Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (20 g, 95.1 mmol), 4-methoxybenzyl chloride (11.6 ml, 85.6 mmol), potassium carbonate (26.3 g, 0.19 mol) and acetonitrile (300 ml) was stirred at 60° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, water (300 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-(4-methoxybenzyl)propionate (26.6 g, 85%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12]CC3C=CC=CC=3)[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:24][CH2:23]2)[CH:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[O:30])[CH2:24][CH2:23]2)[CH:3]=1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)cc(N)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)cc(N)c2cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
10% Palladium on charcoal (250 mg) was added to a solution of 4-amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline (1.01 g, 0.002 mol) in ethanol (100 ml) and the reaction stirred at room temperature under a hydrogen atmosphere of 414 kPa (60 p.s.i.) for 72 hours. The reaction mixture was filtered through Arbocel™, washing well with further ethanol. The filtrate was evaporated under reduced pressure to give the subtitle compound as a solid (770 mg, 93%). Rf 0.40 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 402 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>>[CH3:19][O:18][C:4]1[CH:3]=[C:2]([O:1][CH2:21][CH2:20][O:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOCCBr
Reactant: COC(=O)CC(CC(C)C)c1ccc(O)cc1OC
Product: CCOCCOc1ccc(C(CC(=O)OC)CC(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)-5-methylhexanoate (prepared as described in Preparation 58B) and 2-ethoxyethyl bromide, the title compound was obtained as an oily substance.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]=[CH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]([C:14]2[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:22][CH3:23])=[CH:10][C:11]=1[CH2:12][CH3:13].[OH-].[Na+]>CCO>[CH2:22]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][CH3:21])[C:14]=1[C:9]1[N:8]=[C:7]([CH3:24])[C:6]([CH:5]=[CH:4][C:3]([OH:25])=[O:2])=[C:11]([CH2:12][CH3:13])[CH:10]=1)[CH3:23]
Reactant: CCc1cc(-c2c(CC)cccc2CC)nc(C)c1C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2c(CC)cccc2CC)nc(C)c1C=CC(=O)O
Temperature: 100 °C

Procedure:
A solution of the ester above (403 mg, 1.2 mmol) in EtOH (5 mL) is treated with NaOH (5 mL of 1 N solution in water). The mixture is heated for 2 hours at 100° C. and concentrated in vacuo. The residue is diluted with EtOAc and acidified to pH 4 with 1 N—HCl. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with saturated brine, dried (Na2SO4), and concentrated to yield 3-[6-(2,6-diethyl-phenyl)-4-ethyl-2-methylpyridin-3-yl]-acrylic acid as a white foam. 1H NMR (CDCl3) 7.64 (d, 1H), 7.29 (dd, 1H), 7.15 (d, 2H), 7.09 (s, 1H), 6.20 (d, 1H), 2.76 (q, 2H), 2.71 (s, 3H), 2.33 (m, 4H), 1.22 (t, 3H), 1.04 (m, 6H).
Reaction SMILES: Cl.S([O-])([O-])(=O)=O.[Mg+2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+].[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([Cl:30])[C:24]=1[C:31](=[O:33])[CH3:32]>N(CCO)(CCO)CCO.O>[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([Cl:30])[C:24]=1[C@@H:31]([OH:33])[CH3:32]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)([O-])[O-]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Temperature: 30 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a 500 mL jacketed three neck round bottom flask equipped with an Ace Glass mechanical stirrer (75 mm diameter teflon stirrer blade), and a pH electrode connected to an automatic titrator for pH-controlled addition of base on-demand via a delivery tube into the vessel, was added water (120 mL), triethanolamine (1.8 g) and then hydrochloric acid to adjust the pH to 7.0. Magnesium sulfate was added as a 1M solution (120 μL, 0.12 mmoles, 14.4 mg of MgSO4). The solution was heated to 30° C. with heating fluid circulating through the flask's jacket. Glucose (20 g) was added followed by Na-NADP (120 mg), GDH (0.50 g) and KRED having SEQ ID No. 38 (0.50 g). The pH stat was set to maintain the pH at 7.0±0.1 by the addition of 4N NaOH through the delivery tube. 2′,6′-dichloro-3′-fluoroacetophenone (50 g) was added to start the reaction. The electrode required periodic rinsing to remove enzyme derived material. Additional glucose was added in portions as the reaction proceeded: 10 g at 104 min (after 17.5 mL of 4 N NaOH had been added), 5 g at 275 min (after 35.2 mL of 4 N NaOH had been added), 5 g at 379 min (after 42 mL of 4 N NaOH had been added), and 8 g at 488 min (after 47 mL of 4 N NaOH had been added). The reaction was stopped after 24 hr. Heptane (150 mL) was then added and the mixture was heated to 40° C. for 45 min. After cooling to 30° C. the resulting mixture was poured into a separatory funnel and the majority of the bottom aqueous layer was drained. The top layer, a heptane emulsion, was filtered (350 mL, 85 mm diameter coarse filter) through a celite pad under vacuum. The filter was washed with heptane (150 mL) and the filtrate was transferred to a separatory funnel and the two phases were separated. The heptane phase was concentrated on a rotary vacuum evaporator (˜50° C., ˜150 mmHg increasing to 40 mmHg) to yield (S)-1-[2′,6′-dichloro-3′-fluorophenyl]-ethanol as an oil (47.8 g, 94%) which crystallized upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[H][H]>CO>[CH3:17][C@H:13]([C:14]([OH:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: [H][H]
Reactant: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1
Solvent: CO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 93.4 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.45 g (2 mmoles) of 6-methoxy-α-methylene-2-naphthaleneacetic acid and 20 ml of methanol. Then, 2.0 mg (0.002 mmole) of Ru((-)-T-BINAP)(O2CCF3)2 prepared in Referential Example 4 was added to the mixture to perform hydrogenation for 24 hours at a hydrogen pressure of 40 kg/cm2 and at a reaction temperature of 20° C. Thereafter, the solvent was distilled off to provide 0.43 g of naproxen. The yield thereof was 93.7%.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:21][C:22]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[CH:23][CH:24]=3)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=2)=[C:9]([F:36])[CH:8]=1)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:47]2)=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(#N)C>[F:36][C:9]1[CH:8]=[C:7]([C:6]2[S:47][C:1]([CH3:2])=[N:4][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:23][CH:24]=2)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)s3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
N′-Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzohydrazide (40 mg, 0.076 mmol) synthesized in Example (49a) was dissolved in a mixed solvent of toluene (4.0 mL) and acetonitrile (2.0 mL), and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (45 mg, 0.111 mmol) and pyridine (0.03 mL, 0.372 mmol) were added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (28 mg, yield 70%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]([NH:10][CH:11]([C:13]1[N:18]=[N:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[N:15][CH:14]=1)[CH3:12])=O)=[O:4].P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]([F:37])([F:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:17]2)=[C:11]([CH3:12])[N:10]=1)=[O:4]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(F)(F)F)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4NC(=O)C(F)(F)F)n3n2)cc(OC)c1OC
Yield: 10.4 %

