@H]4C1[C@@H]([C@@H]23)[C@@H]1C2CC3[C@@H]1[C@H]3[C@H]24

Procedure:
Diamantane was prepared from norbornadiene by a modified route based on the procedure given in Grund, T. M.; Thielecke, W.; v. R. Schleyer, P. Org. Syn. 53, 30. Anhydrous cobalt bromide was prepared in 80% yield from cobalt carbonate and HBr. Cobalt bromide was then reacted with triphenylphosphine in toluene to give bis(triphenylphosphine)cobalt bromide in 88% yield; 1.3 Kg of this catalyst was prepared in a single reaction. Reaction of norbornadiene with the cobalt catalyst gave the dimer, Binor-S, in 68% yield, and approximately 1.5 Kg of this material was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1([F:33])[CH2:32][O:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2([F:33])[CH2:32][O:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: FC1(CBr)COC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2(F)COC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 3-bromomethyl-3-fluoro-oxetane (described in US2005215599) gave the title compound. ES-MS m/e (%): 455.2(M+H+).
Reaction SMILES: N[C@@H]1CCCCN(CC2CC2)C1=O.[CH:14]1([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]([NH:25][C:26](=[O:32])OC(C)(C)C)[C:19]2=[O:33])[CH2:16][CH2:15]1.C(O)(C(F)(F)F)=O.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(C(C)C)CC)(C)C.[Cl:63][C:64]1[CH:73]=[C:72]2[C:67]([C:68]([N:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)=[CH:69][C:70]([NH2:74])=[N:71]2)=[CH:66][CH:65]=1>>[NH2:74][C:70]1[CH:69]=[C:68]([N:75]2[CH2:76][CH2:77][N:78]([C:26]([NH:25][C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:18]([CH2:17][CH:14]4[CH2:15][CH2:16]4)[C:19]3=[O:33])=[O:32])[CH2:79][CH2:80]2)[C:67]2[C:72](=[CH:73][C:64]([Cl:63])=[CH:65][CH:66]=2)[N:71]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(CC2CC2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: N[C@@H]1CCCCN(CC2CC2)C1=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC4CC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, (3R)-3-amino-1-(cyclopropylmethyl)hexahydro-2H-azepin-2-one by de-protection of [(3S)-1-(cyclopropylmethyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester with TFA, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 471 (M++1). 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 7.10 (d, 1H), 6.22 (d, 1H), 6.05 (s, 1H), 4.85 (s, 2H), 4.50 (m, 1H), 3.60 (m, 4H), 3.50 (m, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 3.06 (m, 4H), 2.05 (m, 1H), 1.70–1.90 (m, 3H), 1.40 (m, 2H), 0.90 (m, 1H), 0.45 (m, 2H), 0.20 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].Cl>C(OCC)C.O>[CH3:20][CH:19]([CH3:21])[C:18](=[O:22])[CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: CCCCOC(=O)CC(C)=O
Reactant: CC(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCCOC(=O)C(C(C)=O)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, to a reactor was added 0.22 mol of potassium tert-butoxide. After evacuating for 2 hrs, 80 ml of THF was added to dissolve the solid with stirring. Then 0.1 mol of butyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath, and the reaction was continued for further 2 hrs. Then under cooled in the ice-water bath, 0.12 mol of isobutyryl chloride was slowly dropped, and the reaction was continued for further 1.5 hrs. Next, under cooled in the ice-water bath, water was added to dissolve resultant solid, and the reaction mixture was neutralized with hydrochloric acid. Diethyl ether was used to extract product, and the collected organic layer was dried over anhydrous sodium sulfate. Removing solvent by using a rotatory evaporator gave the product.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH:21]([NH:24][CH3:25])([CH3:23])[CH3:22]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]([CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and isopropyl-methyl-amine. Yellow solid. MS (ESI): 336.2 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:20](=[O:21])[NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)[CH2:2]2
Reactant: O=C=Nc1cccc(Br)c1
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
To a solution of quinuclidin-3-ol (635 mg, 5.00 mmol) in THF (15 mL) was added NaH [60% dispersion in mineral oil] (260 mg, 6.50 mmol) at room temperature. The mixture was stirred for 15 min and 3-bromophenyl isocyanate (990 mg, 5.00 mmol) was added under stirring. The resulting mixture was stirred at room temperature for 18 h, quenched with brine and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (eluting with EtOAc/methanol 3:1) to give quinuclidin-3-yl3-bromophenylcarbamate as a white solid (0.70 g, 43%).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])C(=O)C2=CC=CC=C12.O.NN>CO.C(OCC)C>[NH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1CON
Reaction time: 3 h
Yield: 93 %

