Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][C:19]=3[O:29][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N([CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)C3C(SC=2C=1)=CC=CC=3.O1CCOCC1.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.CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:46]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][C:19]=3[O:29][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc2c1Oc1cc(Cl)ccc1N2C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccc2c1Oc1cc(-c3cccnc3)ccc1N2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1p, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2p was obtained. MS m/z (MH+) 474.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cnc(Cl)c(CO)c1

Procedure:
comprising reducing 2-chloro-5-methylpyridine-3-carbaldehyde with sodium borohydride to give 2-chloro-3-hydroxymethyl-5-methylpyridine, followed by reacting the 2-chloro-3-hydroxymethyl-5-methylpyridine thus obtained with thionyl chloride to give 2-chloro-3-chloromethyl-5-methylpyridine, followed by reacting the 2-chloro-3-chloromethyl-5-methylpyridine thus obtained with 2-nitroimino-1,3-diazacyclopentane in the presence of a base and an organic solvent, to give 1-(2-chloro-5-methyl-3-pyridylmethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[OH:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].CN.OC(O)CNC>C(N(CC)CC)C.ClCCl>[CH3:9][N:8]1[CH2:10][CH2:11][O:12][SiH:4]([CH3:2])[O:5][CH2:6][CH2:7]1
Reactant: [SiH3]C(Cl)Cl
Reactant: CN(CCO)CCO
Agent: CN
Agent: CNCC(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCO[SiH](C)OCC1
Yield: 73.5 %

Procedure:
To a sealed 800 mL nitrogen purged glass bottle was added 400 mL anhydrous dichloromethane and 98.2 mL triethylamine. Then, 3.65 mL (35 mmol) of 99+% dichloromethylsilane and 4.02 mL (35 mmol) di(hydroxyethyl)methylamine was added with shaking. This was repeated five times over twenty minutes until a total of 175 mmol of both dichloromethylsilane and di(hydroxyethyl)methylamine had been added. The bottle was agitated in a room temperature bath for 15 minutes. Then, five more additions of 4.02 mL (35 mmol) 99+% dichloromethylsilane and 4.02 mL (35 mmol) dihydroxyethyl)methylamine were done until a total of 36.44 mL (0.35 mol) of 99+% dichloromethylsilane and 40.2 mL (0.35 mol) dihydroxyethylmethylamine were reached. The bottle was then agitated overnight in a room temperature bath. The resulting solution was filtered and dichloromethane removed by rotary evaporation. To the residue was added 400 mL of pentane and solution was filtered again. Pentane was removed by rotary evaporation and product was isolated by vacuum distillation at 78-81° C. and 20 mm Hg (41.7 g, 73.5% yield). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.79 (1H, q), 3.83-3.71 (4H, m), 2.78-2.61 (4H, m), 2.37 (3H, s), 0.03 (3H, d).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>ClCCl.[Ag]C#N>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[C:5]=2[C:10]([F:12])([F:13])[F:11])=[O:8])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Agent: N#C[Ag]
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4.24 g (12.8 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride in 25 ml of dichloromethane p.a. is added to a suspension of 2.38 g (12.8 mmol) of methyl 5-amino-2-chlorobenzoate and 2.57 g (19.2 mmol) of silver(I) cyanide in 50 ml of dichlormethane p.a., and the mixture is stirred at room temperature for 16 h. The suspension is then filtered through silica gel and the product is eluted using a mixture of cyclohexane and ethyl acetate (1:1). The organic phase is washed successively three times with 6N hydrochloric acid and twice with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate, filtered and concentrated on a rotary evaporator under reduced pressure. This gives 5.75 g (93%) of methyl 2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoate.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]=[C:5]([CH2:14][O:15]CC1C=CC=CC=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd].C(O)(=O)C>[CH2:6]([CH:5]1[CH2:14][O:15][C:3](=[O:23])[CH2:4]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C=C(CCc1ccccc1)COCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CC(CCc2ccccc2)CO1
Reaction time: 4 h
Yield: 46.7 %

