Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[Li]CCCC>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:23])([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(=O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-[(3-chlorophenyl)(oxo)acetyl]-L-prolinate (2.2 g, 6.46 mmol) was dissolved in THF (10 mL) and cooled to −78° C. under a nitrogen atmosphere (Vessel A). In a separate vessel containing 3-bromopyridine (0.68 mL, 7.1 mmol) in ethyl ether (50 mL) cooled to −78° C. was added n-BuLi (2.5M in hexanes, 3.1 mL, 7.7 mmol) and the mixture was stirred for one hour (Vessel B). The contents of Vessel B were added to Vessel A via cannula at −78° C. The temperature was increased to 0° C. and the mixture stirred for 2.5 hours. The mixture was then quenched with saturated ammonium chloride solution (40 mL) and extracted with EtOAc. The EtOAc was evaporated in vacuo, and the residue dried and purified on silica gel using a 1:1 then 2:1 mixture of EtOAc to hexane as mobile phase. Pooled fractions were dried to yield: Nonpolar isomer of tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.43 g, HPLC RT=3.01 min, Method A; LCMS m/z=417). Polar isomer of ten-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.12 g, HPLC RT=2.96 min, Method A; LCMS m/z=417).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[OH:24])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1ccccc1O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccccc3O)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2-hydroxybenzoic acid as brown solid (46%). MS 438 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[Br:18])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of bis(4-chlorophenyl)methanol (2.0 g) and carbon tetrabromide (5.2 g) in tetrahydrofuran (30 ml) was added triphenylphosphine (4.2 g). The mixture was stirred at room temperature for 1 hours. After the mixture was filtered off, the solvent was removed in vacuo. The residue was dissolved in n-hexane (30 ml) and filtered off. The filtrate was evaporated and the residue was purified by distillation at reduced pressure to give bis(4-chlorophenyl)bromomethane as an oil (2.43 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (18.3 g, 0.150 mol) was dissolved in N,N-dimethylformamide (150 mL). Subsequently, potassium carbonate (22.80 g, 0.165 mol), and then ethyl 2-bromobutyrate (29.26 g, 0.150 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (35.29 g, 0.149 mol, 99.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(Cl)cc1I
Agent: [Cu]I
Solvent: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A solution of 4-Chloro-2-Iodophenol [71643-66-8] (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.5 g, 50%): Mp=183-185° C.; 1H NMR (CDCl3) δ 7.76 (d, 2 H, J=8.0 Hz), 7.50 (d, 1 H, J=1.6 Hz), 7.39 (d, 1 H, J=8.3 Hz), 7.20-7.18 (m, 1 H), 6.97 (d, 2 H, J=8.3 Hz), 6.82 (s, 1 H), 3.86 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[OH:22].C([O-])([O-])=O.[Na+].[Na+].CC(=O)OCC>O1CCOCC1.O.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH3:1][C:2]1[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:22])=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C1(O)c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccc(F)cc1)C(=O)N2
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3,5-dimethylisoxazol-4-ylboronic acid (120 g, 851 mmol, 2.0 eq), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (10 g, 13.7 mmol, 0.03 eq), 5-bromo-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (136 g, 422 mmol, 1.0 eq) and Na2CO3 (100 g, 943 mmol, 2.2 eq) were dissolved in dioxane/H2O (800 mL/200 mL), which was heated to reflux for 5 h under N2 atmosphere. After cooled to room temperature, IL EA was added, the mixture was filtered through a pad of celite, the filter was washed with brine (1 L×2), dried over Na2SO4, concentrated, which was purified by silical gel to give 70 g yellow solid (yield, 49%). 1H NMR (400 MHz, DMSO-d6): δH 10.56 (s, 1H), 7.31-7.33 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 4.27-4.35 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 339.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:15]1[S:16][C:17]([CH3:20])=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][N:19]=2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: Cc1cnc(Br)s1