Procedure:
(E)-methyl 2-[phthalimidooxymethylphenyl]-3-methoxypropenoate (1.11 g, 3.02 mmol) (prepared as described in Example 4 of EP 0463488) was suspended in methanol (25 ml) at room temperature and hydrazine hydrate (0.151 g, 3.02 mmol) was added. The resulting solution was stirred for 3 hours. The white precipitate which formed was filtered off and the solvent removed to give a white semi-solid. This was diluted with diethyl ether, and the white solid filtered off to give (E)-methyl 2-[2-aminooxymethylphenyl]-3 -methoxypropenoate (93%) as a yellow oil which was used immediately in the next stage without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[BH4-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(CBr)c2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1oc2cccc(C)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 0.291 g (0.98 mmol) of 4-bromomethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 5 mL of DMSO was added 0.074 g (1.96 mmol) of sodium borohydride and the reaction was stirred at room temperature for 2 h. The reaction was diluted with water and extracted with ether. The organics were washed with water and brine, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.209 g of 4-methyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[C@@H:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C@@H:5]([OH:28])[CH2:4][CH2:3]2.C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH3:1][C@@:2]12[CH:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[CH:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C:5](=[O:28])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1
Yield: 189.5 %

Procedure:
A mixture of 488 mg digoxigenin, 7.5 ml toluene, 3.75 ml cyclohexanone, and 550 mg aluminum isopropoxide was heated under reflux for 2.3 hours and then concentrated in vacuo to half of its original volume. Two hundred μl water was added and the mixture was evaporated in vacuo to dryness. The powdery solid was dried in vacuo over overnight. The dry residue was stirred in 25 ml methanol and the resulting mixture was filtered. The residue on the funnel was washed with 25 ml methanol. The filtrate and washing were combined and evaporated in vacuo affording 920 mg white solid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C1COCC1>[F:47][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(N3CCOCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 54, 200 mg, 0.280 mmol) in THF (5 mL) was added morpholine (73.1 mg, 0.840 mmol) and DIEA (0.244 mL, 1.399 mmol). It was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated and the residue was purified on reverse phase HPLC, eluting with 10%-100% acetonitrile in water to give the title compound as a white solid. LCMS (M+H)+: 728.1. 1H NMR (CDCl3, 500 MHz): δ 8.33 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.77 (s, 2H), 5.75 (d, J=8.5 Hz, 1H), 4.77 (d, J=17.0 Hz, 1H), 4.36 (m, 1H), 4.086 (d, J=17.0 Hz, 1H), 3.92 (m, 4H), 3.85 (m, 4H), 2.71 (s, 3H), 2.44 (s, 3H), 0.78 (d, J=7.0 Hz, 3H). RTA IC50: 82 nM.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: [O-][n+]1ccc(Cl)cc1
Product: [O-][n+]1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 48.6 %

Procedure:
4-Chloropyridine-N-oxide (1.5 g, 12 mmol), 2,4-dichlorophenylboronic acid (5.4 g, 29 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (1.40 g, 50%) as a grey solid: 1H NMR (500 MHz, CD3OD) δ 8.26 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H), 7.37-7.35 (m, 3H), 7.29 (d, J=8.3 Hz, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1COCC1>C(OCC)(=O)C>[Cl:3][CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CO)c3[nH]2)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CCl)c3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Thionyl chloride (3.22 mmol, 2.5 eq.) was added to a cooled (0° C.) solution of N-((7-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)methyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (1.29 mmol, 1.0 eq.) in abs. THF (10 ml). The reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with ethyl acetate and washed successively with NaHCO3 solution and NaCl solution. The organic phase was dried over Na2SO4 and the solvent was distilled off in vacuo to obtain the crude product, which led to the desired product by purification by column chromatography over silica gel. Yield: 76%
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([Br:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCCC1>[Br:11][C:10]1[C:4]2[S:3][C:2]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:6][C:5]=2[C:7]([O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)c2sc(Br)nc12
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(Br)c2sc(N3CCOCC3)nc12
Temperature: 80 °C

