Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)(=[O:10])=[O:9])(=O)=O.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:6][CH2:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(S(=O)(=O)CCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 70 °C
Yield: 20.9 %

Procedure:
A mixture of 102 (1.0 g, 3.2 mmol), 4-benzylpiperidine (103) (0.62 g, 3.5 mmol), and potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (10 ml) was heated at 70° C. overnight. It was allowed to cool to room temperature and partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (8:1 to 4:1 to 2:1 hexanes/EtOAc) to give 104 (0.26 g, 21%).
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[Pt](=O)=O.C(O)(=O)C>[CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2ccccc2c1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCCCc1nn2c(c1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)CCCC2
Yield: 0.1 %

Procedure:
220 g of the product of Example 6, 20 ml of acetic acid and 100 mg of 82% platinum dioxide. Filtration was carried out followed by extraction with ethyl acetate. The extracts were purified by chromatography on silica (essence G: 80/ethyl acetate: 20) to obtain 145 mg of the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(C#N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (2.8 g) and 1N sodium hydroxide (10 ml) in ethanol (150 ml) and tetrahydrofuran (20 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated, and the residue was dissolved in water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (2.5 g).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@@H:30]([CH3:32])[OH:31].N[C@H](C(N[C@@H](C(OC(C)(C)C)=O)CC(C)C)=O)[C@@H](C)O>CN(C=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Agent: CC(C)C[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](C)O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Coupling of 7.85 g Z-Val-ONp with 5.53 g H-Thr-Leu-OtBu in 160 ml DMF in the way described in C (2) provides Z-Val-Thr-Leu-OtBu in 72% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:38]=[C:39]([N+:41]([O-])=O)[CH:40]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:18]=2)=[CH:12][CH:11]=1)=[O:8])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:38]=[C:39]([NH2:41])[CH:40]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:18]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: CCCCCCCCCCCCCCCc1cccc(Oc2ccc(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccc(NC(=O)c3cc(N)cc(N)c3)cc2)c1

Procedure:
3 g (0.005 mol) of the 3,5-dinitro-N-(4-(3-pentadecylphenoxy)phenyl)benzamide thus prepared is dissolved in 20 mL of ethanol and reduced using 0.1 g 10% Pd/C catalyst at 40° C. and 40 psi hydrogen pressure until no more hydrogen is absorbed. The catalyst is then filtered and the diamine recrystallized from the filtrate to yield 3,5-diamino-N-(4-(3-pentadecylphenoxy)phenyl)benzamide, of the formula
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([O:9][CH2:10][C:11]#[CH:12])[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)=[N+:2]=[N-:3]>C1(C)C=CC=CC=1>[N:2]1[N:1]2[C@H:4]3[CH2:5][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@@H:8]3[O:9][CH2:10][C:11]2=[CH:12][N:3]=1
Reactant: C#CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2OCc3cnnn3[C@H]2C1
Yield: 95.8 %

Procedure:
A solution of (3S,4S)-tert-butyl 3-azido-4-(prop-2-ynyloxy)pyrrolidine-1-carboxylate (77 mg, 0.29 mmol) in toluene (5 ml) was heated at 120° C. for 16 hours or until TLC analysis shows completed reaction. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, silica gel, gradient hexane:ethyl acetate (3:1) to neat ethyl acetate, to afford the titled compound (74 mg, 96%) as white solid. M.p. 155-157° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:33])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:32])([CH3:31])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]3[C:11]([CH3:31])([CH3:32])[CH2:10][C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([F:33])[CH:8]=4)[NH:13]3)[CH:16]=2)=[CH:26][CH:25]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(F)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a stirred mixture solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (600 mg, 1.3 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (524 mg, 90%) as a white solid: LC/MS m/e calcd for C28H30FNO2 (M+H)+: 432.56, observed: 432.1.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH:19]([CH3:25])[C:20](OCC)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH:19]([CH3:25])[C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)C(C)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C(C)C1CCCCC1)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
74.5 g. of dimethyl methylphosphonate were dissolved in 514 ml. of tetrahydrofuran and the solution cooled to -60°C. To this solution a solution of n-butyl-lithium [prepared from 40.5 g. of n-butyl bromide and 9.2 g. of lithium] in 240 ml. of diethyl ether was added dropwise. A solution of 39.5 g. of ethyl 2-cyclohexylpropionate in 130 ml. of tetrahydrofuran was added dropwise and the mixture stirred at the same temperature for 2 hours and afterwards at 0°C. overnight. The reaction mixture was then neutralized to pH 7 with acetic acid, concentrated under reduced pressure and, after the addition of water to the residue, extracted with diethyl ether. After drying the ethereal extract, the solvent was distilled off and the residue subjected to distillation under reduced pressure to obtain 40 g. (yield 30.2 %) of the title compound as a colourless oil having the following physical characteristics:
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]1[CH2:44][C:43]2[CH:42]=[C:41]([OH:45])[CH:40]=[CH:39][C:38]=2[C@@H:37]2[C@@H:28]1[C@H:29]1[C@@:33]([CH2:35][CH2:36]2)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:45][C:41]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:28]([C@H:29]4[C@@:33]([CH2:35][CH2:36]3)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]4)[C@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:16])[C:9](=[O:10])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:44][C:43]=2[CH:42]=1
Reactant: CNCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)N(C)CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 2.5 h