Reactant: COc1ccc(B(O)O)c(C=O)c1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(C)s2)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
To a solution of 2-formyl-4-methoxyphenylboronic acid (200 mg, 1.11 mmol) in DMF (10 mL) and H2O (2 mL) are added 2-bromo-5-methylthiazole (217 mg, 1.22 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol) and K2CO3 (230 mg, 1.67 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and filtered. The filtrate is washed with H2O (15 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 5-methoxy-2-(5-methyl-thiazol-2-yl)-benzaldehyde (160 mg, 63%) as a white foam.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[N:5]1>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:12])([OH:13])[CH3:1])[CH:8]=1
Reactant: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)Cn1cc(N)cn1
Reaction time: 8 h
Yield: 113.4 %

Procedure:
A stirred suspension mixture of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (2.0 g, 10.8 mmol) and 10% Pd/C (0.2 g, 0.1 w/w) in MeOH (20 mL) was exposed to 1 atm H2 at RT overnight. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a yellow oil (1.9 g, 99%), which was used for the next step without further purification. MS (ES+) C7H13N3O requires: 155, found: 156 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[CH2:74][C:75]([C:77]1[CH:86]=[CH:85][C:80]2[O:81][CH2:82][CH2:83][O:84][C:79]=2[CH:78]=1)=[O:76].[BH4-].[Na+]>CC(C)=O.O.ClCCl>[O:81]1[C:80]2[CH:85]=[CH:86][C:77]([CH:75]([OH:76])[CH2:74][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C@@H:9]3[C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[C:38]([CH3:39])([CH3:41])[CH3:40])=[O:35])=[O:31])=[CH:45][CH:46]=3)=[CH:78][C:79]=2[O:84][CH2:83][CH2:82]1
Reactant: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O

Procedure:
To a solution of N-[(4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetyl]glycyl-3-methyl-D-valine (0.030 g, 0.045 mmol) in acetone/water (2/0.5 ml) was added triphenylphosphine (0.012 g, 0.045 mmol). After 30 minutes the solvent was evaporated and to the residue was added dichloromethane (2 ml) and triethylamine (0.018 g, 0.179 mmol) followed by the addition of 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (0.029 g, 0.112 mmol). After 10 minutes the reaction was quenched by the addition of water (1 ml) followed by concentration of the mixture. MeOH (2 ml) was added followed by the addition of sodium borohydride (0.017 g, 0.447 mmol). Full conversion to the corresponding alcohol was achieved within 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). Preparative HPLC of the mixture using an eluent of 20-45% CH3CN in 0.1M NH4OAc buffer followed by freeze drying of pure fractions afforded the desired compound. m/z: 694.7 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.89 (s, 9H), 2.78-2.89 (m, 2H), 3.82 (d, 2H), 4.05-4.28 (m, 6H), 4.51 (s, 2H), 4.55-4.61 (m, 1H), 5.01-5.03 (m, 1H), 6.72-7.37 (m, 11H), 7.81-7.87 (m, 1H), 8.25 (t, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=[C:3]1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:45][C:46]1[C:47]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:48][C:49]([C:53]([CH3:56])([CH3:55])[CH3:54])=[C:50]([OH:52])[CH:51]=1>C1COCC1>[C:57]([C:47]1[CH:48]=[C:49]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:50]([OH:52])=[CH:51][C:46]=1[NH:45][C:11]([C:3]1[C:2](=[O:1])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=1)=[O:13])([CH3:60])([CH3:58])[CH3:59]
Reactant: O=C(O)c1c[nH]c2ccnn2c1=O
