Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
4-Iodophenol (10 g, 45.4 mmol), 1-bromo-3-chloropropane (7 g, 50.0 mmol) and potassium carbonate (7.54 g, 54.5 mmol) were mixed in DMF, and stirred at room temperature for 15 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=5/95) to obtain the entitled compound (11.1 g, 82.3%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:18][CH2:19]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[C:3]1([C:9]2[N:10]=[C:11]([C:14]3([C:15]#[N:16])[CH2:19][CH2:18]3)[S:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: N#CCc1nc(-c2ccccc2)cs1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(c2nc(-c3ccccc3)cs2)CC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 41.2 %

Procedure:
Benzyltriethyl ammonium chloride (34 mg, 0.15 mmol) and 50% aqueous NaOH solution (0.59 g dissolved in 1 mL of water) were added to a solution of 2-(4-phenylthiazol-2-yl)acetonitrile (0.3 g, 1.5 mmol) in CH2Cl2 (10 mL). The reaction mixture was cooled at 0° C. and 1,2-dibromoethane (0.15 mL, 1.79 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 10 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford 1-(4-phenylthiazol-2-yl)cyclopropanecarbonitrile (0.14 g, yield 41%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.45-7.34 (m, 4H), 2.02-1.95 (m, 2H), 1.93-1.86 (m, 2H). MS (ESI) m/z: Calculated for C13H10N2S: 226.06. found: 227.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5].C1(C)C=CC=CC=1>C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Aqueous sodium hydroxide (2.4 mL of 6 M) was added to a solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoate (2.37 g, 7.26 mmol) in ethanol (25 mL); the reaction was stirred at ambient temperature for two hours and concentrated under reduced pressure. The residue was dissolved in water (15 mL) and adjusted to pH 4 with the addition of 2 M hydrochloric acid. A precipitate formed, was isolated by filtration, and was mixed with toluene, which was removed under reduced pressure to provide 1.78 g of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoic acid as a tan powder.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:30]([CH3:32])[CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:33][CH2:34][CH3:35].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:30]([CH3:32])[CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:33][CH2:34][CH3:35]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(\c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(/C(=C(F)\C=C\C(C)=C\C(=O)O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3,8-dimethyl-nona-2,4,6-trienoate (Compound A-160, 134 mg, 0.25 mmol) in ethanol was treated with a solution of 1 N aqueous NaOH to produce the title compound as a white solid after purification by recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:32](=O)[CH2:33][CH3:34].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH:16][CH2:32][CH2:33][CH3:34])[CH:7]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:9]=1
Reactant: CCC=O
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (500 mg, 2,14 mmol, 1 equiv) in (CH2Cl)2 (10 ml) was added sodium triacetoxyborohydride (640 mg, 3.02 mmol, 1.4 equiv), propionaldehyde (0.156 ml, 2.14 mmol, 1 equiv) and CH3COOH (0.125 ml, 2.18 mmol, 1.02 equiv) The resulting mixture was stirred at room temperature for 2 h, diluted with CH2Cl2 (20 ml), washed with saturated aqueous NaHCO3 solution (20 ml), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 3/2) gave 3-(2-oxo-pyrrolidin-1-yl)-5-propylamino-benzoic acid methyl ester (B35) (250 mg, 42%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][C:10]([CH:13](Br)Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC[OH:18]>[N+]([O-])([O-])=O.[Ag+].O>[Br:1][C:2]1[N:12]=[CH:11][C:10]([CH:13]=[O:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(C(Br)Br)cnc1Br
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc(C=O)cnc1Br
Yield: 48 %

