Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C@@H:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Ic1ccc(I)cc1
Product: Ic1ccc(O[C@H]2CN3CCC2CC3)cc1

Procedure:
3-(R)-Hydroxyquinuclidine (the product of Reference Example 1, 0.64 g, 5.0 mmol) was treated with 1,4-diiodobenzene (1.98 g, 6.0 mmol) according to the procedure of Example 14A. The title compound was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as a solid (0.50 g, yield, 15%). 1H NMR (MeOH-d4, 300 MHz) δ 1.41–1.54 (m, 1H), 1.59–1.73 (m, 1H), 1.73–1.86 (m, 1H), 1.92–2.05 (m, 1H), 2.09–2.17 (m, 1H), 2.71–2.97 (m, 5H), 3.24–3.34 (m, 1H), 4.44–4.52 (m, 1H), 6.72 (d, J=8.8 Hz, 2H), 7.55 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH3): m/z 330 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.Cl.[NH2:19][C@H:20]([C:23]([OH:25])=[O:24])[CH2:21][SH:22].C(O)C>O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][S:22][CH2:21][C@@H:20]([C:23]([OH:25])=[O:24])[NH2:19])=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Triethylamine (206 g) and 4-methoxybenzyl chloride (89 g) were added in turn to a solution of cysteine hydrochloride (107 g) in a 2:1 v/v mixture of ethanol and water (1000 ml). The mixture was stirred at laboratory temperature for 16 hours. The mixture was filtered to give S-(4-methoxybenzyl)cysteine (107.4 g). The filtrate was stored -10° C. for 48 hours and a second crop (22.3 g) of the cysteine derivative was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:42][NH2:43]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:43][CH3:42])[N:4]=1
Reactant: CN
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A solution of Example C2 (0.15 g, 0.357 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.11 g, 0.43 mmol), stirred at RT overnight, treated with methylamine (2.0M in THF, 3.6 mL, 7.2 mmol) and stirred at RT for 4 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (100 mg, 70%). MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.C1C=CC=CC=1.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>CCCCCC>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]([Si:20]([CH3:23])([CH3:22])[CH3:19])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N([Si](C)(C)C)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A glass reactor equipped with a stirrer, nitrogen inlet, reflux condenser and addition funnel was purged with nitrogen and charged with 29.1 g (0.30 mol) of methanesulfonamide, MeSO2NH2, where Me represents the methyl radical, 84.9 ml (0.605 mol) of triethylamine and 240 ml of dry benzene. Trimethylchlorosilane (129.5 ml, 1.00 mol) was then added through the addition funnel over a period of 15 minutes to the stirred mixture, followed by heating at the boiling point for three hours. The mixture was then diluted with 200 ml of hexane and stirring was continued for 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:72][CH:73]([SH:75])[CH3:74]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([S:75][CH:73]([CH3:74])[CH3:72])[CH:12]=1)=[O:17]
Reactant: CC(C)S
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(SC(C)C)c1
Yield: 88.8 %

Procedure:
A tube was charged with 66.15D (213 mg, 552 μmol), N-ethyl-N-isopropylpropan-2-amine (143 mg, 1103 μmol) and toluene, evacuated and back-filled with nitrogen three times. Pd2(dba)3, 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (31.9 mg, 55.2 μmol) and propane-2-thiol (63.0 mg, 827 μmol) were added to the mixture and then the mixture was degassed three times. The suspension was refluxed overnight, filtered, and concentrated to give a residue which was purified by silica gel chromatography to give 69.24A as a pale yellow solid (164 mg, 89%). MS ESI m/e: 335.2 (M+1)+.
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:19][C:20]([C:22]3[NH:26][C:25]4[S:27][C:28]([Cl:30])=[CH:29][C:24]=4[CH:23]=3)=[O:21])[C:10]2=[O:31])[CH2:5][O:4]1>C1COCC1>[Cl:30][C:28]1[S:27][C:25]2[NH:26][C:22]([C:20]([NH:19][CH:11]3[CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]([CH2:8][CH:6]([OH:7])[CH2:5][OH:4])[C:10]3=[O:31])=[O:21])=[CH:23][C:24]=2[CH:29]=1
Reactant: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reaction time: 4 h
Yield: 8.3 %