Procedure:
In a similar manner as described for Example 1, 2-[(trifluoroacetyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 16) (0.118 g, 0.23 mmol) in 1,2-dichloroethane (30 mL) and phosphorus oxychloride (1.0 mL, 11 mmol) gave 2,2,2-trifluoro-N-(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)acetamide (0.012 g) as a yellow solid. 1H NMR (CDCl3): δ13.87 (s, 1H), 8.91 (dd, J=8.0, 1.4 Hz, 1H), 8.88 (s, 1H), 8.63 (dd, J=8.4, 1.1 Hz, 1H), 7.47-7.41 (m, 1H), 7.28-7.22 (m, 1H), 7.08 (s, 1H), 6.86 (s, 2H), 3.85 (s, 3H), 3.80 (s, 6H), 2.60 (s, 3H). MS m/z 503 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:37])[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:15]=[C:14]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:36])[NH2:35])[C:2]1C=CC=CC=1.N(CC1C=CC=CC=1)=C=O>>[CH2:1]([NH:8][C:9](=[O:37])[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:15]=[C:14]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:36])[NH2:35])[CH3:2]
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OC(=O)NCc3ccccc3)cc12
Agent: O=C=NCc1ccccc1
Product: CCNC(=O)Oc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(N)=O)c2c1

Procedure:
4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-yl ethylcarbamate was synthesized in a similar manner to that described for 4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-yl benzylcarbamate substituting isocyanatoethane for (isocyanatomethyl)benzene. The resulting product was analyzed by LCMS: rt=1.11 min, [M+1]+=429.0, 1H-NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 9.66 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 8.87-8.80 (m, 2H), 8.51 (s, 1H), 8.06-7.94 (m, 4H), 7.88 (s, 1H), 7.79-7.63 (m, 3H), 7.24 (t, J=7.6 Hz, 1H), 3.22-3.11 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C(Cl)Cl.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:35][C@@H:32]2[CH2:33][CH2:34][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitro-phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM (1:5) at 0° C. The reaction mixture is kept at 0° C. and a solution of (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 342.10 (MH+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C@@H:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7].C(#N)C>O>[C:18]([O:17][C:15]([N:9]1[CH2:10][C:11]([F:13])([F:14])[CH2:12][C@H:8]1[C:6]([OH:7])=[O:5])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (469 mg, 11.2 mmol) is added to a solution of (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.48 g, 5.59 mmol) in 3:1 acetonitrile in water (20 mL). The reaction is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and diluted with water and extracted with ether. The aqueous layer is acidified to PH˜1 and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. ESI m/z 152 [M+H+−100].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:35])([F:34])[O:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH:19][C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([O:22][C:21]([F:34])([F:20])[F:35])=[CH:24][CH:25]=3)[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reactant: O=C(Cl)COc1ccc(OC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reaction time: 12 h

