Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)O1.[F:27][C:28]1[C:29](I)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1>O1CCOCC1.O.[Pd]>[F:27][C:28]1[C:29]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:48])=[O:49])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(-n3ncnn3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3ncnn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Pd EnCat™ (317 mg, 0.10 mmol) was added to a mixture of potassium carbonate (393 mg, 2.84 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole (258.4 mg, 0.95 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (490 mg, 0.95 mmol), T3, in 1,4-dioxane:water (4:1, 10 mL). The reaction was heated to 80° C. and stirred at this temperature overnight. The reaction was filtered through celite, and the filter pad was washed with methanol (250 mL). The combined filtrates were concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (20-100%) and methanol in EtOAc (0-10%) to afford the title compound as a light tan solid (500 mg, 98%). MS (LCMS) m/z 534.4 (M−1). 0
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][N:21]([C:25](=[O:27])[CH3:26])[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Yield: 78.1 %

Procedure:
To a stirred solution of morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate dihydrochloride (Example 10; 0.52 g, 1.40 mmol) in pyridine (2.25 mL, 27.7 mmol) was slowly added acetyl chloride (0.15 mL, 2.10 mmol). The reaction mixture was stirred at room temperature for 1 h before the pyridine was removed in vacuo and the resulting residue diluted with sat aq NaHCO3 solution (50 mL). The organic product was extracted with EtOAc (3×50 mL). The combined organic layers were washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in EtOAc). The solvents were removed in vacuo and dried in a vacuum oven overnight to afford (4-acetylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate (0.38 g, 78%) as a pale brown oil.
Reaction SMILES: Cl.[C:2](=[N:10][OH:11])(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.I[C:13]([CH:15]1[CH2:17][CH2:16]1)=[CH2:14].C(N(CC)CC)C>C(O)C>[CH:15]1([C:13]2[O:11][N:10]=[C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=2)[CH2:17][CH2:16]1
Reactant: C=C(I)C1CC1
Reactant: ON=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cncc(-c2cc(C3CC3)on2)c1
Reaction time: 1 h

Procedure:
To a stirred mixture containing 1.35 g. of nicotinoyl chloride oxime hydrochloride and 2.6 g. of 1-iodovinylcyclopropane in 50 ml. of ethanol is added dropwise over a 1 hour period, a solution of 4.27 g. of triethylamine in 40 ml. of ethanol. The reaction is stirred for 1 hour and then the solvent is removed under reduced pressure. The residue is dissolved in water and ether and the ether layer is separated. The water layer is extracted twice with ether and then the combined ether layers are dried over sodium sulfate. Filtration and removal of the solvent under reduced pressure gives an orange-yellow solid. This material is recrystallized from isopropyl alcohol to give white crystals, melting point 74°-75°C., nmr spectrum δ6.82 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:7]1[C:8]3[C:13](=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3)[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OCC)cc2cc1Cc1c(O)nc(C(C)C)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 16 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL) The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 46 as a yellow solid (12 mg, 4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Cl.CO[C:15](=N)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1>CO>[CH3:27][O:26][C:20]1[CH:19]=[C:18](/[CH:17]=[CH:16]/[C:15]2[NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: CO
Product: COc1ccc(/C=C/c2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1OC
Yield: 23.2 %