Procedure:
6M Aqueous HCl (1.47 mL) was added to N-{1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 3; 340 mg, 7.45 mmol) in THF (14 mL) and the reaction was stirred for 4 h. The reaction was quenched by addition of triethylamine (1.5 mL) then diluted with water (30 mL) and EtOAc (40 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was triturated with hot Et2O (10 mL) and after cooling was filtered and dried to afford the title compound (260 mg, 83%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][CH2:16][CH2:17][C:18]=1[N+:19]([O-:21])=[O:20]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][CH2:16][CH2:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSC1=C([N+](=O)[O-])CCN1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC1=C([N+](=O)[O-])CCN1
Yield: 65.9 %

Procedure:
A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.3 g, 0.0076 mol) and 2-methylthio-3-nitro-4,5-dihydropyrrole (1.2 g, 0.0075 mol) in ethanol (50 ml) was refluxed for 11/2 hours. The mixture was cooled, and the solid was filtered off and recrystallised from methanol/water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole (1.4 g, 66%) m.p. 207.5°-208°. Found: C, 46.65; H, 6.15; N, 24.6; S, 11.5; C11H17N5O2S requires: C, 46.6; H, 6.05; N, 24.7; S, 11.3%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]1[CH2:17][CH:12]2[CH2:11][CH2:10]1.[B:18](OC)([O:21]C)[O:19]C.Cl>C1COCC1.C(OC)(C)(C)C>[CH:12]12[CH2:17][CH:9]([C:8]3[C:7]([B:18]([OH:21])[OH:19])=[CH:16][CH:15]=[CH:14][C:13]=31)[CH2:10][CH2:11]2
Reactant: Brc1cccc2c1C1CCC2C1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1C1CCC2C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
100 ml (250 mmol) of n-butyllithium (2.5M in hexane) are added dropwise to a solution, cooled to −78° C., of 44.6 g (200 mmol) of 5-bromo-1,2,3,4-tetrahydro-1,4-methanonaphthalene in 500 ml of THF. The reaction mixture is stirred at −78° C. for 1 h, and a mixture of 33.5 ml (300 mmol) of trimethyl borate in 50 ml of THF is then added rapidly. After warming to −10° C., the mixture is hydrolysed using 10 ml of 2.5M hydrochloric acid, and 500 ml of methyl tert-butyl ether are then added. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up in 200 ml of n-heptane, and the colourless solid is filtered off with suction, washed with n-heptane and dried under reduced pressure. Yield: 24.1 g (128 mmol), 64.1% of theory; purity: 98% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[NH2:13]/[C:14](/[CH3:18])=[CH:15]\[C:16]#[N:17]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]([CH:11]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:2]([CH3:10])=[C:3]2[C:4]#[N:5])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: C/C(N)=C/C#N
Reactant: O=Cc1ccc2[nH]ncc2c1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2F)C(C#N)=C(C)N1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
250 mg (1.52 mmols) 4-fluoro-1H-indazole-5-carbaldehyde (Synthetic Preparation 11) and 250.1 mg (3.05 mmols) 3-aminocrotononitrile were dissolved in 1.74 mL acetic acid and refluxed for 1.5 hours. The mixture was allowed to cool to room temperature, filtered and washed with a little amount of acetic acid. The product was dried under vacuum at 40° C. to yield a first crop. The mother liquors were diluted with ethyl acetate, washed with water and saturated sodium hydrogen carbonate solution and dried over sodium sulfate to yield a second crop. Together 232 mg (51, 9%) 4-(4-fluoro-1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarbonitrile were obtained (Cpd. No. 311). 1H-NMR (DMSO-d6): δ=13.42 (br s, 1H), 9.58 (br s, 1H), 8.21 (s, 1H), 7.44 (d, 1H), 7.32 (dd, 1H), 4.86 (s, 1H), 2.04 (s, 6H) ppm.
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.Cl[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]1([CH2:19][O:20][CH2:23][CH2:24][CH2:25][NH2:26])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Reactant: NCCCCl
Agent: Cl
Product: NCCCOCc1scc2c1-c1ccccc1Sc1ccccc1-2

