Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[C:30]([CH:31]=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[C:30](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Reactant: O=Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 2-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 24 hours, at room temperature for 24 hours too and then, quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 24 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98/2) to afford, after trituration with diethyl ether, the compound (48) as a yellow powder (220 mg, 30%). IR νmax (cm−1): 2219 (νCN), 3228 (νN—H); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.81 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.42 (1H, d, J7′-6′=8.9 Hz, H7′), 7.43 (1H, d, J4′-6′=2.4 Hz, H4′), 7.53 (1H, m, H5″), 7.64 (1H, s, H3), 7.84 (1H, s, H2′), 8.29 (1H, d, J6″-5″=4.5 Hz, H6″), 8.49 (1H, m, H4″), 11.73 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.5 (5′-methoxy), 101.5 (C4′), 109.8 (C2), 110.0 (C3′), 112.5 (C6′), 113.3 (C7′), 117.3 (C1), 118.0 (1C, d, 2JC—F=28 Hz, C3″), 122.3 (1C, d, 4JC—F=4 Hz, C5″), 123.9 (C3a′), 125.8 (C3), 128.1 (C2′), 132.2 (C7a′), 139.4 (1C, d, 3JC—F=3 Hz, C4″), 147.5 (1C, d, 3JC—F=15 Hz, C6″), 154.7 (C5′), 159.7 (1C, d, 1JC—F=270 Hz, C2″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 316.0861 (calcd for C17H12N3OFNa+, 316.0862).
Reaction SMILES: O[CH:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH:22]=[CH:21]2
Reactant: COC(=O)c1ccc(C(O)c2ccc3cc(OC)ccc3c2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2ccc3cc(OC)ccc3c2)cc1

Procedure:
The title compound of Example 1, Step A (0.97 g, 3 mmol) was treated with 50 mL of chloroform containing 3% each of TFA and triethylsilane for 2 h. The reaction was partitioned between aq sodium bicarbonate and EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel (mobile phase=15:85 (v/v) EtOAc:hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19][OH:20])O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:15][CH2:16][CH:17]1[CH2:19][O:20][C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:14]1
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCC1(C)OCC(CO)O1
Temperature: 25 °C

Procedure:
Firstly, 100 g (0.5 mol) of 2-tridecanone (Aldrich P/N 17,283-9), 56 g (0.6 mol) of glycerol (Aldrich P/N 32,00-5), 200 mL of benzene, and 1.8 grams of p-toluenesulfonic acid (Aldrich P/N 40,2885) were placed in a 500 mL round bottom flask fitted with a Dean Stark apparatus. The mixture was heated to reflux with stirring until no further separation of water appeared. The reaction mixture was cooled to room temperature and washed successively with a 100 mL portion of 5% sodium carbonate solution and three 100 mL portions of water. The organic layer was dried over sodium sulfate, filtered and the benzene was removed with a rotary evaporator. The residual oil was fractionated by distillation under reduced pressure to give the desired product (b.p. 140° C./0.3 mm Hg). The identity of the product was confirmed by 1H NMR in CDCl3.
Reaction SMILES: [K].O(CC(NC1C(=O)N2C(C(O)=O)C(C)(C)S[C@H]12)=O)C1C=CC=CC=1.OO[S:28]([O-:30])=O.[K+].[CH3:32][C:33]1([CH3:54])S[C@@H:36]2[C@H:38]([NH:41][C:42]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:43])[C:39](=[O:40])[N:35]2[C@H:34]1[C:51]([O-:53])=[O:52].[K+]>O>[CH3:32][C:33]1([CH3:54])[S:28](=[O:30])[C@@H:36]2[C@H:38]([NH:41][C:42]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:43])[C:39](=[O:40])[N:35]2[C@H:34]1[C:51]([OH:53])=[O:52]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: O=S([O-])OO
Agent: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: [K+]
Agent: [K]
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To 50 ml. of water were added 19.4 grams (50 millimoles) of the potassium salt of 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylic acid. A solution of 20 grams (65 millimoles active oxygen) of Oxone® in 100 ml. water was added dropwise to the penicillin solution over a 45 minute period. The mixture was stirred for about 10 minutes at room temperature. The resulting precipitate was collected by filtration and washed with 25 ml. of water. The precipitate was dried in vacuo at 40° C. overnight to afford 17.95 grams (98%) of the corresponding penicillin sulfoxide. Analysis of the product by high performance liquid chromatography (HPLC) indicated the presence of 23.0% of the α-isomer and 74.1% of the β-isomer.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([OH:17])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>C1COCC1>[OH:17][C:7]1([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2ncccn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ncccn2)CC1
Reaction time: 48 h
Yield: 49.3 %