Procedure:
N-Methylmorpholine (0.028 ml.) and isobutyl chloroformate (0.038 ml.) were successively added to a stirred solution of 7α-(9-methylaminononyl)oestra-1,3,5(10)-trien-3,17β-diol (Example 28; 0.08 g.) in tetrahydrofuran (3 ml.) and the mixture was stirred at laboratory temperature for 150 minutes. Saturated aqueous sodium bicarbonate solution (2 ml.) was added and the mixture was extracted three times with methylene chloride (10 ml. each time). The combined extracts were washed with water (5 ml.), dried and evaporated to dryness and there was thus obtained as residual oil isobutyl N-[9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)nonyl]-N-methylcarbamoate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.Cl>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
2,3,4-Trifluoronitrobenzene (1.01 g) and ethyl pyruvate (1.15 g) were dissolved in ethanol (8 ml). After adding 5% Pd-C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.38 g) was obtained as slightly yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][CH2:55][C:56](O)=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][CH2:55][C:56]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 47 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-glycine. Yield 47%. [α]D =+18.7° (c=0.95, (dichloromethane). m.p. 108-109°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:22])[NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1)OC
Reaction time: 24 h
Yield: 31.4 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (500 mg, 1.56 mmol) and 2,2-dimethoxy-ethylamine (163 mg, 1.56 mmol) in dichloromethane (5 mL) were added EDC-HCl (298 mg, 1.56 mmol), HOBt (210 mg, 1.56 mmol) and triethylamine (157 mg, 1.56 mmol). The mixture was stirred at room temp. for 24 h, diluted with water, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 15% EtOAc in hexane as eluent) to give (2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1 -carboxylic acid benzyl ester (200 mg, 31.6% yield) as a light brown liquid. MS calcd. for C21H33N2O6 [(M+H)+] 409.0, obsd. 409.0.
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[Cl:17][C:12]1[C:11](/[C:2](/[NH:27][CH:25]([C:22]2[CH:23]=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH3:26])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Reactant: CC(N)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C(C#N)=C(\NC(C)c1ccc(Cl)nc1)c1cccnc1Cl
Yield: 73 %

Procedure:
To a solution of ethyl 3-chlor-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.150 g, 0.55 mmol, 1 eq.) in 3 ml of acetonitrile was added 1-(6-chloropyridin-3-yl)ethanamine (0.103 g, 0.66 mmol, 1.2 eq.) followed by triethylamine (TEA) (0.167 g, 1.66 mmol, 3 eq.). The reaction was microwaved (130° C., 600 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-3-{[1-(6-chloropyridin-3-yl)ethyl]amino}-2-cyanoacrylate (0.157 g, 68% yield) as a mixture of 2 atropoisomers.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[C:22]([CH3:34])[CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:43]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:36]=[CH:35][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:25]=[CH:24][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[C:22]([CH3:34])[CH:21]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)=[CH:41][CH:42]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)ccc1N1CC(=O)NS1(=O)=O
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)ccc1N1CC(=O)NS1(=O)=O

