Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6](N)[N:7]=1.[Sb](Cl)(Cl)[Cl:13].C(ON=O)(C)(C)C>ClCCCl.C(Cl)(Cl)Cl>[Cl:13][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=1
Reactant: Cl[Sb](Cl)Cl
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Clc1nc(Cl)c2cc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 mL) at −10° C. under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert-butylnitrite (2.50 mL, 20.8 mmol) was added to the solution. The reaction was stirred at −10° C. for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH:20]=[CH:19][O:18][C:17]4=[O:21])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:22])[O:4]1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH:20]=[CH:19][O:18][C:17]5=[O:21])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:22])[O:4]2)=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12)c1ccc(Cl)s1
Yield: 76.9 %

Procedure:
Using compound (3S,3aS)-3-(aminomethyl)-7-(2-oxooxazol-3-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one, 5-chlorothiophene-2-carboxylic acid (0.12 g, 0.737 mmol), HATU (0.38 g, 0.982 mmol), and Et3N (0.15 g, 1.473 mmol) as starting materials, DCM (10 ml) and DMF (2 ml) as a mixed solvent, preparation following the method as described in Example 11 (g) afforded white solid 0.17 g, yield 76.9%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CC#N.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1OCC1CC1
Temperature: 85 °C
Yield: 97 %

Procedure:
A mixture of 2-nitrophenol (1 g, 7.19 mmol), K2CO3 (1.192 g, 8.63 mmol), and (bromomethyl)cyclopropane (0.837 ml, 8.63 mmol) in CH3CN (40 ml) was heated to 85° C. overnight. The mixture was portioned between EtOAc and HCl 1N. The organic phase was dried over Na2SO4 and the solvent was removed. 1-(cyclopropylmethoxy)-2-nitrobenzene was obtained as a crude (1.352 g, 7.00 mmol, 97% yield) and used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH2:13](I)[CH2:14][CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCI
Reactant: Cc1c(O)cccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc(C=O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Sodium hydride (1.15 g, 50% in oil) was added to a stirred solution of 2-methyl-3-hydroxybenzaldehyde (3.00 g) in dry DMF (30 ml). The mixture was stirred for 1 h at room temperature under nitrogen, then n-propyl iodide (4.49 g) was added portionwise over 20 min, followed by stirring for 1 h. The mixture was poured into water and extracted with diethyl ether, and the combined extracts dried (MgSO4) and evaporated to dryness. Purification by chromatography (SiO2 ; hexane/ethyl acetate) gave 2-methyl-3-n-propyloxybenzaldehyde (1.38 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCNc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-((2-nitrophenyl)amino)propanoate (11 g, 48.9 mmol) and Pd/C (3.3 g, 10%) in 300 mL of MeOH and 20 mL of EtOAc was stirred overnight under H2 atmosphere at room temperature. The mixture was filtered off, and the filtrate was concentrated to give methyl 3-((2-aminophenyl)amino)propanoate as a yellow oil. (9.3 g, 98%). LRMS (M+H)+: 193 m/z.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]2)[C:5](/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])=[C:4]([CH3:24])[N:3]=1.CCCCC=CCCCCC.C(N(CC)CC)C>COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:17]=[CH:18][C:19](=[O:20])[N:8]([C@H:9]3[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](OC)CC1
Agent: CCCCC=CCCCCC
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1

