Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][C:34](=O)[N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]5)=[CH:31][C:24]=3[S:23]4)=[CH:18][CH:19]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(CCC(=O)N5CCCCC5)ccc34)cc2)no1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(CCCN5CCCCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
To a suspension of N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-oxo-3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea from Example 12C (0.36 g, 0.63 mmol) in THF (10 mL) at room temperature was added 1.0 M solution of BH3/THF in THF (10 mL). The mixture was heated to reflux over night, but LC-MS showed the reaction was not complete. Therefore, additional 5.0 mL of 1.0 M BH3/THF solution was added and heated to reflux for 8 hours. The reaction was quenched by dropwise addition of 10% HCl solution and stirred at room temperature for 20 min. The mixture was basified with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by Flash chromatography with silica gel using a 0-10% methanol/dichloromethane gradient. The appropriate fractions were collected, combined, and concentrated to give free base, N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea (0.182 g). 1H NMR (DMSO-d6) δ 9.54 (s, 1H), 8.88 (s, 1H), 8.67 (s, 1H), 7.90 (s, 1H), 7.88 (d, 1H), 7.79 (d, 2H), 7.53 (d, 2H), 7.45 (d, 1H), 6.53 (s, 1H), 2.75 (m, 8H), 2.05 (m, 2H), 1.67 (m, 2H), 1.47 (m, 4H), 1.30 (s, 9H); 13C NMR (DMSO-d6) δ 180.55, 158.75, 151.65, 146.97, 146.42, 138.99, 138.38, 130.52, 129.59, 128.77, 127.27, 125.58, 124.70, 119.05, 113.37, 108.58, 92.81, 65.28, 57.96, 32.90, 28.72, 24.93, 22.55, 20.24, 15.53; LC-MS: ESI 557 (M+H)+.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 54 mg of Z-Phe-Phe-OH(Bachem AG, Bubendorf, Switzerland) and 75 mg of H-Leu-Val-Ile-His-NH2, the title compound is obtained after the addition of 26 mg of HOBt and 42 mg of DCCI and chromatographic purification over a LOBAR® prefabricated column (eluant: methylene chloride/methanol/water 50:10:1). Rf (B10)=0.35.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([CH:28]=[O:29])[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:27])[CH3:26])=[C:12]32)[C:3]1([CH3:33])[CH3:32].[C:34]([O:38][C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[CH2:41][C:42](O)=[O:43])([CH3:37])([CH3:36])[CH3:35].C(Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C.C1COCC1>[CH3:45][C:40]([CH3:46])([CH2:41][C:42]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([CH:28]=[O:29])[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:27])[CH3:26])=[C:12]32)[C:3]1([CH3:32])[CH3:33])=[O:43])[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:47]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C=O)CC1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C=O)CC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-Hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde (26.9 g, 1 equiv), 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (14.96 g, 1.25 equiv) and THF (538 ml, 20 vol) were charged to a flask. Benzoyl chloride (10.4 g, 1.25 equiv) was added followed by slow addition of triethylamine (14.97 g, 2.5 equiv) forming a thick slurry. DMAP (0.1.81 g, 0.25 equiv) was added and the reaction was allowed to stir at ambient temperature for approximately 18 hours until complete by HPLC. Reaction was then charged with ethyl acetate (538 mL, 20 vol) and water (269 ml, 10 vol), stirred well and allowed to settle. Aqueous phase was removed and the organic phase washed with saturated sodium bicarbonate solution (2×10 vol) followed by water (269 mL, 10 vol). The reaction solution evaporated under vacuum to approximately 4 volumes to produce solids. Additional hexanes (269 ml, 10 vol) was added and reaction heated back to reflux to nearly form solution and slowly cooled to ambient temperature (seeding with desired product) and let stir for 15 minutes then cooled to 0° C. for approximately two hours and filtered solid. Washed solid with hexanes (2×10 vol) and dried at 50° C. under vacuum to a weight of 32.15 g, 85% yield of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:8]=2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO>[OH:24][C:7]1[C:8]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:15][C:9]=2[C:10]([CH2:12][CH2:13][CH3:14])=[N:11][C:6]=1[C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: NCC(=O)O
Reactant: CCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-propyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (78 mg, 0.23 mmol) and glycine (343 mg, 4.57 mmol) in 0.5 M sodium methoxide/methanol (8.6 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 mL) and extracted three times with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (70 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.02 (br s, 1H), 9.21 (br s, 1H), 8.17 (m, 2H), 7.65 (m, 3H), 4.06 (d, J=6.2 Hz, 2H), 3.33 (m, 2H), 1.92 (m, 2H), 1.04 (t, J=7.0 Hz, 3H); MS: (+) m/z 371.93 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16]>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[S:16][C:4]2[CH:3]=[C:2]([Br:1])[C:9]([F:10])=[CH:8][C:5]=2[CH:6]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: O=Cc1cc(F)c(Br)cc1F
