Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:31]1[CH2:32][CH2:33][C@@H:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Yield: 99.8 %

Procedure:
3,4-Difluoronitrobenzene (16.03 g, 0.101 M) was dissolved in acetonitrile (300 ml), and treated with N,N-diisopropylethylamine (32.63 g, 0.253 M) and (3R)-3-t-butoxycarbonylaminopyrrolidine (20.65 g, 0.111 M). The mixture was stirred and heated to reflux for 18 hours. Solvent was evaporated, and the residue treated with EtOAc (300 ml) and water (200 ml). The organic laver was washed with water (1 50 ml). citric acid solution (10% in water, 2×150 ml), and dried (magnesium sulfate). Evaporation gave the desired product as a yellow solid (32.7 g), of sufficient quality for use without purification. MS (ESP): 326 (MH+) for C15H20FN3O4.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:15]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1cc(Br)ccn1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cc(Br)ccn1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (31.6 mL, 26.6 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (17.7 mL, 26.6 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(4-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (2.4 g, 8.9 mmol, in diethyl ether/tetrahydrofuran 20.0 mL/20.0 mL) prepared in Step 2 solution was slowly added thereto at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, quenched with distilled water at room temperature, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.2 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C@H:15]2[C@H:24]([OH:25])[CH2:23][C:22]3[C:21]([OH:26])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16]2)[CH2:11][CH2:10]1.[N+](=[CH2:29])=[N-]>CO>[CH3:29][O:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][C@@H:24]([OH:25])[C@H:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]1)[CH2:16]2
Reactant: COc1ccccc1N1CCN([C@@H]2Cc3cccc(O)c3C[C@H]2O)CC1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COc1ccccc1N1CCN([C@@H]2Cc3cccc(OC)c3C[C@H]2O)CC1
Reaction time: 48 h

Procedure:
A solution of 2.0 g of trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-piperazinyl]-1,7-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane. The solution is stored at 0° C for 48 hours. The solvent is removed in vacuo. The residue is dissolved in ethyl acetate, washed with dilute sodium hydroxide solution and dried. The solvent is removed in vacuo leaving an oil which crystallizes on trituration with a small amount of ether. This is washed with isopropyl ether and recrystallized from ether to give 1.7 g of the title compound, melting point 123°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH:21]([CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2].[S:30](Cl)([Cl:33])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:30]([Cl:33])(=[O:32])=[O:31])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH:21]([CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 5.6 g (14.1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 19A). This gives 3.7 g (52.9%) of sulphonyl chloride as a slightly yellow foam which is directly reacted further.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:44]=[CH:43][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])=[CH:25][CH:24]=3)[CH:20]=[O:21])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])=[CH:43][CH:44]=3)[CH:20]=[O:21])[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 750.9 %

Procedure:
To a solution of 1.09 g. (0.17 mmol) of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate in 50 mL of glacial acetic acid was added 164 mg of platinum oxide. The suspension was shaken in a Parr hydrogenation apparatus under an atmosphere (50 psi) of hydrogen at 25° C. for 3 hours. The reaction mixture was filtered through Celite and the filtrate evaporated under reduced pressure. The residue was dissolved in 100 mL of methylene chloride and extracted twice with a saturated solution of sodium bicarbonate. The aqueous layers were back extracted with 75 mL of methylene chloride and the organic layers combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the residue chromatographed, eluting with 5% methanol in methylene chloride to give 0.8 g of diethyl N-[N-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate (73% yield). An analytical sample was recrystallized from acetonitrile; mp 149°-151° C.; 1H NMR (Me2SO d6) delta 1.11-1.16 (m, 6H), 1.18 (s, 9H), 1.83-2.15 (m, 4H), 2.30.varies.2.47 (m, 3H), 2.79-3.20 (m, 4H), 3.98-4.11 (m, 4H), 4.36-4.43 (m, 1H), 4.53-4.54 (m, 2H), 6.40-6.51 (m, 1H), 7.33-7.36 (m, 2H, AA'BB'), 7.80-7.85 (m, 2H, AA'BB'), 8.11 and 8.38 (s, 1H), 8.67-8.73 (m, 1 H). Anal. Calcd for C31H42N6O8 : C, 59.41; H, 6.75; N, 13.41. Found: C, 59.14; H, 6.73; N, 13.64.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]([Si:11]([CH3:33])([CH3:32])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])[CH3:15])([CH3:10])[CH3:9].[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1>CC(N(C)C)=O>[N:34]1([C:38]([C:40]2[N:41]=[CH:42][C:43]([O:31][C:29]3[CH:28]=[C:19]([CH:18]=[C:17]([O:16][C@@H:14]([CH3:15])[CH2:13][O:12][Si:11]([C:8]([CH3:9])([CH3:10])[CH3:7])([CH3:33])[CH3:32])[CH:30]=3)[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])=[CH:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2nccs2)c1
Temperature: 160 °C