Procedure:
A solution of (E)-ethyl 3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (674 mg, 2.02 mmol) thiophenol (621 ul, 6.05 mmol), 1,5-diazabicyclo-5,4,0)undec-5-ene (1.81 mL, 12.1 mmol) and triethylamine (1.69 mL, 12.1 mmol) in N′,N-dimethylformamide (15 mL) was heated in the microwave for 30 minutes at 100° C. then in an oil bath at 100° C. overnight. The reaction mixture was diluted with methyltertbutylether and washed with saturated sodium carbonate, brine, 0.1 N hydrochloric acid, brine, dried (MgSO4), filtered and concentrated. The combined aqueous layer was extracted with dichloromethane (2×). The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0-5%) to afford 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 83%).
Reaction SMILES: [N+:1]([O-:8])([O:3][CH2:4][CH2:5][CH2:6][OH:7])=[O:2].[C:9](Cl)(Cl)=[O:10].[CH3:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[O:21][CH2:22][C:16]=2[C:15]=1[OH:30].C(N(C(C)C)CC)(C)C>C1COCC1.O>[C:9](=[O:10])([O:7][CH2:6][CH2:5][CH2:4][O:3][N+:1]([O-:8])=[O:2])[O:30][C:15]1[C:16]2[CH2:22][O:21][CH:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:17]=2[CH:18]=[N:19][C:14]=1[CH3:13]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])OCCCO
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ncc2c(c1OC(=O)OCCCO[N+](=O)[O-])COC2c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-hydroxypropyl nitrate (100 mg, 0.83 mmol) in THF (10 mL) at 0° C. was added phosgene (20% in toluene, 425 mg, 0.86 mmol). After stirring at 0° C. for 45 min, the mixture was allowed to warm to rt. After stirring at rt for 2 hr, the mixture was concentrated. The residue was dissolved in 10 mL CH2Cl2, which was added to a suspension of cicletanine (150 mg, 0.57 mmol) and diisopropylethylamine (185 mg, 1.43 mmol). After stirring at rt over night, the mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column 25M; TLC method: n-hexane/ethyl acetate 7/3; Rf=0.35), affording the title product. 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.40-7.28 (m, 4H), 6.29 (s, 1H), 5.42-5.25 (m, 2H), 4.66 (m, 2H), 4.49 (m, 2H), 2.71 (s, 3H), 2.28-2.23 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[C:15]3[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][N:3]=1.O1CCOCC1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N1C=CC=CC=1>ClS(O)(=O)=O>[N:34]1([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[C:15]4[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:6]=2)(=[O:10])=[O:9])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Agent: O=S(=O)(O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)N1CCCCC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cold (5° C.) solution of the 0.456 M solution of 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl chloride (2 mL, 0.912 mmol) in chlorosulfonic acid from above was added anhydrous dioxane (1 mL) and piperidine (1.8 mL, 18.24 mmol). After 30 minutes of stirring, pyridine (1 mL, 12.3 mmol) was added and the reaction mixture stirred for an additional hour at room temperature. The reaction mixture was concentrated in vacuo, the residue dissolved in CH2Cl2 and the pH adjusted to 14 using 6 N NaOH (aq). The solution was extracted with CH2Cl2 (×4) and the combined organic layers dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified twice by silica gel chromatography (0-5% MeOH in EtOAC) to give the title compound as a pale yellow solid (269 mg, 66% yield). MS (ES)+ m/e 446.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FCCNc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
In a round bottom flask 4-fluoroaniline (1.3 g, 11.6 mmol, 1.6 mL) 2,6-lutidine (1.24 g, 11.6 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) were combined in DMF (5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 383 mg (20%) of (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.30-3.35 (1H, m, NCH2CH2F), 3.40-3.45 (1H, m, NCH2CH2F), 3.90 (1H, s, br, NH), 4.53 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.51-6.72 (2H, m, 2×NCCH), 6.85-7.05 (2H, m, 2×NCCHCH).
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.S(=O)(=O)(O)O.[CH3:24]O>>[F:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][C:2]([CH3:8])=[C:3]2[CH2:4][C:5]([O:7][CH3:24])=[O:6]
Reactant: NNc1ccc(F)cc1
Reactant: CO
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Temperature: 120 °C
Yield: 84 %

Procedure:
A stirred mixture of 39.3 mg (0.34 mmol) of 4-oxopentanoic acid,* 50 mg (0.31 mmol) of (4-fluorophenyl)hydrazine hydrochloride, 1 mL of methanol and 40 μL of concentrated sulfuric acid in a 2 mL microwave process vial was heated for 10 min at 120° C. under argon in a microwave synthesizer. The alcoholic solution was concentrated to about one-third of its original volume and then transferred to a phase separator syringe filled with cold water (2 mL). The organic compound was repeatedly extracted with dichloromethane (3×3 mL) and the combined organic phases were washed with brine (2 mL), dried over Na2SO4 and filtered. Removal of the organic solvent and treatment of the residue with a little hexane afford the title compound in 84% yield (39 mg) as viscous mass. C12H12FNO2, Mr=221.23; 1H NMR (400 MHz, DMSO-d6) d: 2.31 (s, 3H), 3.57 (s, 3H), 3.65 (s, 2H), 6.81 (td, J=2.4/9.2 Hz, 1H), 7.10 (dd, J=2.4/10.0 Hz, 1H), 7.21 (dd, J=4.4/8.8 Hz, 1H), 10.97 (s, 1H); 19F NMR (282 MHz, DMSO-d6) d: −123.78 (d, 5′-F); LCMS (ESI) tR: 2.18 min (95%, UV220, ELSD), m/z: 222.2 [M+1]+. [* instead of the acid one could also use the methyl ester with the same outcome]
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[S:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[N:15]=1
Reactant: Cc1nc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccc2C=O)cs1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of 2-bromobenzaldehyde (0.063 mL, 0.54 mmol) in DMF (5 mL) and H2O (1 mL) are added 2-methylthiazole-4-boronic acid pinacol ester (122 mg, 0.54 mmol), Pd(PPh3)4 (63 mg, 0.054 mmol) and K2CO3 (112 mg, 0.81 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The reaction is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2-methyl-thiazol-4-yl)-benzaldehyde (58 mg, 53%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]#[N:17])[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]3[NH:30][N:29]=[N:28][N:17]=3)[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1
Reactant: N#CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1nnn[nH]1