Solvent: CC#N
Product: COC(=O)c1cc2cc(F)c(Br)cc2s1
Yield: 102.9 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25a above, 4-bromo-2,5-difluoro-benzaldehyde (I-27a: 1.71 g, 7.73 mmol) was reacted with TEA (1.4 mL, 10.05 mmol), mercapto-acetic acid methyl ester (920 mg, 8.51 mmol) and acetonitrile (50 mL) to afford crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane) afforded 2.3 g of the product (Yield 64%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41]C(F)=CC=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:37]1([CH2:36][C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:42][CH2:41]1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)CC4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example 45 and Compound A of Example 279 (21.0 mg, 81%). 1H NMR (CD3OD) δ 7.81 (s, 1H), 7.74 (d, 1H, J=5.5 Hz), 7.25 (m, 3H), 4.18 (t, 2H, J=5.5 Hz), 3.35 (t, 2H, J=1.7 Hz), 2.90 (t, 2H, J=5.5 Hz), 2.74-2.54 (m, 4H), 2.45 (s, 3H), 2.33 (t, 4H, J=2.8 Hz), 1.12 (m, 1H), 0.67-0.64 (m, 2H), 0.29-0.25 (m, 2H); MS(ESI+) m/z 529.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[C:34]([CH3:33])[N:35]=[CH:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: Cc1c[nH]cn1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)cn1
Yield: 32.1 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylimidazole (0.48 g), and dimethylformamide (25 ml), the title compound (0.38 g) was obtained as an amorphous solid, MS, m/z: 403.3 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([OH:21])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:33]1([CH3:40])[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([O:21][C:36]2[CH:37]=[CH:38][C:33]([CH3:40])=[CH:34][CH:35]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cl)cc1
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2cc(C(=O)CNC(C)C)ccc2OC(=O)CC(C)C)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted wirh p-toluyl chloride there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:17]([CH:22]=1)[C:18](OC)=[O:19])(=[O:12])=[O:11].C([BH-](CC)CC)C.[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[C:17]([CH2:18][OH:19])[CH:22]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OCC1CCOCC1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(CO)c2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of methyl 5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (20 mg, 0.041 mmol) in tetrahydrofuran (THF) at 25° C. was added lithium triethylborohydride in THF (Superhydride®, 1.1 M, 0.037 mL, 0.041 mmol) and the reaction mixture stirring at 25° C. for 15 hours. Dilute HCl was added to reaction mixture and stirred for 10 minutes. The reaction mixture was then neutralised with base and the product was extracted into ethyl acetate (3×10 mL). The organics were combined and dried using a hydrophobic frit, then concentrated under a stream of nitrogen to give the crude product. This was purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and concentrated under a stream of nitrogen to give the required product, 16.2 mg, as a colourless oil. LCMS [LCMS2] Rt 1.33 min, m/z (ES+) 462 (M+H).
Reaction SMILES: C1([SiH3])C=CC=CC=1.O.[N+:9](/[CH:12]=[C:13](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)\[CH3:14])([O-:11])=[O:10]>CC(C)([O-])C.[Cu+].C1(C)C=CC=CC=1.C[C@H](P(C1CCCCC1)C1CCCCC1)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe]>[N+:9]([CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([O-:11])=[O:10]
Reactant: C/C(=C\[N+](=O)[O-])c1ccccn1
Agent: [Cu+]
Agent: [Fe]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C[N+](=O)[O-])c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
In a 10 mL Schlenk-flask, 6.8 mg of copper (I) tert-butoxide and 55 μmol of (S)—(R)-JOSIPHOS were dissolved in 5 ml of toluene. After stirring for 30 minutes at room temperature to give an asymmetric copper complex. This solution to the amount containing 10 μmol of the asymmetric copper complex were mixed with 4.9 ml of toluene, and 6 μL (0.1 mmol) of poly(methylhydrosiloxane) (15-40 mPas (20° C.), d=1.004 g/mL, nD20=1.398, produced by Fluka) were added thereto. Further, 185 μL of (1.5 mmol) of phenylsilane and 27 μL (1.5 mmol) of water were added. After stirring for 5 minutes, 1 mmol of (E)-1-nitro-2-(pyridin-2-yl)-1-propene was added, and the mixture was further stirred for 24 hours at room temperature. Water was added to the reaction mixture and the product was extracted with diethyl ether (30 mL×2). After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide optically active 1-nitro-2-(pyridin-2-yl)propane.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([O:28]CC)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([OH:28])=[O:27])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1c1ccccc1)Nc1cccc(C(=O)O)c1