Procedure:
Cesium carbonate (0.478 g, 1.47 mmol) was added to a mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide (200 mg, 0.49 mmol), bromotris(triphenylphosphine)copper (46 mg, 0.049 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (130 mg, 5.39 mmol) in DMA (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 3 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL), brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound. (47 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20](Br)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CN(C)C=O>[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCC(Br)c1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 43.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 113 mg, 1.00 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.5 mL) and a 60% dispersion of sodium hydride in mineral oil (40 mg, 1.00 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and 4-(1-bromo-butyl)-benzoic acid methyl ester (261 mg, 0.97 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×25 mL), saturated aqueous brine solution (2×10 mL), dried over magnesium sulfate and concentrated in vacuo to give an oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 4-[1-(3-nitro-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (127 mg, 42%) as a white waxy solid: ESI-LRMS m/e calcd for C15H17N3O4 [M+] 303.1, found 304.5 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:23][C:20]1[CH:19]=[N:18][C:17]([N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[CH2:7]2)=[N:22][CH:21]=1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Yield: 87.4 %

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (313 mg, 1.28 mmol), 2-chloro-5-bromopyrimidine (248 mg, 1.28 mmol) and diisopropylethylamine (335 μL, 1.91 mmol) in acetonitrile (2 mL) at 80° C. overnight. Concentrate and chromatograph on SCX-2 column to give the title compound (450 mg, 87%). Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 8.41 (2H, s), 7.62-7.67 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 4.46 (2H, d, J=5.62 Hz), 4.16 (1H, m), 3.99-4.05 (1H, m), 3.79-3.86 (2H, m), 3.65 (1H, m), 2.60 (1H, m), 2.28-2.37 (1H, m), MS (ES): m/z=402 [M+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=3)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=2)=[CH:4][CH:3]=1.[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=O)[O:53]C2C=CC=CC=2)[CH:50]=1)([CH3:44])([CH3:43])[CH3:42].C(OC(C)=O)(C)C>CCN(CC)CC>[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=[O:53])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=4)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=3)=[CH:4][CH:3]=2)[CH:50]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cc(Nc2nccc(Oc3ccc(N)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product of step (vi) above (175.5 g, 0.324 mol), the product of step (x) above (145.0 g, 0.369 mmol) and iPrOAc (8800 mL). The resulting solution was heated to 60° C. and NEt3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60° C. overnight, following which HPLC analysis indicated 25.77% product of step (vi), 3.60% product of step (x) and 57.85% product of step (xi). Further product of step (x) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60° C. overnight, whereupon HPLC analysis indicated 5.47% product of step (vi), 3.72% product of step (x) and 73.33% product of step (xi). The reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with iPrOAc (2×500 mL). The pink solid obtained was dried, under vacuum, at 40° C. overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. 1H NMR conformed to structure.
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([CH2:10][CH2:11][O:12][CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:8]=[N:9][C:4]2=[C:3]([NH2:18])[N:2]=1.[CH2:19]([O:35][CH2:36][CH2:37][CH2:38]O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH3:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:35][CH2:36][CH2:37][CH2:38][O:15][P:14]([OH:17])([CH2:13][O:12][CH2:11][CH2:10][N:7]1[C:5]2[N:6]=[CH:1][N:2]=[C:3]([NH2:18])[C:4]=2[N:9]=[CH:8]1)=[O:16]
Reactant: Nc1ncnc2c1ncn2CCOCP(=O)(O)O
Reactant: CCCCCCCCCCCCCCCCOCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCCCOP(=O)(O)COCCn1cnc2c(N)ncnc21
Reaction time: 18 h

Procedure:
To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[Cl:6][C:7]1[C:8]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH:22]=[O:23])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Clc1cccnc1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3.8 ml of N,N-dimethylformamide was added dropwise 4.2 ml of phosphorus oxychloride at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.6 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine was added, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then slowly added to ice-water. The mixture was adjusted to pH 4 by an addition of a 2N aqueous sodium hydroxide solution. A deposited precipitate was collected by filtration to obtain 1.7 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine of the formula:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[C:27]1[CH:28]=[CH:29][C:30]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:31]([CH:36]=1)[C:32]([O:34][CH3:35])=[O:33]>CCOCC>[Br:24][CH2:20][C:27]1[CH:28]=[CH:29][C:30]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[C:31]([CH:36]=1)[C:32]([O:34][CH3:35])=[O:33]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(CO)ccc1Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)c1cc(CBr)ccc1Cc1ccc(F)cc1
Yield: 89.1 %