Procedure:
A mixture of 4-nitro-1,2-phenylenediamine (1.2 g; 8 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (2.0 g; 8 mmol) in methanol (70 mL) was refluxed for 18 hours. Solution was concentrated to dryness. The residue was recrystallized from MeOH to obtain 603 mg (23% yield) of the title compound as a yellow solid, m.p. 223-225° C. Anal. Calcd. for C17H15N3O4: C, 62.76, H, 4.65; N, 12.92. Found: C, 62.67; H, 4.62; N, 13.05. Mass spectrum: (EI; M+) m/z 325. 1H-NMR (DMSO-d6; 400 MHz) δ13.2(broad s, 1H), 8.4 (broad s, 1H), 8.1(dd, 1H), 7.74 (s, 1H), 7.62-7.72 (m, 1H), 7.35 (d 1H), 7.19-7.23 (dd, 1H), 7.17 (s, 1H), 7.0 (d,1H),3.85 (s, 3H), 3.8 ppm (s, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]([O-])=[O:11].[Na+].[Cl-].[K+]>C(O)(=O)C.O>[OH:11][N:10]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(C)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Under N2, a solution of ethyl acetoacetate (286 mL, 292 g, 2.24 mol) dissolved in 300 mL of acetic acid was cooled to -10° C. Maintaining that temperature, NaNO2 (80 g, 2.61 mol) in 400 mL of water was slowly added, and the mixture then stirred 30 minutes at 0° C., at which time KCl (160 g, 2.15 mol) in 800 mL of water was added over 20 minutes, the mixture stirred for an additional 30 minutes at0° C. and then extracted 3×1 L ether. The organic layers were combined, washed 2×1 L water and 1×1L brine, dried (MgSO4) and stripped to yield 343.3 g (96%) of title product as an oil; tlc Rf 0.3 (1:19 CH3OH:CHCl3).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:26]
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) in DMF (3 ml) was added 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 45 mg, 0.204 mmol), TBTU (78 mg, 0.245 mmol) and DIPEA (40 mg, 0.306 mmol). The reaction was stirred at room temperature for 2 hours and was then diluted with water (25 ml) and extracted with ethyl acetate (3×30 ml). The organics were washed with water (25 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography (silica, 0-45% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[Br:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([CH:34]=[C:2]([CH3:4])[CH3:3])[CH:32]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)=Cc1cccc(Br)c1
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a stirred slurry of 17.83 g (41.2 mmol) of isopropyltriphenylphosphonium iodide and 300 mg (1.1 mmol) of 18-crown-6 in 50 mL of THF under nitrogen at 5° C. was added 4.60 g (41.0 mmol) of potassium t-butoxide over 5 minutes. The resulting deep red-orange slurry was stirred 10 minutes and then a solution of 4.31 mL (37.0 mmol) of 3-bromobenzaldehyde in 40 mL of THF was added at a rate to keep the temperature below 10° C. The resulting bright yellow slurry was stirred for 20 minutes and then poured into 300 mL of hexanes. The solids were filtered off and the filtrate evaporated. This residue was purified by flash chromatography (5×15 cm column) and eluted with hexanes to provide 5.88 g (75%) of title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:24]1([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:30])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of {3-[3-(2,2-Diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.03 g, 0.000074 mol) in methanol (3 mL) was treated with 2N NaOH (2 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (15 mL) and water was added (5 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as a solid 0.025 g in 83% yield. Crystallization of the solid from EtOAc gave white crystals, mp: 49.1° C. 1HNMR (CD3OD) δ 7.17 (m, 1H), 6.80 (d, 1H), 6.78 (d, 1H), 6.64 (s, 1H), 4.12 (t, 1H), 3.56 (s, 2H), 3.49 (t, 2H), 3.12 (d, 2H), 2.66 (t, 2H), 1.72 (t, 2H); 13C NMR (CD3OD) δ 176.0, 160.1, 143.5, 137.9, 130.4, 129.9, 129.1, 128.0, 122.9, 116.6, 113.9, 65.9, 60.1, 54.8, 51.9, 42.6, 26.3. Anal. Calcd for C25H27NO3. 2H2O: C, 70.56; H, 6.40; N, 3.29. Found: C, 70.58; H, 6.28; N, 3.20.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.C(OCC)(=O)C.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]>[Cl:17][C:15]1[CH:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[C:13]([NH:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:14]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(Br)cnc21
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(Nc3ccccc3)cnc21
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A solution of Example 171a (0.200 g, 0.366 mmol), aniline (0.044 g, 0.476 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (X-PHOS) (0.009 g, 0.018 mmol), catalytic tris(dibenzylideneacetone)dipalladium (0) and potassium carbonate (0.127 g, 0.916 mmol) in 4 mL tert-butanol was heated at 110° C. for 16 hours. The material was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using flash chromatography (20% ethyl acetate/hexane) to afford 0.025 gm of the title compound. m/z 558.0 (APCI, M+H)+.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][CH:24]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C>[ClH:1].[ClH:1].[C:36]([N:32]1[CH2:33][CH2:34][C@H:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)[CH2:31]1)(=[NH:41])[CH3:37]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCNC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 193.4 %