Procedure:
A mixture of 658 mg (2 mmol) of [2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetonitrile and 8 ml of DMF was put in a 50 ml flask. To the mixture were then added 1.30 g of sodium azide and 1.07 g of ammonium chloride with stirring. The mixture was then stirred at a temperature of 120° C. for 4 hours. The resulting reaction mixture was allowed to cool, poured into water, and then extracted with ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then washed with cold ethanol to obtain 512 mg of 2,3-dihydro-[2-((4-chlorophenyl)imino]-3-(1H-tetrazol-5-ylmethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.N1C=CC=CC=1.[CH2:32]([O:34][C:35]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:36])[CH3:33]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:32]([O:34][C:35](=[O:36])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11]2=[O:16])=[CH:41][CH:40]=1)[CH3:33]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-n2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Nitrophenyl)-1H-pyridin-2-one (P3) (0.2 g, 0.92 mmol), copper (II) acetate (0.334 g, 2 equiv.), diisopropylethylamine (0.31 mL, 2 equiv.), and pyridine (0.15 mL, 2 equiv.) were added to a stirred solution of 4-(2-ethoxycarbonylethyl)phenyl boronic acid (0.308 g, 1.3 mmol) in dichloromethane (10 mL). The reaction mixture was then stirred under argon at room temperature for 4 hours. The solution was then filtered through celite, concentrated and purified by chromatography on silica gel (50% v/v ethyl acetate in hexane) to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1)[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:5]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:13][CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)CC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 56 %

Procedure:
Methyl 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-ethoxy}benzoate (0.242 g, 0.455 mmol) was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), lithium hydroxide (0.218 g, 0.909 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.135 g of 2-{2-[4-(2-{isobutyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoic acid (yield 57.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1/[C:5](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)/[C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.N1C=CC=CC=1.CCOCC>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)/[C:4]=1[CH2:3][CH:2]=[O:1]
Reactant: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CSc1ccc(/C=C2/C(CC=O)=C(C)c3ccccc32)cc1
Reaction time: 1.5 h

Procedure:
A solution of the primary alcohol from Step 4 (1 g, 3.25 mmol) in dichloromethane (10 mL) was added dropwise to a mixture of chromium trioxide (3.3 g, 32 mmol, 10 eq.) in dichloromethane (50 mL) at 0° C. containing pyridine (5.1 mL, 63 mmol, 20 eq.). After 1.5 hour, ether was added to precipitate the chromium salts and the heterogenous mixture was filtered through silica gel and washed with ether. After evaporation to dryness, the residue was purified by chromatography on silica gel eluting with a 15:85 mixture of ethyl acetate-hexane to yield the title compound as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:27]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])[C:5]1[S:1][C:2]([CH2:6][N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[N:3][CH:4]=1)[CH2:28][CH2:29][CH3:30]
Reactant: c1csc(CN2CCCCC2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(CN2CCCCC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of 1-thiazol-2-ylmethylpiperidine (2.73 g, 15.0 mmol) anhydrous THF (100 mL) was added n-butyllithium (8.95 mL, 16.5 mmol). After 30 minutes, a solution of tributyltin chloride (4.93 mL, 18.2 mmol) in anhydrous THF (40 mL) was to the reaction mixture. After 10 minutes, the solution was allowed to warm to ambient temperature and saturated aqueous sodium hydrogen carbonate was added. The aqueous phase was extracted with tert-butylmethyl ether (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (5.1 g, 72%). 1H NMR (CDCl3, 400 MHz): 7.62 (t, J=6.4 Hz, 1H), 3.88 (s, 2H), 2.54-2.47 (m, 4H), 1.69-1.49 (m, 10H), 1.50-1.40 (m, 2H), 1.40-1.26 (m, 6H), 1.15-1.08 (m, 6H), 0.95-0.85 (m, 9H).
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2]C.O.[CH2:8](O)C.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16]>CO>[CH3:8][P:1](=[O:6])([O-:4])[O-:2].[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH3+:16].[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH3+:16]
Reactant: COP([O-])OC
Reactant: CCO
Reactant: COCCCN
Solvent: CO
Solvent: O
Product: COCCC[NH3+]
Product: CP(=O)([O-])[O-]
Yield: 99.9 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 8.51 g. (0.1 moles) of 3-methoxypropyl amine and 30 ml. of methanol as described in Example 1. 18.5 g. of 3-methoxypropyl-ammoniummethyl phosphonate are obtained. Yield: 99.9%. nD30 =1.4449.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>C(Cl)Cl>[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)c(F)c5)cn34)ccnc2c1
Reactant: COCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-ethyl-N-isopropylpropan-2-amine (0.077 ml, 0.44 mmol) and 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoyl chloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added 2-methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution was stirred at room temperature for 5 h. The crude material was concentrated and then triturated with sodium bicarbonate and washed with water. The resultant solid was dissolved in DCM/MeOH and concentrated. The crude material was dissolved in DCM/MeOH and was purified via flash chromatography, eluting with 0-10% MeOH/NH4OH in DCM to yield 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide.