Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([N+:16]([O-])=O)=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1>O1CCCC1.[Zn]>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:4]=1[NH2:16]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1N1CCOCC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1c(F)cc(F)cc1N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
Concentrated hydrochloric acid (6.3 mL) was added slowly to a mixture of zinc dust (4.9 g) and 4-(3,5-difluoro-2-nitro-phenyl)-morpholine (3.69 g) in tetrahydrofuran (40 mL) cooled to 0° C. The reaction mixture was then stirred for 1 hour at 0° C. and 2 hours at 25° C. The reaction mixture was filtered through Celite (10 g), concentrated in vacuo and purified by flash chromatography to furnish 1.76 g (54% yield) of the title compound as an orange solid. GC-MS (m/z) 215 (M+); tR=5.11. 1H NMR (500 MHz, DMSO-d6): 2.81 (t, 4H), 3.76 (t, 4H), 4.52 (s, 2H), 6.66 (dt, 1H), 6.82 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: c1cc[nH+]cc1
Reactant: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)OC
Product: C=CC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol 13 was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane while heating to afford (14) as a tan solid after workup.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].B.[Na].[Cl-].[NH4+]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([CH3:11])[OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
43.5 g of 4-nitrophenoxyacetone crystals were dissolved in 300 ml of ethanol, added portionwise with small amount of sodium boron hydride up to 4.1 g with stirring at room temperature, and stirred thereafter at room temperature for 2 hr. After adding 10 ml of saturated aqueous solution of ammonium chloride under an ice-cold condition in order to decompose the residual sodium borohydride, extraction was carried out with ethyl acetate. The ethyl acetate layer was washed consecutively with water, 3% hydrochloric acid, 5% aqueous solution of sodium hydrogen carbonate, water and saturated saline and subsequently dried with anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and yielded 46.3 g of 2-(4-nitrophenoxy)-1-methylethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CCCC(=O)Cl
Solvent: CC#N
Product: COC(=O)CCCC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 23 h

Procedure:
To a solution of 2,4-dinitroaniline (6.00 g, 32.76 mmol) in acetonitrile (60 mL) was added methyl-5-chloro-5-oxo-valerate (5.44 mL, 39.31 mmol, 1.2 equiv) at 20° C. in one portion. The reaction mixture was then heated to 75° C. Reaction progress was monitored periodically by HPLC (HPLC Method A). The reaction was complete after stirring for 23 hours at 75° C. to give 4-(2,4-dinitro-phenylcarbamoyl)-butyric acid methyl ester. This reaction mixture was cooled to 20° C. and a portion of the solvent was then removed in vacuo to yield a total reaction volume of approximately 25 mL. To the concentrated mixture was then added potassium carbonate (13.58 g, 98.26 mmol, 3.0 equiv) and methyl iodide (10.20 mL, 163.48 mmol, 5.0 equiv.) at 20° C. Reaction progress was monitored periodically by HPLC Method A. The reaction was complete after 17 hours at 20° C. to give 4-[(2,4-dinitro-phenyl)-methyl-carbamoyl]-butyric acid methyl ester. The reaction mixture was filtered to remove excess K2CO3 and the filtrate was poured into cold water (200 mL) to yield off-white solids. The solid product was collected by vacuum filtration and dried at 60° C. under vacuum/N2 sweep overnight to give 8.914 g, (84% yield) as a light tan solid.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Cl.ClC1C=C(C=CC=1F)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Fc1cccc(C[Mg]Cl)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(F)c(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.79 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 52 mL, 13 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6. In this example, Degussa type, 5% palladium on carbon (0.100 g, 0.1 mmol) was used, and the reaction placed under a hydrogen atmosphere in a Parr shaker (40 PSI) for 2 hours. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane afforded the title compound. 0.075 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03-2.11 (m, 1H), 2.47-2.56 (m, 1H), 2.59-2.73 (m, 2H), 2.78 (d, J=7.4 Hz, 2H), 3.24-3.32 (m, 1H), 3.81 (s, 3H), 6.39 (d, J=1.7 Hz, 1H), 6.90-7.00 (m, 3H), 7.20-7.35 (m, 1H), 8.94 (br s, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[CH3:10][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CN(C)C=O
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccc2cccnc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (1.00 g, 8.46 mmol) and DMF (10 mL) is added 60% NaH (0.41 g, 10.16 mmol). After 30 min, MeI (0.63 mL, 10.16 mmol) is added and the solution stirred for 1 h. The solution is diluted with EtOAc (60 mL), washed with water (2×50 mL), brine (50 mL), dried aver MgSO4, filtered and concentrated to furnish the title compound (1.10 g, 0.83 mmol, 99%). 1H NMR (CDCl3), δ 3.90 (s, 3H), 6.45 (d, J=3.5 Hz, 1H), 7.05 (dd, J=8.1, 4.6 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.90 (d, J=7.7, 1.8 Hz, 1H), 8.40 (dd, J=4.8, 1.3 Hz, 1H). LC/MS (m/z): calcd. for C8H8N2 (M+H)+: 133.2. found.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: O=S(=O)(O)O
Product: CCCCC1OC(=O)c2cc(NC(C)=O)ccc21
Reaction time: 0.25 h

Procedure:
A mixture of 0.3 g (1.55 mmol) of compound obtained in Example 4 and 3 ml of acetic anhydride and 1 drop of sulphuric acid is heated until dissolved and kept for 15 minutes. On cooling, white crystals are separated and recrystallised from ethanol to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (314 mg, 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:53]2[N:54]=[C:55]([NH:58]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:56][CH:57]=2)\[C:21]([NH:23][CH:24]2[C:51](=[O:52])[N:26]3[C:27]([C:35]([O:37]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:36])=[C:28]([CH:31]=[CH:32][CH2:33]I)[CH2:29][S:30][C@H:25]23)=[O:22])[CH2:17][CH2:16][CH2:15]1)=[O:13])(C)(C)C>ClCCl.C(OC(C)C)(C)C>[NH2:58][C:55]1[S:56][CH:57]=[C:53](/[C:20](=[N:19]/[O:18][C:14]2([C:12]([OH:13])=[O:11])[CH2:17][CH2:16][CH2:15]2)/[C:21]([NH:23][CH:24]2[C:51](=[O:52])[N:26]3[C:27]([C:35]([O-:37])=[O:36])=[C:28](/[CH:31]=[CH:32]/[CH2:33][N+:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[N:54]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=CCI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C/C[n+]4ccccc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Pyridine (0.1 ml, 1.2 mmole) was added to a solution of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5', 659 mg, 9.6 mmole) in dichloromethane (7 ml). The mixture was stirred at room temperature for 2.5 hours and diluted with diisopropyl ether. The resulting solid (383 mg) was collected by filtration and treated with 90% trifluoroacetic acid (5 ml) and anisole (1 ml) at room temperature for 1 hour. The resulting mixture was concentrated and the residue was triturated with ether to give 237 mg of crude I-5B, which was purified by HP-20 column chromatography [eluted with water (150 ml), 10% methanol (200 ml) and 30% methanol (500 ml)]. The eluate of 30% methanol was concentrated to a small volume, adjusted to pH 7 with sodium bicarbonate and lyophilized to afford 72 mg (21%) of I-5B. M.P. >160° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:14])=[O:11]
Reactant: Cc1occc1/C=C/C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1occc1/C=C/C(=O)Cl

Procedure:
(E)-3-(2-Methyl-3-furyl)acrylic acid (0.30 g, 2 mmol) was dissolved into thionyl chloride (5 ml) and the mixture was heated to reflux for 80 min. Volatiles were removed by evaporation to give crude (E)-3-(2-methyl-3-furyl)acryloyl chloride. The titled compound was prepared from 2-amino-4-methoxy-N-(2-pyridyl)aniline (0.43 g, 2 mmol) and (E)-3-(2-methyl-3-furyl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). Recrystallization from a mixture of isopropyl ether (3 ml) and ethyl acetate (3 ml) to give 0.10 g (16%) of the titled compound.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH:10]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:17](=[O:18])[CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)CC1CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a 5° C. solution of dimethylaniline (320 ml, 2.54 mol) in t-butyl alcohol (480 ml) was added dropwise a solution of cyclohexyl-acetyl chloride (250.9 g, 1.56 mol) in dichloromethane (320 ml) over 30 min. At the end of the addition, the addition funnel was rinsed with dichloromethane (80 ml). The reaction mixture was stirred 90 min at 5° C. and then allowed to warm to room temperature. After 15 hours at room temperature, the reaction solution was heated to reflux for 6 hours and then cooled to 5° C. The cold reaction mixture was acidified with 6 n hydrogen chloride (640 ml) and extracted with ethyl acetate. The organic layer was washed with 1 N hydrogen chloride (860 ml), water (2×860 ml), saturated aqueous sodium bicarbonate solution (2×860 ml), and brine (860 ml). The organic solution was dried (magnesium sulfate), filtered, and concentrated (room temperature/20 mm Hg). The remaining liquid was distilled to afford the desired product as a yellow oil (259.32 g, 84%). bp.: 70-75° C./0.6 mm Hg; MS m/z: 199 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([CH2:51]Br)[CH:45]=1>CC#N>[Br:43][C:44]1[CH:45]=[C:46]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:51][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cc(F)cc(Br)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-3-(bromomethyl)-5-fluorobenzene (501 mg, 1.871 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (688 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=6.2 Hz, 2H), 7.18-7.12 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 6.87-6.80 (m, 1H), 4.46 (s, 2H), 3.82 (s, 2H), 2.80 (t, J=6.7 Hz, 2H), 1.83 (t, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H). 19F NMR (471 MHz, CDCl3) δ LRMS [ESI, MH+] m/z calcd for C24H30BrFNO5S 542.10, found 542.1.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnccn1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnccn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 54A, 200 mg, 0.70 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with a 2M solution of oxalyl chloride in methylene chloride (0.52 mL, 1.0 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-aminopyrazine (133 mg, 1.4 mmol) in tetrahydrofuran (10 mL) followed by pyridine (0.28 ml, 3.5 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide (192 mg, 76%) as a colorless oil: [α]23589=−62.1° (c=0.095, chloroform); EI-HRMS m/e calcd for C18H19N3OCl2 (M+) 363.0905, found 363.0893.
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:26])/[CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:26])/[CH2:13][CH2:14][C:15]1[C:16]([CH3:25])=[C:17]([OH:24])[C:18]([CH3:23])=[C:19]([CH3:22])[C:20]=1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C)C(=O)C(CC/C(C)=C/COC(=O)c2ccccc2)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\COC(=O)c1ccccc1)CCc1c(C)c(O)c(C)c(C)c1O
Yield: 84.6 %