Procedure:
In 1,000 ml of ethanol was dissolved 105.3 g of ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. With stirring at room temperature, the thus prepared solution was mixed with 51.5 g of ethyl acetimidate hydrochloride. With ice cooling and stirring, 89 ml of triethylamine was added dropwise to the above solution while keeping the inner temperature at 3 to 5° C., and the stirring was continued for 2.5 hours while keeping the temperature at 5° C. or below. After distilling off the solvent under a reduced pressure at a low temperature, the resulting reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid, followed by further distillation under a reduced pressure to remove the solvent. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 110.1 g of the title compound was obtained in the form of a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC3CCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and cyclopentanol (67.3 mg; 0.781 mmol), example 65 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:21](=[O:29])([O:26][CH2:27][CH3:28])[O:22][CH:23](Cl)[CH3:24]>C1COCC1.[Na+].[I-]>[CH3:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:23]([O:22][C:21]([O:26][CH2:27][CH3:28])=[O:29])[CH3:24])=[O:18]
Reactant: CCOC(=O)OC(C)Cl
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)OC(C)OC(=O)CCCCCCCC(=O)OC
Temperature: 60 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
A heterogeneous solution of Cs2CO3 (1.30 g, 4.0 mmol), NaI (30 mg, 0.20 mmol) and nonanedioic acid monomethyl ester (0.95 g, 4.0 mmol) in THF (15 ml) was stirred for ½ hour at 60° C. 1-Chloroethyl ethyl carbonate (0.61 g, 4.0 mmol) in THF (5 ml) was added dropwise to the solution and stirred at 60° C. for 48 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. Diethyl ether (25 ml) was added and the residue was washed with saturated NaHCO3 (3×25 ml), dried with MgSO4 and filtered. Evaporation in vacuo gave the product as a colourless oil (0.96 g, 75.1%). 1H-NMR (CDCl3) δ 6.74 (q, 1H), 4.19 (q, 2H), 3.64 (s, 3H), 2.34-2.24 (m, 4H), 1.63-1.53 (m, 4H), 1.49 (d, 2H), 1.33-1.24 (m, 9H). 13C-NMR (CDCl3) δ 174.55, 172.04, 162.92, 153.39, 91.48, 64.75, 51.79, 36.85, 34.37, 31.78, 29.24, 25.19, 24.82, 19.09, 14.48.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.[I-].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH:19][C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2cc(OCc3ccccc3)ccc12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cccc2cc(OCc3ccccc3)ccc12
Temperature: 146 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-benzyloxy-naphthalen-1-ylamine (4.71 grams, 16.2 mmol) in DMF (25.0 mL) at room temperature was added NaH (372 mg, 16.2 mmol). After 0.5 h, 2-chloro-3-nitropyridine (5.53 grams, 35 mmol) and potassium iodide (2.8 grams, 17 mmol) were added. The reaction mixture was heated at 146° C. for 17 hours. The cooled solution was diluted with ether (300 mL) and the ether solution was washed with saturated aqueous NaCl (2×50 mL). The aqueous solution was extracted with CHCl3 (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using a gradient of 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to 3.0 grams of a yellow product. 1H NMR (250 MHz, CDCl3): d 8.63 (dd, 1H, J=1.65, 4.8 Hz), 8.58 (dd, 1H, J=1.7, 8.3 Hz), 8.41 (dd, 1H, J=1.73, 4.43 Hz), 8.23 (dd, 1H, J=1.63, 10.2 Hz), 7.93 (d, 1H, J=10 Hz), 7.75 (d, 1H, J=7.32 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.26 (m, 6 H), 6.80 (dd, 1H, J=4.4, 8.1 Hz), 5.25 (s, 2 H).
Reaction SMILES: [F:1]C1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1N1C[C@@H]2[C@@H](CN(CCO)C2)C1.[F:30][C:31]1[CH:32]=[C:33]([N:49]2[CH2:53][C@H:52]([CH2:54][NH:55][C:56](=[O:58])[CH3:57])[O:51][C:50]2=[O:59])[CH:34]=[CH:35][C:36]=1[N:37]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][N:41]([CH2:45][CH2:46]OC)[CH2:42]2)[CH2:38]1.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1N1C[C@@H]2[C@@H](CN(CC#N)C2)C1.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1N1C[C@@H]2[C@@H](CN(C(OC)=O)C2)C1>>[F:30][C:31]1[CH:32]=[C:33]([N:49]2[CH2:53][C@H:52]([CH2:54][NH:55][C:56](=[O:58])[CH3:57])[O:51][C:50]2=[O:59])[CH:34]=[CH:35][C:36]=1[N:37]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][N:41]([CH2:45][CH2:46][F:1])[CH2:42]2)[CH2:38]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(CCO)C[C@H]4C3)c(F)c2)C(=O)O1
Reactant: COCCN1C[C@@H]2CN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)C[C@@H]2C1
Agent: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(CC#N)C[C@H]4C3)c(F)c2)C(=O)O1
Agent: COC(=O)N1C[C@@H]2CN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)C[C@@H]2C1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(CCF)C[C@H]4C3)c(F)c2)C(=O)O1

Procedure:
(S)-N-[[3-[3-fluoro-4-[cis-3-(2-hydroxyethyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (S)-N-[[3-[3-fluoro-4-[cis-3-(2-methoxyethyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (S)-N-[[3-[3-fluoro4-[cis-3-(cyanomethyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (S)-N-[[3-[3-fluoro4-[cis-3-(carbomethoxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
Reaction SMILES: Br.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[Cl:12][C:13](Cl)(Cl)[S:14]Cl.[OH-].[Na+].O>ClCCl>[Cl:12][C:13]1[S:14][N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[Cl:2])[N:6]=1
Reactant: N=C(N)c1ccccc1Cl
Reactant: ClSC(Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2Cl)ns1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 37 g of 2-chlorobenzamidine hydrobromide in 160 ml of dichloromethane, cooled to -10° C., are added dropwise 36 g of trichloromethanesulphenyl chloride dissolved in 160 ml of dichloromethane. After stirring for 30 min, 65 ml of aqueous 50% NaOH solution are added dropwise to the medium, still at -10° C. The solution is allowed to return to room temperature and is stirred for 2 h. Water is added to the reaction medium and the phases are separated after settling has taken place. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness.