Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[NH2:18][OH:19]>C(O)C>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(=NO)CC1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
4-Dimethylamino-4-phenylcyclohexanone (10 g) and hydroxylamine hydrochloride (4.8 g) were dissolved in absolute ethanol (120 ml), basic ion exchanger Amberlyst A 21 (30.7 g) was added to the solution, and stirring was carried out overnight at RT. The ion exchanger was filtered off and washed with ethanol (3×50 ml) on the frit. The ethanol was removed in vacuo and the residue was adjusted to pH 11 with 5M NaOH, diluted with water and extracted with ethyl acetate (4×30 ml). The combined extracts were dried with Na2SO4 and concentrated. 11 g of 4-dimethylamino-4-phenyl-cyclohexanone oxime were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH2:12][CH3:13])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH2:12][CH3:13])[C:9]=2[CH:10]=1
Reactant: CCCn1ncc2c(C(=O)O)cc(Br)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2CCC
Yield: 42.4 %

Procedure:
The title compound was prepared in the same manner as described for example 42 (step b, part 2) from 6-bromo-1-propyl-1H-indazole-4-carboxylic acid (300 mg, 1.06 mmol) and 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (190 mg, 1.06 mmol). The crude product was triturated with diethyl ether (10 mL) and n-pentane (10 mL) to afford the title compound as a white solid (200 mg, 42.5%). 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 0.90 (t, 3H), 1.48-1.46 (t, 2H), 1.86-1.80 (m, 2H), 2.13 (s, 3H), 2.50-2.32 (t, 2H), 4.40-4.35 (m, 4H), 5.90 (s, 1H), 7.69 (s, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.62 (s, 1H), 11.52 (s, 1H). LCMS (ES+): m/z=445.17.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)(=[O:8])[CH3:1]
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
MeMgBr (1 M solution in THF, 50 mL, 50 mmol) was added dropwise at −78° C. to a solution of N,5-dimethoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (6.32 g, 16.4 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH to give the title compound (1.53 g, 27% yield) as pale yellow prisms: mp 193-196° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 6.54 (1H, dd, J=1.9, 2.3 Hz), 7.30 (1H, dd, J=2.3, 8.7 Hz), 7.57 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=2.3 Hz), 7.77-7.78 (2H, m), 8.00 (1H, d, J=2.3 Hz). Anal. Calcd for C17H16N4O4: C, 59.99; H, 4.74; N, 16.46. Found: C, 59.68; H, 5.00; N, 16.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[C:34]([F:40])[C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[C:38]2[C:33]=1[CH2:32][CH2:31][N:30]2[C:28]([C:26]1[CH:27]=[CH:22][N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=1)=[O:29]
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5c4ccc(F)c5F)ccn3)CC1)C(=O)N2

Procedure:
0.18 g (0.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.020 g (0.68 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL NMP for 4 h at 130° C., then overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]CC)=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:29].[OH-]>CO>[NH2:29][C:24]([CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 5 mL of MeOH was added 5 mL of 30% NH4OH solution. The resulting solution was allowed to stir at rt for 12 hr. The MeOH was evaporated in vacuo and water (10 mL) was added. A colorless solid precipitated. The solid was collected by filtration and dried in vacuo giving the title product (218 mg, 62%): mp 100-101° C.; 1H NMR (CDCl3) 1.31 (m, 2 H), 1.60 (m, 1 H), 1.609 (m, 2 H), 2.04 (m, 2 H), 2.53 (d, J=6.6 Hz, 2 H), 2.80 (t, J=4.8 Hz, 2 H), 2.95 (d, J=11.4 Hz, 2 H), 3.55 (s, 2 H), 4.08 (t, J=6 Hz, 2 H), 5.35 (s, 2 H), 6.82 (m, 2 H), 7.13-7.27 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][N:3]=1.Cl[CH:28]([C:31]1([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][CH:38]=[CH:37]3)[CH2:33][CH2:32]1)[CH:29]=O>C(O)(C)C.CO>[N:40]1[C:41]2[C:36](=[CH:35][C:34]([C:31]3([C:28]4[N:7]5[CH:6]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([N:14]7[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]7)=[N:12][CH:13]=6)[CH:4]=[N:3][C:2]5=[N:1][CH:29]=4)[CH2:33][CH2:32]3)=[CH:43][CH:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N)nc3)cn2)CC1
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of tert-butyl 4-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]piperazine-1-carboxylate (0.120 g, 0.337 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.0827 g, 0.337 mmol) in isopropyl alcohol (2.0 mL) was heated at 100° C. overnight. The mixture was diluted with methanol and purified by RP-HPLC (pH 10.0) to give the desired product (80 mg, 43.4%). LCMS: (M+H)=548.2.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30]Br)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:35]([NH2:38])[CH2:36][CH3:37].Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][NH:38][CH2:35][CH2:36][CH3:37])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CBr
Reactant: CCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCNCc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(bromomethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (27 mg, 0.0479 mmol) in MeCN (0.5 mL) was added n—PrNH2.HCl (5.5 mg, 0.0575 mmol) and i—Pr2NEt (20.8 μL, 0.120 mmol). The solution was heated at 80° C. for 16 hours. The reaction was then cooled to room temperature and purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA). The fractions containing the desired product were lyophilized to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-[(propylamino)methyl]-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (TFA salt). LCMS=543.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 9.72 (s, 2H), 7.90 (s, 1H), 7.76 (s, 2H), 7.72 (d, J=6.9 Hz, 1H), 7.56 (d, J=6.4 Hz, 1H), 7.49 (s, 1H), 5.87 (d, J=7.5 Hz, 1H). 4.98 (d, J=15.3 Hz, 1H), 4.35-4.28 (m, 2H), 4.18 (m, 2H), 3.01 (bs, 2H), 1.75-1.60 (m, 2H), 0.96 (m, 3H), 0.90 (d, J=5.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[CH2:38](I)[CH3:39]>>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH2:38][CH3:39])[S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC)S(=O)(=O)C2CCC2)C1=O

Procedure:
By the method of Example 290, Step A, N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide (Example 298, Step A) was treated with ethyl iodide to afford the title compound as a white foam. LCMS (ESI) m/z=591.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:16]1([N:22]=[C:23]=S)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C.[Pd]>[C:16]1([NH:22][C:23]2[O:1][C:2]3[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=3[N:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
In ethanol (10 ml) was dissolved methyl 3-hydroxy-4-nitrophenylacetate (592 mg, 2.81 mmol), followed by the addition of 5% palladium/carbon (194 mg). The resulting mixture was subjected to catalytic hydrogenation overnight under stirring at room temperature and normal pressure. After removal the catalyst from the reaction mixture by filtration through Celite under reduced pressure, the filtrated cake was washed with ethanol (30 ml). The filtrate was stirred at room temperature. After addition of phenyl isothiocyanate (370 μl, 3.09 mmol) and stirring at room temperature for one hour, mercuric oxide (yellow) (1.1 g, 5.07 mmol) was added. The reaction mixture was heated under reflux for 3 hours. The mixture was then cooled and the insoluble matter was filtered out under reduced pressure. The filtrate was distilled under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby methyl 2-phenylaminobenzoxazol-6-acetate (480 mg, 61%) was obtained as a white solid from chloroform-ethyl acetate (10:1, v/v) eluate fractions.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.[CH3:22][O:23][C:24](=[O:31])[C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:22][O:23][C:24]([C:25]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:14][N:15]2[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=12)=[O:31]
Reactant: COC(=O)C#CC(C)(C)C
Reactant: N[n+]1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(C)(C)C)nn2cc(Br)ccc12
Temperature: 25 °C
Yield: 23.6 %

Procedure:
To a solution of 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate (example 41, step 1) (1.98 g, 14.16 mmol) in DMF (20 ml) were added 4,4-dimethyl-pent-2-ynoic acid methyl ester (CAS 20607-85-6) (5 g, 14.16 mmol, 1 equiv.) and K2CO3 (3.9 g, 28.3 mmol, 2 equiv.) and stirred at 25° C. while purging air. DMF was completely evaporated, the residue dissolved in ethyl acetate and washed with water (100 ml). The organic extract was dried with sodium sulfate, filtered and evaporated to dryness. The resulting crude product along with the undesired regioisomer 4-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester was purified by column chromatography. The desired 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (1.04 g, 24% yield) was obtained as a white solid, MS: m/e=312.2 (M+H+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1Br.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 330 ml) was added dropwise with stirring to a solution of 2,6-dichloro-4-trifluoromethylbromobenzene (163.3 g) in ether while maintaining the temperature below -70° C. The mixture was stirred for 1 hour at -78° C. then ethyl chloroformate (61.7 g) was added while maintaining the temperature below -70° C. The mixture was stirred at room temperature overnight. It was cooled to 0° C. and a saturated aqueous solution of ammonium chloride was added. The layers were separated and the organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give ethyl 2,6-dichloro4-trifluoromethylbenzoate (123.9 g) as a colourless liquid bp 90°-96° C. at 5 mmHg.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][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][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])[CH:12]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:46]([O:45][P:40]([CH2:39][CH2:38][CH2:37][O:36][C:13]1[CH:14]=[C:15]([O:17][CH2:18][CH2:19][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][CH2:34][CH3:35])[CH:16]=[C:11]([NH2:10])[CH:12]=1)(=[O:41])[O:42][CH2:43][CH3:44])[CH3:47]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCP(=O)(OCC)OCC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCP(=O)(OCC)OCC)c1
Yield: 92 %

