Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[S:6][CH:7]=1.C(C1C=CC([C:24]([NH2:26])=S)=CC=1)(C)C.ClCC(CCl)=O.[C-]#N.[Na+]>CS(C)=O.O>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][C:24]#[N:26])[N:4]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(C(N)=S)cc1
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C(CCl)CCl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc(-c2nc(CC#N)cs2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
14.5 g (57.6 mmol) of 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) and 4.08 g (83.4 mmol) of sodium cyanide in 50 ml of dimethyl sulfoxide were stirred at 40° C. for 2 hours. Then, the reaction mixture was poured into a mixture of ice and water and was subsequently extracted with 3 portions of 75 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, 13.4 g (96% of theory) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetonitrile were obtained as brown solid.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH2:21][N:22]([CH3:38])[CH:23]=[C:24]4[C:33]=3[NH:32][N:31]=[C:30]3[C:26]5[C:27](=[CH:34][C:35]([F:37])=[CH:36][C:25]4=5)[CH:28]=[CH:29]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[F:37][C:35]1[CH:34]=[C:27]2[CH:28]=[CH:29][C:30]3=[N:31][NH:32][C:33]4[C:24](=[CH:23][N:22]([CH3:38])[CH2:21][C:20]=4[C:17]4[CH2:18][CH2:19][N:14]([CH:11]5[CH2:10][CH2:9][C:8](=[CH:7][C:6]([OH:39])=[O:5])[CH2:13][CH2:12]5)[CH2:15][CH:16]=4)[C:25](=[C:26]23)[CH:36]=1
Reactant: CN1C=C2C(=C(C3=CCN(C4CCC(=CC(=O)OC(C)(C)C)CC4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C=C2C(=C(C3=CCN(C4CCC(=CC(=O)O)CC4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31

Procedure:
A mixture of Example 175B (90 mg, 0.119 mmol) in 1:1 dichloromethane/trifluoroacetic acid (0.6 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to provide the title compound as bis-trifluroacetic acid salt. 1H NMR (400 MHz, Pyridine-d5) δ 1.68-2.43 (m, 8H), 2.99 (s, 3H), 3.18-3.61 (m, 4H), 4.05 (d, J=3.7 Hz, 2H), 4.32-4.47 (m, 3H), 5.93-6.15 (m, 2H), 7.15-7.32 (m, 2H), 7.44 (d, J=5.2 Hz, 1H), 7.88 (dd, J=10.4, 3.0 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 12.82 (s, 1H). MS (ESI+) m/z 473.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[C:20]([F:25])[CH:19]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:10]2([NH2:16])[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[N:13]([CH3:14])[N:12]=[C:11]2[CH3:15])=[C:20]([F:25])[CH:19]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC1=NN(C)C(c2ccc(F)cc2Cl)C1(N)c1ccc(Cl)cc1F
Temperature: 180 °C

Procedure:
A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amine (i.e. the product of Step F) (7.07 g, 23.8 mmol), 4-chloro-2-fluoroiodobenzene (256 μL, 2.0 mmol), sodium tert-butoxide (0.192 g, 2.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.117 g, 0.16 mmol) in toluene (5 mL) was heated at 180° C. in a Biotage Initiator™ microwave apparatus for 1 h. The resulting material was purified by flash chromatography on a silica gel (40 g), Varian Bond Elute SI® column (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a dark purple/brown oil (164 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(N)(=S)C1C=CC=CC=1.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[S:24][CH:25]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: NC(=S)c1ccccc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccccc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 4-chloromethyl-2-phenyl-thiazole (prepared from thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[3-fluoro-4-(2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-[3-fluoro-4-(2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].[H-].[Na+].Cl[CH2:20][C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][CH:2]([C:5]1[N:6]([CH2:20][C:21]2[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2[nH]1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of 2-(butan-2-yl)-6-chloro-5-methoxy-1H-indole (289 mg) in N,N-dimethylformamide (6.1 mL) was added sodium hydride (dispersed in liquid paraffin, 55% or more, 73 mg) under ice-cooling. This mixture was stirred for 1 hour under ice-cooling. Subsequently, methyl 6-chloromethylpyridine-2-carboxylate (271 mg) was added thereto, followed by stirring at 80° C. for 21 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride solution/water (2/1, 30 mL) was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (328 mg). 1H-NMR (CDCl3) δ ppm: 0.84 (3H, t, J=7.4 Hz), 1.23 (3H, d, J=6.9 Hz), 1.45-1.80 (2H, m), 2.60-2.75 (1H, m), 3.93 (3H, s), 4.06 (3H, s), 5.50 (2H, s), 6.31 (1H, s), 6.40-6.50 (1H, m), 7.12 (1H, s), 7.15 (1H, s), 7.64 (1H, t, J=7.9 Hz), 7.95-8.05 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[N+](=[C:14](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+].[Cl-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[C:8]#[CH:14]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: Nc1nc(CO)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(CO)nc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a mixture of 2-amino-6-hydroxymethyl-pyridine-3-carbaldehyde (16 mg, 0.11 mmol) described in Manufacturing Example 169-1-1 and methanol (1.5 mL) were added dimethyl (1-diazo-2-oxopropyl)phosphonate (30 mg, 0.16 mmol) and potassium carbonate (23 mg, 0.17 mmol) at −10° C., which was stirred for 10 minutes at 0° C., and then for another 6 hours at room temperature. A saturated ammonium chloride aqueous solution and saturated aqueous sodium chloride were added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (13 mg, 47%, purity: 57%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M152) (377 mg, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (118 mg, 39%).
Reaction SMILES: [Br:1][CH:2]1[CH:7]([Br:8])[CH2:6][CH:5]([OH:9])[CH:4]([OH:10])[CH2:3]1.CO[C:13](OC)([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:1][CH:2]1[CH:7]([Br:8])[CH2:6][CH:5]2[O:9][C:13]([CH3:15])([CH3:14])[O:10][CH:4]2[CH2:3]1
Reactant: COC(C)(C)OC
Reactant: OC1CC(Br)C(Br)CC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)OC2CC(Br)C(Br)CC2O1
Reaction time: 3 h