Procedure:
A suspension of 2,7-dibromo-4-methoxybenzothiazole (1.8 g) and morpholine (10 ml) in tetrahydrofuran (10 ml) was heated at 80° C. for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over magnesium sulphate (3 g), filtered and the filtrate evaporated in vacuo to yield an off white solid. This was purified by recrystallisation from ethyl acetatelhexane to yield the title compound as a white solid (1.2 g). TLC Rf 0.39 (50% ethyl acetate in hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:51][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:22])([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCCCCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and octylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-octylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (42.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1>[Pd].C(O)(=O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:11](=[O:22])[CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)penta-1,4-diene-3-one of Example 6 (20 g, 0.068 mole), glacial acetic acid (200 ml) and 3.0 g of palladium/carbon (5%) was hydrogenated on a Parr hydrogenator for 4 hours. The solution was filtered and concentrated to give 18.5 g of colorless liquid.
Reaction SMILES: [NH3:1].CO.[NH2:4][C:5]1[N:13]=[C:12]([S:14][CH2:15][C:16](OC)=[O:17])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([OH:27])[N:9]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:4][C:5]1[N:13]=[C:12]([S:14][CH2:15][C:16]([NH2:1])=[O:17])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([OH:27])[N:9]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: COC(=O)CSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Solvent: CO
Product: NC(=O)CSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 89 %

Procedure:
A 28% ammonia/methanol solution was added to 6-amino-9-benzyl-8-hydroxy-2-(methoxycarbonylmethyl)thiopurine (75 mg, 0.22 mmol). The solution was heated in autoclave for 6 hours and then the solvent was removed in vacuo. To the residue was added methanol and the resulting crystals were filtered to give the subject compound (64 mg, yield 89%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:14][C@@H:15]([CH3:18])[CH2:16][OH:17]>C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: C[C@H](N)CO
Reactant: Brc1ccc(-c2csc(Br)n2)cc1
Solvent: ClCCl
Product: C[C@@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 150 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A mixture of 2-bromo-4-(4-bromophenyl)-1,3-thiazole (1.01 g, 3.16 mmol), prepared in step 2 of Example 1, and (S)-(+)-2-amino-1-propanol (738 μL, 9.48 mmol) was stirred under nitrogen at 150° C. for 1 h. After cooling to room temperature, the solid was taken up in methylene chloride and purified on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 10% ethyl acetate-methylene chloride to 40% ethyl acetate-methylene chloride as the eluent. Isolation of the more polar fraction gave (2S)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol (415 mg, 42%) as a yellow oil; MS (ES) m/z 313.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)C>CC(O)=O.[Fe]>[O:3]=[C:4]1[CH2:5][O:6][C:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][C:16]=2[NH:17]1
Reactant: CCOC(=O)COc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cnc2c(c1)NC(=O)CO2
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of methyl 6-(2-ethoxy-2-oxoethoxy)-5-nitronicotinate (2.43 g, 8.55 mmol) in AcOH (50 mL) was added iron powder (1.910 g, 34.2 mmol). The reaction was heated to 70° C. and stirred at that temperature for 2 hours. The reaction was concentrated in vacuo and diluted with water (300 mL). The solution was adjusted to pH=6 by addition of solid K3PO4. The aqueous layer was extracted with EtOAc (8×200 mL) and the combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. Methyl 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (1.24 g, 5.96 mmol, 69.7% yield) was isolated as an off-white solid and used without purification. LCMS (+ESI) m/z=209.0 [M+H]+; 1H-NMR (DMSO-d6) δ 11.0 (s, 1H), 8.35 (d, 1H), 7.67 (d, 1H), 4.90 (s, 2H), 3.85 (s, 3H).