Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:38]3[CH2:39][CH2:40][N:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:37]3)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 46 h
Yield: 61.9 %

Procedure:
To the suspension of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol), tert-Butyl 1-piperazinecarboxylate (20.8 mg, 0.112 mmol) and Acetic acid (11 mg, 0.18 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) was added Sodium triacetoxyborohydride (27.0 mg, 0.128 mmol). The mixture was stirred at r.t. for 46 hours. The mixture was washed with water (2×2 mL) and brine, dried over Na2SO4, filtered and the filtrate was chromatographed in an 8 g AnaLogix column using MeOH/DCM (0/100 to 5/95) to give a solid product (0.0253 g, 61.9% yield). LCMS: (FA) ES+ 641. 1H NMR (400 MHz, d-chroloform) 9.91 (s, 1H), 8.28 (s, 1H), 7.94-7.97 (m, 2H), 7.58-7.60 (m, 1H), 7.34-7.46 (m, 4H), 5.47-5.51 (m, 1H), 4.05-4.13 (m, 1H), 3.70-3.76 (m, 1H), 3.58 (s, 2H), 3.42 (s, br, 4H), 2.81 (s, 3H), 2.45 (s, br, 4H), 2.00-2.17 (m, 3H), 1.65-1.72 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[S:14][C:13]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Oc1cccc(I)c1
Reactant: OB(O)c1ccc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Oc1cccc(-c2ccc(Cl)s2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
To a solution of 3-iodophenol (1.0 g, 4.55 mmol) in DME (10 ml) was added Pd(PPh3)4 (263 mg, 0.227 mmol) at ambient temperature under N2. After stirring for 20 min., 5-chlorothiophene-2-boronic acid (886 mg, 5.45 mmol) and a solution of Na2CO3 (723 mg, 6.82 mmol) in H2O (3 ml) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (30 ml) and H2O. The organic layer was washed with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (15 g) chromatography eluting with hexane/ethyl acetate (10:1) to give 3-(5-chloro-2-thienyl)phenol (0.88 g, 91.9%).
Reaction SMILES: C([Si]([C:8]1[C:13]([F:14])=[C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][CH:22]=3)[NH:17][N:16]=2)[N:11]=[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([CH3:39])([O:34][Si](C)(C)C)[CH:31]([CH3:33])[CH3:32])[CH2:25]2)[C:9]=1[F:40])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:40][C:9]1[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([OH:34])([CH:31]([CH3:32])[CH3:33])[CH3:39])[CH2:25]2)=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][CH:22]=3)[NH:17][N:16]=2)=[C:13]([F:14])[CH:8]=1
Reactant: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncncc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@](C)(O)[C@@H]1CN(c2nc(-c3n[nH]c4ncncc34)c(F)cc2F)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of tert-butyl-[2-[(3S)-3-[(1R)-1,2-dimethyl-1-trimethylsilyloxy-propyl]piperazin-1-yl]-3,5-difluoro-6-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-pyridyl]-dimethyl-silane (134 mg, 0.23 mmol) in THF (3 mL) was added TBAF (1M in THF) (499.8 μL of 1 M, 0.50 mmol) and stirred at ambient temperature for 1 hour. After this time, the reaction mixture was diluted with EtOAc and the organics were washed with water (×3), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated and TFA was removed using PS-carbonate cartridge and freeze-dried to give the title compound as an off-white solid (38 mg, 40.2% Yield). H1 NMR (400.0 MHz, DMSO) δ 9.74 (s, 1H), 9.05 (s, 1H), 7.96 (dd, 1H), 4.15 (br s, 1H), 4.01 (d, 1H), 3.76 (d, 1H), 3.11 (d, 1H), 2.85 (d, 2H), 2.77-2.70 (m, 2H), 1.80 (quintet, 1H), 1.05 (s, 3H), 0.89 (d, 3H) and 0.84 (d, 3H) ppm; MS (ES+) 404.2.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([C:21](=[O:55])[NH:22][C@H:23]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C:24]([N:26]3[CH2:43][CH2:42][CH2:41][C:28]4([C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH:29]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:27]3)=[O:25])([CH3:20])[CH3:19])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:17][C:18]([CH3:20])([CH3:19])[C:21]([NH:22][C@H:23]([CH2:44][O:45][CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[C:24]([N:26]1[CH2:43][CH2:42][CH2:41][C:28]2([C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH:29]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:25])=[O:55]
Reactant: COc1ccc(COC[C@@H](NC(=O)C(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(COC[C@@H](NC(=O)C(C)(C)N)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {1-[(R)-1-(4-Methoxy-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (70 mg, 0.09 mmol) in DCM (2 ml) was treated with piperidine (0.20 ml, 2.0 mmol). The resulting solution was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the title compound.
Reaction SMILES: C[Si](C)(Cl)Cl.N.C[Si]1(C)[NH:15][Si:14]([CH3:17])([CH3:16])[NH:13][Si:12]([CH3:19])([CH3:18])[NH:11][Si:10]([CH3:21])([CH3:20])N1>>[CH3:21][Si:10]1([CH3:20])[NH:11][Si:12]([CH3:18])([CH3:19])[NH:13][Si:14]([CH3:16])([CH3:17])[NH:15]1
Reactant: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N[Si](C)(C)N1
Agent: C[Si](C)(Cl)Cl
Agent: N
Product: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N1

Procedure:
The starting octamethylcyclotetrasilazane should effectively be one which is secondarily produced when hexamethylcyclotrisilazane is prepared by reaction between dimethyl dichlorosilane and ammonia. Using such secondarily produced octamethylcyclotetra-silazane, the amount of hexamethylcyclo-trisilazane formed per unit starting material can be maximized. At the same time, some technical problems can be solved including elimination or treatment of octamethylcyclo-tetrasilazane in the form of a solid (melting point of 97° C.) which is left in the distillation column after removal of hexamethylcyclo-trisilazane by distillation.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:22]3[C:21](=[O:23])[N:20]([CH2:24][CH2:25][C:26](O)=[O:27])[CH2:19][C:18]([CH3:30])([CH3:29])[O:17][C:16]=3[N:15]=[C:14]([N:31]3[CH2:37][CH:36]4[O:38][CH:33]([CH2:34][CH2:35]4)[CH2:32]3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].C[CH2:41][N:42](C(C)C)[CH:43](C)C.Cl.CNC.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(#N)C>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:22]3[C:21](=[O:23])[N:20]([CH2:24][CH2:25][C:26]([N:42]([CH3:43])[CH3:41])=[O:27])[CH2:19][C:18]([CH3:30])([CH3:29])[O:17][C:16]=3[N:15]=[C:14]([N:31]3[CH2:37][CH:36]4[O:38][CH:33]([CH2:34][CH2:35]4)[CH2:32]3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)nc3c2C(=O)N(CCC(=O)O)CC(C)(C)O3)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)nc3c2C(=O)N(CCC(=O)N(C)C)CC(C)(C)O3)cc1
Yield: 46.2 %

Procedure:
70 mg (0.13 mmol) of 3-[4-[4-(3-ethylureido)phenyl]-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-7,8-dihydro-5H-9-oxa-1,3,6-triazabenzocyclohepten-6-yl]propionic acid are placed in 3 ml of DCM. 0.66 ml of DIEA (0.39 mmol), 12 mg of dimethylamine hydrochloride (0.14 mmol), 21 mg of hydroxybenzotriazole (0.14 mmol) and 27 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (0.14 mmol) are successively added, with stirring. After stirring for 3 days at room temperature, the DCM is evaporated off. The residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution and then with brine, dried over MgSO4, filtered and evaporated. The solid obtained is taken up in acetonitrile, filtered off and rinsed with pentane to give 34 mg of 3-[4-[4-(3-ethylureido)phenyl]-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-7,8-dihydro-5H-9-oxa-1,3,6-triazabenzocyclohepten-6-yl]-N,N-dimethylpropionamide.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([C:21](OCC)=[O:22])[CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([CH2:21][OH:22])[CH:12]([C:17]([F:18])([F:20])[F:19])[C:13]([F:15])([F:16])[F:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)s1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1ccc(Br)s1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of ethyl N-[(5-bromo-thien-2-yl)sulfonyl]-4,4,4,4′,4′,4′-hexafluorovalinate (2.4 g, 5.02 mmol) in THF (20 mL) was added LiBH4 (20 mL, 20.07 mmol) under N2 atmosphere at 0° C. The reaction was allowed to warm to 25° C. for 19 h. The reaction was cooled to 0° C. and quenched with 2N HCl (slow addition), diluted in ether (50 mL) and the organic layer washed sequentially with 1N aqueous. HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (2.31 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-bromo-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (1.3 g, 59.63%). Mass Spectrum (−ESI): 435 (M−H)−.
Reaction SMILES: Cl.CN(C)CCC[N:7]=[C:8]=[N:9]CC.NC(N[C:17]1[N:18]([C@@H:25]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]2[OH:27])[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=1)=O>O.CO>[CH:17]1[N:18]([C@@H:25]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]2[OH:27])[C:19]2[N:7]=[C:8]([NH2:9])[O:24][C:22](=[O:23])[C:20]=2[N:21]=1
Reactant: NC(=O)Nc1nc(C(=O)O)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol) was added to a solution of 5-[[(amino)carbonyl]amino-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid (19 mg, 0.063 mmol) in water (2 mL) and CH3OH (5 mL) and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of excess 60% aqueous acetic acid. After 30 minutes, the mixture was diluted with water, concentrated to remove CH3OH and lyophilized. The resulting powder (100 mg) was chromatographed on reverse phase silica gel [10 g, flash, stepwise gradient elution: water (200 mL), 10% CH3OH in water (v/v, 100 mL), 20% CH3OH in water (v/v, 100 mL), 10-mL fractions]. Fractions containing the product were combined, concentrated under reduced pressure and lyophilized to give oxanosine: 16 mg (89%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH:11]([O:13]CCCC)=[CH2:12].C(N(CC)CC)C.C([O-])(=O)C.[Tl+].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:11]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C#N)c(F)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzonitrile (5.0 g, 20.0 mmol), butyl vinyl ether (12.5 g, 124.0 mmol), triethylamine (4.0 g, 40.0 mmol) 1,3-bis(diphenylphosphino)propane (453 mg, 1.1 mmol), thallium acetate (5.8 g, 22.0 mmol), and palladium acetate (224 mg, 1.0 mmol) in dry dimethylformamide (50 mL) under nitrogen was heated at 90° C. for 3 hours. An additional charge of 1,3-bis(diphenyl-phosphino)propane (453 mg, 1.1 mmol) and palladium acetate (244 mg, 1.0 mmol) was added and the reaction mixture was heated at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, 25 mL of 2N hydrochloric acid was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into 300 mL of water and extracted with diethyl ether (2×300 mL). The organic extracts were combined and then washed with water and brine, and thereafter dried over magnesium sulfate (MgSO4) and concentrated to give an oil. The oil was purified using flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:3) to give 2.5 g of 4-acetyl-2-fluoro-benzonitrile final product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.4 %

Procedure:
To a solution of of 4-bromo-3-methylbenzonitrile (1.0 g, 5.0 mmol) in carbon tetrachloride (7.5 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) followed by of benzoylperoxide (50 mg 0.2 mmol) and the mixture was refluxed. After 10 hours, the reaction was cooled to rt, filtered, and the filtrate was washed with 10% NaHSO3 (5 mL) followed by water (5 mL). The organic layer was dried (Na2SO4), filtered, volatiles removed, and the residue was purified by flash chromatography on silica gel. Elution with 10% Ethyl acetate in hexanes gave the title compound (0.5 g, 36%) as a white solid. 1H NMR (270 MHz, CDCl3) δ4.55 (s, 2 H), 7.38-7.42 (m, 1 H), 7.65-7.77 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[CH:7][C:8]([OH:15])=[C:9](C(=NO)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C[N:23](C)[C:24](=O)[CH3:25]>C(#N)C>[C:1]([C:5]1[C:6]([OH:16])=[CH:7][C:8]2[O:15][C:24]([CH3:25])=[N:23][C:9]=2[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=NO)c1cc(C(C)(C)C)c(O)cc1O
Reactant: CC(=O)N(C)C
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cc(C(C)(C)C)c(O)cc2o1
Temperature: 0 °C
Yield: 85 %

Procedure:
In a mixture of 30 ml of N,N-dimethylacetamide and 30 ml of acetonitrile was dissolved 11 g of 5'-t-butyl-2',4'-dihydroxyacetophenone oxime. To the resulting solution, which was cooled on an ice bath with stirring, was dropwise added 20 ml of phosphorus oxychloride over a period of 30 minutes. The reaction mixture continued to be stirred for an additional 30 minutes as it was and, then, 200 mol of ice water was gradually added thereto over a period of an hour. The crystals thus precipitated were recovered by filtration, and 50 g of 5-t-butyl-2-methyl-6-benzoxazolol (Compound 1) was obtained. Yield 85%, Melting Point 264° to 266° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)c(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.967 g, 4.90 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.290 mL, 4.90 mmol) in water (2.000 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.300 mL, 4.90 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (25.3 mL, 151.92 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.354 g, 74.6%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.84-2.10 (m, 4H), 2.48-2.54 (m, 1H), 2.69-2.76 (m, 1H), 2.96-3.03 (m, 1H), 3.10-3.18 (m, 1H), 3.64 (s, 3H), 3.94-4.01 (m, 1H), 4.18-4.25 (m, 1H), 5.73 (s, 1H), 6.69-6.75 (m, 2H). MS m/z 369 (M−H)−
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([OH:48])=O)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.[N:56]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CO.N>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([NH2:56])=[O:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(N)=O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
The resulting 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoic acid (64 mg, 0.095 mmol) was dissolved in chloroform (2 mL), and stirred overnight at room temperature after adding O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 72 mg, 0.190 mmol), diisopropylethylamine (0.083 mL, 0.476 mmol), and a 2 mol/L ammonia methanol solution (0.238 mL, 0.476 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to give compound 57 (46.1 mg, 72.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27]>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: COc1ccccc1CC(=O)O
Product: COc1ccccc1CC(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 53 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 2-methoxyphenylacetic acid in 53% yield following procedure 1. The product was crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 3.45 s (3H, OMe), 3.67 s (2H), 6.17 s (1H), 6.75 d, 8 Hz (1H), 6.83 t, 8 Hz (1H), 7.06 t, 8 Hz (1H), 7.14 t, 8 Hz (1H), 7.17–7.21 m (3H), 7.23–7.36 m (2H), 7.49 t, 8 Hz (2H), 8.13 d, 8 Hz (1H).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[NH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1>O>[N:8]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: O=C(O)CCl
Reactant: C1=CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CC=CCC1
Yield: 87.4 %

Procedure:
Monochloroacetic acid (8.5 g.) in water (10 ml.) was neutralised with sodium hydroxide (3.6 g.) in water (10 ml.). 1,2,5,6-Tetrahydropyridine (7.57 g.) was added. An exothermic reaction set in and after 30 minutes the pH of he dark red solution had changed from 9 to 8. After 24 hours the reaction mixture was evaporated, the residue was triturated with absolute ethanol ( 100 ml.) and filtered. The filtrate was evaporated, barium hydroxide (14 g.) in water (40 ml.) was added to the residue and evaporated repeatedly from water. The residue was redissolved in hot water, treated with CO2 gas, and filtered. The filtrate was evaporated to dryness and the residue, dissolved in hot absolute ethanol, (100 ml.) was acidified to pH 3-4 (2N H2SO4) and centrifuged to remove inorganic material. The supernatant liquor was evaporated to give 1,2,5,6-tetrahydropyridinyl acetic acid (11.1 g.) as an intractable dark brown gum.
Reaction SMILES: CC(C)([O-])C.[Na+].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.Br[C:50]1[CH:55]=[CH:54][C:53]([S:56][CH3:57])=[CH:52][CH:51]=1.[OH:58][C:59]([CH3:64])([CH3:63])[C:60](=[O:62])[CH3:61]>C1COCC1.O.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]>[OH:58][C:59]([CH3:64])([CH3:63])[C:60](=[O:62])[CH2:61][C:50]1[CH:55]=[CH:54][C:53]([S:56][CH3:57])=[CH:52][CH:51]=1
Reactant: CSc1ccc(Br)cc1
Reactant: CC(=O)C(C)(C)O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(CC(=O)C(C)(C)O)cc1
Temperature: 75 °C

Procedure:
To a solution of sodium tert-butoxide (12 g, 125 mmol), XANTPHOS (2.05 g, 3.5 mmol) and Pd2(dba)3 (1.35 g, 1.5 mmol) in THF (600 mL) was added 4-bromothioanisole (20 g, 98 mmol) and 3-hydroxy-3-methyl-butan-2-one (12 g, 117 mmol). The resulting reaction mixture was heated to 75° C. for 2 h then cooled to r.t. and diluted with water. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 85:15-80:20) provided the title compound as a pale brown solid.