Procedure:
A mixture of 6 (9.8 g, 0.024 mol), AgNO3 (8.8 g, 0.052 mol), EtOH (100 mL) and H2O (25 mL) was heated on a steam bath for 1 hour. The yellow solid was filtered and the solution concentrated to dryness. The residue was treated with H2O and extracted with CHCl3 (3×). The organic layer was dried, filtered and concentrated to dryness. Distillation of the resulting oil at 105°-135° C. at 0.5 mm gave 3.0 g (48%) of 3; 1H NMR (CDCl3) 1.45 δ (3H, t, J=7), 4.4 (2H, q, J=7, 8.6 (1H, d, J=2),/8.9 (1H, d, J=2) and 10.1 (1H, s).
Reaction SMILES: [CH2:1]([CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C(=O)N([Br:29])C(=O)C1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:29][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 3-(2-hexyldecyl)thiophene (10 g, 32.4 mmol) and THF (100 ml) were added and then cooled to 0° C. NBS (5.75 g, 32.4 mmol) was slowly added, and the temperature was increased to room temperature. The mixture was then stirred overnight. Then, a saturated sodium hydrogen carbonate aqueous solution (50 ml) was added to the reaction solution, followed by extraction with hexane, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which hexane was used as a mobile phase, 2-bromo-3-(2-hexyldecyl)thiophene (A2) was obtained as clear oil (12.4 g, 99% yield). The product (A2) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.17 (d, J=5.4 Hz, 1 H), 6.75 (d, J=5.4 Hz, 1 H), 2.49 (d, J=7.0 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[OH:24].Cl.[CH:26]1([C:29](=N)OCC)[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[NH:11][C:9]1[NH:8][C:7]2[C:2]3[N:1]=[C:29]([CH:26]4[CH2:28][CH2:27]4)[O:24][C:3]=3[C:4]([C:20]([O:22][CH3:23])=[O:21])=[CH:5][C:6]=2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c(N)c1O
Reactant: CCOC(=N)C1CC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
Under N2 atmosphere to a cold solution of methyl 7-amino-2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.400 g, 1.05 mmol) in DCM (25 mL), was added HCl salt of ethyl cyclopropanecarboximidate (Intermediate-57, 0.234 g, 1.57 mmol) at 0° C. The reaction mass was stirred at 0-5° C. for 1 h and at RT for 24 h. The obtained crude was purified by column chromatography on neutral alumina eluting with 1.0-2.0% MeOH:DCM to afford 0.150 g of the desired product. (DMSO-d6): δ 1.23 (m, 4H), 2.26 (m, 1H), 3.88 (s, 3H), 6.75 (s, 1H), 7.39 (m, 1H), 7.51 (m, 2H), 7.70 (s, 1H), 9.37 (s, 1H), 11.59 (s, 1H); MS [M+H]+: 401.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:14]1[S:18][C:17]([C:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=2)=[N:16][N:15]=1.Cl>O1CCOCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:14]1[S:18][C:17]([C:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]=2)=[N:16][N:15]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-n2cccn2)ccc1-c1nnc(C2=CCNCC2)s1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of tert-butyl 4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.18 mmol) in 1,4-dioxane (1 mL) was added 4 M HCl in 1,4-dioxane (0.9 mL). The mixture was stirred for 1 h. The mixture was then diluted with MeOH, loaded on the SCX, washed with MeOH, eluted with 2 N NH3 in MeOH, and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2/MeOH) to give 32 mg of 2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4-thiadiazole: HRMS (M+1) calcd. for C17H17N5OS 340.1232, found 340.1228; 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.53 Hz, 1H), 8.40 (d, J=8.59 Hz, 1H), 7.83 (d, J=1.52 Hz, 1H), 7.73 (d, J=2.02 Hz, 1H), 7.68 (dd, J=2.02, 8.59 Hz, 1H), 6.73 (m, 1H), 6.54-6.68 (m, 1H), 4.12 (s, 3H), 3.52 (m, 2H), 3.02 (t, J=5.81 Hz, 2H), 2.62 (m, 2H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Yield: 98.7 %

Procedure:
Methyl 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 31) (439 mg, 1.0 mmol) was dissolved in THF (6 mL) and methanol, (2 mL) and 1 N lithium hydroxide (1.24 mL) was added. Water (8 mL) was then added dropwise and the resultant solution stirred for 1 hour at room temperature. The majority of the organic solvents were removed by distillation under reduced pressure. The aqueous residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated under reduced pressure to afford the product (406 mg, 96%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 2H), 2.29-2.43 (m, 2H), 2.55-2.69 (m, 1H), 2.96 (s, 3H), 3.36-3.59 (m, 4H), 4.26 (t, 2H), 4.71 (t, 2H), 4.98 (t, 1H), 6.95 (s, 1H), 7.29 (s, 3H), 7.34 (d, 2H), 7.55 (s, 1H), 8.09 (d, 1H), 8.30 (s, 1H); m/z 411 (M+H)+.
Reaction SMILES: N1C=CC(CNC(C2C3OCCOC=3C=CC=2)=O)=CC=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31](S(CCCI)(=O)=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[I-].[Na+]>C(#N)C.CO.O.[Pt](=O)=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCI)CC1
Agent: O=[Pt]=O
Agent: O=C(NCc1ccncc1)c1cccc2c1OCCO2
Agent: [I-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCNCC1
Yield: 39 %