Procedure:
A mixture of 3-benzyloxymethyl-5-phenyl-pent-2-enoic acid methyl ester, (3.2 g, 13.5 mmol), 10 wt. % palladium on activated carbon (3.2 g), and acetic acid (40 mL) is placed in a Parr® Shaker under hydrogen (45 PSI) and shaken 4 h. The mixture is filtered through a pad of Celite® and concentrated in vacuo. The residue is dissolved in toluene (30 mL), treated with p-tolunesulfonic acid (0.1 g), refluxed for 2 h and concentrated in vacuo. The residue is chromatographed on SiO2 (10% ethyl acetate/hexanes then 50% ethyl acetate/hexanes) to yield the title compound 1.2 g (62%) as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].C(N(CC)CC)C.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1>[CH3:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][Br:16])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 2-aminoheptane (1.67 ml, 0.011 mol) and triethylamine (1.55 ml, 0.011 mol) in dry THF (100 ml) was added powdered 4-bromomethylbenzenesulphonyl chloride (3.0 g, 0.011 mol) in one portion. The mixture was stirred for 3 h at room temperature. The reaction mixture was treated with saturated ammonium chloride (60 ml), extracted with ethyl acetate (3×80 ml), the organics combined and washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. The resulting oil was purified by chromatography (silica: 1:2 hexane:ethyl acetate) to give N-1-methylhexyl 4-bromomethylbenzenesulphonamide (1.45 g, 39%) as a pale yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]=[N:17]O)[NH:13][C:12]1=[S:19].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+].O>C1COCC1.C(OCC)(=O)C>[NH2:17][CH2:16][C:14]1[NH:13][C:12](=[S:19])[N:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH:15]=1
Reactant: ON=Cc1cn(C2CCc3ccccc3C2)c(=S)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NCc1cn(C2CCc3ccccc3C2)c(=S)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde oxime (0.158 g, 0.58 mmol), prepared as in Example 22, in 20 mL of THF was cooled to 0° C. and LAH (1.0M, 1.16 mL, 1.16 mmol) in THF was added slowly. The mixture was stirred at 0° C. for 1 hour and then saturated ammonium chloride, water and ethyl acetate were added. The aqueous layer was separated and extracted with ethyl acetate. The combined ethyl acetate was dried over magnesium sulfate and concentrated by evaporation. Purification of the residue by flash chromatography (elution: 3-10% methanol/methylene chloride) gave 4-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione, m.p. 197°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[C:33](=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-]CC.[Na+]>C(O)C>[CH2:34]([C:33]1[C:21]2[CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25][C:20]=2[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2)C1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Yield: 91.8 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (300 mg, 1.22 mmol, example 43a), tert-butyl 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (466 mg, 1.47 mmol, example 41d) and sodium ethoxide (83 mg, 1.22 mmol) in ethanol (4 mL) were heated at 100° C. in a microwave reactor for 20 minutes. The reaction mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent was evaporated under reduced pressure yielding tert-butyl 4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (590 mg, 92%) which was used in the subsequent step as such. MS (ES+) m/z 527.3 (M+H)+
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5](=[C:9]([OH:15])[CH:10]=[C:11]([NH:13][CH3:14])[CH3:12])[C:4](=O)[O:3]1.[F:18][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F>C(#N)C>[F:18][C:10]1[C:9]([OH:15])=[C:5]([C:6]([OH:7])=[O:8])[C:4](=[O:3])[N:13]([CH3:14])[C:11]=1[CH3:12]
Reactant: CNC(C)=CC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: F[B-](F)(F)F
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([O:24]CC)=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([OH:24])=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 252 b), ethyl 2-(5-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamido)-2-ethylbutanoate was treated with sodium hydroxide to give the title compound as white solid. MS: 389.3 [M−H]−.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:29]1[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([S:25]([CH3:28])(=[O:27])=[O:26])([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1.CC(C[Al]CC(C)C)C>C(Cl)Cl>[CH3:28][S:25]([C:22]([C:14]1[CH:15]=[C:16]2[C:21](=[C:12]([C:8]3[CH:7]=[C:6]([CH2:5][CH:4]([C:29]4[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=4)[CH2:3][OH:2])[CH:11]=[CH:10][CH:9]=3)[CH:13]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)([CH3:24])[CH3:23])(=[O:26])=[O:27]
Reactant: COC(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(SC)cc1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: CSc1ccc(C(CO)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: 21 °C
Reaction time: 3 h

