Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.Br[CH2:37][C:38]1[C:43]2[S:44][CH:45]=[CH:46][C:42]=2[C:41]([O:47][CH2:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:53][C:54]=2[CH3:55])=[CH:40][CH:39]=1.Cl>O1CCCC1.O>[CH3:55][C:54]1[O:53][C:52]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[N:51][C:50]=1[CH2:49][CH2:48][O:47][C:41]1[C:42]2[CH:46]=[CH:45][S:44][C:43]=2[C:38]([CH2:37][CH:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:39][CH:40]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Reactant: O=C1CSC(=O)N1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: -2 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
A 1500-ml 4-necked flask was equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet. To a solution of 11.71 g of 2,4-thiazolidinedione (0.100 mol) in 600 ml of tetrahydrofurane 100 ml of lithium diisopropylamide 2.0 M in THF/heptane/ethylbenzene (0.200 mol) were added dropwise within 30 min at a temperature between −2° and 0° C. The light brown suspension was stirred at −2° C. for 10 min and then a solution of 17.14 g of 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole in 250 ml of tetrahydrofuran was added dropwise at −20° C. within 1 h 15 min. After stirring for 30 min, 160 ml of deionized water were added to the yellow suspension within 12 min at −20°-−4° C. The resulting yellow emulsion was stirred for 70 min at 2° C., transferred to a rotary evaporator with aid of a total of 75 ml of tetrahydrofurane and of a total of 75 ml of deionized water. The largest part of organic solvents was removed (45° C., 250 mbar) and the residue (237 g of turbid aqueous phase) was treated with 200 ml of t-butyl methylether. The resulting yellow thick suspension was stirred in an ice bath for 1 h, then 22 ml of hydrochloric acid 25% (170 mmol) were added dropwise and the resulting beige suspension was stirred for 15 min in an ice bath and filtered with suction. The filter cake was washed three times with 10 ml, a total of 30 ml of cold (2° C.) deionized water, three times with 10 ml, a total of 30 ml of t-butyl methylether and dried to constant weight (80° C., 0.15 mbar, 17 h), affording 15.97 g (85.9%) of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione as off-white crystals with a m.p. of 195.5-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: NC(=O)c1ccc(F)cc1Cl
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccc(F)cc1Cl

Procedure:
starting from 2-chloro-4-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 2-chloro-4-fluorobenzimidate as an oil; 1H-NMR(CDCl3): 1.43 (t, CH3), 4.40 (q, CH2), 6.9-7.8 (3 aromatic H+NH).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:12].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:13]1([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[I:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC2CCCC2)c(I)c1
Reaction time: 2 h

Procedure:
A mixture of methyl 4-amino-3-iodobenzoate from above (27.69 g, 100 mmol), cyclopentanone (52.8 mL, 600 mmol), and anhydrous sodium sulfate (1000 g, 142 mmol) in 500 mL of glacial acetic acid was stirred for two hours. Solid sodium triacetoxyborohydride (76.92, 345 mmol) was added in portions and stirred for 16 hrs at room temperature. The mixture was poured on to cool 900 mL of saturated aqueous sodium bicarbonate solution carefully and extracted with 150 mL (3×) of ethyl acetate. The ethyl acetate fraction was dried and evaporated. Purification with silica gel and 0.5% ethyl acetate in hexane gave 24 g (70%).
Reaction SMILES: Cl.[CH3:2][CH2:3][C@@H:4]1[C@H:22]([OH:23])[C@H:21]([CH3:24])[CH:20]=[C:19]([CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:15](=[O:16])[O:14][C@H:13]([C@H:28]([C@@H:30]([OH:58])[C@@H:31]([C@:33]2(OC)[O:38][C@H:37](/[CH:39]=[CH:40]/[CH3:41])[C@@H:36]([CH3:42])[C@H:35]([O:43][C@@H:44]3[O:49][C@H:48]([CH3:50])[C@@H:47]([O:51][C:52]([NH2:54])=[O:53])[C@H:46]([OH:55])[CH2:45]3)[CH2:34]2)[CH3:32])[CH3:29])[C@@H:12]([O:59][CH3:60])[CH:11]=[CH:10][CH:9]=[C:8]([CH3:61])[CH2:7][C@@H:6]([CH3:62])[C@@H:5]1[OH:63].[BH3-]C#N.[Na+].COC1C=CC(C=O)=CC=1.OS(O)(=O)=O.P([O-])([O-])([O-])=O>CCO>[CH3:2][CH2:3][C@@H:4]1[C@H:22]([OH:23])[C@H:21]([CH3:24])[CH:20]=[C:19]([CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:15](=[O:16])[O:14][C@H:13]([C@H:28]([C@@H:30]([OH:58])[C@@H:31]([C@@H:33]2[O:38][C@H:37](/[CH:39]=[CH:40]/[CH3:41])[C@@H:36]([CH3:42])[C@H:35]([O:43][C@@H:44]3[O:49][C@H:48]([CH3:50])[C@@H:47]([O:51][C:52]([NH2:54])=[O:53])[C@H:46]([OH:55])[CH2:45]3)[CH2:34]2)[CH3:32])[CH3:29])[C@@H:12]([O:59][CH3:60])[CH:11]=[CH:10][CH:9]=[C:8]([CH3:61])[CH2:7][C@@H:6]([CH3:62])[C@@H:5]1[OH:63]
Reactant: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: COc1ccc(C=O)cc1
Solvent: CCO
Product: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Temperature: 25 °C