Procedure:
To the product from step A (190 mmol, 44 g) in THF (200 mL) was added HCl solution (300 mmol, 100 mL). The reaction was stirred over 2 days after which the reaction was washed using diethyl ether. The aqueous layer was then quenched using NaOH (50%) to obtain a pH of 11. The aqueous layer was extracted using EtOAc (6×300 mL). The organic layer was combined and dried over MgSO4 and concentrated in vacuo. The residue was purified via flash chromatography to afford the desired ketone (18 g, 49%). MS [M+H]+ 193.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:29])[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C@H:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[NH2:20][C@H:16]([CH:17]([CH3:19])[CH3:18])[C:15]([N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)([OH:29])[CH2:14][CH2:13]1)=[O:28]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@@H](N)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 4M solution of HCl in dioxane (10 mL) was added to (R)-tert-butyl 1-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (2.0 g) and the resulting solution was allowed to stir at rt. for 1 h. After this time, the solvent was removed by rotary evaporation to provide an oil. The oil was dried overnight in vacuo to provide (R)-2-amino-1-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-3-methylbutan-1-one hydrochloride as a white foam.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])(=[O:21])[CH3:20]
Reactant: CC(O)CCc1ccccc1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCc1ccccc1
Yield: 98.3 %

Procedure:
Into a four-necked flask provided with a thermometer and a stirrer, 150 g (1 mol) of 4-phenyl-2-butanol (XXX-35), 500 ml of toluene and 200 ml of pyridine were charged. 122.4 g (1.2 mol) of anhydrous acetic acid and 1 g of 4-dimethylaminopyridine were further added thereto to react them for 4 hours, while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid solution, extracted and fractionated, and then an organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water in the order. The thus-obtained Organic layer was concentrated under a reduced pressure to obtain 189 g of 2-acetoxy-4-phenylbutane (XXIX-35) with yield of 98.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=O)[C:8]2=O.COC1C=CC=C2C=1CCCC2=O.[Se](=O)=O.C(O)(=O)C.C(O)(=O)C.[NH2:39][C:40]1[C:48]([NH2:49])=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([OH:44])=[O:43].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]2=[CH:5][CH:6]=[C:7]3[C:8]([N:39]=[C:40]4[C:48]([CH:47]=[CH:46][CH:45]=[C:41]4[C:42]([OH:44])=[O:43])=[N:49]3)=[C:9]2[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: COc1cccc2c1C=CC(=O)C2=O
Agent: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12

Procedure:
A mixture of 5-methoxy-[1,2]naphthoquinone (prepared by treatment of 5-methoxytetralone with selenium dioxide, A. Bekaert et al Tetrahedron Letters 38, 24, 4219–4220, 1997) (1.98 g), 2,3-diamino-benzoic acid, diacetate salt, (J. Chem. Soc. Perkin. Trans I, 1984, p2019) (4.03 g) and conc. hydrochloric acid (2.2 mL) was heated to reflux in ethanol (20 mL) for 4 hours. The reaction mixture was cooled and the precipitate collected by filtration, and washed with ethanol and ether to yield the title compound as a beige solid (2.74 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc2c1OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cccc2c1OCCO2)OCC
Temperature: 140 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of 2,3-dihydro-5-hydroxy-1,4-benzodioxin (0.13 mol), 2-bromo- 1,1-diethoxyethane (0.13 mol) and potassium carbonate (0.13 mol) in N,N-dimethyl- acetamide (250 ml) was stirred overnight at 140° C. The solvent was evaporated. The residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated. The residual oil was crystallized from 2,2'-oxybispropane. The precipitate was filtered off and dried, yielding 21 g (60.2%) 5-(2,2diethoxyethoxy)-2,3- dihydro-1,4-benzodioxin; mp. 73.1° C. (interm.11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][N:28](C(OCC)=O)[CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[N:16](C(OCC)=O)[C:17]([CH:18]=1)=[C:12]23.[OH-].[K+]>CCCCO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][NH:28][CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[NH:16][C:17]([CH:18]=1)=[C:12]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC1CN2c3c(cc(-c4ccc(Cl)cc4Cl)cc3C3CNCCC32)N1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a solution of diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 0.06 mmol) in 10 mL of n-BuOH was added KOH (33 mg, 0.6 mmol) and stirred at 120° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with water (10 mL). The organic layer was collected and washed with 1N HCl (10 mL) and water (10 mL). This time the aqueous layer was collected and neutralized with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated to afford 5-(2,4-dichlorophenyl)-2-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (10 mg, 45%) as a solid. MS [M+H]+374.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([SH:56])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]>>[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([S:56][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]
Reactant: NC(=O)C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(C(N)=O)N(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 82.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (174 mg, 0.29 mmol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I (160 mg, 0.28 mmol, compound of Reference Example 13) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer I (223 mg, yield: 82.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)([OH:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
3-Methyl-4-oxo-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester 3-methyl ester (1.1 g, 4.07 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added 4-chlorophenyl magnesium bromide (12.2 mL, 12.2 mmol) dropwise over ˜½ h and then stirred at 0° C. for 1 h. The reaction was quenched with saturated solution of NH4Cl and extracted with ethyl acetate (3×). The organics were collected, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/90% hexane to 20% ethyl acetate/80% hexane) to yield the title compound (1.1 g, 70%). 1H-NMR (CDCl3): δ 1.17 (s, 3H), 1.44 (s, 9H), 1.55 (m, 1H), 1.96 (d, 1H) 3.00 (m, 1H), 3.37 (m, 2H), 3.53 (s, 3H), 3.91 (m, 2H), 4.07 (d, 1H), 7.27 (d, 2H), 7.43 (d, 2H). ESI-MS m/z: 384.1 (M+1), retention time 2.95.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:16]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:16])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800 mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol;) and iodine (244.2 g, 1.04 mol;). The reaction mixture was stirred rt 4 h. The aqueous layer containing product was separated and washed with hexane (400 mL×2). The aqueous layer was neutralized to pH=7 with HCl and then extracted EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated to the crude product, which was washed with EtOAc to afford 163 g of 6-chloro-2-iodopyridin-3-ol, yield: 75%. 1H NMR (DMSO, 400 MHz): δ11.13 (s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)(=O)C.CCO>[Cl:12][C:13]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1Cl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 2-chloro-3-(trifluoromethyl)benzaldehyde (0.42 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.64 g, in 93% yield, mp: 261.5° C. 1H NMR (CD3OD) δ 8.89 (s, 1H), 8.51 (d, 1H), 7.85 (m, 3H), 7.56 (t, 1H), 6.89 (d, 2H). 13C NMR (CDCl3) δ 166.9, 163.1, 144.3, 135.7, 132.8, 132.5, 131.0, 130.3, 130.1, 128.5, 125.4, 124.3, 123.2, 116.4. Anal. Calcd for C15H10ClF3N2O2.½H2O: C, 51.22; H, 2.86; N, 7.96; Cl, 10.08; F, 16.20. Found: C, 51.17; H, 3.04; N, 7.53; Cl, 10.25; F, 15.93.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1cc(N)cc(N)c1