Procedure:
The compound obtained in Step (10) (20.6 g, 75.62 mmol) was placed in a reaction vessel, and air in the vessel was replaced with nitrogen. 2,2-dimethoxypropane (12.92 ml) and p-toluenesulfonic acid (0.9 g) were added to the vessel, and the mixture was stirred for 3 hours. After the completion of the reaction had been confirmed, the mixture was filtrated through activated alumina, and the filtrate was concentrated under reduced pressure, whereby 5,6-dibromo-2,2-dimethylhexahydro-1,3-benzodioxol was obtained (17.1 g, 72%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7](O)=[O:8])=[O:4].N1C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7]([Cl:22])=[O:8])=[O:4]
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in step 1) (17.2 g, 0.0845 mol) was dissolved in 300 ml of dichloromethane, and 1 ml of pyridine was added. The reaction mixture was cooled in ice-water bath to 0˜3, and oxalyl chloride (25.8 g, 0.203 mol) was added dropwise. After the completion of the addition, the temperature was slowly raised to room temperature, and a reaction was allowed to proceed for 3 hours. Evaporation was carried out under reduced pressure to remove the solvent, and 50 ml×2 benzene was added to remove residual solvent by azeotropism. The obtained (R)—N-trifluoroacetyl-2-amino propionyl chloride can be directly used for the subsequent reaction.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]#[N:7].[C:23]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]=O)[CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]([CH2:35][C:31]1[CH:30]=[C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:34]=[CH:33][N:32]=1)[CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]#[N:7]
Reactant: O=Cc1cc(-c2ccccc2)ccn1
Reactant: N#Cc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CN(Cc2cc(-c3ccccc3)ccn2)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of 3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzonitrile in CH2Cl2 with 4-phenyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3-hydroxymethyl-4-{[(4-phenyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzonitrile as a colorless oil. 1H NMR (CDCl3) δ 1.63 (m, 1H), 2.08 (m, 2H), 2.29 (m, 1H), 2.72 (m, 1H), 2.81 (m, 1H), 3.61 (d, 1H, J=12.0 Hz), 3.73 (d, 1H, J=12.0 Hz), 3.85 (m, 3H), 4.08-4.23 (m, 3H), 4.43 (d, 1H, J=9.0 Hz), 7.06 (dd, 1H, J=7.5, 3.0 Hz), 7.36-7.64 (m, 8H), 7.86 (d, 2H, J=9.0 Hz), 8.00 (s, 1H), 8.51 (dd, 2H, J=12.0, 4.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]([O:26][CH3:27])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:10]2[C:9]3[C:8]([O:26][CH3:27])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OC)c2c1c1ccccc1n2Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Yield: 89.1 %

Procedure:
To a solution of 9-(4-fluoro benzyl)-1-methoxy-4-carbazole carboxylic acid methyl ester (490 mg, 1.35 mmoles) in methanol (15 ml), an aqueous (10 ml) solution of sodium hydroxide (108 mg, 2.7 mmoles) was added and the reaction mixture was refluxed for 6 hours. Methanol was evaporated from the reaction mixture under reduced pressure, acidified the residue with 1N HCl and the precipitated product was filtered washed with water and dried under vacuum, to give 420 mg of the title product
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][CH2:20][C:21]#[N:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:20]([CH2:21][NH:22][C:15]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])#[N:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: N#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To 5.05 g (20.75 mmol) of the acid of step 2 dissolved in 40 mL DMF was added 1.92 g (20.75 mmol) aminoacetonitrile hydrochloride, 3.98 g (20.75 mmol) of EDCI, 2.80 g (20.75 mmol) of HOBT and 7.98 mL (72.63 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to obtain 5.83 g of the crude tert-butyl (1S,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexylcarbamate.
Reaction SMILES: C(C1C=C(C(C)(C)C)C=CC=1O[C@H](C)C([N:19]1[C@H:23]([CH:24]=[CH2:25])[CH2:22][CH2:21][C:20]1=[O:26])=O)(C)(C)C.[OH-:28].[K+].Cl>O>[NH2:19][C@H:23]([CH:24]=[CH2:25])[CH2:22][CH2:21][C:20]([OH:26])=[O:28]
Reactant: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: C=C[C@@H](N)CCC(=O)O
Temperature: 25 °C