Yield: 70.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3 g of ethyl (cis)-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoate in solution in 50 cm3 of methanol and 0.7 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment and recrystallization in ethanol, 2 g of (cis)-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 255° C., are obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[NH:6][C:7]([CH:28](OCC)[O:29]CC)=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.Cl>CC(C)=O>[CH:4]([C:5]1[NH:6][C:7]([CH:28]=[O:29])=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of diethyl 2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.7 g) in acetone (17 ml) was added 6N-hydrochloric acid (1.5 ml) and stirred at room temperature for 3 hours. After removing the solvent, the residue was extracted with diethyl ether and the extract was washed with water and dried. The solvent was removed from the extract to give diethyl 2,6diformyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.35 g). The product was recrystallized from diethyl ether to give pure yellowish granules, m.p. 85° to 86° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]([C:11]([O:13][C@H:14]([CH3:25])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]([C:11]([O:13][C@H:14]([CH3:25])[C:15]([OH:17])=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O[C@H](C)C(=O)OCc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc(Cl)c(C(=O)O[C@H](C)C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
10% Palladium on carbon (59 mg, 0.55 mmol) was added to a stirred ethanol (5.5 mL) solution of (1R)-2-(benzyloxy)-1-methyl-2-oxoethyl 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate. The mixture was stirred under hydrogen for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.67-7.62 (m, 2H), 7.56-7.50 (m, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.87 (q, J=5.5 Hz, 1H), 5.67 (d, J=16.5 Hz, 1H), 5.57 (d, J=16.5 Hz, 1H), 5.15 (q, J=6.5 Hz, 1H), 2.65 (t, J=7.5 Hz, 2H), 1.56 (quintet, J=7.5 Hz, 6H), 1.49 (d, J=7.0 Hz, 3H), 1.31 (sextet, J=7.5 Hz, 2H), 0.87 (t, J=7.5 Hz, 3H); LCMS (M+H) found 509.2.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[NH:14][C@H:15]([C:23](=[O:35])[NH:24][C@H:25]1[CH2:30][C@@H:29]2[C:31]([CH3:33])([CH3:32])[C@@:26]1([CH3:34])[CH2:27][CH2:28]2)[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:14][C@@H:15]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:23]([NH:24][C@H:25]1[CH2:30][C@@H:29]2[C:31]([CH3:33])([CH3:32])[C@@:26]1([CH3:34])[CH2:27][CH2:28]2)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NC(=O)[C@@H](N)CC1CCCCC1)C2
Reaction time: 3 h

Procedure:
50 ml of TFA were slowly added to a solution of 6.5 g of tert-butyl[(S)-2-cyclohexyl-1-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethyl]-carbamate (16.0 mmol) in 50 ml of CH2Cl2 at 0° C. under argon. The mixture was allowed to reach RT. After 3 h, the reaction mixture was concentrated. The title compound was obtained as a pale yellow oil which was employed directly in the next step. LC-MS Rt(min) 1.60; calc.: [M+H]+ 307.27 found: 307.39 (method C).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)COc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(COc1ccc(C(=O)O)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 7 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(2-hydrazino-2-oxoethoxy)benzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 6 mg of the title compound (7%) as a yellow solid in 97.8% purity by HPLC (Rt: 3.63, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH2:15])(=O)C.Cl>CO>[OH:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[CH2:15]
Reactant: C=C(CCCOC(C)=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C(CCCO)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing 0.52 g (1.0 eq) of dry potassium carbonate in 100 ml of anhydrous methanol was added 1.0 g (1.0 eq) of methyl 4-(5-acetoxy-pent-1-en-2-yl)benzoate in anhydrous methanol. The resulting reaction mixture was stirred for two hours at room temperature, neutralized by the addition of 7.6 ml of 1N hydrochloric acid (2.0 eq), and extracted twice with dichloromethane. The extracts were dried over magnesium sulfate, and concentrated under reduced pressure to yield the product. mp. 28-30° C. M.S.:m/z= 220.1094, (M+ calc. for CH13H16O3 : 220.1099), 189 (M+ --CH3) ), 176 (100%), 145. 1H-N M.R.(CDCl3, 300 MHz): δ=1.56(s (broad), 1H, OH); 1.75(quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 2.60(t, 2H, CH2 --C=, J=7.5 Hz); 3.68(t, broad), 2H, CH2OH, J=7.5 Hz; 3.94(s, 3H, CH3O); 5.20(s, 1Holef.); 5.42(s, 1Holef.); 7.48 (d, 2Harom., J=9 Hz); 8.00(d, 2Harom., J=9 Hz).