Procedure:
A solution of 1.22 g (3.5 mmol) of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl benzoate in 10 ml of THF was treated dropwise with a solution of 0.9 g of sodium dithionite in 8 ml of water. After 1 hour the mixture was extracted with chloroform (2 x) and the combined extracts were washed three times with water. The residue remaining after removal of the solvent was washed with hexane and dried under vacuum, yielding 1.05 g of colourless (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl benzoate. M.P. 112°-114° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Cl:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Cl
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Cl)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.46 g) in N,N-dimethylacetamide (6 mL) was rapidly added thionyl chloride (0.35 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Chloro-4-aminobenzophenone (0.45 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into ice water and filtered through diatomaceous earth. The diatomaceous earth was washed with methylene chloride, the organic solution dried and the solvent removed. Chromatography (eluent methylene chloride, then 5% ethyl acetate in methylene chloride) gave the title compound (0.31 g) as a white solid; mp 142-144° C. Analysis for C17H13ClF3NO3 : Calculated: C, 54.92; H, 3.53; N, 3.77; Found: C, 54.89; H, 3.63; N, 3.68.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][CH2:49][C:50](O)=[O:51])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:50](=[O:51])[CH2:49][CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1

Procedure:
5-Amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.100 g, 0.213 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}-β-alanine (0.040 g, 0.213 mmol), DIPEA (0.19 mL, 1.07 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.163 g, 0.639 mmol) in a similar manner as in the general procedure described herein to afford crude 1,1-dimethylethyl {3-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-3-oxopropyl}carbamate as a yellow solid. This crude material (0.027 g, 0.042 mmol) was suspended in dichloromethane (1 mL) and treated with trifluoroacetic acid (0.25 mL, 3.24 mmol) at RT for 1 h. The solvent was evaporated and the residue was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.017 g, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 10.01 (s, 1H), 9.00 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.63-7.79 (m, 2H), 7.44-7.57 (m, 2 H), 7.31-7.44 (m, 1H), 7.22-7.31 (m, 1H), 7.11 (s, 1H), 4.57 (s, 2H), 2.94-3.19 (m, 2H), 2.62-2.77 (m, 2H). MS: m/z 540 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH:6]([OH:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1.[CH3:28][CH:29]1[CH2:35][C:34](=[O:36])[O:33][C:31](=[O:32])[CH2:30]1.[Li+].[OH-].C1COCC1.O>O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][CH:6]([OH:23])[CH2:5][O:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:34]([CH2:35][CH:29]([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[O:36])[CH2:13][CH2:12]1
Reactant: CC1CC(=O)OC(=O)C1
Reactant: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(=O)O)CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol (75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225 uL 0.2M /NMP) to get a product containing both esther and amide. After evaporation of the mixture it was treated with 3 eq 0.5M LiOH in (THF/water 1:4) for two hours at 80° C. to hydrolyse the esther. The reaction mixture was diluted with more water (2 mL) and the desired product was extracted with 5×500 uL EtOAc which was evaporated to dryness.