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][CH3:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 71 h
Yield: 95.1 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (9.98 g, 27.9 mmol) and NaHCO3 (4.68 g, 55.7 mmol) in DMF (45 mL) is added Ethyl iodide (6.75 mL, 84 mmol) at room temperature under nitrogen. After stirring for 71 hours, the reaction is quenched with H2O (300 mL), and then precipitated solid is collected and washed with H2O (500 mL) to give (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (10.25 g, 94%). HPLC retention time=1.48 minutes (condition B); MS (ES+)=329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.2 Hz, 3H) 1.40 (s, 9H), 2.43 (A of ABX, Jab=15.8 Hz, Jax=5.7 Hz, 1H) 2.50 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1H) 2.74-2.90 (m, 2H) 4.11 (br s) 4.15 (q, J=7.1 Hz, 2H) 5.04 (br d) 7.07 (d, J=8.3 Hz, 2H) 7.40-7.43 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:45][C@H:44]([CH3:46])[O:43][C@H:42]([CH3:47])[CH2:41]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:49][OH:50]>C(O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:41][C@H:42]([CH3:47])[O:43][C@H:44]([CH3:46])[CH2:45]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=[N:49][OH:50])[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:21])([CH3:23])[CH3:22])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Pyridine (2597 μl, 32.11 mmol) was added to a mixture of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2,2,2-trifluoroethanone (Intermediate 130, 1900 mg, 3.21 mmol) and hydroxylamine hydrochloride (223 mg, 3.21 mmol) in 50 ml of ethanol and the solution was heated at 80° C. for 40 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude title compound (1.95 g, 98%), which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+].Cl>CO>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccccc3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Oc2ccccc2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An ice-cold yellow solution of (1-hydroxy-4-methyl-6-phenoxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester G45 (0.19 g, 0.58 mmol) in MeOH (3 mL) was treated with lithium hydroxide (0.07 g, 2.92 mmol, in 2 mL of H2O) dropwise. The mixture was stirred at 0° C. for 2 h, then rt for 3 h. The mixture was acidified with 2 N HCl to pH 3, then extracted with EtOAc, dried (Na2SO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, AcOH/EtOAc/hexanes; 0.5:4:100) to afford 1-hydroxy-4-methyl-6-phenoxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.14 g, 83%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 9.16 (s, 1H), 7.40 (t, J=7.42 Hz, 2H), 7.14 (t, J=7.42 Hz, 1H), 7.07 (d, J=2.35 Hz, 1H), 7.06-6.97 (m, 3H), 5.48 (dd, J=9.38, 2.34 Hz, 1H), 3.05 (dd, J=15.44, 2.74 Hz, 1H), 2.29 (s, 3H), 2.16-2.06 (m, 1H); MS (ES) m/z: 297 (M−1).
Reaction SMILES: [Mg+2:1].[Cl-].[Cl-].[CH3:4][N:5]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][K])[CH3:6]>C1COCC1>[CH3:4][N:5]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Mg:1][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N:5]([CH3:6])[CH3:4])[CH3:6]
Reactant: CN(C)c1ccccc1C[K]
Reactant: [Mg+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)c1ccccc1C[Mg]Cc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Under argon, 0.20 g of MgCl2 (2.1 mmol) and 0.70 g of ortho-N,N-dimethylaminobenzyl potassium (4.0 mmol) are introduced into a Schlenk flask. Around 25 ml of THF are recondensed under vacuum at −78° C. The mixture is stirred at ambient temperature for 30 minutes, then heated at reflux under static vacuum for 5 h, at 50° C. The insoluble MgCl2 crystals have then disappeared. After 1 night at 50° C., the mixture is centrifuged; the white-grey centrifugation pellet of KCl is removed, and the orange solution is concentrated to 1-2 ml, then around 0.5 ml of petroleum ether is added. Colourless crystals appear in the red solution. XRD analysis (Annex 4) of one of the crystals indicates a monomeric structure of the bis(ortho-N,N-dimethylaminobenzyl) magnesium complex (THF). M=0.30 g (yield=42%). 1H NMR (THF-d8, 22° C.): δ=7.00 (d, 2H, CH(6), J(C-H)=7 Hz), 6.90 (d, 2H, CH(3), J(C-H)=7 Hz), 6.75 (t, 2H, CH(4), J(C-H)=7 Hz), 6.55 (t, 2H, CH(5), J(C-H)=7 Hz), 3.65 (t, 4H, free non-deuterated THF), 2.65 (s, 12H, C(8) and C(9), N(CH3)2), 1.80 (m, 4H, free non-deuterated THF), 1.17 (s, 4H, C(1), Mg—CH2—). 13C NMR (THF-d8): δ=152.8 (C(2)), 148.4 (C(7)), 128.9 (C(6)), 125.9 (C(4)), 118.9 (C(5)), 118.4 (C(3)), 45.7 (N(CH3)2), 19.0 (Mg—CH2—).