Procedure:
To a solution of the ester from Step 1, Example 13 (1.0 g, 5 mmol) in CH2Cl2 (25 mL) at −78° C. was added dibal-H (20.1 mL, 12 mmol). The resulting reaction mixture was warmed slowly to 21° C., then quenched with sodium potassium tartrate solution and stirred at 21° C. for 3 h. The reaction mixture was diluted with ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 50:50) provided the title compound as a white foam.
Reaction SMILES: Br[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH3:16])[CH:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[O:23]([C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:16])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 160 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
2.5 g of methyl 4-bromo-5-methylsulfonyl-2-methylbenzoate, 0.94 g of phenol and 7.8 g of Cs2CO3 were dissolved in 40 ml of N-methylpyrrolidone and stirred at 160° C. for 4 h. The reaction mixture was poured onto 100 ml of a saturated aqueous NaHCO3 solution and 100 ml of water and extracted 5 times with 100 ml of EA each time. The aqueous phase was slowly adjusted to pH=2-3 using 6 N aqueous HCl solution and again extracted 5 times with 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using DIP/2% HOAc yielded 1.85 g of a colorless solid,
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=O)=[CH:6][CH:5]=1>>[CH2:1]([NH:3][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:5][CH:6]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1ccnc2ccccc12
Product: CCNCc1ccnc2ccccc12

Procedure:
prepared by reaction of ethylamine with quinoline-4-carbaldehyde
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=1[O:11][CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=1[O:11][CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COc2ccccc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@H](COc2ccccc2O)C1
Reaction time: 2 h

Procedure:
Additional debenzylation reaction: To a solution of (S)-2-(2-benzyloxy-phenoxymethyl)-morpholine-4-carboxylic acid, tert-butyl ester (obtained as above, General Procedure D) in ethanol was treated with 10% Pd/C. The room temperature sample was hydrogenated at balloon pressure for 2 h, filtered then concentrated. The sample was dissolved into EtOAc, washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to give (S)-2-(2-hydroxy-phenoxymethyl)-morpholine-4-carboxylic acid, tert-butyl ester as a light yellow oil.
Reaction SMILES: BrC1C=CC(CC[OH:10])=C(C)C=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:23][CH3:24])[C:16]([CH:21]=[CH2:22])=[C:17]([CH2:19][CH3:20])[CH:18]=1.B1C2CCCC1CCC2>>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([CH2:21][CH2:22][OH:10])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: C=Cc1c(CC)cc(Br)cc1CC
Reactant: Cc1cc(Br)ccc1CCO
Agent: B1C2CCCC1CCC2
Product: CCc1cc(Br)cc(CC)c1CCO
Yield: 58 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 37B (1.2 g, 5 mmol) was heated in a pressure vessel with 9-BBN at 115° C. for 1 h to yield 37C (735 mg, 58%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.58 Hz, 6 H) 2.66 (q, J=7.49 Hz, 4 H) 2.92 (t, J=7.58 Hz, 2 H) 3.66-3.77 (t, J=7.57 Hz, 2 H) 7.17 (s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[CH:32][CH:33]=1)[CH3:2]
Reactant: CCOc1ccccc1CCNC(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1CCNC(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 54.3 %