Procedure:
A stirred solution of the 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (pyridin-4-ylmethyl)amide (1.30 g, 4.8 mmol) and 4-(3-iodopropane-1-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (prepared from the corresponding chloro compound by treatment with sodium iodide in actone) (2.12 g, 5.1 mmol) in acetonitrile (25 mL) was heated under reflux for 8 hours. The mixture was concentrated in vacuo and the residue was triturated with ethyl acetate. Filtration gave the crude pyridinium iodide which was dissolved in methanol (25 mL) and water (5 mL), and hydrogenated over platinum(IV) oxide (450 mg) at atmospheric pressure for 16 hours. The mixture was filtered through Celite® and the filtrate was partitioned between dichloromethane and aqueous ammonium hydroxide. The dichloromethane was dried (Na2SO4) and evaporated in vacuo. Purification of the residue by silica gel chromatography gave 4-[3-(4-{[2,3-dihydrobenzo[1,4]dioxin-5-carbonyl)amino]methyl}pyridin-1-yl)propane-1-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (1.05 g, 39%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1
Reactant: O=C1COc2ccc(CO)cc2N1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1COc2ccc(COC3CCCCO3)cc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The solution of 5.0 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one in 60 ml of dichloromethane is admixed successively with 5.20 ml of 3,4-dihydro-2H-pyran and 0.236 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 14 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×400 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of crystallization (EtOAc/heptane). Rf=0.25 (1:1 EtOAc-heptane); Rt=3.45.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36]1
Reactant: OC1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC(O)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-hydroxy-piperidine. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: C(OC([N:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[NH:10]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)c1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Reaction time: 1.5 h

Procedure:
2-(3-(N,N′-di(t-Butoxycarbonyl)guanidino)phenyl)-3-((4-phenylbutyl)-(hydroxy)phosphinoyl)propanoic acid was dissolved in 9 mL 2:1 methylene chloride:TFA. After 1.5 hours, the reaction mixture was concentrated and purified by prep HPLC to afford 2-(3-guanidinophenyl)-3-((4-phenylbutyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 1.25-1.60 (m, 6), 2.00 (m, 1), 2.40-2.50 (m, 2), 3.85 (m, 1), 7.0-7.45 (m, 9) ppm, (2.9 mg).
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:20])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[C:8]([Cl:21])=[CH:7][C:6]=1[CH2:22][CH2:23][CH3:24])(=O)C.[OH-].[Na+].Cl>CO>[Cl:21][C:8]1[C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([CH3:20])[C:10]=2[C:5]([OH:4])=[C:6]([CH2:22][CH2:23][CH3:24])[CH:7]=1
Reactant: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-acetoxy-7-chloro-3-methyl-2-phenyl-5-propylbenzofuran (Step c) (1.5 g, 4.6 mmol), methanol (75 mL) and 3N sodium hydroxide (10 mL) was heated to obtain a solution which was then stirred at room temperature for 2 hours. The mixture was acidified with 1N hydrochloric acid (100 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO4), filtered and concentrated. The residue was slurried with hexane, filtered and washed with hexane to obtain the title compound, m.p. 102°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.O.[BH4-].[Na+]>CO.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([OH:12])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: OC1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 8-(4-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (2.6 g, 10.25 mmol), concentrated hydrochloric acid (12 ml), water (10 ml), and ethanol (50 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue 10% sodium hydroxide aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), to which sodium borohydride (388 mg, 10.25 mmol) was added while cooling in an ice-bath, and the mixture was stirred for 30 minutes. To the reaction mixture, 10% hydrochloric acid was added, and the mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 1-(4-chlorophenyl)piperidin-4-ol (1.73 g, yield 80%) as a pale yellow crystalline powder.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1>>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:3])[C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of HNO3 (65 mL) was added 4-methoxy-2-nitro-phenylamine (15 g, 89.3 mmol). The reaction mixture was stirred at room temperature overnight. The dark red precipitate was filtered and washed with H2O (400 mL) affording 10.01 g (53%) of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([NH:17][C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([NH:17][C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Yield: 108.4 %

Procedure:
A solution of 2-[3-(3-acetamidophenyl)phenylamino]-3-nitropyridine (10 g) in 3N hydrochloric acid (100 ml) was refluxed for 2 hours. The cold reaction was adjusted to pH 8 with saturated sodium bicarbonate solution and precipitated reddish crystals were collected, washed with water and dried to give 2-[3-(3-aminophenyl)phenylamino]-3-nitropyridine (9.53 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]2)[O:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:15][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:7]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2cc(C)no2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2onc(C)c2Br)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol) in anhydrous DMF (50 mL) was added N-bromosuccinimide (10.31 g, 57.9 mmol). The reaction mixture was stirred at room temperature for 24 h. To the orange mixture was added water and the aqueous layer was extracted with MTBE (3×). The combined organic layers were washed with aqueous 10% sodium thiosulfate, water (2×) and dried to provide the product ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (12.5 g, 45.6 mmol, 94% yield) as a light yellow oil. The product was used directly in the subsequent reaction without further purification. LC/MS m/z 274 [M+H]+.