Procedure:
A mixture of 2.47 g of [3-[3-(diethoxyphosphinyl)propoxy]-5-(octadecyloxy)phenyl]carbamic acid phenylmethyl ester and 0.4 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from ether-hexane to give 1.83 g (92% yield, mp 63°-65°) of [3-[3-amino-5-(octadecyloxy)phenoxy]propyl]phosphonic acid diethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.[F:37][CH2:38][C:39](OCC)=[O:40]>C1COCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:39](=[O:40])[CH2:38][F:37])[CH:31]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)CF
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(CF)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A 2.0 M solution of LDA in heptane/THF/ethylbenzene (100 mL, 200 mmol) was added dropwise via syringe to a solution of 1-bromo-4-fluorobenzene (20 mL, 182 mmol) in THF (600 mL) at −78° C. After stirring for 2.5 hours at −78° C., ethyl monofluoroacetate (18.47 mL, 191 mmol) was added dropwise via syringe, and the reaction was stirred at −78° C. for 20 minutes and then stirred at −45° C. for 30 minutes before being quenched with saturated aqueous ammonium chloride at −45° C. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous ammonium chloride, water, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was dissolved in a minimal amount of methanol and placed in a −20° C. freezer overnight. The resulting solid was collected and washed with cold methanol to afford the title intermediate (12.07 g, 51.6 mmol, 28% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:5][CH2:4][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][OH:1]
Reactant: N#CC(CO)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CO)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 3-hydroxy-2,2-diphenylpropanenitrile in tetrahydrofuran (50 mL) was slowly added dropwise to a suspension of LAH in tetrahydrofuran (20 mL) at 23° C. The reaction was stirred overnight, then quenched with sodium sulfate decahydrate. The resulting solid was removed by filtration and the filtrate was concentrated to dryness to give the title material (0.45 g, 88%) as an oil which was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 2.49 (2H, s), 3.77 (1H, ddd, J=6.63, 4.23 and 2.53 Hz), 3.82 (2H, s), 4.30 (2H, s), 7.25-7.36 (10H, m). LC/MS (M+H)+: 228. HPLC ret. time (Condition A): 1.228 min.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[CH:30][C:29]([O:35][CH3:36])=[CH:28][CH:27]=2.C(OCC)(=O)C>C(#N)C>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[CH:33]=[O:34])=[C:30]([F:21])[C:29]([O:35][CH3:36])=[CH:28][CH:27]=2
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COc1ccc2ncc(Cl)c(C=O)c2c1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(C=O)c2c1F
Temperature: 10 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
Selectfluor (2.4 g, 6.77 mmol, 1.5 eq) is added at 10° C. to a stirred solution of 3-chloro-6-methoxy-quinoline-4-carbaldehyde (1.0 g, 4.5 mmol, 1.0 eq) in acetonitrile (50 mL). After 24 hours stirring at 10° C., the reaction mixture is extracted with ethyl acetate (3×100 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 3-chloro-5-fluoro-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (620 mg, 57% yield).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[C:13]3[S:20][C:19]([C:21]4[N:25]5[N:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[CH:18][C:14]=3[CH:15]=[N:16][CH:17]=2)(=O)=O)=CC=1.[OH-].[Na+]>CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]2[N:25]([C:21]([C:19]3[S:20][C:13]4[C:12]([OH:11])=[CH:17][N:16]=[CH:15][C:14]=4[CH:18]=3)=[CH:22][N:23]=2)[N:26]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cncc3cc(-c4cnc5ccc(Cl)nn45)sc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of 2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-yl 4-methylbenzenesulfonate (200 mg, 0.349 mmol, 1.0 equiv) in MeOH (5.0 mL) was added sodium hydroxide (70 microliter, 5.0 M aqueous solution, 1.0 equiv). The reaction mixture was stirred at rt for 3 h, then quenched with water and extracted with ethyl acetate. Purification using column chromatography gave 80 mg of the white product, 76%.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1.Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][N:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=1)[C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1
Reactant: CN(c1ccc(O)cc1)c1ncc([N+](=O)[O-])s1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1ccc(N(C)c2ncc([N+](=O)[O-])s2)cc1
Yield: 35.6 %

Procedure:
A mixture of 4-[N-methyl-N-(5-nitro-2-thiazolyl)amino]phenol (2.51 g), methyl 2-bromopropionate (1.67 g), anhydrous potassium carbonate (1.52 g) and methyl ethyl ketone (50 ml) was heated under reflux for a period of 18 hours. The mixture was cooled, extracted with dichloromethane and the organic extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give a brown oil. The crude product was purified by chromatography over silica gel with dichloromethane elution to give the required product (1.2 g) as a colourless oil. The pmr spectrum of the product was consistent with the assigned structure (CDCl3 ; chemical shift δ ppm): 1.65, d, 3H; 3.55, s, 3H; 3.85, s, 3H; 4.80, q, 1H; 7.20, m, 4H; 8.20, s, 1H.