Procedure:
A solution of (5S)-N-((2R)-2-(2,4-di-t-butylphenyloxy)-propanoyl)-5-ethenylpyrrolidin-2-one (19a, 1.0 g, 2.5 mmol) and 87% potassium hydroxide (317 mg, 5.7 mmol) in water (2 mL) is refluxed for 1.5 hours. The solution is allowed to cool to room temperature. Water is added (15 mL) and the solution is acidified to pH 7 with concentrated hydrochloric acid and extracted with diethyl ether (3×10 mL) to remove the chiral auxiliary. The aqueous solution is then acidified to pH 5.5 with concentrated hydrochloric acid and extracted with diethyl ether (3×15 mL). The second series of organic extracts are combined and dried (MgSO4). Concentration by rotary evaporation affords (4S)-4-amino-5-hexenoic acid (B).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH:17]3[O:24][C:25]([N:27]3[CH2:31][CH2:30][C@H:29](O)[CH2:28]3)=[O:26])[CH2:15]1)[CH2:21]2.[O:33]=[C:34]1[NH:39][CH:38]=[C:37]([C:40]#[N:41])[CH:36]=[CH:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[OH:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH:17]3[O:24][C:25]([N:27]3[CH2:31][CH2:30][C@@H:29]([N:39]4[CH:38]=[C:37]([C:40]#[N:41])[CH:36]=[CH:35][C:34]4=[O:33])[CH2:28]3)=[O:26])[CH2:15]1)[CH2:21]2
Reactant: N#Cc1ccc(=O)[nH]c1
Reactant: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(=O)n([C@@H]2CCN(C(=O)OC3C4CC5CC3CC(O)(C5)C4)C2)c1
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (40% in toluene, 1.7 mL) is added to a mixture of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid 5-hydroxy-adamantan-2-yl ester (ca. 1:1 mixture of cis- and trans-isomer, 0.50 g), 6-oxo-1,6-dihydro-pyridine-3-carbonitrile (0.22 g), triphenylphosphine (0.97 g), and tetrahydrofuran (10 ml) at room temperature. The resulting mixture is stirred for 2 h and then concentrated. The residue is chromatographed on silica gel (ethyl acetate/methanol 95:5→80:20) and then on reversed phase (HPLC, acetonitrile/water containing 1.36% trifluoroacetic acid) to give the title compound as a mixture of two diastereomers (cis/trans ca. 1:1). Yield: 8 mg (1% of theory); LC (method 1): tR=1.03/1.06 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].Cl.N.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:38])[C:20]([CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 82, 3.98 g, 8.00 mmol) in DMF (20 mL) at room temperature was added ammonia hydrochloride (0.856 g, 16.00 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (4.56 g, 12.00 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.57 mL, 32.00 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. The crude product was purified with silica gel chromatography (220 g, 10%-80% ethyl acetate/hexanes) to yield the desired product (2.79 g, 70.2%) as an yellow foam.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Br

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (21.5 g, 100 mmol) in 500 mL of methanol and 8 mL of concentrated sulfuric acid is refluxed overnight. Methanol is removed under reduced pressure, the residue is taken up in ether, washed with sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/C)=[CH:24]/C(O)=O)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl>[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[CH3:24])=[CH:1]/[C:2]([Cl:4])=[O:3])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCc1ccc(/C(C)=C/C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCc1ccc(/C(C)=C/C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (3.2 mL, 36.60 mmol) and DMF (50 μL) were added drop wise to a solution of compound 1003 (5.0 g, 21.52 mmol) in dichloromethane (100 mL) at 0° C. The reaction solution was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuum and the residue was dried under hi-vacuum for 3 hours. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:33])[N:5]([C@@H:6]2[C@@H:14]([O:15]C(=O)C)[C@H:13]([O:19]C(=O)C)[C@@H:12]([CH2:23][O:24]C(=O)C)[O:11][C@H:7]2[O:8][CH2:9][CH3:10])[C:4](=[O:28])[C:3]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:2]12.[Na]>CO>[C:4]1(=[O:28])[N:5]([C@@H:6]2[C@@H:14]([OH:15])[C@H:13]([OH:19])[C@@H:12]([CH2:23][OH:24])[O:11][C@H:7]2[O:8][CH2:9][CH3:10])[C:1](=[O:33])[C:2]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:3]12
Reactant: CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: [Na]
Solvent: CO
Product: CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 2-deoxy-2-phthalamido-3,4,6-tri-O-acetyl-β-D-glucopyranosyide (compound 13) from example 17 was taken up in 100 mL of dry methanol and treated with 100 mg of sodium metal. The solution was stirred at room temperature for 24 hours and then neutralized with Amberlite [R-120(H+)] resin, filtered, and evaporated to dryness in vacuo. This compound was used in the preparation of compound 15 and compound 66.