Procedure:
Starting from the alcohol 15 (0.27 mmole) and 3-chloropropylamine-hydrochloride (2.7 mmoles), an oily product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
A slurry of 3-bromophenol 100 g (580 mmol), benzylchloride 80 g (700 mmol), and K2CO3 168 g (1210 mmol) in 2 L of DMF was stirred for sixteen hour at ambient temperature. The reaction mixture was filtered and evaporated to dryness. The solid was partioned between CHCl3 and water. The organic layer was separated, washed twice with brine, and dried by filtration through anhydrous Na2SO4. The solution was evaporated to dryness. This yielded 142.5 g of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(Nc5ccccc5)sc4c3)c2cc1OC
Temperature: 120 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (60 mg, 0.148 mmol) from Step 4 of Example 2 in aniline (0.6 mL) was added DIEA (23 mg, 0.178 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. for 48 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine (31 mg, 50%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.53 (br s, 1H), 8.18 (s, 1H), 7.71-7.82 (m, 3H), 7.56 (d, J=8.3 Hz, 1H), 7.26-7.42 (m, 3H), 7.19 (d, J=3.2 Hz, 2H), 7.01 (t, J=7.3 Hz, 1H), 5.48 (s, 2H), 3.77 (s, 6H). LCMS (ESI) m/z 417 (M+H)+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[CH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[OH:9][CH:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1cccc(CCCC=O)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(CCCC(O)c2ccccc2)c1
Temperature: 23 °C

Procedure:
A 1.0 M solution of PhMgBr (1 equiv, 0.45 mmol) was added dropwise to a solution of methyl 2-(3-(4-oxobutyl)phenyl)acetate (1 equiv, 100 mg, 0.45 mmol) in THF (2 mL) at 0° C. The reaction was then allowed to warm to 23° C. over 1 h. The reaction was quenched by the addition on sat. aq. NH4Cl (10 mL). The aqueous phase was separated and extracted with EtOAc (2×5 mL). The organic layers were then combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes to afford methyl 2-(3-(4-hydroxy-4-phenylbutyl)phenyl)acetate in 78 mg (58%) as a clear translucent oil. LRMS: 298.4 (calc) 321.2 (found)(MH)+.
Reaction SMILES: [C:1]1(=O)[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][N:4]2[CH:3]=[N:2]1.I[C:12]1[CH:19]=[C:18]([CH3:20])[C:15]([C:16]#[N:17])=[C:14]([CH3:21])[CH:13]=1>>[CH3:21][C:14]1[CH:13]=[C:12]([CH:6]2[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:19]=[C:18]([CH3:20])[C:15]=1[C:16]#[N:17]
Reactant: Cc1cc(I)cc(C)c1C#N
Reactant: O=C1N=CN2CCCC=C12
Product: Cc1cc(C2CCCn3cncc32)cc(C)c1C#N

Procedure:
starting from 6,7-dihydro-5H-imidazo[1,5-a]pyridin-one [426219-51-4] and 4-iodo-2,6-dimethylbenzonitrile [160682-00-8]
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCN=C=NCCCN(C)C.[CH:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32](O)[CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([O:6][C:32]1[CH:31]=[CH:30][C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1)=[O:5]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
To a solution of 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 300 mg, 1.12 mmol) in THF (5 mL) were added EDCI (210 mg, 1.09 mmol), p-nitrophenol (154 mg, 1.10 mmol) and DIPEA (558 mg, 4.39 mmol) and the reaction mixture was stirred at rt for 4 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 222 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.36 (d, J=9.0 Hz, 2H), 8.20 (t, 1H), 7.97 (s, 1H), 7.62-7.59 (m, 3H), 7.51 (d, J=8.1 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 1.11 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH2:20][C:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[C:30]([O:29][C:28](=[O:34])[NH:27][C:21]([CH3:26])([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][O:19][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Yield: 34.3 %