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide (0.54 g, 1.8 mmol) was dissolved in methylene chloride (15 mL). (4-Trifluoromethoxyphenoxy)-acetyl chloride (0.47 g, 1.8 mmol) was added followed by pyridine (0.3 mL, 4 mmol) and DMAP (0.02 g, 0.1 mmol). The mixture was stirred for 12 hours. Saturated, aqueous NH4Cl was added and the mixture was extracted with methylene chloride ×3. The combined organic extracts were washed with 1N HCl, saturated, aqueous NaHCO3, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was purified by recrystallization from ethanol/diethyl ether to afford the title compound (0.65 g, 68% from the Boc protected amine): 1H NMR (400 MHz, d6-DMSO): 9.08 (t, 1H), 8.40 (t, 1H), 8.10 (s, 1H), 7.27 (m, 5H), 7.17 (d, 1H), 7.06 (d, 2H), 4.65 (s, 2H), 4.62 (d, 2H), 3.48 (m, 2H), 2.84 (t, 2H); MS (ESI-LCMS) for C22H20ClF3N3O4S: 514 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N+:27]([O-:29])=[O:28])[C:14](OS(C(F)(F)F)(=O)=O)=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=1[NH2:41].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2=[C:13]([N+:27]([O-:29])=[O:28])[C:14]([NH:41][C:32]3[CH:33]=[CH:34][C:35]([Si:37]([CH3:39])([CH3:38])[CH3:40])=[CH:36][C:31]=3[F:30])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Reactant: C[Si](C)(C)c1ccc(N)c(F)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: Cc1ccccc1
Product: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Yield: 85.7 %

Procedure:
Trifluoro-methanesulfonic acid 1-benzyl-6-methyl-8-nitro-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-7-yl ester (I-1e: 500 mg, 0.001 mol) in toluene (15 mL) was reacted with 2-fluoro-4-trimethylsilanyl-phenylamine (221 mg, 0.001 mol) in the presence of Pd2(dba)3 (63.3 mg, 0.0001 mol), xantphos (40 mg, 0.0001 mol) and K3PO4 (367 mg, 0.002 mol) and the reaction mixture was heated to reflux for 1 hour. Reaction workup yields the crude product which was purified by column chromatography on silica gel (40% ethylacetate in hexane) to afford 400 mg of the product (74.48% yield).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:19][CH2:16][CH2:15][CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCSCCCBr

Procedure:
3-Dodecylthiopropanol (3.0 g) was dissolved in 60 ml of dichloromethane and 7.66 g of carbon tetrabromide and 5.44 g of triphenylphosphine were added thereto under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes. The reaction mixture was concentrated, and the residue was extracted with hexane. The extract was concentrated and purified by silica gel column chromatography using hexane as an eluent to give 3.255 g of pale yellow, oily 3-bromopropyldodecyl sulfide.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)(=[O:5])[CH3:4].[Cl-].[NH4+]>C(O)C>[Br:12][C:8]1[N:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)c1cccc(Br)n1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
With cooling with ice, 426 mg of sodium borohydride was added to ethanol (50 mL) solution of 4.50 g of 2-acetyl-6-bromopyridine. After stirred for 1 hour, aqueous saturated ammonium chloride solution was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. After concentrated under reduced pressure, 4.58 g of the entitled compound was obtained as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][CH2:31][C@H:32]([OH:45])[C:33]5[CH:38]=[CH:37][C:36]([OH:39])=[C:35](S(C)(=O)=O)[C:34]=5N)[CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-:46].[Na+].Cl>CO>[OH:45][C@H:32]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([NH:23][S:20]([CH3:17])(=[O:21])=[O:46])[CH:34]=1)[CH2:31][NH:30][CH2:29][CH:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[C:6]=4[CH:7]=[CH:8]3)=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH2:28][CH2:27]1
Reactant: COC(=O)c1cccc2c1ccn2-c1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(S(C)(=O)=O)c3N)CC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-n4ccc5c(C(=O)O)cccc54)cc3)CC2)ccc1O

Procedure:
A solution of 1-[4-(4-{[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonyl-amino-phenyl)-ethylamino]-methyl}-piperidine-1-sulfonyl)-phenyl]-1H-indole-4-carboxylic acid methyl ester (0.118 g, 0.18 mmol) and 0.8 mL of 1N NaOH in 10 mL methanol was heated at reflux overnight. On cooling the reaction was neutralized with 0.8 mL of 1N HCl. The reaction mixture was concentrated in vacuo and triturated with H2O. The solids were filtered and dried (high vac) to give 0.095 g of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(Cl)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC

Procedure:
A solution of 8.0 g of ethyl 2-(4-chlorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 70 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.2 and 44.1 ppm (CDCl3).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:3]([CH:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(C1CCCN1)N1CCCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-tert-butoxycarbonyl)-L-proline was reacted with piperidine to give (2S)-1-tert-butoxycarbonyl)-2-piperidinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.5–1.9 (m, 10H), 1.9–2.0 (m, 1H), 2.1–2.2 (m, 1H), 2.4–2.5 (m, 1H), 2.55–2.65 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 6H), 4.3 (br s, 1H); Mass Spectrum: M+H+ 227.