Procedure:
4 ml of 0.5N HCl are added to a solution of 388 mg (0.44 mmol) of 21-O-methyl-concanamycin A and 193 mg of NaBH3CN (3.08 mmol, 7 equiv.) in 50 ml of EtOH and the reaction mixture is stirred at room temperature until the starting material can no longer be detected by TLC chromatography. Owing to the similarity in the chromatographic behaviour of the starting material and the product, the TLC monitoring of the course of the reaction proves to be difficult; the product spot can, however, be stained yellow-brown with anisaldehyde/H2SO4 spray reagent, while the starting material can be stained blue-violet. After 3 hours 60 ml of phosphate buffer (pH=7) are added, EtOH is removed in vacuo and the aqueous solution is extracted with CHCl3. Customary working-up is followed by chromatography on silica gel (system D, 4×40 cm). M.p. 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)[O:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:27])[CH:3]=1.C(N(CC)CC)C.CN1C(=O)N(C)CC1>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)[O:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:27])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Nc4ccc(Cl)cc4F)ncnc3o2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc3c(Nc4ccc(Cl)cc4F)ncnc3o2)cc1

Procedure:
0.95 g (2.5 mmols) of 4-(4-chloro-2-fluoranilino)-6-(4-nitrophenyl)furo[2,3-d]pyrimidine suspended in ca. 50 ml of THF, 2 ml of triethylamine and 2 ml of DMEU, mixed with a spatula tip of catalyst suspension (ethanolic Raney nickel) and shaken over night under H2 at normal pressure. The suspension is filtered by suction through Celite, concentrated by evaporation, mixed with H2O, set at pH 10 with 5% NaOH solution, filtered by suction, and the residue washed with a lot of H2O. The product is worked up by column chromatography (dissolved in acetone and added to the column as a silica gel adsorbate, silica gel, pentane:ethyl acetate=3:2, m.p.: 229-232° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].CS([C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]([NH2:22])=[N:19][C:18]=2[CH3:23])[CH:14]=[C:13]([CH3:24])[N:12]=1)=O>CN1C(=O)CCC1>[NH2:22][C:20]1[S:21][C:17]([C:15]2[CH:14]=[C:13]([CH3:24])[N:12]=[C:11]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:16]=2)=[C:18]([CH3:23])[N:19]=1
Reactant: CNCCN(C)C
Reactant: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2sc(N)nc2C)nc(N(C)CCN(C)C)n1
Temperature: 70 °C

Procedure:
N,N,N′-Trimethyl-ethane-1,2-diamine (0.62 g, 6.16 mmol) is added to a stirred solution of 5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AD, 0.33 g, 1.23 mmol) in NMP (15 ml). The reaction is heated at 70° C. for 18 hours then the solvent is removed in vacuo. The residue is purified by reverse phase chromatography (C18 Jones Flashmaster™ chromatographic system, gradient elution conditions MeCN/H2O) to give the titled product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:41](=[O:42])[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2)[CH3:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(C)N)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(C)NC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
2.30 g (8.48 mmol) of crude 2-(4-benzyloxy-3-methoxyphenyl)-1-methylethylamine, 1.03 g (10.2 mmol) of triethylamine and 25 ml of tetrahydrofuran were mixed and cooled to about 0° C. and then 1.42 g (8.48 mmol) of (4-methylphenyl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 2.40 g of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-2-(4-methylphenyl) acetamide.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[CH2:3][C:4]#[N:5].[OH-:16].[NH4+]>S(=O)(=O)(O)O>[O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:13])([F:14])[F:15])[CH2:3][C:4]([NH2:5])=[O:16]
Reactant: [OH-]
Reactant: N#CCC(=O)c1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)CC(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 14.5 g (0.068 mole) of 3-oxo-3(2-trifluoromethyl-phenyl)-propionitrile in 340 mL of sulfuric acid was stirred for 5 hours at room temperature. The mixture was slowly poured into ice water with stirring. The mixture was made basic by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 13.82 g of 3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:10]([CH3:24])[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].[Li+].[OH-].C(OCC)(=O)C>C(O)(C)C.O>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1c(C(=O)CCCC(=O)OC)n(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCc1c(C(=O)CCCC(=O)O)n(C)c2ccccc12
Reaction time: 3 h