Procedure:
Methyl 2-{[4-(3-{[2-(2-ethoxyphenyl)ethyl]amino}-3-oxopropyl)phenoxy]methyl}-benzoate (0.26 g, 0.56 mmol) was dissolved in a mixture of THF/water (7/1, 5 ml) and lithium hydroxide (54 mg, 2.25 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 136 mg of 2-{[4-(3-{[2-(2-ethoxyphenyl)ethyl]amino}-3-oxopropyl)phenoxy]methyl}benzoic acid (yield 53.9%).
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]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.CO[BH-](OC)OC.[Na+]>ClCCl.O>[CH:5]1([CH2:6][NH:26][CH2:25][C:24]([C:15]2[NH:16][C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[N:14]=2)([CH3:28])[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:3][CH2:4]1
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Agent: CO[BH-](OC)OC
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cc(-c3nc(C(C)(C)CNCC4CCCCC4)[nH]c3-c3ccncc3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A solution of the product of Example 2 (20 mg, 0.05 mmol) in dichloromethane (2 mL) was treated with cyclohexaldehyde (3 mg, 0.07 mmol) and sodium trimethoxyborohydride (9 mg, 0.07 mmol). The solution was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on a Gilson HPLC to give the title compound (10 mg, 40%) as a yellow solid; MS(ES) m/e 469 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[CH3:11])=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:27]([O:26][C:24]([N:22]1[CH2:23][CH:20]([C:7]2[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:10]([CH3:11])=[C:5]([CH:6]=2)[C:3]([OH:4])=[O:2])[CH2:21]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(N(C)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(C2CN(C(=O)OC(C)(C)C)C2)cc1N(C)C1CCOCC1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a dry flask was added zinc dust (436 mg, 6.67 mmol) and the flask was heated using a heat gun for a few minutes. Then anhydrous DMA (20 ml) was added under nitrogen whilst stirring vigorously and heating to 65° C. TMS-Cl (102 μl, 0.8 mmol) and 1,2-dibromoethane (70 μl, 0.8 mmol) were added and the reaction was stirred at 65° C. for 30 min followed by the dropwise addition of N-Boc-3-iodoazetidine (1.46 g, 5.16 mmol) as a solution in anhydrous DMA (15 ml). The reaction was then cooled to room temperature and methyl 5-bromo-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate (1.06 g, 3.09 mmol) was added as a solution in anhydrous DMA (15 ml). The resulting solution was degassed with nitrogen for 10 mins after which Pd(dppf)Cl2.DCM (76 mg, 0.09 mmol) and copper (I) iodide (35 mg, 0.19 mmol) were added as solids. The reaction was heated to 80° C. for 90 min and then cooled to room temperature followed by the addition of distilled water (100 ml) and saturated NH4Cl solution (10 ml). The aqueous phase was extracted with TBME (3×50 ml), and then the combined organic phases were dried with Na2SO4, filtered and evaporated. The residue was purified over a 25 g Isolute column using 0%-40% EtOAc in heptane as the eluent to afford the title compound as a pale brown oil (507 mg). LC-MS 97%, m/z=420.0. To a stirred solution of tert-butyl 3-[3-(methoxycarbonyl)-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl]azetidine-1-carboxylate (85 mg, 0.2 mmol) in THF (2 ml) and MeOH (0.1 ml) was added 2M NaOH solution (1.02 ml, 2.03 mmol) and the reaction was stirred at 50° C. for 16 h after which time 4M NaOH solution (0.5 ml, 2.0 mmol) was added and the reaction was heated for a further 24 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH3 using 1M HCl. The product was extracted into DCM (2×50 ml), washed with brine (20 ml), dried with Na2SO4 and filtered to afford the title compound as an off-white solid (47 mg, 21% over two steps). LC-MS 95%, m/z=405.1, 1H NMR (500 MHz, Chloroform-d) δ 7.66 (t, J=7.0 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 4.34 (t, J=8.7 Hz, 2H), 3.98 (dd, J=16.6, 10.2 Hz, 4H), 3.79-3.69 (m, 2H), 3.35 (dd, J=11.5, 10.0 Hz, 2H), 2.97 (td, J=10.8, 5.3 Hz, 1H), 2.67 (s, 3H), 2.55 (d, J=6.6 Hz, 3H), 1.74 (ddd, J=15.5, 12.1, 4.3 Hz, 2H), 1.66 (d, J=11.1 Hz, 2H), 1.48 (s, 9H).