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccnn3c2=O)cc1O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a vial charged with 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (50 mg, 0.28 mmol) and HATU (117 mg, 0.31 mmol) was added 2 mL of THF followed by triethylamine (85 mg, 0.84 mmol). The reaction mixture was allowed to stir for 10 minutes at room temperature, upon which 5-amino-2,4-di-tert-butylphenol (62 mg, 0.28 mmol) was added and the reaction was heated at 65° C. for 16 h. After 16 h, the reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2 0 (0.05% TFA)). LC/MS (10-99% CH3CN/0.05% TFA in H2O/0.05% TFA gradient over 3 min) to give N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide; M+H m/z 383.3, retention time 1.71 minutes. 1H NMR (400.0 MHz, DMSO) δ 13.48 (s, 1H), 10.68 (s, 1H), 9.24 (s, 1H), 8.78 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.17 (s, 1H), 7.13 (s, 1H), 6.41 (d, J=2.0 Hz, 1H), 1.36 (d, J=4.5 Hz, 18H).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)([CH3:3])[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.O>C(Cl)Cl>[CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:12]([CH3:11])(=[O:14])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)SC1=NC(=O)CS1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
8 g of 2-isopropylthio-1,3-thiazoline-4-one was dissolved in 100 ml of methylene chloride and cooled below 10° C. Then, 7.8 g of methanesulfonyl chloride and 12.6 ml of triethylamine were added dropwise to the solution below 15° C. with attention to out-break of heat. After that, the reaction was continued with stirring at room temperature for 2 hours. Water was added to the reaction mixture and extracted by ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to obtain 9.1 g of the objective compound as a pale brown crystal (yield: 78.8%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][C@@H:24]([N:26]([CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH2:27][CH3:28])[CH3:25])=[CH:22][C:17]=2[CH2:16][CH2:15]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][N:26]([C@@H:24]([CH3:25])[CH2:23][C:21]2[CH:20]=[CH:19][C:18]3[O:14][CH2:15][CH2:16][C:17]=3[CH:22]=2)[CH2:27][CH3:28])[CH2:31][CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of N-tert-butoxycarbonyl-β-alanine (0.31 grams, 165 mmole) in dichloromethane (5 ml) was added N,N′-carbonyldiimidazole (0.3 grams, 185 mmole). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidine-4-ylmethyl)amine (0.5 grams, 1.65 mmole) in dichloromethane (2 ml). The reaction mixture was stirred for 16 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using 2% methanol in dichloromethane containing 0.1% ammonium hydroxide. Appropriate fractions were combined and concentrated to give (S)-3-tert-butoxycarbonylamino-1-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-ethylamino}methyl)piperidin-1-yl]propan-1-one as a solid (0.76 grams, 97%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)C=C.Cl[C:22]1[CH:27]=CC=C[C:23]=1Cl>>[CH2:27]([C:6]1[C:5]([OH:4])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[CH:22]=[CH2:23]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc2c(ccn2-c2ccc(Cl)cc2)c1
Product: C=CCc1c(O)ccc2c1ccn2-c1ccc(Cl)cc1

Procedure:
5-allyloxy-N-(4-chlorophenyl)indole (Step B; 1.4 g, 4.93 mmol) was refluxed in 20 mL 1,2-dichlorobenzene for 4 hours. The reaction mixture was cooled and immediately purified by flash chromatography on silica gel (gradient elution: hexane then 10% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]=[C:7]1[NH:11][C@@:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)([CH3:12])[C:9](=[O:21])[N:8]1[C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=1)C.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Al](C)C>C1(C)C=CC=CC=1>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@:10]2([CH3:12])[N:11]3[C:4](=[O:3])[CH2:5][N:6]=[C:7]3[N:8]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)[C:9]2=[O:21])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN=C1N[C@](C)(Cc2ccc(Br)cc2)C(=O)N1c1cc(Cl)cc(Cl)c1
Agent: C[Al](C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)C2=NCC(=O)N21
Temperature: -10 °C
Yield: 88.9 %

Procedure:
Toluene (450 mL) was added to 76.9 g of a mixture of the product of Example 2(47.1 g, 91.7 mmol) and triphenylphosphine oxide (29.2 g, 105 mmol), and the resulting solution was cooled down to −10° C. Trimethylaluminum (46 mL of a 2 M solution in toluene, 92 mmol) was added dropwise keeping the temperature at or below 0° C. and the mixture was then allowed to reach ambient temperature. The mixture was stirred at ambient temperature for two h and more trimethylaluminum (27.6 mL of a 2 M solution in toluene, 55.2 mmol) was added in two portions at two h intervals. The mixture was placed over an ice bath and slowly quenched with 1 N HCl (360 mL). The organic portion was separated and the aqueous portion was extracted with toluene (200 mL). The combined organic portions were washed with water and concentrated under reduced pressure to afford an orange oil. Flash chromatography (silica gel, hexane/ethyl acetete 4:1 v/v) afforded 38.1 g (89%) of product as an oil that solidified upon standing: mp 52-54° C.; 1H NMR (400 MHz, CDCl3) δ 1.84 (s, 3H), 3.24(d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 4.18 (d, J=21.9 Hz, 1H), 4.30 (d, J=21.9 Hz, 1H), 6.95(d, J=8.3 Hz, 2H), 7.29 (d, J=1.8 Hz 2H), 7.33 (t, J=1.8 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 40.8, 61.3, 65.1, 122.3, 122.6, 128.5, 131.0, 132.0, 132.5, 132.7, 135.5, 154.6, 174.3, 174.9; Anal. calcd for C19H14BrC12N3O2: C, 48.85; H, 3.02; N, 9.00. Found C, 48.89; H, 3.02; N, 8.81.
Reaction SMILES: [CH3:1]C1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1.[C:17]([CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[CH3:20])#[N:18]>ClCCl>[C:24]([C:23]1[CH:22]=[C:21]([CH:19]([CH3:20])[C:17]#[N:18])[CH:29]=[CH:28][CH:27]=1)(=[O:25])[CH3:1]
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C(C)C#N)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Next, to a solution of Meldrum's acid (408 mg, 2.84 mmol) in dichloromethane (15 mL) at 0° C. was added pyridine (0.457 mL, 5.68 mmol). The resulting mixture was stirred for 15 min and then 3-(1-cyanoethyl)benzoyl chloride (482.5 mg, 2.5 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then for 1 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in AcOH—H2O (1:2) and heated at reflux for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with NaHCO3 solution and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane-ethyl acetate (9:1) as eluent to give 13 (138 mg, 28%). 1H NMR (CDCl3, 400 MHz) δ 1.68 (d, J=7.2 Hz 3H), 2.63 (s, 3H), 3.99 (q, J=7.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:17]=[CH:16]4)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]4)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc4c(ccn4CC(=O)OC(C)(C)C)c3)no2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc4c(ccn4CC(=O)O)c3)no2)cc1C
Reaction time: 6 h

Procedure:
tert-butyl {5-[5-(2,2′-dimethylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetate obtained in step 1 was taken up in DCM (2 mL) and TFA (0.50 ml) was added at 0° C. and allowed to return to RT. After 6 hours, solvents were evaporated under vacuum to give a light yellow oil. Purification by silica column chromatography (c-Hexane/EtOAc, 85/15 then 50/50+1% AcOH) gave a colourless oil which was triturated in a mixture of Et2O and n-Hexane to give the title compound as an off-white solid. HPLC (Method A) Rt 5.41 min (Purity: 97.1%). LC/MS (method A): 422.0 (M−H)−.
Reaction SMILES: O.[OH-].[K+].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22]>CO>[NH2:23][CH:20]([CH:19]([OH:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:21][OH:22]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)C(N)CO
Reaction time: 8 h

Procedure:
158 g of the above compound are dissolved in 1054 cm3 of methanol including 10% of water containing 129.1 g of potassium hydroxide. The reaction medium is brought to reflux for 6 hours and then filtered through paper while hot. The filtrate is made up with 300 cm3 of water and left at 4° C. overnight. The solid formed is isolated by filtration on a glass sinter. 145 g of 2-amino-3-hydroxyoctadecanol or dihydrosphingosine are thereby obtained in pure erythro form.