Procedure:
A solution of 20.5 gm. (0.097 mole) of 3,5-dinitrobenzamide in 450 ml. of an ethyl acetate-ethanol mixture (2:1) is hydrogenated at 3 atmospheres of hydrogen using 1 gm. of 10% palladium on charcoal as catalyst. When absorption of hydrogen is complete, the catalyst is removed by filtration and the filtrate is concentrated to dryness under reduced pressure and the residue recrystallized from water. There is obtained 11.65 gm. (79%) of long yellow needles melting at 108°-9°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=O)([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([Cl:17])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1CCC(=O)Cl

Procedure:
A mixture of 3-(2-isopropylphenyl)propanoic acid (prepared in 3 steps from 1-isopropyl-2-iodobenzene, 2.01 g, 10.5 mmole), thionyl chloride (4.30 ml, 59.0 mmole) and toluene (40 ml) was refluxed for 2 hours. Concentration in vacuo gave 3-(2-isopropylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([O:10][C:11]([F:14])([F:13])[F:12])=[C:2]([B:20]([OH:25])[OH:21])[CH:7]=1
Reactant: COc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)c(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of 2-Bromo-4-methoxy-1-trifluoromethoxy-benzene (Preparation 59, 19.0 g, 73.9 mmol) in anhydrous tetrahydrofuran (400 ml) was added n-butyl lithium (2.5M solution in hexanes, 44.2 ml, 110.9 mmol) while maintaining the temperature below −70° C. under an atmosphere of nitrogen. The resulting solution was stirred at −70° C. for 1 hour. Tri-isopropyl borate (20.9 g, 110.9 mmol) was added and the mixture stirred at −70° C. for an additional 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (400 ml). The resulting mixture was acidified to pH˜5 by addition of hydrochloric acid (1N aqueous solution). The layers were separated and the organic layer was washed with water (200 ml) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo. Residue was purified by recrystallization from ethyl acetate:petroleum ether (2 ml:50 ml) to afford the title compound as a white solid (7.5 g, 43%).
Reaction SMILES: [N:1]1([C:5]2([C:15]#N)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>O1CCCC1>[C:15]1([C:5]2([N:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C2(N3CCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-azetidin-1-yl-1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.20 g, 9.9 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise under argon and with ice cooling to a 2 M solution of phenyl magnesium chloride in tetrahydrofuran (12 ml, 24 mmol) and then the mixture was stirred overnight at room temperature. After adding saturated ammonium chloride solution (5 ml) and water (5 ml) the phases were separated and the aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/cyclohexane (1:1). Yield: 670 mg (25%), colorless oil.