Procedure:
To a solution of 5-(3-hexyl-1-methyl-1H-indol-2-yl)-5-oxo-pentanoic acid methyl ester in isopropanol and water was added LiOH and stirred for 3 hours. The reaction was treated with 1M HCL and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:29])[O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:29])[O:17][C:15]=2[CH:16]=1
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Reaction time: 12 h
Yield: 88.1 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.15 g, 0.319 mmol) in dichloromethane (25 mL) at room temperature was added TFA (0.246 mL, 3.19 mmol) and the mixture stirred for 12 h. After completion of reaction, the solvent was removed under reduced pressure to afford N-(8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (0.18 g, 0.281 mmol, 58% yield) as a brown oil. The product was carried forward into the next step without further purification. LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H28N3O3 370.2]; LC/MS retention time (Method C): tR=1.14 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17]OS(C)(=O)=O)[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH3:23][NH:24][CH3:25].[Na+].[I-]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][N:24]([CH3:25])[CH3:23])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: CNC
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Temperature: 65 °C

Procedure:
A solution of 258 mg (corresponding to 0.41 mmol) of crude trans-Methanesulfonic acid 4-[2-(5-bromo-pyrimidin-2-ylamino)-ethyl]-cyclohexylmethyl ester in 5 ml of methanol was treated with 0.73 ml (4.1 mmol) Dimethylamine (33% in EtOH, 5.6M) and heated at 65° C. for 4 h, a catalytic amount of NaI was added and heated for 16 h. After cooling and evaporation, the residue was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 9:1) gave 105 mg (76%) of trans-(5-Bromo-pyrimidin-2-yl)-[2-(4-dimethylaminomethyl-cyclohexyl)-ethyl]-amine, mp: 108.3–109.5° C.; MS: 341 (MH+, 1Br).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Yield: 6.9 %

Procedure:
Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring room temperature solution of 56 0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (50 min): The reaction was concentrated and purified by preparative reverse phase HPLC with the following conditions: 0 to 24 min, 55:45 H2O:CH3CN; 24-25 min, 55:45 to 0:100 H2O: CH3CN; 20 mL/min.; λ=214 nM; 100 mg/mL, 0.2 mL/injection. 0.0489 g of 57 was obtained. 1H (CDCl3, 300 MHz): δ 10.77 (1H, broad s), 7.36-7.14 (5H, m), 6.49 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.16-2.86 (3H, m), 1.33 (3H, t, J=7.0 Hz), 1.27 (3H, d, J=5.9Hz) ppm. 13C (CDCl3, 75 MHz): δ 162.01, 145.94, 145.75, 141.50, 128.43, 126.76, 126.32, 106.98, 60.87, 39.94, 34.64, 21.34, 14.12 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 21.34, 14.12; CH2 carbons: 60.87, 34.64; CH carbons: 128.43, 126.77, 126.32, 106.98, 39.94 ppm. HPLC: 10.052 min.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:42]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 100 mg, 0.193 mmol), 3-(methanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3), (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60° C. overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].O>ClCCl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CCCN3CCOCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: c1cc(N2CCNCC2)ccc1CCCN1CCOCC1
Reaction time: 2 h

Procedure:
A solution of Example 5B (671 mg, 1.725 mmol) in dichloromethane (2 mL) at room temperature was treated with TFA (1.8 mL) and water (0.2 mL) allowed to stand for 2 hours The solution was concentrated to provide the desired product.
Reaction SMILES: [CH3:1][Mg+].[Br-].[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]=[O:21])=[CH:15][CH:16]=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[Cl-]>C1COCC1>[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([OH:21])[CH3:1])=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Mg+]
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into the THF (50 ml) solution of MeMgBr (3M in Et2O, 5.6 mL, 1.5 eq.) was added dropwise the THF (40 ml) solution of 2-phenylquinoline-7-carbaldehyde (2625 mg, 11.25 mmol) under N2 at rt over 20 min. After stirring at rt for 3 h, the reaction mixture was treated with saturated aqueous NH4Cl solution (100 ml), and the organic phase was separated. The aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were then washed with H2O (2×100 ml) and brine (100 ml), dried over MgSO4, filtered and concentrated to give the title compound as brown oil. The crude material was used for the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ=1.60-1.62 (d, 3H, J=6.4 Hz), 2.08 (brs, 1H), 5.11-5.14 (m, 1H), 7.44-7.60 (m, 4H), 7.81-7.83 (d, 1H, J=8.4 Hz), 7.85-7.87 (d, 1H, J=8.4 Hz), 8.13-8.17 (m, 3H), 8.19-8.21 (d, 1H, J=8.4 Hz). MS (ES+): 250.3 [MH+]. HPLC: tR=2.9 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(N)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 3-amino-5-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:7][P:8]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]2=[O:26])([O:10][CH2:11][CH3:12])=[O:9])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.O.NN>O1CCOCC1>[C:4]([NH:5][CH:6]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:7][P:8]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]1=[O:26])([O:10][CH2:11][CH3:12])=[O:9])(=[O:34])[C:3]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:2]=1
Reactant: CCOC(=O)CN1CCC[C@H](NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)C1=O
Agent: NN
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CC(Cc2ccccc2)NC(=O)c2ccccc2)OCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-3-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature. The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase is washed with water and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is taken up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is chromatographed on silica gel to give (S)-3-[[[2-(benzoylamino)-3-phenylpropyl]ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.