Procedure:
Triphenylphosphine (9.7 g., 37.0 mmol) and then carbon tetrabromide (12.3 g., 37.0 mmol) were added to a stirred solution of methyl 5-hydroxymethyl-2-(4-fluorobenzyl)benzoate (4.6 g., 16.8 mmol) in anhydrous ether (150 ml) at ambient temperature. After 4 hours the reaction was filtered and the filtrate concentrated under reduced pressure. The product was purified by column chromatography eluting with ethyl acetate/isohexane (5:95) to give methyl 5-bromomethyl-2-(4fluorobenzyl)benzoate as a colourless oil (5.05 g). NMR data (CDCl3) δ: 3.83 (3H, s), 4.37 (2H, s), 4.50 (2H, s), 6.92-6.99 (2H, m), 7.06 7.13 (2H, m), 7.19 (1H, d). 7.43 (1H, dd), 7.95 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH:4]([NH2:17])[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1
Reactant: COC(=O)C(CN1Cc2cn[nH]c2C(C)(C)C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)CN1Cc2cn[nH]c2C(C)(C)C1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.49 g, 1 equiv) in methylene chloride (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and loaded onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2M ammonia in methanol to afford the product as its free base (250 mg, 94%). 1H-NMR (CDCl3, 500 MHz) δ 1.27 (s, 3H), 1.28 (s, 3H), 2.41 (d, J=11.3, 1H), 2.50 (d, J=11.3, 1H), 2.69 (dd, J=12.5, 7.9, 1H), 2.82 (dd, J=12.5, 5.2, 1H), 3.45 (d, J=12.8, 1H), 3.52 (d, J=12.8, 1H), 3.67 (m, 1H), 3.69 (s, 3H), 7.19 (s, 1H). Mass spec.: 253.16 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8]C1C=CC=C(C(OO)=[O:16])C=1.C(OCC)C.Cl>CC(C)=O>[ClH:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:16]
Reactant: Nc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: Nc1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of amino pyridine (50 g, 0.53 mol) in acetone (900 OmL) a solution of 3-chloro perbenzoic acid (112.2 g, 0.65 mol) in acetone (300 mL) was added and the reaction mixture stirred at room temperature for 30 min. Diethyl ether (500 mL) was added and the solution acidified to pH 4 with concentrated HCl. The amino pyridine-N-oxide hydrochloride salt was then isolated by filtration as an off-white powder (62 g, 80%); m/z (ES+) 111; 1H NMR (d6 DMSO) d 8.14 (dd, J=6.9, 1.8 Hz, 1H), 7.66 (s, 2H, NH2), 7.47 (dt, J=7.6, 1.5 Hz, 1H), 6.99 (dd, J=8.1, 1.5 Hz, 1H), 6.72 (dt, J=7.6, 1.8 Hz, 1H).
Reaction SMILES: [C:1]1([CH:6]([N:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pt](=O)=O>[CH:1]1([CH:6]([N:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(C3=CCCC3)N3CCc4ccccc4C3)c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(C3CCCC3)N3CCc4ccccc4C3)c2)CC1
Reaction time: 5 h

Procedure:
102 mg (0.2 mmol, purity 72%) of rac-tert-butyl 1-(3-{[cyclopent-1-en-1-yl(3,4-dihydroisoquinolin-2(1H)-yl)acetyl]amino}-4-fluorobenzyl)cyclopropanecarboxylate were initially charged in 14.4 ml of methanol, 14.4 mg (0.06 mmol) of platinum(IV) oxide were added and the mixture was hydrogenated at RT and standard pressure for 5 h. The mixture was then filtered through kieselguhr, the residue was washed thoroughly with methanol and the filtrate was concentrated under reduced pressure. This gave 102 mg (purity 36%) of the title compound which was reacted further without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:17])[C:12]([O:16][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: Clc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a mixture of 5.0 g of 4-benzyloxy-2,6-dichlorophenol, 4.7 g of 1-bromo-3-(4-chlorophenoxy)propane and 30 ml of N,N-dimethylformamide was added 2.7 g of potassium carbonate with stirring at room temperature. After stirring at room temperature for 12 hours, the reaction solution was poured into iced water and extracted twice with 200 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain a crude product. This crude product was subjected to silica gel chromatography to give 6.5 g of 4-benzyloxy-1-(3-(4-chlorophenoxy)propyloxy)-2,6-dichlorobenzene(yield: 85 %).