Procedure:
8-Chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.580 mmol), prepared as described in Example 16, Part G, and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.161 g, 0.696 mmol) were subjected to the Buchwald coupling as described in Example 16, Part H, to afford tert-butyl(1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (0.22 g, 0.199 mmol, 34% crude yield). Crude product was used for next step without further purification. LC/MS (ESI) m/e 454.1 [(M+H)+, calcd for C26H36N3O4, 454.3]; LC/MS retention time (method D): tR=0.93 min.
Reaction SMILES: [OH:1][C:2]([P:15](=[O:18])([OH:17])[OH:16])([P:11](=[O:14])([OH:13])[OH:12])[CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.I[CH3:20]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:15]([OH:16])([OH:17])=[O:18])([P:11]([OH:12])([OH:13])=[O:14])[CH2:3][CH2:4][C:5]1[CH:6]=[N+:7]([CH3:20])[CH:8]=[CH:9][CH:10]=1
Reactant: O=P(O)(O)C(O)(CCc1cccnc1)P(=O)(O)O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[n+]1cccc(CCC(O)(P(=O)(O)O)P(=O)(O)O)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
[1-Hydroxy-3-(3-pyridinyl)propylidene]bis[phosphonic acid](3.37 mmol 1.0 g) is dissolved in 8.4 ml of 1N NaOH solution with 29 ml of distilled water. Iodomethane (16.83 mmol, 1.05 ml) is added in 19 ml of ethanol. This reaction mixture is heated at 80° C. overnight. The solvent is evaporated in vacuo and the residue is triturated with acetone then recrystallized from ethanol and water to yield 0.5 g of 3-(3-hydroxy-3,3-diphosphonopropyl)-1-methyl pyridinium hydroxide, inner salt.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:24]=[C:25](Br)[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.[Cl-].[Li+]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.CCCCCC>[F:22][C:23]1[CH:28]=[C:27]([C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[C:10]3[N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Fc1cccc(Br)c1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1CCN(c2cccc3ccc(-c4cccc(F)c4)cc23)CC1

Procedure:
The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-fluoro-1-bromobenzene (0.13 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 2 hours at 120 to 130° C. The product obtained was 0.13 g (59%) in yield. A sample was obtained by recrystallization from ether/hexane for analysis: mp 116°-116.5° C. Analysis calculated for C22H21FN2 : C, 79.49; H, 6.37; N, 8.43. Found: C, 79.07; H, 6.46; N, 8.66.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)=O.O>CC(C)=O.[Cl-].[Na+].O>[I:1][CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](CCCI)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Anhydrous sodium iodide (600 mg, 4.0 mmol, 2 equiv) is added to a solution of (S)-1-methanesulfonyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 7 (622 mg, 2.0 mmol) in 3.0 ml of absolute acetone. The mixture is stirred for 2 h at 50° C. 10 ml of a mixture of brine and water (1:1) are added, and the mixture is extracted with diethyl ether (3×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 20:1) affords (S)-1-iodo-5-(tert-butyidimethylsilyloxy)-4-methyl-pentane 8 (647 mg, 94%) as a colourless oil. FG 342.34; 13C-NMR (100 MHz, CDCl3): δ=68.1, 35.1, 34.3, 31.3, 26.0, 16.7, 7.4, −5.3
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:22][C:23]1[C:31]([F:32])=[CH:30][C:29]([O:33][Si](C(C)C)(C(C)C)C(C)C)=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].O>O1CCCC1>[F:22][C:23]1[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: CC(C)[Si](Oc1cc(F)c(F)c(C(=O)O)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(O)cc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Tetrabutylammonium fluoride trihydrate (191 g, 731.8 mmol) was added in portions to a solution of 2,3-difluoro-5-(triisopropylsilyloxy)benzoic acid (99.13 g, 300.0 mmol) in tetrahydrofuran (500 mL), and the resulting mixture stirred overnight at room temperature. The reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine (2×500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2,3-difluoro-5-hydroxybenzoic acid (50 g, 95%) as a light yellow solid. MS (ESI, neg. anion) m/z 173 [M−H]−.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: Cc1ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of [(S)-1-(6-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (969 mg, 2.76 mmol) in DCM (7.5 mL) was added TFA (2.5 mL) and the mixture was stirred at RT for 20 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (30 mL) and washed with a saturated solution of NaHCO3 (40 mL). The two phase system was stirred for 10 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(6-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (583 mg, 84%). LCMS: RT 3.02 min [M+H]+ 252.2